Subclinical remodelling of draining lymph node structure in early and established rheumatoid arthritis assessed by power Doppler ultrasonography

Manzo, Antonio; Caporali, Roberto; Vitolo, Barbara; Alessi, S.; Benaglio, Francesca; Todoerti, Monica; Bugatti, Serena; Calliada, Fabrizio; Montecucco, Carlomaurizio

doi:10.1093/rheumatology/ker076

Cited by 36 publications

(37 citation statements)

References 21 publications

(30 reference statements)

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“…In contrast, we predict that RA flares that take place sporadically in patients with chronic disease are associated with the loss of lymphatic egress from joints, and can be assessed by “collapsed” efferent LN and the absence of a lymphatic pulse. With the recent development of clinical PD-US [41] and NIR-ICG [58] imaging of draining LN instruments to measure and assess the lymphatic pulse are now available providing a unique opportunity to examine the diagnostic and prognostic potential of these biomarkers. Moreover, elucidation of the mechanism of efferent LN collapse may catalyze new drug development to specifically target lymphatics in a population of RA patients with advanced disease for whom effective therapies are limited.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, there are benefits to using a more cost-effective technique, such as ultrasound (US). Others have demonstrated that US can be used to monitor changes in the LN of RA patients undergoing treatment [41], and we have demonstrated that US is comparable to CE-MRI for determining relative PLN volume in mice [42]. Power Doppler (PD) is an US technique that can be used to observe blood flow in various tissues.…”

Section: Use Of Ultrasound For Pln Phenotypingmentioning

confidence: 99%

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The role of the lymphatic system in inflammatory-erosive arthritis

Bouta

et al. 2015

Seminars in Cell & Developmental Biology

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Rheumatoid arthritis (RA) is a prevalent inflammatory joint disease with enigmatic flares, which causes swelling, pain, and irreversible connective tissue damage. Recently, it has been demonstrated in murine models of RA that the popliteal lymph node (PLN) is a biomarker of arthritic flare, as it “expands” in size and contrast enhancement during a prolonged asymptomatic phase, prior to when it “collapses” with accelerated synovitis and joint erosion. This PLN collapse is associated with adjacent knee flare, decreases in PLN volume and contrast enhancement, lymphatic pulse and pumping pressure, and an increase in PLN pressure. Currently, it is known that PLN collapse is accompanied by a translocation of B cells from the follicles to the sinuses, effectively clogging the lymphatic sinuses of the PLN, and that B cell depletion therapy ameliorates arthritic flare by eliminating these B cells and restoring passive lymphatic flow from inflamed joints. Here we review the technological advances that have launched this area of research, describe future directions to help elucidate the potential mechanism of PLN collapse, and speculate on clinical translation towards new diagnostics and therapies for RA.

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Section: Discussionmentioning

confidence: 99%

Section: Use Of Ultrasound For Pln Phenotypingmentioning

confidence: 99%

The role of the lymphatic system in inflammatory-erosive arthritis

Bouta

et al. 2015

Seminars in Cell & Developmental Biology

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“…Former histologic studies on lymph node biopsies from different anatomic sites in established RA described follicular hyperplasia and interfollicular plasmacytosis [85] as well as increased GCs with high B-cell activity [86]. More recent data exploiting power Doppler ultrasound demonstrated the possibility to capture significant structural and vascular flow changes in axillary lymph node of patients with active disease, including hypertrophy of cortical regions [87]. Supporting these data, flow cytometry analysis of inguinal lymph node cells isolated from ultrasound-guided biopsies in in early arthritis patients showed an increase in activated CD69+ CD8+ cells and CD19+ B cells compared to healthy controls, suggesting an increased immune cell activation within the lymph node compartment [88].…”

Section: B Cells In Different Compartmentsmentioning

confidence: 99%

B Cells in Rheumatoid Arthritis: From Pathogenic Players to Disease Biomarkers

Bugatti

Vitolo

Caporali

et al. 2014

BioMed Research International

137

113

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The therapeutic benefit of depleting B cells in rheumatoid arthritis (RA) has refocused attention on B cells with increasing awareness on their role in autoimmunity and their function beyond autoantibody production. The rapid increase in our comprehension of B-cell pathobiology is progressively opening novel perspectives in the area of B cell-targeted therapies with the expectation to define more specific approaches able to preserve the homeostasis of the humoral response while disrupting the pathogenic components. In parallel, B-cell activity in RA is starting to be explored in its clinical value, in search of novel biomarkers embedded in the pathogenic process that could help classifying the disease and predicting its heterogeneous outcome beyond inflammation dynamics. In this review, we summarize current knowledge on the multiple roles that B cells play in several aspects of RA. We also analyze their distribution and potential function in different anatomic compartments with specific reference to the main sites in which the disease may be sustained and exert its detrimental effects: the systemic circulation, synovium, bone marrow, and draining lymph nodes. We also highlight novel data encouraging further research in the field of biomarkers related to B cells and their regulatory factors.

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“…Taken together, these studies are consistent with a model in which the TNF-induced inflammatory cascade leads not only to localized effects in the targeted joints, but also to more regional effects on lymphatic vessels, lymph node histology, cellular composition and lymphoid subset function that directly contribute to chronic disease progression and flares. Structural and functional changes in draining lymph nodes, and pre-clinical alterations in resident cell populations are beginning to be recognized in RA patients, suggesting that these observations may be translatable to human disease [18–20]. …”

Section: Discussionmentioning

confidence: 99%

TNF signals are dispensable for the generation of CD23+ CD21/35-high CD1d-high B cells in inflamed lymph nodes

Kuzin

Bouta

Schwarz

et al. 2015

Cellular Immunology

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Tumor necrosis factor (TNF) is a key cytokine in rheumatoid arthritis (RA) pathogenesis, as underscored by the clinical effectiveness of TNF antagonists. While several of TNF’s key targets in RA are well understood, its many pleiotropic effects remain to be elucidated. TNF-transgenic mice develop inflammatory-erosive arthritis associated with disruption of draining lymph node histology and function, and accumulation of B cells with unique phenotypic and functional features consistent with contribution to pathogenesis (B cells in inflamed nodes, Bin). Bin cell induction depends on the inflamed microenvironment, but the specific signals are unknown. Using anti-TNF treatment and TNF-receptor-deficient mice, here we show that Bin cells are induced and maintained independently of B cell-intrinsic TNF signals.

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Subclinical remodelling of draining lymph node structure in early and established rheumatoid arthritis assessed by power Doppler ultrasonography

Cited by 36 publications

References 21 publications

The role of the lymphatic system in inflammatory-erosive arthritis

The role of the lymphatic system in inflammatory-erosive arthritis

B Cells in Rheumatoid Arthritis: From Pathogenic Players to Disease Biomarkers

TNF signals are dispensable for the generation of CD23+ CD21/35-high CD1d-high B cells in inflamed lymph nodes

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