Abstract
IntroductionRheumatoid arthritis (RA) is a chronic disease causing recurring inflammatory joint attacks. These attacks are characterized by macrophage infiltration contributing to joint destruction. Studies have shown that RA treatment efficacy is correlated to synovial macrophage number. The aim of this study was to experimentally validate the use of in vivo superparamagnetic iron oxide nanoparticle (SPION) labeled macrophages to evaluate RA treatment by MRI.MethodsThe evolution of macrophages was monitored with and without dexamethasone (Dexa) treatment in rats. Two doses of 3 and 1 mg/kg Dexa were administered two and five days following induction of antigen induced arthritis. SPIONs (7 mg Fe/rat) were injected intravenously and the knees were imaged in vivo on days 6, 10 and 13. The MR images were scored for three parameters: SPION signal intensity, SPION distribution pattern and synovial oedema. Using 3D semi-automated software, the MR SPION signal was quantified. The efficacy of SPIONs and gadolinium chelate (Gd), an MR contrast agent, in illustrating treatment effects were compared. Those results were confirmed through histological measurements of number and area of macrophages and nanoparticle clusters using CD68 immunostaining and Prussian blue staining respectively.ResultsResults show that the pattern and the intensity of SPION-labeled macrophages on MRI were altered by Dexa treatment. While the Dexa group had a uniform elliptical line surrounding an oedema pocket, the untreated group showed a diffused SPION distribution on day 6 post-induction. Dexa reduced the intensity of SPION signal 50-60% on days 10 and 13 compared to controls (P = 0.00008 and 0.002 respectively). Similar results were found when the signal was measured by the 3D tool. On day 13, the persisting low grade arthritis progression could not be demonstrated by Gd. Analysis of knee samples by Prussian blue and CD68 immunostaining confirmed in vivo SPION uptake by macrophages. Furthermore, CD68 immunostaining revealed that Dexa treatment significantly decreased the area and number of synovial macrophages. Prussian blue quantification corresponded to the macrophage measurements and both were in agreement with the MRI findings.ConclusionsWe have demonstrated the feasibility of MRI tracking of in vivo SPION-labeled macrophages to assess RA treatment effects.
Highlights
Rheumatoid arthritis (RA) is a chronic disease causing recurring inflammatory joint attacks
Results show that the pattern and the intensity of superparamagnetic iron oxide nanoparticles (SPION)-labeled macrophages on Magnetic resonance imaging (MRI) were altered by Dexa treatment
Prussian blue quantification corresponded to the macrophage measurements and both were in agreement with the MRI findings
Summary
Rheumatoid arthritis (RA) is a chronic disease causing recurring inflammatory joint attacks These attacks are characterized by macrophage infiltration contributing to joint destruction. Diagnosis of RA mainly depends on clinical scoring, serum rheumatoid factor and identification of erosive lesions on conventional radiographs. These methods do not allow early intervention at a point when permanent joint damage can be prevented. They do not address the complicated nature of the disease where patients can show little or no signs of inflammation during ongoing episodes of joint damage [2]. New technology allowing early onset and precise assessment and follow-up during and after treatment would be of great value to RA management
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