Dysregulated endothelial cell markers in systemic lupus erythematosus: a systematic review and meta-analysis

Abstract

Objectives: To perform a systematic literature review and meta-analysis on endothelial cell (EC) markers that are involved and dysregulated in systemic lupus erythematosus (SLE) in relation to disease activity, as EC dysregulation plays a major role in the development of premature atherosclerosis in SLE.

Methods: Search terms were entered into Embase, MEDLINE, Web of Science, Google Scholar and Cochrane. Inclusion criteria were 1) studies published after 2000 reporting measurements of EC markers in serum and/or plasma of SLE patients (diagnosed according to ACR/SLICC criteria), 2) English language peer reviewed articles, and 3) disease activity measurement. For meta-analysis calculations, the Meta-Essentials tool by Erasmus Research Institute and of Management (ERIM) was used. Only those EC markers, which were 1) reported in at least two articles and 2) reported a correlation coefficient (i.e. Spearman's rank or Pearson's) between the measured levels of the EC marker and disease activity were included. For meta-analyses, a fixed effect model was used.

Results: From 2133 hits, 123 eligible articles were selected. The identified SLE-related endothelial markers were involved in EC activation, EC apoptosis, disturbed angiogenesis, defective vascular tone control, immune dysregulation and coagulopathy. Meta-analyses of primarily cross-sectional studies showed significant associations between marker levels and disease activity for the following endothelial markers: Pentraxin-3, Thrombomodulin, VEGF, VCAM-1, ICAM-1, IP-10 and MCP-1. Dysregulated EC markers without associations with disease activity were: Angiopoeitin-2, vWF, P-Selectin, TWEAK and E-Selectin.

Conclusions: We provide a complete literature overview for dysregulated EC markers in SLE comprising a wide range of different EC functions. SLE-induced EC marker dysregulation was seen with, but also without, association with disease activity. This study provides some clarity in the eminent complex field of EC markers as biomarkers for SLE. Longitudinal data on EC markers in SLE are now needed to guide us more in unravelling the pathophysiology of premature atherosclerosis and cardiovascular events in SLE patients.

Keywords: Cardiovascular disease; Endothelial cell; Endothelial cell markers; Premature atherosclerosis; Systemic lupus erythematosus.

Fig. 1

Flow chart. Flow chart reflecting the selection process of articles following the PRISMA-P guidelines

Fig. 2

Ferris Wheel Plot. Ferris Wheel Plot summarizing the identified EC markers in SLE per category of dominant EC dysfunction of each EC marker. The surface area of each EC marker represents the number of articles with EC marker data on the corresponding dysfunction. The EC marker with the highest number of articles in which the EC marker was reported as dysregulated, can be recognized by the darkened background color and white text). EC = endothelial cell, DV = disturbed vasculogenesis, DVT = defective vascular tone control, M = mixed (adipocytokines and EC apoptosis). Markers in Ferris Wheel Plot: ADAMTS13: A Disintegrin-like and Metalloprotease with Thrombospondin Type 1 Motif Adipo: Adiponectin AM: Adrenomedullin Ang-1: Angiopoietin-1 Ang-2: Angiopoietin-2 bFGF: basic fibroblast growth factor Endoglin Endostatin EPCR: Endothelial protein C receptor E-Selectin ET-1: Endothelin-1 FasL: Fas ligand GAS6: growth arrest-specific gene 6 HGF: Hepatocyte growth factor ICAM-1: Intercellular Adhesion Molecule 1 IP-10: interferon-inducible protein 10 L-Selectin MCP-1: Monocyte chemoattractant protein-1 Neopterin PAI-1: Plasminogen activator inhibitor-1 PECAM-1: Platelet and endothelial cell adhesion molecule 1 PlGF: Placental growth factor P-Selectin PTX3: Pentraxin-3 sEPCR: Soluble endothelial protein C receptor Tie2: Tyrosine kinase with immunoglobulin-like and EGF-like domain 2 TM: Thrombomodulin VCAM-1: Vascular Cell Adhesion Molecule 1 VEGF: Vascular Endothelial Growth-Factor VWF: Von Willebrand Factor TWEAK: Tumor necrosis factor (TNF)-like weak inducer of apoptosis

Fig. 3

Overview of the number of articles per SLE-related EC marker. Overview of the number of articles per EC marker, indicating for each marker on the y-axis whether there was a significant increase (no symbol) or decrease (*) of plasma/serum levels when compared to healthy controls (yes (green box), no (red box), not determined (N.D.) (black box). The percentage indicates the number of articles per EC marker that showed a significant increase of EC marker levels (% ‘yes’ of total citations). EC- Endothelial cell

Fig. 4

Meta-analyses (Spearman’s rho correlations). Meta-analysis of 12/31 identified EC markers fulfilling the inclusion criteria for meta-analysis. Overview of overall Spearman’s correlations (rho, with 95% CI) between SLE disease activity and serum/plasma levels of each included EC marker. n = total number of SLE patients from all articles per EC marker. In the Forest Plot, significant correlations (95% CI does not include ‘0’ and p < 0.05) are indicated by black text and filled diamonds (♦) and non-significant correlations (95% CI includes ‘0’ and p > 0.05) are indicated by grey text and open diamonds (♢). Calculated p-values are based on Fisher's Z Transformation. Markers that are not produced or expressed solely/primarily by EC: Pentraxin-3, GAS6, MCP-1, P-Selectin, TWEAK and IP-1

Fig. 5

Meta-analyses Pearson’s r correlations. Meta-analysis of 4/31 identified EC markers fulfilling the inclusion criteria for meta-analysis. Overview of overall Pearson’s correlations (r, with 95% CI) between SLE disease activity and serum/plasma levels of each included EC marker. n = total number of SLE patients from all articles per EC marker. In the Forest Plot, significant correlations (95% CI does not include ‘0’ and p < 0.05) are indicated by black text and filled diamonds (♦) and non-significant correlations (95% CI includes ‘0’ and p > 0.05) are indicated by grey text and open diamonds (♢) Calculated p-values are based on Fisher's Z Transformation