Altered Lymphatic Vessel Anatomy and Markedly Diminished Lymph Clearance in Affected Hands of Patients With Active Rheumatoid Arthritis

Abstract

Objective To assess differences between lymphatic function in the affected hands of rheumatoid arthritis (RA) patients with active synovitis and that of healthy controls, using indocyanine green (ICG) dye and near‐infrared (NIR) imaging. Methods NIR imaging of the hands of 8 patients with active RA and 13 healthy controls was performed following web space injection of 0.1 ml of 100 μM ICG. The percentage of ICG retention in the web spaces was determined by NIR imaging at baseline and at 7 days (±1 day) after the initial injections; image analysis provided contraction frequency. ICG+ lymphatic vessel (LV) length and branching architecture were assessed. Results Retention of ICG in RA hands was higher compared to controls (P < 0.01). The average contraction frequency of ICG+ LVs in RA patients and in controls did not differ (mean ± SD 0.53 ± 0.39 contractions/minute versus 0.51 ± 0.35 contractions/minute). Total ICG+ LV length in RA hands was lower compared to healthy controls (58.3 ± 15.0 cm versus 71.4 ± 16.1 cm; P < 0.001), concomitant with a decrease in the number of ICG+ basilic LVs in the hands of RA patients (P < 0.05). Conclusion Lymphatic drainage in the hands of RA patients with active disease was reduced compared to controls. This reduction was associated with a decrease in total length of ICG+ LVs on the dorsal surface of the hands, which continued to contract at a similar rate to that observed in controls. These findings provide a plausible mechanism for exacerbation of synovitis and joint damage, specifically the accumulation and retention of inflammatory cells and catabolic factors in RA joints due to impaired efferent lymphatic flow. NIR/ICG imaging of RA hands is feasible and warrants formal investigation as a primary outcome measure for arthritis disease severity and/or persistence in future clinical trials.

Ex vivo Demonstration of Functional Deficiencies in Popliteal Lymphatic Vessels from TNF-Tg Mice with Inflammatory Arthritis

“…We have focused on the synovial lymphatic system during arthritic progression and flare (10,12,16,20,25,26,35,43,44), and the effects of interventions that specifically target lymphatic contractions, whose physiologic importance in supporting lymphatic drainage and subsequent onset of lymphedema have been established in preclinical and clinical studies (7,29,45,46). We have also performed transmission electron microscopy studies on WT, Expanding and Collapsed PLVs (42).…”

“…Subsequently, we used CE-MRI to show that RA patients with the smallest change in lymph node volume during anti-TNF therapy experienced the greatest pain relief in symptomatic knee joints with a remarkably linear inverse correlation (28). Most recently, we utilized NIR-ICG imaging (10) to show that lymphatic drainage in the hands of RA patients with active disease is decreased compared to healthy controls (29). Furthermore, this reduced lymphatic drainage was associated with a decrease in the total length of ICG + lymphatic vessels on the dorsal surface of the hands, which continued to contract at a similar rate as controls (29).…”

“…Most recently, we utilized NIR-ICG imaging (10) to show that lymphatic drainage in the hands of RA patients with active disease is decreased compared to healthy controls (29). Furthermore, this reduced lymphatic drainage was associated with a decrease in the total length of ICG + lymphatic vessels on the dorsal surface of the hands, which continued to contract at a similar rate as controls (29). Collectively, these findings support the hypothesis that there is an intrinsic defect in RA joint draining lymphatic vessels in advanced disease and/or flare, which warrants direct testing via ex vivo functional analyses.…”

Near-Infrared Imaging of Indocyanine Green Identifies Novel Routes of Lymphatic Drainage from Metacarpophalangeal Joints in Healthy Human Hands

“…While the gold-standard clinical approach of lymphoscintography is effective for assessing lymphatic drainage in certain disorders, such as lymphedema, 16 it does not provide adequate resolution to monitor more subtle changes in CLV numbers and contractile function that have been noted by NIR-ICG imaging in both RA animal models and human subjects. 5, 6, 1-17, 28, 29 Thus, future work continuing to utilize and validate NIR-ICG imaging as a biomarker of lymphatic dysfunction has the potential to provide major advances in clinically screening and monitoring diseases with lymphatic pathology.…”

<p>Lymphatic Flow: A Potential Target in Sepsis-Associated Acute Lung Injury</p>

“…The results showed that lymphatic drainage in the hands of RA patients was reduced compared to that of healthy volunteers. 30 Interesting research on chronic inflammation including periodontitis also exists. For example, Hua Wang and colleagues demonstrated that there was impaired lymphatic flow in mice and patients with periodontitis.…”