Dataset Information

Cell-specific Systemic Immune Signatures Associated with Treatment Burden in Neovascular Age-related Macular Degeneration.

ABSTRACT:

Purpose

Choroidal neovascularization (CNV) accounts for the majority of severe vision loss in neovascular age-related macular degeneration (AMD). Despite therapies that target VEGF, patients are often under-responsive, require frequent eye injections to control disease, and eventually lose some vision despite chronic therapy implicating a multifactorial etiology in treatment response. Genetic studies implicate systemic immunity in AMD and systemic immune cells accumulate within CNV lesions, yet a role for these cells in anti-VEGF response remains undetermined. The purpose of this study was to identify transcriptional signatures of circulating immune cells that are associated with high anti-VEGF treatment burden.

Design

Experimental pilot study.

Participants

Patients with neovascular AMD seen at Washington University School of Medicine in St. Louis and BJC Health System.

Methods

We profiled by single cell RNA sequencing the peripheral blood mononuclear cells of 27 treatment-experienced patients with wet AMD. We stratified this cohort into 2 groups with low and high treatment burden (≤ 5 or ≥ 6 injections in the past 12 months, respectively).

Main outcome measures

Identification of immune cells associated with high treatment burden.

Results

Gene expression signature of CD16+ monocytes may be associated with high treatment burden.

Conclusions

These studies delineate potential signatures of circulating immune cells that may be associated with high treatment burden in neovascular AMD, potentially informing the development of diagnostic predictors of anti-VEGF response and new precision medicine-based approaches to complement anti-VEGF therapies.

Financial disclosures

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

SUBMITTER: Lin JB

PROVIDER: S-EPMC10960064 | biostudies-literature | 2024 Mar-Apr

REPOSITORIES: biostudies-literature

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Publications

Cell-specific Systemic Immune Signatures Associated with Treatment Burden in Neovascular Age-related Macular Degeneration.

Lin Joseph B JB Santeford Andrea A Usmani Darksha D Shah Aaditya V AV Ruzycki Philip A PA Apte Rajendra S RS

Ophthalmology science 20231011 2

<h4>Purpose</h4>Choroidal neovascularization (CNV) accounts for the majority of severe vision loss in neovascular age-related macular degeneration (AMD). Despite therapies that target VEGF, patients are often under-responsive, require frequent eye injections to control disease, and eventually lose some vision despite chronic therapy implicating a multifactorial etiology in treatment response. Genetic studies implicate systemic immunity in AMD and systemic immune cells accumulate within CNV lesio ...[more]

PMID: 38524380

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Project description:There is early evidence of extraocular systemic signals effecting function and morphology in neovascular age-related macular degeneration (nAMD). The prospective, cross-sectional BIOMAC study is an explorative investigation of peripheral blood proteome profiles and matched clinical features to uncover systemic determinacy in nAMD under anti-vascular endothelial growth factor intravitreal therapy (anti-VEGF IVT). It includes 46 nAMD patients stratified by the level of disease control under ongoing anti-VEGF treatment. Proteomic profiles in peripheral blood samples of every patient were detected with LC-MS/MS mass spectrometry. The patients underwent extensive clinical examination with a focus on macular function and morphology. In silico analysis includes unbiased dimensionality reduction and clustering, a subsequent annotation of clinical features, and non-linear models for recognition of underlying patterns. The model assessment was performed using leave-one-out cross validation. The findings provide an exploratory demonstration of the link between systemic proteomic signals and macular disease pattern using and validating non-linear classification models. Three main results were obtained: (1) Proteome-based clustering identifies two distinct patient subclusters with the smaller one (n = 10) exhibiting a strong signature for oxidative stress response. Matching the relevant meta-features on the individual patient's level identifies pulmonary dysfunction as an underlying health condition in these patients. (2) We identify biomarkers for nAMD disease features with Aldolase C as a putative factor associated with superior disease control under ongoing anti-VEGF treatment. (3) Apart from this, isolated protein markers are only weakly correlated with nAMD disease expression. In contrast, applying a non-linear classification model identifies complex molecular patterns hidden in a high number of proteomic dimensions determining macular disease expression. In conclusion, so far unconsidered systemic signals in the peripheral blood proteome contribute to the clinically observed phenotype of nAMD, which should be examined in future translational research on AMD.

Project description:PURPOSE:To determine whether oral beta-blockers (BBs) are associated with the development of neovascular age-related macular degeneration (nAMD). METHODS:Retrospective cohort study of patients from 2000 to 2014 using data from a large national U.S. insurer's administrative medical claims database. Patients with nonexudative AMD who initiated (index date) BB, a calcium channel blocker (CCB), an angiotensin-converting enzyme/angiotensin receptor blocker, or a diuretic. Patients were excluded for <2 years in the plan before the index date, any history of nAMD or diagnosis, or treatment for an ocular disease that could be confused with nAMD. Hazard of developing of nAMD was the main outcome measure. Primary analysis compared BB with CCB patients with BB versus the other classes as secondary analyses. In addition, a sensitivity analysis was performed between BB and CCB cohorts using 1:1 propensity score matching. Cox proportional hazard regression was performed to estimate the hazard ratio (HR) of developing nAMD at 90, 180, and 365 days for BB. Covariates of interest included demographic information, year of index date, number of antihypertensive medications, and other comorbid systemic conditions. RESULTS:Eighteen thousand seven hundred and fifty-four BB patients and 12,784 CCB patients met criteria for inclusion. After controlling for covariates, patients on BB had a lower hazard for nAMD at both 90 and 180 days than patients on CCB (HRs: 0.67-0.71; P < 0.01 for both) and diuretics (HRs: 0.55-0.62; P < 0.01). Patients on BB versus angiotensin-converting enzyme/angiotensin receptor blocker at all time points and BB versus CCB and diuretics at 365 days did not have a significantly lower association with nAMD (HR: 0.73-0.85; P > 0.06 for all comparisons). A sensitivity analysis using propensity score matching yielded similar results with patients on BB significantly less likely to develop nAMD at 90 and 180 days (HR: 0.70-0.76; P < 0.049 for both) but not at 365 days (HR: 0.88; P = 0.30) compared with patients on CCB. CONCLUSION:No evidence was found that BB usage increased the hazard for nAMD relative to other antihypertensive medications.

Dataset Information

Cell-specific Systemic Immune Signatures Associated with Treatment Burden in Neovascular Age-related Macular Degeneration.

Purpose

Design

Participants

Methods

Main outcome measures

Results

Conclusions

Financial disclosures

Publications

Cell-specific Systemic Immune Signatures Associated with Treatment Burden in Neovascular Age-related Macular Degeneration.

Similar Datasets

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