The Morphologic and Functional Relationship Between the Draining PLN and Synovial Inflammation in the Knee Joints of RA Patients Before and After Anti-TNF or B Cell Depletion Therapy

The specific aim of this study is to examine the morphologic and functional relationship between the draining PLN and synovial inflammation in the knee joints of RA patients before and after therapy with TNF antagonists or B cell depletion therapy. The extensive search for informative and practical clinical biomarkers of RA has produced several candidates including CRP, anti-CCP antibodies and matrix metalloproteinase-3 (MMP-3), but none of these soluble molecules can predict disease progression with a high degree of certainty, and no biomarker has been identified that can predict flare. Thus, our findings that PLN collapse precedes arthritis flare in the murine model offers a novel biomarker that may be of great value in RA, but requires validation in humans. To this end, we propose two clinical pilots that are designed to test the validity and feasibility of PLN assessment and quantification in active RA by 3T CE-MRI and Doppler US. The second goal of these pilots is to see if there is a relationship between the clinical response to either a TNF antagonist or B cell depletion and a change in the size or CE pattern of PLN. The pilot studies outlined below are designed to test the hypotheses that an effective clinical response to anti-TNF or BCDT is associated with an increase in draining LN function. While our overall goal is to determine if Doppler US can predict flare, we must first establish the validity and feasibility of this approach so that we can design a clinical trial that is properly designed and adequately powered.

Aim A: To assess the effect of TNF inhibition on volume and CE in the PLN in RA patients by MRI, and compare the effectiveness of Doppler US to achieve the same outcome measures.

Hypothesis: Rheumatoid synovitis in the knee is triggered by TNF over-expression by monocytes/macrophages in the synovium and/or the draining PLN, which produces inflammation that exceeds PLN draining capacity. This results in decreased inflammatory cell egress from the joint and arthritic flare. Effective anti-TNF therapy in RA will result in increased PLN function due to decreased cellularity and lymphatic flow from the synovium to the draining node.

Rationale: To address our first hypothesis, we plan to determine the validity and feasibility of draining LN function by analyzing the ability of 3T CE-MRI and Doppler US to quantify PLN in inflamed RA knees. While CE-MRI (volume x CE) will be the primary outcome measure of PLN function based on our pre-clinical studies, this approach is not adaptable to standard clinical practice. Furthermore, serial MRIs to monitor flare in RA are not feasible due to cost, time, convenience and availability of resources. Thus, parallel US studies will be performed to determine if this instrument, which is gaining acceptance in rheumatology practice, can generate accurate and quantifiable PLN measurements.

Aim B. To assess the effect of anti-CD20 therapy on volume and CE in the PLN in RA patients who "flare" after a period of effective anti-TNF therapy.