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Cited by 542Retinal Diseases and TreatmentsRetinal Imaging and AnalysisRetinal Development and Disorders

Age-related macular degeneration

Open access
Coleman, Hanna R, Chan, Chi-Chao, Ferris, Frederick L, Chew, Emily Y·2008·The Lancet
DOI 10.1016/s0140-6736(08)61759-6PMC PMC2603424
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Abstract

Age-related macular degeneration is the leading cause of blindness in elderly populations of European descent. The most consistent risk factors associated with this ocular condition are increasing age and cigarette smoking. Genetic investigations have shown that complement factor H, a regulator of the alternative complement pathway, and LOC387715/HtrA1 are the most consistent genetic risk factors for age-related macular degeneration. Although the pathogenesis of this disease is unknown, oxidative stress might have an important role. Treatment with antioxidant vitamins and zinc can reduce the risk of developing advanced age-related macular degeneration by about a quarter in those at least at moderate risk. Intravitreal injections of ranibizumab, a monoclonal antibody that inhibits all forms of vascular endothelial growth factor, have been shown to stabilise loss of vision and, in some cases, improve vision in individuals with neovascular age-related macular degeneration. These findings, combined with assessments of possible environmental and genetic interactions and new approaches to modulate inflammatory pathways, will hopefully further expand our ability to understand and treat age-related macular degeneration.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes age-related macular degeneration (AMD) epidemiology, risk factors, genetics, pathophysiology, and management. It emphasizes age and smoking as consistent risks, complement factor H and LOC387715/HtrA1 as major genetic loci, and antioxidant/zinc prevention plus anti-VEGF therapy for advanced disease.

Key findings

  • AMD is the leading cause of blindness in elderly populations of European descent; it accounts for more than 54% of all vision loss in the white US population. Pooled data from Beaver Dam, Rotterdam, and Blue Mountains studies estimated advanced AMD prevalence at 0·2% in ages 55–64 years, rising to 13% in those older than 85 years.
  • Age and cigarette smoking are the most consistent risk factors. Genetic studies implicate complement factor H and LOC387715/HtrA1; siblings of individuals with end-stage AMD have about a five-fold increased risk for intermediate AMD and a twenty-fold increased risk for advanced AMD, with about 23% of advanced AMD attributed to a genetic component.
  • The AREDS formulation of antioxidant vitamins and zinc reduced the risk of developing advanced AMD and associated visual loss by as much as 25% over 5 years in individuals at least at moderate risk, with a 19% reduction in moderate vision loss at 5 years.
  • Ranibizumab: at 12 months, 95% of patients given 0·5 mg lost fewer than 15 letters versus 62% of placebo (p<0·001), and 34% improved by 15 or more letters versus 5% of placebo (p<0·001); benefits persisted through 24 months. Pegaptanib stabilized vision in 70% versus 55% with placebo.

Methods

  • Narrative review. The authors searched PubMed and Web of Knowledge for “age-related macular degeneration,” limited to English-language publications, mostly from the past 8 years, plus older commonly referenced or highly regarded references.
  • Evidence synthesized includes population-based studies (e.g., Beaver Dam, Rotterdam, Blue Mountains, Visual Impairment Project, Multi-ethnic Study of Atherosclerosis), genetic association studies, and randomized trials (e.g., AREDS, TAP, VIP, pegaptanib, ranibizumab).
  • No new primary data or quantitative meta-analysis are reported; the main analysis is a qualitative synthesis of epidemiology, risk factors, pathophysiology, and treatment.

Limitations

  • The paper states its search was limited to English-language publications and mostly to the past 8 years, with older references included only if commonly referenced or highly regarded.
  • The paper reports inconsistent findings for cardiovascular risk factors, dietary antioxidants, lutein/zeaxanthin, and sunlight exposure, and notes that no definitive gene/gene or gene/environment interaction has yet been found.
  • Evident from the text: as a narrative review, it does not report systematic quality appraisal or quantitative pooling; direct comparative data for ranibizumab versus bevacizumab were not available at the time of writing.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/s0140-6736(08)61759-6

Cites

169 of 169 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 198 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Individuals with both large drusen and pigmentary changes in both eyes, or with these lesions in one eye and advanced age-related macular degeneration in the other, have about a 50% risk of developing advanced age-related macular degeneration in 5 years.

    “For example, based on the simplified scale, individuals with both large drusen and the pigmentary changes in both eyes, or with these lesions in one eye and advanced age-related macular degeneration in the other, have about a 50% risk of developing advanced age-related macular degeneration in 5 years.8”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] 2005, A simplified severity scale for age-related macular degeneration, Arch Ophthalmol source

      Not checked in the free run.

  • Premisecitation

    Treatment with antioxidant vitamins and zinc can reduce the risk of developing advanced age-related macular degeneration by about a quarter in those at least at moderate risk.

    “Treatment with antioxidant vitamins and zinc can reduce the risk of developing advanced age-related macular degeneration by about a quarter in those at least at moderate risk.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] 2001, A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss, Arch Ophthalmol source

      Not checked in the free run.

  • Premisecitation

    The 5-year progression rate to advanced age-related macular degeneration in individuals who had intermediate age-related macular degeneration and who were 80 years or older was 42% in the Rotterdam Study.

    “The 5-year progression rate to advanced age-related macular degeneration in individuals who had intermediate age-related macular degeneration and who were 80 years or older was 42% in the Rotterdam Study.20”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] van Leeuwen, 2003, The risk and natural course of age-related maculopathy: follow-up at 6½ years in the Rotterdam Study, Arch Ophthalmol source

      Not checked in the free run.

  • Premisenone given

    Complement factor H and LOC387715/HtrA1 are the most consistent genetic risk factors for age-related macular degeneration.

    “Genetic investigations have shown that complement factor H, a regulator of the alternative complement pathway, and LOC387715/HtrA1 are the most consistent genetic risk factors for age-related macular degeneration.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Drusen are seen at similar frequencies in white and non-white individuals.

    “Data from the Barbados Eye Study,42 the Baltimore Eye Study,25 the Age-Related Eye Disease Study (AREDS),28 and the National Health and Nutrition Examination Survey III (NHANES III)41 have shown that drusen are seen at similar frequencies in white and non-white individuals.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [42] Schachat, 1995, Features of age-related macular degeneration in a black population, Arch Ophthalmol source

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    • cites [25] Friedman, 1999, Racial differences in the prevalence of age-related macular degeneration: the Baltimore Eye Survey, Ophthalmology source

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    • cites [28] 2000, Risk factors associated with age-related macular degeneration: a case-control study in the Age-Related Eye Disease Study, Ophthalmology source

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  • May combine two claims. 35
  • Classified as probably not a substantial claim. 11
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    The Blue Mountains Eye Study estimated the overall 5-year incidence of advanced age-related macular degeneration to be 1.1%, increasing from 0% in individuals under 60 years of age to 5.4% in those aged 80 years or older.

    “The Blue Mountains Eye Study estimated the overall 5-year incidence of advanced age-related macular degeneration to be 1·1%; increasing from 0% in individuals under 60 years of age to 5·4% in those aged 80 years or older.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Mitchell, 2002, Five-year incidence of age-related maculopathy lesions: the Blue Mountains Eye Study, Ophthalmology source

      Not checked in the free run.

    • cites [18] Wang, 2000, Age-specific prevalence and causes of bilateral and unilateral visual impairment in older Australians: the Blue Mountains Eye Study, Clin Experiment Ophthalmol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    The most consistent risk factors associated with age-related macular degeneration are increasing age and cigarette smoking.

    “The most consistent risk factors associated with this ocular condition are increasing age and cigarette smoking.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Intravitreal injections of ranibizumab, a monoclonal antibody that inhibits all forms of vascular endothelial growth factor, have been shown to stabilise loss of vision and, in some cases, improve vision in individuals with neovascular age-related macular degeneration.

    “Intravitreal injections of ranibizumab, a monoclonal antibody that inhibits all forms of vascular endothelial growth factor, have been shown to stabilise loss of vision and, in some cases, improve vision in individuals with neovascular age-related macular degeneration.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The overall 5-year incidence of the development of large drusen or pigmentary changes was 8.7%, ranging from 3.2% in those aged less than 60 years to 18.3% in those aged 70-79 years and 14.8% in those older than 80 years.

    “The overall 5-year incidence of the development of large drusen or pigmentary changes was 8·7%, ranging from 3·2% in those aged less than 60 years to 18·3% in those aged 70–79 years and 14·8% in those older than 80 years.17,18”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Mitchell, 2002, Five-year incidence of age-related maculopathy lesions: the Blue Mountains Eye Study, Ophthalmology source

      Not checked in the free run.

    • cites [18] Wang, 2000, Age-specific prevalence and causes of bilateral and unilateral visual impairment in older Australians: the Blue Mountains Eye Study, Clin Experiment Ophthalmol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Age-related macular degeneration is the leading cause of blindness in elderly populations of European descent.

    “Age-related macular degeneration is the leading cause of blindness in elderly populations of European descent.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] 2004, Causes and prevalence of visual impairment among adults in the United States, Arch Ophthalmol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The incidence of advanced age-related macular degeneration increases with age, as does the development of large drusen and pigmentary changes.

    “These three large population-based studies have found that the incidence of advanced age-related macular degeneration increases with age, as does the development of large drusen and pigmentary changes.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [16] Smith, 2001, Risk factors for age-related macular degeneration: pooled findings from three continents, Ophthalmology source

      Not checked in the free run.

    • cites [17] Mitchell, 2002, Five-year incidence of age-related maculopathy lesions: the Blue Mountains Eye Study, Ophthalmology source

      Not checked in the free run.

    • cites [18] Wang, 2000, Age-specific prevalence and causes of bilateral and unilateral visual impairment in older Australians: the Blue Mountains Eye Study, Clin Experiment Ophthalmol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Age is the strongest risk factor for age-related macular degeneration; all population-based studies confirm that the prevalence of age-related macular degeneration increases with age in white individuals.

    “Age is the strongest risk factor for age-related macular degeneration; all population-based studies confirm that the prevalence of age-related macular degeneration increases with age in white individuals.3,22–27”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [3] Bird, 1995, An international classification and grading system for age-related maculopathy and age-related macular degeneration, Surv Ophthalmol source

      Not checked in the free run.

    • cites [22] Mitchell, 1995, Prevalence of age-related maculopathy in Australia, Ophthalmology source

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    • cites [23] Klein, 1992, Prevalence of age-related maculopathy, Ophthalmology source

      Not checked in the free run.

    • cites [24] Cruickshanks, 1997, The prevalence of age-related maculopathy by geographic region and ethnicity, Arch Ophthalmol source

      Not checked in the free run.

    • cites [25] Friedman, 1999, Racial differences in the prevalence of age-related macular degeneration: the Baltimore Eye Survey, Ophthalmology source

      Not checked in the free run.

    • cites [26] Bressler, 1989, The grading and prevalence of macular degeneration in Chesapeake Bay waterman, Arch Ophthalmol source

      Not checked in the free run.

    • cites [27] VanNewkirk, 2000, The prevalence of age-related maculopathy: the visual impairment project, Ophthalmology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The 15-year incidence of neovascular macular degeneration in the Beaver Dam Eye Study ranged from 0.4% in individuals under 55 years of age to 4.4% in those older than 75 years; the 15-year incidence of soft indistinct drusen ranged from 4.7% to 16.3% in the same age-groups.

    “The 15-year incidence of neovascular macular degeneration in the Beaver Dam Eye Study ranged from 0·4% in individuals under 55 years of age to 4·4% in those older than 75 years; the 15-year incidence of soft indistinct drusen ranged from 4·7% to 16·3% in the same age-groups.19”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Klein, 2007, Fifteen-year cumulative indicence of age-related macular degeneration, Ophthalmology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Female sex may be a risk factor in individuals aged over 75 years, with the relative risk for neovascular age-related macular degeneration in women possibly as much as twice that observed in age-matched men.

    “Female sex may be a risk factor in individuals aged over 75 years,16 with the relative risk for neovascular age-related macular degeneration in women possibly as much as twice that observed in age-matched men.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Smith, 2001, Risk factors for age-related macular degeneration: pooled findings from three continents, Ophthalmology source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Oxidative stress might have an important role in the pathogenesis of age-related macular degeneration.

    “Although the pathogenesis of this disease is unknown, oxidative stress might have an important role.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Age-related macular degeneration is the most common cause of visual impairment in individuals over the age of 55 years in developed countries.

    “Age-related macular degeneration is the most common cause of visual impairment in individuals over the age of 55 years in developed countries.1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] 2004, Causes and prevalence of visual impairment among adults in the United States, Arch Ophthalmol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The pathogenesis of age-related macular degeneration is not well known, although theories include oxidative stress, mitochondrial dysfunction, and inflammatory processes.

    “The pathogenesis of age-related macular degeneration is not well known, although a number of theories have been put forward, including oxidative stress, mitochondrial dysfunction, and inflammatory processes.9–13”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [9] de Jong, 2006, Age-related macular degeneration, N Engl J Med source

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    • cites [10] Ambati, 2003, Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies, Surv Ophthalmol source

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    • cites [11] Zarbin, 2004, Current concepts in the pathogenesis of age-related macular degeneration, Arch Ophthalmol source

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    • cites [12] Holz, 2004, Pathogenesis of lesions in late age-related macular disease, Am J Ophthalmol source

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    • cites [13] Nussenblatt, 2007, Age-related macular degeneration and the immune response: implications for therapy, Am J Ophthalmol source

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  • May combine two claims.

    Premisecitation

    Cigarette smoking is a risk factor for age-related macular degeneration, confirmed by case-control, population-based, and prospective studies.

    “Results from a number of case-control studies,28–33 population-based studies,34–36 and prospective studies of both physicians37 and nurses38 strongly confirm cigarette smoking as a risk factor for age-related macular degeneration.”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [28] 2000, Risk factors associated with age-related macular degeneration: a case-control study in the Age-Related Eye Disease Study, Ophthalmology source

      Not checked in the free run.

    • cites [29] Delcourt, 1998, Smoking and age-related macular degeneration, Arch Ophthalmol source

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    • cites [30] Hyman, 1983, Senile macular degeneration: a case-control study, Am J Epidemiol source

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    • cites [31] Vinding, 1992, Risk factor analysis for atrophic and exudative age-related macular degeneration. An epidemiologic study of 1000 aged individuals, Acta Ophthalmol source

      Not checked in the free run.

    • cites [32] McCarty, 2001, Risk factors for age-related maculopathy: the Visual Impairment Project, Arch Ophthalmol source

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    • cites [33] 1992, Risk factors for neovascular age-related macular degeneration, Arch Ophthalmol source

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    • cites [34] Vingerling, 1996, Age-related macular degeneration and smoking, Arch Ophthalmol source

      Not checked in the free run.

    • cites [35] Klein, 1993, The Beaver Dam Eye Study: the relation of age-related maculopathy to smoking, Am J Epidemiol source

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    • cites [36] Smith, 1996, Smoking and age-related maculopathy, Arch Ophthalmol source

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    • cites [37] Seddon, 1996, A prospective study of cigarette smoking and age-related macular degeneration in women, JAMA source

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  • May combine two claims.

    Premisecitation

    Siblings of individuals with end-stage age-related macular degeneration have about a five-fold increased risk for intermediate age-related macular degeneration and a twenty-fold increased risk for advanced age-related macular degeneration.

    “Klaver and colleagues47 have estimated that siblings of individuals with end-stage age-related macular degeneration have about a five-fold increased risk for intermediate age-related macular degeneration and a twenty-fold increased risk for advanced age-related macular degeneration.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Klaver, 1998, Genetic risk of age-related maculopathy. Population-based familial aggregation study, Arch Ophthalmol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The complement system may have an important role in the pathogenesis of age-related macular degeneration, since factor B and complement components C2 and C3 are also associated with age-related macular degeneration.

    “The complement system may indeed have an important role in the pathogenesis of age-related macular degeneration, since other factors such as factor B and complement components C2 and C3 are also associated with age-related macular degeneration.66,67”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [66] Gold, 2006, Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration, Nat Genet source

      Not checked in the free run.

    • cites [67] Yates, 2007, Complement C3 variant and the risk of age-related macular degeneration, N Engl J Med source

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  • May combine two claims.

    Premisecitation

    The finding of increased myocardial infarction risk in patients with age-related macular degeneration was not confirmed in other studies, although these studies included fewer individuals with advanced age-related macular degeneration.

    “These findings were not confirmed in other studies, although these studies included fewer individuals with advanced age-related macular degeneration.77–79”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [77] Wong, 2007, Age-related macular degeneration and risk of coronary heart disease: the Atherosclerosis Risk in Communities Study, Ophthalmology source

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    • cites [78] Tan, 2007, Cardiovascular risk factors and the long-term incidence of age-related macular degeneration, Ophthalmology

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    • cites [79] Klein, 2007, Cardiovascular disease, its risk factors and treatment and age-related macular degeneration: Women's Health Initiative Sight Exam ancillary Study, Am J Ophthalmol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some evidence exists for a link between risk for age-related macular degeneration and increased levels of total dietary fat, although other studies have refuted this link.

    “Some evidence exists for a link between risk for age-related macular degeneration and increased levels of total dietary fat,84 although other studies have refuted this link.85”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [84] Cho, 2001, Prospective study of dietary fat and the risk of age-related macular degeneration, Am J Clin Nutr source

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    • cites [85] Heuberger, 2001, Relationship of dietary fat to age-related maculopathy in the Third National Health and Nutrition Examination Survey, Arch Ophthalmol source

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  • May combine two claims.

    Premisecitation

    The Multi-ethnic Study of Atherosclerosis showed the prevalence of age-related macular degeneration in individuals aged 45-85 years to be 2.4% in African-American people, 4.2% in Hispanic individuals, 4.6% in Chinese, and 5.4% in white individuals.

    “More recently, the Multi-ethnic Study of Atherosclerosis showed the prevalence of age-related macular degeneration in individuals aged 45–85 years to be 2·4% in African-American people, 4·2% in Hispanic individuals, 4·6% in Chinese, and 5·4% in white individuals.43”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Klein, 2006, Prevalence of age-related macular degeneration in 4 racial/ethnic groups in the multi-ethnic study of atherosclerosis, Ophthalmology source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Another study found no association between late age-related macular degeneration and hypertension, a history of cardiovascular disease, or serum lipid concentrations.

    “Another study found no association between late age-related macular degeneration and hypertension, a history of cardiovascular disease, or with serum lipid concentrations.82”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Delcourt, 2001, Associations of cardiovascular disease and its risk factors with age-related macular degeneration: the POLA study, Ophthalmic Epidemiol source

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  • May combine two claims.

    Premisecitation

    On microscopy, geographic atrophy is seen as abnormal retinal pigment epithelium cells with hypotrophy, hypertrophy, hypopigmentation, hyperpigmentation, atrophy, migration, loss of outer retinal cells, attenuation of Bruch's membrane, and choriocapillaris degeneration.

    “On microscopy, geographic atrophy is seen as abnormal retinal pigment epithelium cells with hypotrophy, hypertrophy, hypopigmentation, hyperpigmentation, atrophy, migration, loss of outer retinal cells (particularly the photoreceptors), attenuation of Bruch’s membrane, and choriocapillaris degeneration.115,125,126”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [115] Green, 1993, Age-related macular degeneration histopathologic studies. The 1992 Lorenz E Zimmerman Lecture, Ophthalmology source

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    • cites [125] Lutty, 1999, Changes in choriocapillaris and retinal pigment epithelium in age-related macular degeneration, Mol Vis

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    • cites [126] McLeod, 2002, Quantifying changes in RPE and choroidal vasculature in eyes with age-related macular degeneration, Invest Ophthalmol Vis Sci

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  • May combine two claims.

    Premisecitation

    Soft drusen are often large and are associated with the detachment of the retinal pigment epithelium and diffusely abnormal Bruch's membrane alterations.

    “Soft drusen are often large and are associated with the detachment of the retinal pigment epithelium and diffusely abnormal Bruch’s membrane alterations.122,124”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [122] Sarks, 1999, Early drusen formation in the normal and aging eye and their relation to age related maculopathy: a clinicopathological study, Br J Ophthalmol source

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    • cites [124] Bressler, 1994, Clinicopathologic correlation of drusen and retinal pigment epithelial abnormalities in age-related macular degeneration, Retina source

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  • May combine two claims.

    Interpretationcitation

    Lutein and zeaxanthin might affect processes modulating light and oxidant exposure; both compounds reflect short-wavelength light, and reduced exposure to these wavelengths might reduce photochemical and oxidant damage to cellular lipids, proteins, and nuclear material.

    “Lutein and zeaxanthin might affect processes modulating light and oxidant exposure:104 both compounds reflect short-wavelength light, and reduced exposure to these wavelengths might reduce both photochemical and oxidant damage to cellular lipids, proteins, and nuclear material.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] Krinsky, 2003, Biologic mechanisms of the protective role of lutein and zeaxanthin in the eye, Annu Rev Nutr source

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  • May combine two claims.

    Premisecitation

    The Blue Mountains Eye Study showed that a reduction in incident early changes of age-related macular degeneration and the eating of fish three times per week could reduce the risk of advanced age-related macular degeneration.

    “The Blue Mountains Eye Study showed that a reduction in incident early changes of age-related macular degeneration and the eating of fish three times per week could reduce the risk of advanced age-related macular degeneration.108”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Chua, 2006, Dietary fatty acids and the 5-year incidence of age-related maculopathy, Arch Ophthalmol source

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  • May combine two claims.

    Interpretationreasoning

    Soft drusen might be associated with further damage to the retina, retinal pigment epithelium, and choroid, thereby leading to choroidal neovascularisation or cell death in the retinal pigment epithelium and geographic atrophy.

    “Soft drusen might be associated with further damage to the retina, retinal pigment epithelium, and choroid, thereby leading to choroidal neovascularisation or cell death in the retinal pigment epithelium and geographic atrophy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Blue iris colour has been inconsistently implicated as a risk factor for age-related macular degeneration and has been considered a possible marker for pigment content in the retinal pigment epithelium.

    “Blue iris colour has been inconsistently implicated as a risk factor for age-related macular degeneration and has been considered a possible marker for pigment content in the retinal pigment epithelium.109,110”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [109] Hyman, 1983, Senile macular degeneration: a case-control study, Am J Epidemiol source

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    • cites [110] Klein, 1998, The relationship of ocular factors to the incidence and progression of age-related maculopathy, Arch Ophthalmol source

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  • May combine two claims.

    Interpretationreasoning

    The generation of lipofuscin is a pathogenic cascade; the A2E that is produced interferes with the function of cells in the retinal pigment epithelium, leading to apoptosis of the retinal pigment epithelium and subsequent geographic atrophy.

    “The generation of lipofuscin is a pathogenic cascade; the A2E that is produced interferes with the function of cells in the retinal pigment epithelium, leading to apoptosis of the retinal pigment epithelium and subsequent geographic atrophy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Basal linear deposits are more specific for early age-related macular degeneration and are composed mainly of membraneous material located external to the basement membrane of the retinal pigment epithelium in Bruch's membrane.

    “basal linear, which is more specific for early age-related macular degeneration and composed mainly of membraneous material located external to the basement membrane of the retinal pigment epithelium in Bruch’s membrane.117”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [117] Sarks, 2007, Relationship of basal laminar deposit and membranous debris to the clinical presentation of early age-related macular degeneration, Invest Ophthalmol Vis Sci source

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  • May combine two claims.

    Interpretationcitation

    Macrophages have been detected in regressing drusen, suggesting that macrophages are recruited to eliminate the age-accumulated deposits within Bruch's membrane.

    “Macrophages have been detected in regressing drusen,122 suggesting that macrophages are recruited to eliminate the age-accumulated deposits within Bruch’s membrane (figure 5).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Sarks, 1999, Early drusen formation in the normal and aging eye and their relation to age related maculopathy: a clinicopathological study, Br J Ophthalmol source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ARMS2 has been reported to be involved in mitochondrial homoeostasis.

    “Recently, ARMS2 has been reported to be involved in mitochondrial homoeostasis.146”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Allikmets, 2008, Bringing age-related macular degeneration into focus, Nat Genet source

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  • May combine two claims.

    Premisecitation

    The Complications of Age-Related Macular Degeneration Prevention Trial showed that although drusen disappeared with laser photocoagulation, there was no reduction in the risk for the development of advanced age-related macular degeneration.

    “The Complications of Age-Related Macular Degeneration Prevention Trial, a controlled clinical trial that assessed the role of laser photocoagulation for the treatment of individuals with large drusen, showed that although drusen disappeared with treatment, there was no reduction in the risk for the development of advanced age-related macular degeneration.156”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [156] 2006, Laser treatment in patients with bilateral large drusen: the complications of age-related macular degeneration prevention trial, Ophthalmology source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The review searched PubMed and Web of Knowledge for the term "age-related macular degeneration" and limited the search to English language publications.

    “We searched PubMed and Web of Knowledge for the term “age-related macular degeneration”. Most publications were from the past 8 years, but we also included older references that were commonly referenced or highly regarded. We limited our search to English language publications only.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Ranibizumab is a fragment of a monoclonal antibody that binds to and inhibits all forms of VEGF-A.

    “Ranibizumab is a fragment of a monoclonal antibody that binds to and inhibits all forms of VEGF-A.164,165”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [164] Rosenfeld, 2006, Ranibizumab for neovascular age-related macular degeneration, N Engl J Med source

      Not checked in the free run.

    • cites [165] Brown, 2006, Ranibizumab versus verteporfin for neovascular age-related macular degeneration, N Engl J Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    One meta-analysis found no increased risk of mortality overall, although subgroup analyses that excluded those studies that had no deaths found an increased risk of mortality.

    “One meta-analysis found no increased risk of mortality overall, although subgroup analyses that excluded those studies that had no deaths found an increased risk of mortality.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [150] Bjelakovic, 2007, Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Among adverse events with pegaptanib, the most serious were endophthalmitis (1.3%), traumatic injury to the lens (0.7%), and retinal detachment (0.6%), leading to severe visual loss in 0.1% of patients.

    “Among the adverse events that occurred, the most serious were endophthalmitis (1·3%), traumatic injury to the lens (0·7%), and retinal detachment (0·6%), leading to severe visual loss in 0·1 % of patients.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [163] Gragoudas, 2004, Pegaptanib for neovascular age-related macular degeneration, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    At 5 years in the Complications of Age-Related Macular Degeneration Prevention Trial, about 20% of both the treated and untreated group experienced vision loss; 15% in each group developed neovascular age-related macular degeneration and about 7% developed geographic atrophy.

    “At 5 years, about 20% of both the treated and untreated group experienced vision loss; 15% in each group developed neovascular age-related macular degeneration and about 7% developed geographic atrophy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [156] 2006, Laser treatment in patients with bilateral large drusen: the complications of age-related macular degeneration prevention trial, Ophthalmology source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Another meta-analysis concluded that vitamin E in high doses (400 IU) was associated with an increased risk of mortality, while further analyses of three large clinical trials that used a dose of about 400 IU showed no statistical differences.

    “Another meta-analysis concluded that vitamin E in high doses (400 IU) was associated with an increased risk of mortality,154 while further analyses of three large clinical trials that used a dose of about 400 IU showed no statistical differences.155”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [154] Miller, 2005, Meta-analysis: high dosage vitamin E supplementation may increase all-cause mortality, Ann Intern Med source

      Not checked in the free run.

    • cites [155] Chew, 2005, Vitamin E and the Age-Related Eye Disease Study supplementation for age-related macular degeneration, Arch Ophthalmol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    About 3-4% of treated patients experience severe vision loss in the normal administration of verteporfin, although some of this loss is reversible.

    “About 3–4% of treated patients experience severe vision loss in the normal administration of this drug, although some of this loss is reversible.162”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] 2002, Guidelines for using verteporfin (visudyne) in photodynamic therapy to treat choroidal neovascularization due to age-related macular degeneration and other causes, Retina source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Activated macrophages and microglia may secrete chemokines and cytokines, causing further cellular damage, Bruch's membrane degradation, and angiogenesis.

    “Activated macrophages and microglia may secrete chemokines and cytokines, causing further cellular damage, Bruch’s membrane degradation, and angiogenesis.143”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [143] Chen, 2007, Overstaying their welcome: defective CX3CR1 microglia eyed in macular degeneration, J Clin Invest source

      Not checked in the free run.

  • The quote only partly states this claim.

    Interpretationown data

    Only a portion of treated patients with neovascular age-related macular degeneration experience an improvement in visual acuity with current treatments.

    “since only a portion of treated patients experience an improvement in visual acuity”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The off-label use of bevacizumab for neovascular age-related macular degeneration spread worldwide because ranibizumab had not yet been approved by the FDA and bevacizumab was licensed for use in colon cancer.

    “Because ranibizumab had not yet been approved by the FDA, and since bevacizumab was licensed for use in colon cancer, the off-label use of the latter drug spread worldwide.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Bevacizumab was licensed for use in colon cancer.
    • Rests on an assumption: Ranibizumab had not yet been approved by the FDA at the time bevacizumab off-label use began.

  • May combine two claims.

    Premisecitation

    Adverse effects of ranibizumab included endophthalmitis (1%) and serious uveitis (1%).

    “The adverse effects included endophthalmitis (1%) and serious uveitis (1%).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [164] Rosenfeld, 2006, Ranibizumab for neovascular age-related macular degeneration, N Engl J Med source

      Not checked in the free run.

    • cites [165] Brown, 2006, Ranibizumab versus verteporfin for neovascular age-related macular degeneration, N Engl J Med source

      Not checked in the free run.

41 of 41

  • The paper relies on this without support.

    At the time of writing, there were no data directly comparing ranibizumab and bevacizumab for neovascular age-related macular degeneration.

    “At present, there are no data to compare the two drugs directly”

  • The paper relies on this without support.

    Bevacizumab was licensed for use in colon cancer.

    “since bevacizumab was licensed for use in colon cancer”

  • The paper relies on this without support.

    Ranibizumab had not yet been approved by the FDA at the time bevacizumab off-label use began.

    “Because ranibizumab had not yet been approved by the FDA”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In advanced dry AMD called geographic atrophy, the RPE has well-demarcated atrophy and the neurosensory retina is severely affected.

    “In the advanced stage of dry AMD called geographic atrophy, the RPE has well-demarcated atrophy and the neurosensory retina is severely affected (Coleman et al., 2008).”

    From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Coleman et al., 2008

  • Classic pathology of early AMD is multiple small or intermediate drusen (drusen size ≥63 microns but <125 microns) in the macular area.

    “The classic pathology of early AMD is multiple small or intermediate drusen (drusen size of ≥ 63 microns but < 125 microns) in the macular area (Coleman et al., 2008).”

    From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Coleman et al., 2008

  • Subretinal fibrous tissue, or minimal subretinal fibrosis, and widespread RPE atrophy are also often noted in neovascular AMD.

    “Subretinal fibrous tissue, or minimal subretinal fibrosis, and widespread RPE atrophy are also often noted (Coleman et al., 2008).”

    From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Coleman et al., 2008

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • A photodynamic-therapy study is cited as a pegaptanib study

    Minor

    In the photodynamic-therapy discussion, the text calls reference 163 one of the verteporfin studies, but the reference list identifies 163 as a study of pegaptanib.

  • Laser treatment is described as delaying a condition that the cited study says it hastens

    Minor

    The text says prophylactic laser treatment delayed choroidal neovascularisation in patients with unilateral disease, but the title of cited study 157 says it hastened choroidal neovascularization in those patients.

  • A cited randomised trial is listed as treatment guidelines

    Minor

    The text identifies reference 162 as one of two large randomised controlled trials of photodynamic therapy, whereas the reference list identifies it as guidelines for using verteporfin.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 4

  1. Tomany, 2004, Risk factors for incident age-related macular degeneration. Pooled findings from 3 continents, Ophthalmology, 111, 1280, 10.1016/j.ophtha.2003.11.010 · DOI · Paper page
  2. Albanes, 2007, Letter to the editor, JAMA, 298, 400
  3. Gluud, 2007, Response from authors, JAMA, 298, 402
  4. Huang, 2007, Letter to the editor, JAMA, 298, 400

Cited by

Sorted by citations

Related

Authors
Coleman, H. R., Chan, C.-C., Ferris, F. L., & Chew, E. Y.
Affiliations
National Institutes of Health (US)
Corresponding author
Chew, Emily Y
ORCID
Venue
The Lancet
Publisher
Elsevier BV
Published
2008-11
Volume
372
Issue
9652
Pages
1835-1845
ISSN
  • 0099-5355 (ISSN-L)
  • 0140-6736
DOI
10.1016/s0140-6736(08)61759-6
PMC
PMC2603424
OpenAlex
W4211214508
Cited by
542
References
169
Citations by year
2026: 17 · 2025: 23 · 2024: 32 · 2023: 32 · 2022: 38 · 2021: 40 · 2020: 38 · 2019: 33 · 2018: 25 · 2017: 29 · 2016: 40 · 2015: 36 · 2014: 36 · 2013: 28 · 2012: 30
FWCI
21.59
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • The Lancet (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (Z99 EY999999)
  • National Eye Institute (Z01EY000222, Z01EY000418)
Topics
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal Imaging and Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
Keywords
age-related macular degeneration, genetic risk factors, complement factor H, alternative complement pathway, oxidative stress, antioxidant vitamins, zinc supplementation, ranibizumab, neovascular age-related macular degeneration, vascular endothelial growth factor, smoking, vision loss
MeSH terms
Ranibizumab, Verteporfin, Aged, Aged, 80 and over, Aging, Antibodies, Monoclonal, Antioxidants, Female, Humans, Macular Degeneration, Male, Middle Aged, Porphyrins, Risk Factors, Smoking, Zinc, Prevalence, Laser Coagulation, Photosensitizing Agents, Vascular Endothelial Growth Factor A, Antibodies, Monoclonal, Humanized

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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