Near-infrared fluorescence imaging of experimentally collagen-induced arthritis in rats using the nonspecific dye tetrasulfocyanine in comparison with gadolinium-based contrast-enhanced magnetic resonance imaging, histology, and clinical score

Abstract

Abstract. Using 15 rats with collagen-induced arthritis (30 joints) and 7 control rats (14 joints), we correlated the intensity of near-infrared fluorescence (NIRF) of the nonspecific dye tetrasulfocyanine (TSC) with magnetic resonance imaging (MRI), histopathology, and clinical score. Fluorescence images were obtained in reflection geometry using a NIRF camera system. Normalized fluorescence intensity (I NF ) was determined after intravenous dye administration on different time points up to 120 min. Contrast-enhanced MRI using gadodiamide was performed after NIRF imaging. Analyses were performed in a blinded fashion. Histopathological and clinical scores were determined for each ankle joint. I NF of moderate and high-grade arthritic joints were significantly higher (p < 0.005) than the values of control and low-grade arthritic joints between 5 and 30 min after TSC-injection. This result correlated well with post-contrast MRI signal intensities at about 5 min after gadodiamide administration. Furthermore, I NF and signal increase on contrast-enhanced MRI showed high correlation with clinical and histopathological scores. Sensitivities and specificities for detection of moderate and high-grade arthritic joints were slightly lower for NIRF imaging (89%∕81%) than for MRI (100%∕91%). NIRF imaging using TSC, which is characterized by slower plasma clearance compared to indocyanine green (ICG), has the potential to improve monitoring of inflamed joints.

In vivotherapy monitoring of experimental rheumatoid arthritis in rats using near-infrared fluorescence imaging

“…We have recently shown 14 and herein reproduced the finding that TSC-induced I NF signals are highly correlated (r s ¼ 0.758) with the arthritis grade throughout disease progression. Synovitis, a hallmark of arthritis, develops early in the disease process and can be visualized by NIRF-enhanced imaging using TSC.…”

“…14,22 Moreover, this 4-point scale well matches the histological assessment of human synovitis score provided by Krenn et al 18 For the first time within the therapeutic period, we monitored the animals after 2 weeks, as from our experience, disease progression or amelioration typically become obvious after this time.…”

“…Based on macroscopic and microscopic patterns, CIA progression was divided into three stages: (1) preclinical (from first collagen injection to clinically evident disease onset), (2) acute clinical [from disease onset (day 0) to day 14], and (3) chronic clinical (after day 14), where clinical (hind and fore paw swelling) and structural (inflammation and articular erosions in hind paws) evidence of joint involvement plateaus. 15 Skeletal erosion begins 1 to 2 days after the onset of paw swelling and is associated with acute synovitis.…”

“…A 4-point arthritis scale was used for grading the clinical symptoms of each hind paw as follows: "without arthritis signs" (no clinical symptoms), "low-grade arthritis" (mild swelling, erythema, and functional deficits), "moderate arthritis" (moderate swelling, erythema, and functional deficits), or "high-grade arthritis" (severe swelling with erythema and reduced mobility). 14 …”

“…These data are in accordance with our previous findings in humans and experimental arthritis. 11,14,21,22 …”