{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T05:54:11Z","timestamp":1781589251952,"version":"3.54.5"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Age-related macular degeneration (AMD) is a severe eye disease that affects the macula, the central area of the retina. Current treatment consists of intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors. However, some patients remain refractory to treatment even after maximal anti-VEGF dosage. We longitudinally analyzed angiogenic and inflammatory biomarkers in the aqueous humor (AH) of these patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>1) To confirm the presence of angiogenic and inflammatory biomarkers before (in the naive state) and after two anti-VEGF injections; and 2) to characterize the inflammatory response according to the type of anti-VEGF used (ranibizumab, aflibercept, brolucizumab, or faricimab).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>AH samples were collected from two groups of patients: 35 patients with AMD and 17 control patients with no retinopathy. Eleven of the 35 patients with AMD were characterized as refractory (rAMD) after long-term anti-VEGF treatment. Multiplex and proximity extension assays (PEA) were performed on these samples to define their inflammatory profiles. Free VEGFA was detected using an additional AlphaLISA VEGFA assay.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Several inflammatory molecules are upregulated in AMD, while a smaller subset is downregulated in rAMD, indicating that these could serve as markers of a refractory state. In contrast, no differences were observed in the biomarkers previously reported as increased in rAMD after long term treatment. These findings suggest that anti-VEGF treatment induces the expression of angiogenic and inflammatory biomarkers. Analysis of the inflammatory response following the injection of different anti-VEGF agents revealed exacerbated inflammation in patients treated with brolucizumab, whereas ranibizumab caused the lowest inflammatory response. In addition, we compared three different assays to assess AH VEGFA, but only the AlphaLISA assay could detect free VEGFA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our results indicate that anti-VEGFA therapy shapes AMD-associated inflammation; therefore, the choice of anti-VEGFA therapy remains important in reducing secondary inflammatory effects. Furthermore, the detection of free VEGF is dependent on the assay used.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1793714","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T05:39:00Z","timestamp":1781588340000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Proteomic profiling reveals treatment-dependent inflammatory signatures and identifies biomarkers of refractory age-related macular degeneration"],"prefix":"10.3389","volume":"17","author":[{"given":"Chiara M.","family":"Eandi","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital","place":["Lausanne, Switzerland"]},{"name":"Department of Surgical Sciences, University of Torino","place":["Turin, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelica","family":"Borgo","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital","place":["Lausanne, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"de Oliveira Figueiredo","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital","place":["Lausanne, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"de Haro","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Lausanne University Hospital (CHUV) and Universit\u00e9 de Lausanne","place":["Lausanne, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel E.","family":"Kaufmann","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Lausanne University Hospital (CHUV) and Universit\u00e9 de Lausanne","place":["Lausanne, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael","family":"Roduit","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital","place":["Lausanne, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2809","DOI":"10.3389\/fimmu.2018.02809","article-title":"The emerging role of CD244 signaling in immune cells of the tumor microenvironment","volume":"9","author":"Agresta","year":"2018","journal-title":"Front. Immunol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/s40942-021-00307-7","article-title":"Mechanisms of Sterile inflammation after intravitreal injection of antiangiogenic drugs: a narrative review","volume":"7","author":"Anderson","year":"2021","journal-title":"Int. J. Retina Vitreous"},{"key":"B3","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1089\/jop.2016.0121","article-title":"A novel neuroprotective small molecule for glial cell derived neurotrophic factor induction and photoreceptor rescue","volume":"33","author":"Baranov","year":"2017","journal-title":"J. Ocular Pharmacol. Ther."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2092","DOI":"10.3390\/cells12162092","article-title":"The role of inflammation in age-related macular degeneration\u2014therapeutic landscapes in geographic atrophy","volume":"12","author":"Borchert","year":"2023","journal-title":"Cells"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1432","DOI":"10.1056\/NEJMoa062655","article-title":"Ranibizumab versus verteporfin for neovascular age-related macular degeneration","volume":"355","author":"Brown","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"981","DOI":"10.3390\/jcm10050981","article-title":"Inflammatory complications of intravitreal Anti-VEGF injections","volume":"10","author":"Cox","year":"2021","journal-title":"J. Clin. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1631","DOI":"10.1136\/bjo.2010.186361","article-title":"Cytokines in neovascular age-related macular degeneration: fundamentals of targeted combination therapy","volume":"95","author":"Dias","year":"2011","journal-title":"Br. J. Ophthalmol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1038\/s41433-018-0021-7","article-title":"Clinical pharmacology of intravitreal anti-VEGF drugs","volume":"32","author":"Fogli","year":"2018","journal-title":"Eye"},{"key":"B9","doi-asserted-by":"publisher","first-page":"2537","DOI":"10.1016\/j.ophtha.2012.09.006","article-title":"Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration","volume":"19","author":"Heier","year":"2012","journal-title":"Ophthalmology"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1016\/j.ophtha.2015.12.030","article-title":"Single-chain antibody fragment VEGF inhibitor RTH258 for neovascular age-related macular degeneration A randomized controlled study","volume":"123","author":"Holz","year":"2016","journal-title":"Ophthalmology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"e381","DOI":"10.1111\/j.1755-3768.2012.02414.x","article-title":"Cytokine concentration in aqueous humour of eyes with exudative age\u2010related macular degeneration","volume":"90","author":"Jonas","year":"2012","journal-title":"Acta Ophthalmol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1001\/jamaophthalmol.2020.2699","article-title":"Efficacy of every four monthly and quarterly dosing of faricimab vs ranibizumab in neovascular age-related macular degeneration: the STAIRWAY phase 2 randomized clinical trial","volume":"138","author":"Khanani","year":"2020","journal-title":"JAMA Ophthalmology"},{"key":"B13","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1097\/IIO.0000000000000073","article-title":"Inflammatory mechanisms of age-related macular degeneration","volume":"55","author":"Knickelbein","year":"2015","journal-title":"Int. Ophthalmol. Clin."},{"key":"B14","first-page":"352","article-title":"Aqueous humor cytokine profiling in patients with wet AMD","volume":"22","author":"Liu","year":"2016","journal-title":"Mol. Vision"},{"key":"B15","doi-asserted-by":"publisher","first-page":"594087","DOI":"10.3389\/fphar.2020.594087","article-title":"Molecular biomarkers of neovascular age-related macular degeneration with incomplete response to anti-vascular endothelial growth factor treatment","volume":"11","author":"Mantel","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1007\/s00417-014-2738-8","article-title":"Serum cytokines as biomarkers for age-related macular degeneration","volume":"253","author":"Nassar","year":"2015","journal-title":"Graefe's Archive Clin. Exp. Ophthalmol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"22913","DOI":"10.1038\/s41598-024-73782-1","article-title":"Incidence of intraocular inflammation and its risk factors in patients treated with brolucizumab: a nationwide cohort study","volume":"14","author":"Park","year":"2024","journal-title":"Sci. Rep."},{"key":"B18","doi-asserted-by":"publisher","first-page":"2134","DOI":"10.1097\/iae.0000000000003582","article-title":"Risk of intraocular inflammation after injection of antivascular endothelial growth factor agents","volume":"42","author":"Patil","year":"2022","journal-title":"Retina"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1707","DOI":"10.1080\/09273948.2023.2290624","article-title":"Macrophage migration inhibitory factor (MIF) is a key player in dry eye disease","volume":"32","author":"Rivera","year":"2024","journal-title":"Ocular Immunol. Inflamm."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1419","DOI":"10.1056\/nejmoa054481","article-title":"Ranibizumab for neovascular age-related macular degeneration","volume":"355","author":"Rosenfeld","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1098","DOI":"10.1038\/s41598-018-19594-6","article-title":"Intraocular inflammatory cytokines in patients with neovascular age-related macular degeneration before and after initiation of intravitreal injection of anti-anti-VEGF inhibitor","volume":"8","author":"Sato","year":"2018","journal-title":"Sci. Rep."},{"key":"B22","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/s41586-023-06592-6","article-title":"Plasma proteomic associations with genetics and health in the UK biobank","volume":"622","author":"Sun","year":"2023","journal-title":"Nature"},{"key":"B23","doi-asserted-by":"publisher","first-page":"2989","DOI":"10.7150\/ijbs.49890","article-title":"The role of inflammation in age-related macular degeneration","volume":"16","author":"Tan","year":"2020","journal-title":"Int. J. Biol. Sci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1007\/s12079-015-0302-x","article-title":"A network map of Interleukin-10 signaling pathway","volume":"10","author":"Verma","year":"2016","journal-title":"J. Cell. Commun. Signal."},{"key":"B25","doi-asserted-by":"publisher","first-page":"4106","DOI":"10.1167\/iovs.18-24792","article-title":"Comments on assays used to measure VEGF in the presence of anti-VEGF therapeutics","volume":"59","author":"Wakshull","year":"2018","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"112678","DOI":"10.1016\/j.intimp.2024.112678","article-title":"91 circulating inflammatory proteins and the risk of age-related macular degeneration: a bidirectional Mendelian randomization study","volume":"139","author":"Wang","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1857","DOI":"10.2147\/dddt.s97653","article-title":"Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: a comprehensive review","volume":"10","author":"Yang","year":"2016","journal-title":"Drug Design, Development Therapy"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1311","DOI":"10.1084\/jem.20182304","article-title":"Human interleukin-2 receptor \u03b2 mutations associated with defects in immunity and peripheral tolerance","volume":"216","author":"Zhang","year":"2019","journal-title":"J. Exp. Med."},{"key":"B29","doi-asserted-by":"publisher","first-page":"e157038","DOI":"10.1172\/jci.insight.157038","article-title":"CDCP1 regulates retinal pigmented epithelial barrier integrity for the development of experimental autoimmune uveitis","volume":"7","author":"Zhang","year":"2022","journal-title":"JCI Insight"},{"key":"B30","doi-asserted-by":"publisher","first-page":"309","DOI":"10.4103\/1673-5374.379020","article-title":"The roles of macrophage migration inhibitory factor in retinal diseases","volume":"19","author":"Zhang","year":"2023","journal-title":"Neural Regen. Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"109014","DOI":"10.1016\/j.exer.2022.109014","article-title":"Fibroblast growth factor-21 alleviates phenotypic characteristics of dry age-related macular degeneration in mice","volume":"218","author":"Zhao","year":"2022","journal-title":"Exp. Eye Res."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1793714\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T05:39:01Z","timestamp":1781588341000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1793714\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,16]]},"references-count":31,"alternative-id":["10.3389\/fphar.2026.1793714"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1793714","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,16]]},"article-number":"1793714"}}