{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T09:03:04Z","timestamp":1779181384420,"version":"3.51.4"},"reference-count":27,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,4,23]],"date-time":"2022-04-23T00:00:00Z","timestamp":1650672000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01 EY030088"],"award-info":[{"award-number":["R01 EY030088"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018133","name":"VitreoRetinal Surgery Foundation","doi-asserted-by":"publisher","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}],"id":[{"id":"10.13039\/100018133","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Although complement inhibition has emerged as a possible therapeutic strategy for age-related macular degeneration (AMD), there is not a clear consensus regarding what aspects of the complement pathway are dysregulated in AMD and when this occurs relative to disease stage. We recently published a systematic review describing systemic complement activation profiles in patients with early\/intermediate AMD or geographic atrophy (GA) compared to non-AMD controls. Here, we sought to meta-analyze these results to estimate the magnitude of complement dysregulation in AMD using restricted maximum likelihood estimation. The seven meta-analyzed studies included 710 independent participants with 23 effect sizes. Compared with non-AMD controls, patients with early\/intermediate nonexudative AMD (N = 246) had significantly higher systemic complement activation, as quantified by the levels of complement proteins generated by common final pathway activation, and significantly lower systemic complement inhibition. In contrast, there were no statistically significant differences in the systemic levels of complement common final pathway activation products or complement inhibition in patients with GA (N = 178) versus non-AMD controls. We provide evidence that systemic complement over-activation is a feature of early\/intermediate nonexudative AMD; no such evidence was identified for patients with GA. These findings provide mechanistic insights and inform future clinical trials.<\/jats:p>","DOI":"10.3390\/jcm11092371","type":"journal-article","created":{"date-parts":[[2022,4,23]],"date-time":"2022-04-23T08:14:06Z","timestamp":1650701646000},"page":"2371","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Systemic Complement Activation Profiles in Nonexudative Age-Related Macular Degeneration: A Meta-Analysis"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2792-7821","authenticated-orcid":false,"given":"Jonathan B.","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Mass Eye and Ear and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2477-6060","authenticated-orcid":false,"given":"Stylianos","family":"Serghiou","sequence":"additional","affiliation":[{"name":"Google LLC, Mountain View, CA 94043, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joan W.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Mass Eye and Ear and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Demetrios G.","family":"Vavvas","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Mass Eye and Ear and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e106","DOI":"10.1016\/S2214-109X(13)70145-1","article-title":"Global Prevalence of Age-Related Macular Degeneration and Disease Burden Projection for 2020 and 2040: A Systematic Review and Meta-Analysis","volume":"2","author":"Wong","year":"2014","journal-title":"Lancet Glob. Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1001\/jamaophthalmol.2013.7376","article-title":"Secondary Analyses of the Effects of Lutein\/Zeaxanthin on Age-Related Macular Degeneration Progression: AREDS2 Report No. 3","volume":"132","author":"Chew","year":"2014","journal-title":"JAMA Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"(2013). Lutein + Zeaxanthin and Omega-3 Fatty Acids for Age-Related Macular Degeneration: The Age-Related Eye Disease Study 2 (AREDS2) Randomized Clinical Trial. JAMA, 309, 2005.","DOI":"10.1001\/jama.2013.4997"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"E696","DOI":"10.1073\/pnas.1718059115","article-title":"CFH and ARMS2 Genetic Risk Determines Progression to Neovascular Age-Related Macular Degeneration after Antioxidant and Zinc Supplementation","volume":"115","author":"Vavvas","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"(2001). Age-Related Eye Disease Study Research Group 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: AREDS Report No. 8. Arch. Ophthalmol., 119, 1417\u20131436.","DOI":"10.1001\/archopht.119.10.1417"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1016\/j.ophtha.2013.01.021","article-title":"Age-Related Eye Disease Study Research Group Long-Term Effects of Vitamins C and E, \u03b2-Carotene, and Zinc on Age-Related Macular Degeneration: AREDS Report No. 35","volume":"120","author":"Chew","year":"2013","journal-title":"Ophthalmology"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Lin, J.B., Halawa, O.A., Miller, J.W., and Vavvas, D.G. (2021). Complement Inhibition for Geographic Atrophy: A Tempting Target with Mixed Results. J. Clin. 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Surg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1001\/jama.283.15.2008","article-title":"Meta-Analysis of Observational Studies in Epidemiology: A Proposal for Reporting. Meta-Analysis Of Observational Studies in Epidemiology (MOOSE) Group","volume":"283","author":"Stroup","year":"2000","journal-title":"JAMA"},{"key":"ref_12","unstructured":"R Core Team (2020). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1136\/ebmental-2019-300117","article-title":"How to Perform a Meta-Analysis with R: A Practical Tutorial","volume":"22","author":"Balduzzi","year":"2019","journal-title":"Evid. Based Ment. Health"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v036.i03","article-title":"Conducting Meta-Analyses in R with the Metafor Package","volume":"36","author":"Viechtbauer","year":"2010","journal-title":"J. Stat. Softw."},{"key":"ref_15","unstructured":"Cohen, J. (1988). Statistical Power Analysis for the Behavioral Sciences, L. Erlbaum Associates. [2nd ed.]."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Lin, L. (2018). Bias Caused by Sampling Error in Meta-Analysis with Small Sample Sizes. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0204056"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e000361","DOI":"10.1136\/bmjophth-2019-000361","article-title":"Complement Factors and Reticular Pseudodrusen in Intermediate Age-Related Macular Degeneration Staged by Multimodal Imaging","volume":"5","author":"Lynch","year":"2020","journal-title":"BMJ Open Ophthalmol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1177\/1120672119857896","article-title":"Systemic Activation of the Complement System in Patients with Advanced Age-Related Macular Degeneration","volume":"30","author":"Lynch","year":"2020","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1159\/000219686","article-title":"Elevated Plasma Levels of C3a Complement Compound in the Exudative Form of Age-Related Macular Degeneration","volume":"42","author":"Dziedziejko","year":"2009","journal-title":"Ophthalmic Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5818","DOI":"10.1167\/iovs.09-3928","article-title":"Plasma Complement Components and Activation Fragments: Associations with Age-Related Macular Degeneration Genotypes and Phenotypes","volume":"50","author":"Reynolds","year":"2009","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1177\/0962280216669183","article-title":"Optimally Estimating the Sample Mean from the Sample Size, Median, Mid-Range, and\/or Mid-Quartile Range","volume":"27","author":"Luo","year":"2018","journal-title":"Stat. Methods Med. Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Wan, X., Wang, W., Liu, J., and Tong, T. (2014). Estimating the Sample Mean and Standard Deviation from the Sample Size, Median, Range and\/or Interquartile Range. BMC Med. Res. Methodol., 14.","DOI":"10.1186\/1471-2288-14-135"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1001\/archopht.125.4.515","article-title":"Estimation of Systemic Complement C3 Activity in Age-Related Macular Degeneration","volume":"125","author":"Sivaprasad","year":"2007","journal-title":"Arch. Ophthalmol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Lashkari, K., Teague, G.C., Beattie, U., Betts, J., Kumar, S., McLaughlin, M.M., and L\u00f3pez, F.J. (2020). Plasma Biomarkers of the Amyloid Pathway Are Associated with Geographic Atrophy Secondary to Age-Related Macular Degeneration. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0236283"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Lashkari, K., Teague, G., Chen, H., Lin, Y.-Q., Kumar, S., McLaughlin, M.M., and L\u00f3pez, F.J. (2018). A Monoclonal Antibody Targeting Amyloid \u03b2 (A\u03b2) Restores Complement Factor I Bioactivity: Potential Implications in Age-Related Macular Degeneration and Alzheimer\u2019s Disease. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0195751"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1007\/s00417-020-04910-6","article-title":"Association of Imaging Biomarkers and Local Activation of Complement in Aqueous Humor of Patients with Early Forms of Age-Related Macular Degeneration","volume":"259","author":"Sitnilska","year":"2020","journal-title":"Graefe Arch. Clin. Exp. Ophthalmol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1038\/s41433-019-0501-4","article-title":"Early Local Activation of Complement in Aqueous Humour of Patients with Age-Related Macular Degeneration","volume":"33","author":"Altay","year":"2019","journal-title":"Eye"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/9\/2371\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:59:27Z","timestamp":1760137167000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/9\/2371"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,23]]},"references-count":27,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["jcm11092371"],"URL":"https:\/\/doi.org\/10.3390\/jcm11092371","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,23]]}}}