Certolizumab and Lower Extremity Lymph Flow in Rheumatoid Arthritis (RA)

Ten RA subjects with unilateral knee synovitis, who have not responded to methotrexate, will be recruited from our early RA Clinics. Following enrollment, the subjects will have a technetium sulfur colloid scan performed on both lower extremities followed by a baseline 3 Tesla contrast-enhanced magnetic resonance imaging (3T CE-MRI) study and Doppler US on the involved knee as described below. The overall disease activity will be determined by the DAS 28 and activity in the involved knee with the RAOS instrument; an outcome measure that quantifies the degree of tenderness, swelling and function in monoarthritis. The subjects will then receive 18 weeks of certolizumab and three of the ten subjects will undergo repeat technetium sulfur colloid scans. To test our hypotheses, we will select three responders based on the RAOS response. We will select only three of the 10 for repeat nuclear studies because this number of subjects will allow us to test our hypothesis without the need to perform the scan on all the subjects. All ten subjects with have 3T CE-MRI, Doppler US and clinical evaluations performed at the 18 week time point. The subjects will continue on certolizumab for a total of 24 weeks. Sulfur Colloid Technetium Scan. A nuclear radiology technician will inject 0.25cc of technetium sulfur colloid into the first through third web spaces of the feet in both lower extremities. In healthy controls the transit time from the feet to the aortic bifurcation is about 30 minutes. The transit time of the tracer will be measured in both lower extremities at the knee, inguinal ligament and at the aortic bifurcation. Images will be obtained with a nuclear camera according to standard protocol serially over the first hour and delayed images acquired in 4 to 6 hours if necessary. Three subjects who have responded to certolizumab will have the scan repeated at 18 weeks as outlined above. 3T CE-MRI. Two radiologists will independently quantify LN volume and CE of all nodes in the popliteal area from the MRI. These radiologists will also quantify the extent of synovial inflammation, cartilage erosion and bone marrow edema via the RA MRI scoring system (RAMRIS). Consensus findings will be reached and the volume and CE for each node identified together with the RAMRIS will be entered into a database for this study. At the end of the study, we will assess the trend of anti-TNF therapy on: 1. The number of detectable LN in the popliteal fossa 2. Mean LN volume for detectable LN 3. Mean LNCE for detectable LN 4. LNcap for detectable LN 5. RAMRIS, by plotting the change over 8 weeks for each knee independently as we have previously described for anti-TNF effects on bone marrow edema in PsA subjects. The relationship between LN and clinical response to therapy will be assessed from deriving the significance of the correlation coefficient (x2) of LNcap vs DAS28 respectively, as we have done for bone marrow edema vs. DAS28 in PsA subjects on anti-TNF therapy. Doppler US. Ultrasound examinations of PLN will be obtained at baseline and 18 weeks after anti-TNF therapy as follows. All US examinations will be performed by a rheumatologist (RT) certified in musculoskeletal ultrasound. All subjects will be examined sonographically for the presence of inflammatory changes in the knee joint. The involved knee will be examined sonographically for the presence of the following: 1. Effusion. A distension of pre-femoral and suprapatellar fat pads of \>4.8 mm will be noted as an effusion in the suprapatellar recess of the knee joint. 2. Synovial thickening. Hypoechoic, often nodular or villous appearing tissue within the suprapatellar recess that is distinct from the hyperechoic capsular structures and prefemoral and suprapatellar fat pads will be noted as synovitis. 3. Synovial hyperemia. If proliferative synovial tissue is identified, this tissue will be examined with Doppler ultrasound for the presence of increased blood flow. This will be defined as the presence of color pixels in such synovial tissue that appear in synchronicity with the subject's pulse. In all subjects, affected joints will be examined with gray scale and Doppler ultrasound. Affected joints will be examined sonographically for the presence of the following: 1. Effusion in a joint will be defined as a hypoechoic area within the hyperechoic joint capsule. Such anechoic intra-articular fluid will be displaceable by pressure of the US probe. This helps distinguish joint fluid from intra-articular hyaline cartilage, which is also anechoic to hypoechoic in appearance but is not displaceable by pressure of the probe. The distension of the joint capsule will be measured using sonographic calipers. This distension will be compared with normal values to assess the degree of effusion. 2. Synovial thickening. The synovial lining cells are only one to three cell layers strong in an unaffected joint, so intra-articular, hypoechoic proliferative synovial tissue can be readily distinguished sonographically from more hyperechoic capsular structures. Thickening, if present, will be measured using sonographic calipers. 3. Synovial hyperemia. If synovial thickening is detected, this tissue will be examined sonographically for the presence of Doppler flow as a measure of hyperemia and inflammation. 4. Bony erosions. Erosions will be defined as breaks in the cortical bony contour seen in two perpendicular planes. The dimensions of all the PLN that can be imaged and cataloged for longitudinal analysis. Synovitis and erosions will also be scored by ultrasound before and after therapy. Outcome Measures: 1. Technetium sulfur colloid scan 1. The primary outcome measure for this study is the transit time from foot to the umbilicus (T3) after injection of radioisotope in the limb with the inflamed knee compared to the transit times (T3) in the extremity of the uninflamed knee. 2. Secondary outcome measures are: * the transit times from the foot to the knee (T1) and inguinal ligament (T2) of the radioisotope in both lower extremities * Intensity of counts (intensity/area of interest) in the knee, inguinal ligament and umbilicus in both lower extremities. * Change in transit times and tracer intensity in the three sites after 12 weeks of certolizumab treatment in the involved extremity (3 subjects only) 2. MRI (secondary): 1. The amount of contrast enhancement and volume of the draining PLN will be analyzed before and 18 weeks after treatment with certolizumab. 2. The amount of synovitis, joint effusion, erosion and bone marrow edema will be quantified using the RAMRIS scoring system before and 18 weeks after treatment. 3. Doppler ultrasound (secondary): 1. Number of detectable LN in the popliteal fossa. 2. Mean LN size (maximum area). 3. Secondary measures: synovitis, joint effusion, erosions, and blood flow will also be assessed in the involved joint. 4. Clinical Assessments: 1. Degree of tenderness (0-3) with subject visual analogue scale (VAS) and swelling with MD VAS (0-3) of the inflamed before and after treatment. 2. Rheumatoid Arthritis Outcome Score (RAOS)before and after treatment. 3. Disease Activity Score (DAS 28) score to assess overall joint response to therapy with certolizumab