Background/Purpose: Near infrared (NIR) imaging studies of subdermal indocyanine green (ICG) in murine models of inflammatory arthritis have established abnormal lymphatic vessel (LV) function during arthritic progression. Quantitatively, LV dysfunction is primarily assessed by ICG clearance from the injection site via longitudinal (days) NIR imaging.  As the role of LV function in rheumatoid arthritis (RA) pathogenesis is unknown, we tested the hypothesis that ICG clearance from the hands and LV contraction frequency of RA patients experiencing flare are significantly decreased compared to normal healthy volunteers. We also assessed the characteristics of filled LVs to examine if structural differences are present in RA lymphatics compared to healthy controls.

Methods: The web spaces of both hands of 12 healthy controls (CTL) and 7 subjects with RA (ACR 2010 RA criteria) flare were injected with 0.1ml of 100μM ICG on 2-4 separate occasions and the NIR fluorescence of the dorsal aspect of the hands was imaged. To measure clearance of ICG from the web spaces, 7 CTL and 5 RA subjects returned to the clinic either 7-9 or 13-15 days after the first injections and any remaining NIR fluorescence in each hand was measured via region of interest analysis. Controlling for the number of days between subjects, the change in intensity between the initial and second visit was divided by the number of days between visits. Lymphatic contractions for LVs were determined from graphs of region of interest intensity across time to calculate contractions per minute; differences were evaluated using a Wilcoxon Rank Test. To assess the branching structure of the vessels, manual segmentation of the lymphatic network and subsequent spatial mapping was performed. Two independent graders quantified the total number of bifurcations of the LVs. Median values for each hand across all visits and graders were used to test for differences (Wilcoxon Rank-Sum Test).

Results: NIR images of CTL and RA hands at baseline and at the second visit demonstrated dramatic retention of ICG at the injections sites in RA subjects and statistical analysis confirmed a decrease in ICG clearance in the RA subjects compared to CTLs (p< 0.05). When controlling for days between the initial visit and second visit, the relationship persisted (p< 0.01). Interestingly, no difference in contraction frequency was observed between CTL and RA subjects. However, there was significantly decreased total length in the spatial structure of the lymphatic network (p< 0.01).  This decreased length was primarily attributed to a lack of basilic associated ICG-filled vessels in RA subjects.

Conclusion: Imaging outcome measures of LV function in mice have demonstrated diminished clearance of lymph from the inflamed joint during arthritic progression. Herein, we show a significant reduction in ICG clearance and altered anatomic structure in RA subjects during flare. The accumulation and retention of inflammatory cells and molecules in rheumatoid joints as a result of diminished lymphatic clearance may be a critical factor in the initiation and persistence of synovitis. This clinical pilot demonstrates the feasibility of quantifying LV function, and warrants formal investigation in clinical trials.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/near-infrared-indocyanine-green-imaging-reveals-altered-anatomy-and-diminished-function-in-lymphatic-vessels-in-the-hands-of-rheumatoid-arthritis-patients-during-flare-2/