Usefulness of Liquid Biopsy Biomarkers from Aqueous Humor in Predicting Anti-VEGF Response in Diabetic Macular Edema: Results of a Pilot Study

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Abstract

The objective was to investigate the usefulness of the “liquid biopsy” of aqueous humor (AH) to predict the clinical response after intravitreal injections (IVT) of anti-VEGF agents for treating diabetic macular edema (DME). For this purpose, AH samples obtained during the first anti-VEGF IVT from 31 type two diabetic patients were analyzed. Patients were classified into three groups according to their anti-VEGF response: rapid responders ( n = 11), slow responders ( n = 11), and non-responders ( n = 9). In addition, patients ( n = 7) who showed good response to corticosteroids but a delayed or no response to anti-VEGF therapy were analyzed. Levels of 17 different cytokines, chemokines, and growth factors in AH were measured using a multiplex immunoassay. We found higher concentrations of VEGF in rapid responders to anti-VEGF therapy compared to non-responders. In addition, slow responders to anti-VEGF treatment showed higher levels of inflammatory markers than rapid responders, but did not reach statistical significance. Finally, those patients who responded to corticosteroids but not to anti-VEGF therapy showed significantly lower levels of VEGF than patients with rapid response ( p = 0.01). In conclusion, “liquid biopsy” of AH could be useful to determine whether the predominant pathogenic event is primarily angiogenic or inflammatory in nature. This approach would allow physicians to select a more rational and cost-effective treatment. Further studies to validate these preliminary results are warranted.

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Diabetic macular oedema.

Gavin Tan, Ning Cheung, Rafael Simó … (2017)

Diabetic macular oedema, characterised by exudative fluid accumulation in the macula, is the most common form of sight-threatening retinopathy in people with diabetes. It affects one in 15 people with diabetes resulting in more than 20 million cases worldwide. Few epidemiological studies have been done to specifically investigate risk factors for diabetic macular oedema, although poor glycaemic and blood pressure control are associated with the presence and development of the disorder. The pathophysiological processes begin with chronic hyperglycaemia, and interplay between vascular endothelial growth factor (VEGF) and inflammatory mediators. Non-invasive imaging using optical coherence tomography has allowed clinicians to detect mild levels of diabetic macular oedema in order to monitor progress and guide treatment. Although focal or grid laser photocoagulation was the traditional mode of treatment, intraocular pharmacotherapy with anti-VEGF agents is now the standard of care. However, these therapies are expensive and resource intensive. Emerging therapeutic strategies include improving efficacy and duration of VEGF suppression, targeting alternative pathways such as inflammation, the kallikrein-kinin system, the angiopoietin-Tie2 system, and neurodegeneration, and using subthreshold and targeted laser therapy. Ongoing research should lead to improvements in screening, diagnosis, and management of diabetic macular oedema.

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Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study.

Paolo Lanzetta, Emma Lang, Frank G. Holz … (2014)

To evaluate long-term efficacy and safety profiles during 3 years of individualized ranibizumab treatment in patients with visual impairment due to diabetic macular edema (DME). Phase IIIb, multicenter, 12-month, randomized core study and 24-month open-label extension study. Of the 303 patients who completed the randomized RESTORE 12-month core study, 240 entered the extension study. In the extension study, patients were eligible to receive individualized ranibizumab treatment as of month 12 guided by best-corrected visual acuity (BCVA) and disease progression criteria at the investigators' discretion. Concomitant laser treatment was allowed according to the Early Treatment Diabetic Retinopathy Study guidelines. Based on the treatments received in the core study, the extension study groups were referred to as prior ranibizumab, prior ranibizumab + laser, and laser. Change in BCVA and incidence of ocular and nonocular adverse events (AEs) over 3 years. Overall, 208 patients (86.7%) completed the extension study. In patients treated with ranibizumab during the core study, consecutive individualized ranibizumab treatment during the extension study led to an overall maintenance of BCVA and central retinal subfield thickness (CRST) observed at month 12 over the 2-year extension study (+8.0 letters, -142.1 μm [prior ranibizumab] and +6.7 letters, -145.9 μm [prior ranibizumab + laser] from baseline at month 36) with a median of 6.0 injections (mean, 6.8 injections; prior ranibizumab) and 4.0 (mean, 6.0 injections; prior ranibizumab + laser). In the prior laser group, a progressive BCVA improvement (+6.0 letters) and CRST reduction (-142.7 μm) at month 36 were observed after allowing ranibizumab during the extension study, with a median of 4.0 injections (mean, 6.5 injections) from months 12 to 35. Patients in all 3 treatment groups received a mean of <3 injections in the final year. No cases of endophthalmitis, retinal tear, or retinal detachment were reported. The most frequently reported ocular and nonocular adverse effects over 3 years were cataract (16.3%) and nasopharyngitis (23.3%). Eight deaths were reported during the extension study, but none were suspected to be related to the study drug/procedure. Ranibizumab was effective in improving and maintaining BCVA and CRST outcomes with a progressively declining number of injections over 3 years of individualized dosing. Ranibizumab was generally well tolerated with no new safety concerns over 3 years. Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

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Ocular Anti-VEGF therapy for diabetic retinopathy: the role of VEGF in the pathogenesis of diabetic retinopathy.

Rafael Simó, Jeffrey Sundstrom, David A Antonetti (2014)

Diabetic retinopathy is the leading cause of visual impairment and preventable blindness, and represents a significant socioeconomic cost for health care systems worldwide. Therefore, new approaches beyond current standards of diabetes care are needed. Based on the crucial pathogenic role of vascular endothelial growth factor (VEGF) in the development of diabetic macular edema (DME), intravitreal anti-VEGF agents have emerged as new treatments. To provide an understanding of the rationale for use and clinical efficacy of anti-VEGF treatment, we examine this topic in a two-part Bench to Clinic narrative. In the Bench narrative, we provide an overview of the role of VEGF in the pathogenesis of diabetic retinopathy, the molecular characteristics of anti-VEGF agents currently used, and future perspectives and challenges in this area. In the Clinic narrative that follows our contribution, Cheung et al. provide an overview of the current evidence from clinical trials on anti-VEGF therapy for diabetic retinopathy.

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Journal ID (nlm-ta): J Clin Med

Journal ID (iso-abbrev): J Clin Med

Journal ID (publisher-id): jcm

Title: Journal of Clinical Medicine

Publisher: MDPI

ISSN (Electronic): 2077-0383

Publication date (Electronic): 02 November 2019

Publication date Collection: November 2019

Volume: 8

Issue: 11

Electronic Location Identifier: 1841

Affiliations

[1 ]Department of Ophthalmology, Hospital Universitari i Politècnic La Fe, 46009 Valencia, Spain; patyudaondo@ 123456hotmail.com (P.U.); salvadorgarciadelpech@ 123456gmail.com (S.G.-D.)

[2 ]Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute, 08035 Barcelona, Spain; cristina.hernandez@ 123456vhir.org (C.H.); laura.brianso@ 123456vhir.org (L.B.-L.); olga.simo@ 123456vhir.org (O.S.-S.)

[3 ]Universitat Autònoma de Barcelona, 08193 Barcelona, Spain

[4 ]Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain

Author notes

[* ]Correspondence: rafael.simo@ 123456vhir.org ; Tel.: +34-934-894-172

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Cristina Hernández https://orcid.org/0000-0002-3109-1721

Rafael Simó https://orcid.org/0000-0003-0475-3096

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Publisher ID: jcm-08-01841

DOI: 10.3390/jcm8111841

PMC ID: 6912573

PubMed ID: 31684007

SO-VID: 32cec85a-622a-4d38-9a80-c29283305da5

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Usefulness of Liquid Biopsy Biomarkers from Aqueous Humor in Predicting Anti-VEGF Response in Diabetic Macular Edema: Results of a Pilot Study

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Most cited references 24

Diabetic macular oedema.

Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study.

Ocular Anti-VEGF therapy for diabetic retinopathy: the role of VEGF in the pathogenesis of diabetic retinopathy.

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