Abstract
IntroductionNeovascularization contributes to the development of sustained synovial inflammation in the early stages of Rheumatoid Arthritis. Ultrasound (US) provides an indirect method of assessing synovial blood flow and has been shown to correlate with clinical disease activity in patients with Rheumatoid Arthritis. This study examines the relationship of US determined synovitis with synovial vascularity, angiogenic / lymphangiogenic factors and cellular mediators of inflammation in a cohort of patients with early Rheumatoid Arthritis (RA) patients prior to therapeutic intervention with disease modifying therapy or corticosteroids.MethodsAn ultrasound guided synovial biopsy of the supra-patella pouch was performed in 12 patients with early RA prior to treatment. Clinical, US and biochemical assessments were undertaken prior to the procedure. Ultrasound images and histological samples were obtained from the supra-patella pouch. Histological samples were stained for Factor VIII and a-SMA (a-smooth muscle actin). Using digital imaging analysis a vascular area score was recorded. QT-PCR (quantitative-PCR) of samples provided quantification of angiogenic and lymphangiogenic gene expression and immunohistochemistry stained tissue was scored for macrophage, T cell and B cell infiltration using an existing semi-quantitative score.ResultsPower Doppler showed a good correlation with histological vascular area (Spearman r - 0.73) and angiogenic factors such as vascular endothelial growth factor- A (VEGF-A), Angiopoietin 2 and Tie-2. In addition, lymphangiogenic factors such as VEGF-C and VEGF-R3 correlated well with US assessment of synovitis. A significant correlation was also found between power Doppler and synovial thickness, pro-inflammatory cytokines and sub-lining macrophage infiltrate. Within the supra-patella pouch there was no significant difference in US findings, gene expression or inflammatory cell infiltrate between any regions of synovium biopsied.ConclusionUltrasound assessment of synovial tissue faithfully reflects synovial vascularity. Both grey scale and power Doppler synovitis in early RA patients correlate with a pro-angiogenic and lymphangiogenic gene expression profile. In early RA both grey scale and power Doppler synovitis are associated with a pro-inflammatory cellular and cytokine profile providing considerable validity in its use as an objective assessment of synovial inflammation in clinical practice.
Highlights
Neovascularization contributes to the development of sustained synovial inflammation in the early stages of Rheumatoid Arthritis
Histologically assessed synovial vascular area was an independent predictor of ultrasound assessment of power Doppler signal as assessed by power Doppler quantitative area (PQuant) and power Doppler threshold area of high signal (PDHi)
We demonstrated that expression of lymphangiogenic factors correlated with ultrasound parameters and in particular, synovial area assessment
Summary
Neovascularization contributes to the development of sustained synovial inflammation in the early stages of Rheumatoid Arthritis. Neovascularization is defined as the development of new blood vessels from the existing microvascular bed. It involves a number of steps including endothelial cell division, selective degradation of vascular basement membranes, alteration of the surrounding extracellular matrix and endothelial cell migration [1,2]. A concert of angiogenic factors is at work within the rheumatoid synovium to promote new vessel formation. This is an early, critical aspect to synovial pannus formation and facilitates the perpetuation of the inflammatory process within synovial joints [7]. Lymphatic vascular networks have previously been described in both patients and animal models of arthritis with VEGF-C, and its ligand VEGF-R3, appearing to promote sprouting of lymphatic vessels in a similar fashion to neoangiogenesis [8,9,10]
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