Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Anti-CD20 Therapy Inhibits the Progression of Synovitis and Focal Erosion in the Knee Joints but Not in the Ankle Joints of TNF-Tg Mice.
Li, Jie, Kuzin, Igor, Ritchlin, Christopher, Sanz, Ignacio, Bottaro, Andrea, Xing, Lianping, Schwarz, Edward
B cell depletion therapy (BCDT) is effective for some RA patients. However, its mechanism of action and variable efficacy remains an enigma. Previously we utilized contrast enhanced (CE) MRI, micro-CT and near infrared-indocyanine green (NIR-ICG) lymphatic imaging to evaluate arthritis in TNF-Tg mice, and demonstrated that disease commences in the ankle, which is consistent with reports defining tenosynovitis in the foot as the initiating pathology. We also found that arthritic progression occurs following a sudden decrease in lymphatic flow from the lower limb to the popliteal lymph node (PLN). This decrease leads to a "collapsed" phenotype characterized by the translocation of CD23+/CD21hi B cells from the follicles into the sinus space, resulting in "clogging" lymphatic flow of the PLN. Thus, we hypothesize that BCDT ameliorates TNF-induced arthritis by increasing lymphatic flow through the depletion of these B cells, and tested this in our murine model.
TNF-Tg mice with collapsed PLNs and ankle synovitis were identified by CE-MRI and followed with scans every two weeks. NIR-ICG footpad clearance (T-clearance) and micro-CT scans were performed before and after treatment with anti-CD20 (n=8; 16 knees) (10mg/kg/i.v. every two weeks) or placebo (n=4; 4 knees) for 6 weeks. PLNs were harvested for flow cytometry or immunohistochemistry (IHC). Ankle and knee joints were harvested for H&E and TRAP stained histology.
1) Anti-CD20 significantly decreased knee synovial volume (SynVol=4.55+/-2.39mm3, p=0.002) and synovitis progression (p=0003) vs. placebo (SynVol=8.98+/-4.16mm3), and PLN B cells (8095% depletion). 2) Anti-CD20 significantly increased T-clearance from 82.3+/-0.16% to 90.4+/-0.08% (p=0.02). 3) Anti-CD20 protected the knee from focal erosions, as there was no significant change in patellar bone volume (p=0.1). However, it failed to prevent bone erosion in the ankle joint, as the talus volume dramatically decreased from 0.64+/-0.32mm3 to 0.30+/-0.27mm3 (p=2×10-6) during the 6-week treatment.
Our results show BCDT effectively inhibits progression of arthritis in knee, but not in the ankle, suggesting distinct etiologies for large and small joint pathogenesis. The lack of efficacy observed in the foot is consistent with unabated tenosynovitis in which B cells play little if any role, as evidenced by arthritis in the ankles of TNF-TgxRAG1-/- mice. In contrast, the absence of tendon insertions proximal to synovium in large joints precludes tenosynovitis as a mechanism of inflammatory-erosive arthritis in the knee. Our observations that draining lymph function and the location of B cells in PLNs correlates with disease in the adjacent knee of TNF-Tg mice is consistent with a novel mechanism of action for BCDT in which removal of the B cells that are "clogging" the lymphatic vessels restores draining function to ameliorate synovitis. Our current clinical pilot to test this hypothesis in anti-TNF refractory RA patients receiving BCDT will be discussed.
To cite this abstract, please use the following information:
Li, Jie, Kuzin, Igor, Ritchlin, Christopher, Sanz, Ignacio, Bottaro, Andrea, Xing, Lianping, et al; Anti-CD20 Therapy Inhibits the Progression of Synovitis and Focal Erosion in the Knee Joints but Not in the Ankle Joints of TNF-Tg Mice. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :712