Abstract
Rheumatoid arthritis is a chronic inflammatory disease manifested by episodic flares in affected joints that are challenging to predict and treat. Longitudinal contrast enhanced-MRI (CE-MRI) of inflammatory arthritis in tumor necrosis factor-transgenic (TNF-Tg) mice has demonstrated that popliteal lymph nodes (PLN) increase in volume and contrast enhancement during the pre-arthritic “expanding” phase of the disease, and then suddenly “collapse” during knee flare. Given the potential of this biomarker of arthritic flare, we aimed to develop a more cost-effective means of phenotyping PLN using ultrasound (US) imaging. Initially we attempted to recapitulate CE-MRI of PLN with subcutaneous footpad injection of US microbubbles (DEFINITY®). While this approach allowed for phenotyping via quantification of lymphatic sinuses in PLN, which showed a dramatic decrease in collapsed PLN versus expanding or wild-type (WT) PLN, electron microscopy demonstrated that DEFINITY® injection also resulted in destruction of the lymphatic vessels afferent to the PLN. In contrast, Power Doppler (PD) US is innocuous to and efficiently quantifies blood flow within PLN of WT and TNF-Tg mice. PD-US demonstrated that expanding PLN have a significantly higher normalized PD volume (NPDV) versus collapsed PLN (0.553±0.007 vs. 0.008±0.003; p<0.05). Moreover, we define the upper (>0.030) and lower (<0.016) quartile NPDVs in this cohort of mice, which serve as conservative thresholds to phenotype PLN as expanding and collapsed, respectively. Interestingly, of the 12 PLN phenotyped by the two methods, there was disagreement in 4 cases in which they were determined to be expanding by CE-MRI and collapsed by PD-US. Since the adjacent knee had evidence of synovitis in all 4 cases, we concluded that the PD-US phenotyping was correct, and that this approach is currently the safest and most cost-effective in vivo approach to phenotype murine PLN as a biomarker of arthritic flare.
Highlights
Rheumatoid arthritis (RA) is a debilitating immune-mediated inflammatory disorder characterized by recurrent arthritic flares that lead to joint inflammation and destruction, and cause significant morbidity in RA patients [1]
LN contrast enhancement (LNCE) phenotyping of popliteal lymph node (PLN) as a method to randomize a cohort of arthritic mice into a prospective study suffers from the finding that values are a continuum as the PLN progress from expanding to collapsed
While arthritic flare remains an enigmatic hallmark of RA, advances in in vivo imaging have identified valuable biomarkers that may be useful towards the elucidation of arthritic flare pathophysiology and clinical management of patients
Summary
Rheumatoid arthritis (RA) is a debilitating immune-mediated inflammatory disorder characterized by recurrent arthritic flares that lead to joint inflammation and destruction, and cause significant morbidity in RA patients [1]. Contrast enhanced (CE)-MRI has emerged as a longitudinal outcome measure to quantify synovial and draining lymph node volume in murine models of inflammatory arthritis [4,5,6,7,8,9,10,11] These studies have found that TNF-Tg mice with frank ankle arthritis had both larger popliteal lymph node (PLN) volume (PLNvol) and greater LN contrast enhancement (LNCE) when compared to their wild type (WT) littermates. To quantify this as a metric, LN capacity (LNCap = LNCE*PLNvol) was developed as a primary outcome measure to study PLN as a biomarker of inflammatory arthritis in the lower limbs of mice [4]. Formal associations between altered PLNvol, LNCE and the onset of arthritic flare have been established
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