Dramatic changes in lymphatic vessel contraction and in the lymph nodes that drain inflamed joints are associated with disease progression and response to therapy in murine models of rheumatoid arthritis (RA)
During mild to moderate experimental arthritis, lymphatic vessels and nodes that drain the joint undergo an initial 'expansion' phase that facilitates efficient lymphatic clearance and lymphatic vessel contractions
In preclinical models, the expansion phase is followed by a 'collapsed' phase, in which B cells in the draining lymph node translocate from the follicles to lymphatic sinuses and the lymph node collapses
The collapsed phase is characterized by lymphatic vessel structural damage, loss of contraction, and reduction in lymphatic clearance
Pilot clinical studies indicate that alterations in lymph node volume and/or lymphatic flow could serve as biomarkers of treatment response with the potential to predict RA flare
Several lymphatic system-modulating therapies show promise in preclinical models of inflammatory arthritis and RA
Although clinical outcomes for patients with rheumatoid arthritis (RA) have greatly improved with the use of biologic and conventional DMARDs, approximately 40% of patients do not achieve primary clinical outcomes in randomized trials, and only a small proportion achieve lasting remission. Over the past decade, studies in murine models point to the critical role of the lymphatic system in the pathogenesis and therapy of inflammatory-erosive arthritis, presumably by the removal of catabolic factors, cytokines and inflammatory cells from the inflamed synovium. Murine studies demonstrate that lymphatic drainage increases at the onset of inflammatory-erosive arthritis but, as inflammation progresses to a more chronic phase, lymphatic clearance declines and both structural and cellular changes are observed in the draining lymph node. Specifically, chronic damage to the lymphatic vessel from persistent inflammation results in loss of lymphatic vessel contraction followed by lymph node collapse, reduced lymphatic drainage, and ultimately severe synovitis and joint erosion. Notably, clinical pilot studies in patients with RA report lymph node changes following treatment, and thus draining lymphatic vessels and nodes could represent a potential biomarker of arthritis activity and response to therapy. Most importantly, targeting lymphatics represents an innovative strategy for therapeutic intervention for RA.
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E.M.B. and R.D.B. are supported by a training grant from the NIH (T32 AR053459). H.R. is supported by an NIH grant (K08 AR067885). L.X. is supported by NIH grants (AR069789 and AR063650), a University of Rochester CTSA award (UL1 TR000042), a grant from the National Natural Science Foundation of China (grant 81220108027), and a grant from the Lymphatic Malformation Institute. R.W.W. is supported by an NIH grant (AR061307). C.T.R. is supported by NIH grants (R01 AR056702 and R01 AR069000). E.M.S. is supported by NIH grants (P30 AR069655 and R01 AR056702).
C.T.R. declares that he has received consulting fees and research support from UCB Pharmaceuticals. E.M.B., R.W.W., L.X. and E.M.S. declare that they have applied for patents related to the content of the manuscript. R.D.B. and H.R. declare no competing interests.
Supplementary video S1
NIR-ICG imaging of lymphatic functioning of a TNFtg mouse in the 'expansion' phase. At 3 months of age, TNF transgenic (TNFtg) mice have inflammatory arthiritis in their ankle joints, and expanding popliteal lymph nodes as determined by power Doppler ultrasonography. This video demonstrates lymphatic drainage in the lower limb of a 3-month-old TNFtg mouse by near-infrared indocyanine green (NIR-ICG) imaging. This 20-minute video was taken 60 minutes after ICG injection, and is shown at 20× real time. Note the consistent contractions (∼1 per minute) throughout the imaging period. (AVI 2410 kb)
Supplementary video S2
NIR-ICG imaging of lymphatic dysfunctioning in a TNFtg mouse during the 'collapsed' phase. Indocyanine green (ICG) was injected into the footpad of an 8-month-old TNF transgenic (TNFtg) mouse with a collapsed popliteal lymph node, which was phenotyped using power Doppler ultrasonography. Near-infrared (NIR) imaging was performed to demonstrate lymphatic dysfunction in the lower limb, which was affected by advanced inflammatory arthritis. This 20-minute video was taken 60 minutes after ICG injection, and is shown at 20× real time. Note the complete absence of lymphatic vessel contractions, and lack of popliteal lymph node signal enhancement, throughout the imaging period. (AVI 1475 kb)
Supplementary video S3
Injection of ICG into the web spaces of a healthy volunteer, and indentification of lymphatic vessels adjacent to veins in the hands. Indocyanine green (ICG) was injected into the web spaces of a heathly human volunteer. This video (shown at 4× real time) shows the injection procedure and the ICG entering the lymphatic system directly adjacent to the major veins of the dorsal hand. Note the dramatic uptake of ICG in lymphatic vessels efferent to the first and second web spaces, relative to ICG uptake in the third and fourth web spaces, potentially owing to differences in interstial pressure from the injection volume and/or proximatity to the intial lymphatic bed. The video also shows that manipulation of the web space during removal of excess iodine at the injection site increases interstial pressure, pushing ICG into the lymphatics as well (fourth web space). (AVI 14679 kb)
Supplementary video S4
Quantification of cephalic lymphatic vessel contrations at the wrist. Indocyanine green (ICG) was injected into the web spaces of a healthy human volunteer. Approximately 15 minutes later, near-infrared imaging was performed to quantify lymphatic vessel contractions. This 10-minute video (shown at 20× real time) shows lymphatic drainage in the vessels of the dorsal hand. To quantify cephalic lymphatic vessel contractions, a region of interest (ROI) is defined (green box), and the signal intensity within the ROI is quantified in real time (graph of mean signal intensity over time). Note how the dye moves as a bolus to collection points (presumed valves), and then moves proximally after a contraction. (MP4 13587 kb)
Supplementary video S5
Quantification of the cephalic lymphatic vessel at the antecubital fossa. Approximately 40 minutes after after injection of indocyanine green (ICG) into the web spaces of a healthy human volunteer, near-infrared imaging was performed to quantify lymphatic contractions in the forearm. This 10-minute video (shown at 20× real time) shows lymphatic activity in the vessels of the antecubital fossa. Region of interest (ROI; indicated by the green box) quantification of contraction frequency of the cephalic lymphatic vessel was also performed. Note how the dye moves as a bolus as it crosses the antecubital fossa. (MP4 13740 kb)
Supplementary video S6
Sildenafil (a short-acting PDE5 inhibitor) increases ICG uptake into collateral lymphatic vessels in a wild-type mouse. Indocyanine green (ICG) was injected into the footpad of a healthy wild-type mouse, and near-infrared (NIR) imaging was performed to assess lymphatic drainage after intraperitoneal administration of sildenafil (12 mg/kg), a short-acting inhibitor of phosphodiesterase 5 (PDE5). The video (shown at 20× real time) was taken 40 minutes after ICG injection, and 20 minutes after the sildenafil injection. Note the ICG filled collateral lymphatic vessels following sildenafil injection, indicating lymphatic rerouting. (MOV 15521 kb)
Supplementary video S7
NIR-ICG imaging of lymphatic functioning in a healthy mouse. Indocyanine green (ICG) was injected into the footpad of a wild-type mouse, and was imaged by near-infrared imaging to enable visualization of the lymphatic vessels. This 10-minute video (shown at 20× real time) was taken 40 minutes after ICG injection. Note that the ICG travels from the injection site in the footpad (bottom) to the popoliteal lymph node (top) in two lymphatic vessels that contract with a normal frequency (once per minute). (MOV 1504 kb)
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Bouta, E., Bell, R., Rahimi, H. et al. Targeting lymphatic function as a novel therapeutic intervention for rheumatoid arthritis. Nat Rev Rheumatol 14, 94–106 (2018). https://doi.org/10.1038/nrrheum.2017.205
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