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pmid:33447243
Molecular Biomarkers of Neovascular Age-Related Macular Degeneration With Incomplete Response to Anti-Vascular Endothelial Growth Factor Treatment.
Irmela Mantel · Angelica Borgo · Jacopo Guidotti · Edwige Forestier · Olga Kirsch · Yasmine Derradji · Patrice Waridel · Frédéric Burdet · Florence Mehl · Claude Schweizer · Raphaël Roduit
Frontiers in pharmacology · 2020 doi:10.3389/fphar.2020.594087
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Complete file
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However, for some patients, even maximal anti-VEGF treatment does not entirely suppress exudative activity. The goal of this study was to identify molecular biomarkers in nAMD with incomplete response to anti-VEGF treatment. Aqueous humor (AH) samples were collected from three groups of patients: 17 patients with nAMD responding incompletely to anti-VEGF (18 eyes), 17 patients affected by nAMD with normal treatment response (21 eyes), and 16 control patients without any retinopathy (16 eyes). Proteomic and multiplex analyses were performed on these samples. Proteomic analyses showed that nAMD patients with incomplete anti-VEGF response displayed an increased inflammatory response, complement activation, cytolysis, protein-lipid complex, and vasculature development pathways. Multiplex analyses revealed a significant increase of soluble vascular cell adhesion molecule-1 (sVCAM-1) [ p = 0.001], interleukin-6 (IL-6) [ p = 0.009], bioactive interleukin-12 (IL-12p40) [ p = 0.03], plasminogen activator inhibitor type 1 (PAI-1) [ p = 0.004], and hepatocyte growth factor (HGF) [ p = 0.004] levels in incomplete responders in comparison to normal responders. Interestingly, the same biomarkers showed a high intercorrelation with r2 values between 0.58 and 0.94. In addition, we confirmed by AlphaLISA the increase of sVCAM-1 [ p < 0.0001] and IL-6 [ p = 0.043] in the incomplete responder group. Incomplete responders in nAMD are associated with activated angiogenic and inflammatory pathways. The residual exudative activity of nAMD despite maximal anti-VEGF treatment may be related to both angiogenic and inflammatory responses requiring specific adjuvant therapy. 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"0.144", "*0.011", "0.174"], ["Adiponectin", "100 ± 33.65 (4)", "131.7 ± 32.36 (9)", "173.2 ± 60.66 (8)", "0.762", "0.741", "0.762"], ["Eotaxin-3", "100 ± 18.98 (5)", "145.9 ± 27.1 (9)", "120.3 ± 19.7 (10)", "0.781", "0.857", "0.781"], ["Ghrelin", "100 ± 5.83 (4)", "105.3 ± 5.74 (9)", "103 ± 8.74 (8)", "0.960", "0.960", "0.960"], ["IL-3", "100 ± 25.06 (5)", "122.7 ± 36.17 (4)", "110.5 ± 23.78 (5)", "0.946", "0.946", "0.928"], ["IL-7", "100 ± 18.25 (8)", "290.5 ± 44.59 (12)", "360.1 ± 40.22 (11)", "**0.006", "#0.0005", "0.203"], ["MIF", "100 ± 17.19 (4)", "138.9 ± 20.84 (9)", "133.5 ± 20.95 (8)", "0.619", "0.619", "0.848"], ["NGAL", "100 ± 19.1 (9)", "120.1 ± 10.53 (13)", "135.4 ± 13.54 (12)", "0.451", "0.187", "0.451"], ["PaI-1", "100 ± 8.5 (12)", "179.9 ± 18.39 (13)", "425.7 ± 89.64 (13)", "0.304", "#0.0005", "**0.005"], ["Gro-alpha-KC", "100 ± 8.27 (14)", "94.71 ± 5.60 (19)", "162.7 ± 42.79 (17)", "0.887", "0.199", "0.1669"], ["IL-1RA", "100 ± 32.02 (12)", "70.77 ± 14.78 (16)", "149 ± 61.91 (14)", "0.652", "0.652", "0.4121"], ["IL-13", "100 ± 0.90 (10)", "96.14 ± 3.46 (10)", "97.66 ± 2.16 (10)", "0.608", "0.749", "0.749"]], "row_count": 25, "column_count": 7, "numeric_cells": 152, "header_rows": 2, "locator": "section[17]/table-wrap[1]#T2"}}, {"id": "asset:table:pmid:33447243:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:9433448ec5580580b89013d72a94685d735ef3a7ba74f99dc7c6d5127b033258", "bytes": 1735, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[13]/table-wrap[1]#T1", "version": null, "note": "Demographic, phenotypic and treatment characteristics of each group based on the type of molecular analysis.", "structure": {"pmcid": "PMC7802772", "section_index": 13, "section_title": "Clinical Characteristics", "row_count": 25, "column_count": 4}, "table": {"label": "TABLE 1", "caption": "Demographic, phenotypic and treatment characteristics of each group based on the type of molecular analysis.", "rows": [["", "rAMD (R)", "nAMD (N)", "Control (C)"], ["N patients", "17", "17", "16"], ["Mean age (SD)", "81.6 (±6.5)", "81.6 (±5.9)", "70.44 ± 2.47"], ["Females (%)", "13 (76.5%)", "13 (76.5%)", "8/8"], ["N eyes", "18", "19", "16"], ["Right eyes/left eyes", "14/4", "7/13", "10/6"], ["Neovascularization type: 1/2/3", "15/2/1", "16/3/1", "—"], ["Presence of reticular pseudodrusen (%)", "5 (28%)", "7 (35%)", "—"], ["Presence of fibrosis (%)", "3 (17%)", "4 (20%)", "—"], ["Presence of cRORA", "4 (22%)", "10 (50%)", "—"], ["Presence of iRORA", "6 (33%)", "14 (70%)", "—"], ["Recurrences including IRF (%)", "9 (50%)", "17 (85%)", "—"], ["Recurrences including SRF (%)", "12 (67%)", "8 (40%)", "—"], ["Mean CRT in micrometers (SD)", "323 (±83)", "286 (±76)", "—"], ["Mean subfoveal choroidal thickness in micrometers (SD)", "150 (±121)", "166 (±64)", "—"], ["Treatment duration in months ± SD", "69.7 ± 35.1", "55.4 ± 36.2", "—"], ["Number of injections received ± SD", "59.6 ± 29.9", "36.4 ± 26.7", "—"], ["Weeks from preceding injection ± SEM", "5.89 ± 0.94", "3.97 ± 0.29", "—"], ["Anti-VEGF agent used (ranib./Aflib.)", "8/10", "8/12", "—"], ["Number of switches performed", "", "", ""], ["0", "3", "13", "—"], ["1", "9", "7", "—"], ["2", "6", "0", "—"], ["Mean visual acuity at treatment initiation in ETDRS letters ± SD", "61.7 ± 12.5", "63.1 ± 16.1", "—"], ["Mean visual acuity change from baseline in ETDRS letters ± SD", "7.9 ± 12.5", "Before cataract surgery −9.4 ± 12.9 after cataract surgery 12.8 ± 11.8", "—"]], "row_count": 25, "column_count": 4, "numeric_cells": 55, "header_rows": 1, "locator": "section[13]/table-wrap[1]#T1"}}, {"id": "asset:table:pmid:33447243:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:4c72cb3d2ee6e9e926bc3ef335e5dfa9eb0eba95c8efbbdc9fe98a6203823d3a", "bytes": 2618, "access": "open", "state": 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(10)", "105 ± 3.26 (10)", "110.5 ± 1.71 (10)", "0.242", "*0.016", "0.242"], ["Eotaxin", "100 ± 12.57 (13)", "165 ± 23.5 (19)", "238.8 ± 41.1 (18)", "0.154", "*0.011", "0.151"], ["HGF", "100 ± 10.03 (14)", "129.4 ± 10.82 (19)", "232 ± 35.43 (18)", "0.388", "**0.001", "**0.004"], ["IL-12p40", "100 ± 7.40 (14)", "155.9 ± 14.15 (19)", "210 ± 20.47 (18)", "*0.031", "#0.0001", "*0.031"], ["sVCAM-1", "100 ± 8.93 (14)", "122.8 ± 12.63 (19)", "242.7 ± 35.69 (18)", "0.511", "#0.0005", "**0.001"], ["IL-6", "100 ± 25.70 (6)", "86.12 ± 64.25 (7)", "10,546 ± 7,320 (10)", "*0.042", "0.11", "**0.009"], ["IP-10", "100 ± 16.91 (14)", "235.5 ± 42.06 (19)", "280.2 ± 62.2 (18)", "0.107", "*0.038", "0.490"], ["MCP-1", "100 ± 6.46 (14)", "137.8 ± 11.16 (19)", "154.3 ± 11.35 (18)", "*0.032", "**0.002", "0.253"], ["MMP-9", "100 ± 18.31 (13)", "233.3 ± 42.79 (19)", "325.4 ± 64.23 (18)", "0.144", "*0.011", "0.174"], ["Adiponectin", "100 ± 33.65 (4)", "131.7 ± 32.36 (9)", "173.2 ± 60.66 (8)", "0.762", "0.741", "0.762"], ["Eotaxin-3", "100 ± 18.98 (5)", "145.9 ± 27.1 (9)", "120.3 ± 19.7 (10)", "0.781", "0.857", "0.781"], ["Ghrelin", "100 ± 5.83 (4)", "105.3 ± 5.74 (9)", "103 ± 8.74 (8)", "0.960", "0.960", "0.960"], ["IL-3", "100 ± 25.06 (5)", "122.7 ± 36.17 (4)", "110.5 ± 23.78 (5)", "0.946", "0.946", "0.928"], ["IL-7", "100 ± 18.25 (8)", "290.5 ± 44.59 (12)", "360.1 ± 40.22 (11)", "**0.006", "#0.0005", "0.203"], ["MIF", "100 ± 17.19 (4)", "138.9 ± 20.84 (9)", "133.5 ± 20.95 (8)", "0.619", "0.619", "0.848"], ["NGAL", "100 ± 19.1 (9)", "120.1 ± 10.53 (13)", "135.4 ± 13.54 (12)", "0.451", "0.187", "0.451"], ["PaI-1", "100 ± 8.5 (12)", "179.9 ± 18.39 (13)", "425.7 ± 89.64 (13)", "0.304", "#0.0005", "**0.005"], ["Gro-alpha-KC", "100 ± 8.27 (14)", "94.71 ± 5.60 (19)", "162.7 ± 42.79 (17)", "0.887", "0.199", "0.1669"], ["IL-1RA", "100 ± 32.02 (12)", "70.77 ± 14.78 (16)", "149 ± 61.91 (14)", "0.652", "0.652", "0.4121"], ["IL-13", "100 ± 0.90 (10)", "96.14 ± 3.46 (10)", "97.66 ± 2.16 (10)", "0.608", "0.749", "0.749"]], "row_count": 25, "column_count": 7, "numeric_cells": 152, "header_rows": 2, "locator": "section[17]/table-wrap[1]#T2"}}, {"id": "asset:table:pmid:33447243:4", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:60d7eb0ee8ab4d0c44bf2396ba1dbe52b111c6c2797865d8207d7d31d2956d09", "bytes": 1783, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[18]/table-wrap[1]#T3", "version": null, "note": "Clinical-Molecular Association Analysis: The five relevant molecules, associated with incomplete anti-VEGF response, were explored for potential associations with clinical parameters, in all neovascular age-related macular degeneration (nAMD) eyes included. Correlation analysis was performed for continuous variable, and Anova test for categorical variables.", "structure": {"pmcid": "PMC7802772", "section_index": 18, "section_title": "Exploratory Clinical-Molecular Correlation", "row_count": 16, "column_count": 13}, "table": {"label": "TABLE 3", "caption": "Clinical-Molecular Association Analysis: The five relevant molecules, associated with incomplete anti-VEGF response, were explored for potential associations with clinical parameters, in all neovascular age-related macular degeneration (nAMD) eyes included. Correlation analysis was performed for continuous variable, and Anova test for categorical variables.", "rows": [["", "sVCAM-1", "IL-12p40", "IL-6", "PAI-1", "HGF", "VEGF-A"], ["Continuous variables", "r2", "p", "r2", "p", "r2", "p", "r2", "p", "r2", "p", "r2", "p"], ["Age", "0.20", "0.22", "0.32", "0.05", "0.17", "0.29", "0.24", "0.13", "0.38", "0.01", "0.07", "0.67"], ["N anti-VEGF injections", "0.26", "0.10", "0.30", "0.06", "0.26", "0.11", "0.13", "0.42", "0.26", "0.10", "0.13", "0.42"], ["N months of treatment", "0.14", "0.40", "0.21", "0.19", "0.25", "0.10", "0.08", "0.60", "0.15", "0.35", "0.09", "0.60"], ["VA change from baseline", "0.18", "0.25", "0.01", "0.93", "−0.35", "0.03", "0.16", "0.32", "0.18", "0.27", "−0.11", "0.47"], ["Central retinal thickness", "0.19", "0.24", "0.29", "0.07", "0.04", "0.80", "0.26", "0.12", "0.18", "0.26", "0.04", "0.82"], ["Subfoveal choroidal thickness", "−0.40", "0.01", "−0.46", "0.003", "−0.27", "0.10", "−0.26", "0.10", "−0.44", "0.005", "−0.14", "0.38"], ["Categorical variables", "p", "p", "p", "p", "p", "p"], ["Reticular pseudodrusen", "0.38", "0.69", "0.36", "0.56", "0.86", "0.58"], ["Intraretinal fluid", "0.74", "0.87", "0.22", "0.41", "0.8", "0.55"], ["Subretinal fluid", "0.73", "0.4", "0.42", "0.99", "0.93", "0.69"], ["cRORA", "0.83", "0.7", "0.36", "0.36", "0.7", "0.51"], ["iRORA", "0.97", "0.61", "0.42", "0.89", "0.71", "0.65"], ["CNV type", "0.1", "0.62", "0.83", "0.005", "0.36", "0.38"], ["Fibrosis", "0.95", "0.92", "0.66", "0.5", "0.99", "0.5"]], "row_count": 16, "column_count": 13, "numeric_cells": 118, "header_rows": 2, "locator": "section[18]/table-wrap[1]#T3"}}], "gaps": ["asset:data:geo:PXD022471 not downloaded", "asset:data:geo:PXD022471 licence not read"]}, "analysis": {"state": "partial", "methods": [{"id": "method-1", "family": null, "specific": null, "label": "Linear models adjusted for batches", "dsl_operations": [], "missing_operations": [], "expressible": null, "parameters": {}, "data_shapes": [], "evidence": {"score": 1.0, "band": "verbatim", "quote": "For analysis of the proteomics results, linear models (R function lm) adjusted for batches were used to identify differentially expressed proteins (p < 0.1) to compare group N and group R and to compare groups C/N and group R."}}], "targets": [], "gaps": ["method.reader_named_unmapped"]}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "blocked", "tier": "R4", "blocking_axis": "method", "blocked_on": "method:not_determinable", "axes": {"method": {"tier": "R4", "expressible": false, "required_operations": [], "missing_operations": [], "basis": "The reader quoted the method the paper names (Linear models adjusted for batches), but the corpus's method extractor could not map it onto a DSL operation, so the method is published but not expressible."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["PXD022471"], "resolved_accessions": ["PXD022471"], "statements": ["The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD022471."], "basis": "The paper names PXD022471 in ProteomeXchange Consortium via the PRIDE partner repository and the accession resolves in the repository. 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