Linking systemic angiogenic markers to synovial vascularization in rheumatoid arthritis.

Agathe Leblond,Jérôme Avouac,Sonia Pezet,Muriel Elhai,Yannick Allanore,Anne Priscille Trouvin,Virginie Gonzalez,Chi Zhang

doi:10.1371/journal.pone.0203607

Abstract

BackgroundNeoangiogenesis is a crucial event to promote the development of the hyperplasic proliferative pathologic synovium in Rheumatoid arthritis (RA). Ultrasound (US) is sensitive for detection of power Doppler (PD) vascularization.ObjectiveTo explore the associations between a set of complementary circulating angiogenic markers and a comprehensive US assessment in patients with RA.Patients and methodsSerum levels of eight angiogenic markers were measured by quantitative ELISAs in a total of 125 patients with RA, who were all systematically assessed in parallel by PDUS, performed on 32 joints.ResultsSerum levels of soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1) and Tie-2 were more likely to be increased in patients with synovial hyperemia detected on at least one joint (Power Doppler grade ≥1). sVCAM-1, Tie-2 and Angiostatin concentrations gradually increased together with the grade of the semiquantitative PDUS scale and concentrations of these three markers were markedly increased in patients with moderate to marked hyperemia (Power Doppler grade 2 and 3). Levels of sVCAM-1, Tie-2, and Angiostatin correlated with a global arthritis sum score, defined by the sum of the semiquantitative PDUS scores for all joints examined. Levels of Tie-2 and Placenta Growth Factor (PlGF) were associated with PDUS features indicating residual disease activity.ConclusionOur results support the relevance of measuring serum levels of vascular markers to evaluate the intensity and extent of synovial vascularization. Angiogenic markers, and particularly Tie-2, could be a valuable surrogate of active synovitis and their place in relation to PDUS in clinical practice deserve further investigation.

Highlights

Rheumatoid arthritis (RA) is the most common cause of chronic inflammatory arthritis with a prevalence ranging from 0.5% to 1% of the adult population worldwide [1, 2]
Serum levels of soluble Vascular Cell Adhesion Molecule-1 and Tie-2 were more likely to be increased in patients with synovial hyperemia detected on at least one joint (Power Doppler grade !1). sVCAM-1, Tie-2 and Angiostatin concentrations gradually increased together with the grade of the semiquantitative power Doppler Ultrasound (PDUS) scale and concentrations of these three markers were markedly increased in patients with moderate to marked hyperemia (Power Doppler grade 2 and 3)
Levels of sVCAM-1, Tie-2, and Angiostatin correlated with a global arthritis sum score, defined by the sum of the semiquantitative PDUS scores for all joints examined

Summary

Results

From the 140 consecutive RA patients initially selected, 15 patients were excluded because of incomplete assessment (absence or incomplete PDUS assessment and/or absence of angiogenic marker measurements). We observed that serum levels of sVCAM-1 (808±293 ng/mL vs 697±240 ng/mL, P = 0.022) (Fig 1C) and Tie-2 (16.2±7.5 ng/mL vs 13.8 ±4.9 ng/mL, P = 0.038) (Fig 1D) were more likely to be increased in patients with synovial hyperemia detected on at least one joint (Power Doppler grade !1). Since our previous analysis focused on the highest PDUS semiquantitative scale detected for each patient, we studied the association between angiogenic marker levels and the global arthritis sum score, to take into account the number of synovitis detected by PDUS and the extent of their vascularization This global arthritis score correlated with serum levels of sVCAM-1 (r = 0.20, P = 0.028), Tie-2 (r = 0.28, P = 0.001), and Angiostatin (r = 0.25, P = 0.006) (S1A–S1C Fig).

Conclusion

Introduction

Study design

Discussion