Track topics on Twitter Track topics that are important to you
Anti-TNF therapies include a group of medications such as Enbrel, Remicade and Humira that affect your body's inflammatory response. These medications are routinely prescribed for the treatment of rheumatoid arthritis.
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.
Hypothesis: RA flare in patients who had been effectively managed by anti-TNF therapy is caused by a local insult that triggers B-cell migration and precipitates LN shutdown and decreased inflammatory cell egress from the joint. Effective anti-CD20 BCDT therapy in these patients will correlate with increased PLN function and decreased inflammation in the synovium.
Rationale: RA is a complex syndrome in which excess TNF production is central to disease pathogenesis. While ~70% of these patients can be effectively managed by anti-TNF therapy, an additional insult (i.e. local immune response or trauma) results in a flare that cannot be adequately suppressed by standard anti-TNF therapy in some patients (80, 81). Many patients who flare on one or more anti-TNF therapies do respond to BCDT (26). An explanation for this that fits our preliminary findings in the TNF-Tg mice is that a local immune-inflammatory response that shares lymphatics with RA synovium can induce CXCL13 expression in monocyte/macrophages in the draining LN and these cells and soluble CXCL13 enter the LN via the lymphatics and triggers mass migration of B-cells into the paracortical sinuses. This B cell translocation results in decreased egress of inflammatory cells, which had been maintained by anti-TNF therapy, and manifests as an arthritic flare. To provide a human correlate for the murine experiments designed to test this hypothesis outlined in Aim 2, and to produce feasibility data for a clinical trial to test this novel mechanism of action, we will evaluate PLN radiographic changes following anti-CD20 BCDT in RA patients who flare on anti-TNF therapy. We will also assess DAS28 clinical responses.
Observational Model: Cohort, Time Perspective: Prospective
University of Rochester
University of Rochester
Published on BioPortfolio: 2014-08-27T03:15:22-0400
Primary aim: examine a possible connection between cigarette smoking, disease activity and perceived pain in patients with rheumatoid arthritis. Secondary aim: Evaluate cardiovascular ris...
The purpose of this study is to compare the incidence rates of infection, malignancy and death among patients with rheumatoid arthritis who are treated with abatacept and those who are tre...
Objective: To evaluate what factors contribute to activity limitations in subjects with rheumatoid arthritis considering the International Classification of Functioning, Disability and Hea...
Patients with rheumatoid arthritis are at increased risk of having cardiovascular deaths. Our study is aimed at looking at the effects of proven cholesterol lowering treatment drug called ...
This study will look at whether this new drug is effective in the treatment of rheumatoid arthritis, and at whether it is safe and well-tolerated by patients with the disease.
Rheumatoid arthritis (RA) as an inflammatory autoimmune disease affects the synovial joints as well as other organs and tissues. Since aberrant expression of MIC molecules has been observed in RA pati...
We estimated the incidence and prevalence of depression, anxiety disorder, bipolar disorder and schizophrenia in a population-based cohort with rheumatoid arthritis (RA) as compared to an age-, sex- a...
Rheumatoid arthritis is associated with an increased cardiovascular risk, secondary to endothelial dysfunction. There is accumulating evidence that methotrexate reduces cardiovascular risk in rheumato...
Chronic inflammation of rheumatoid arthritis (RA) is associated with disturbances in muscle and bone metabolism.
To explore the role of TNF-α in the peripheral blood of patients with rheumatoid arthritis (RA) and its underlying mechanism.
Arthritis in children, with onset before 16 years of age. The terms juvenile rheumatoid arthritis (JRA) and juvenile idiopathic arthritis (JIA) refer to classification systems for chronic arthritis in children. Only one subtype of juvenile arthritis (polyarticular-onset, rheumatoid factor-positive) clinically resembles adult rheumatoid arthritis and is considered its childhood equivalent.
Rheumatoid arthritis of children occurring in three major subtypes defined by the symptoms present during the first six months following onset: systemic-onset (Still's Disease, Juvenile-Onset), polyarticular-onset, and pauciarticular-onset. Adult-onset cases of Still's disease (STILL'S DISEASE, ADULT-ONSET) are also known. Only one subtype of juvenile rheumatoid arthritis (polyarticular-onset, rheumatoid factor-positive) clinically resembles adult rheumatoid arthritis and is considered its childhood equivalent.
A variable mixture of the mono- and disodium salts of gold thiomalic acid used mainly for its anti-inflammatory action in the treatment of rheumatoid arthritis. It is most effective in active progressive rheumatoid arthritis and of little or no value in the presence of extensive deformities or in the treatment of other forms of arthritis.
Systemic-onset rheumatoid arthritis in adults. It differs from classical rheumatoid arthritis in that it is more often marked by acute febrile onset, and generalized lymphadenopathy and hepatosplenomegaly are more prominent.
Antibodies found in adult RHEUMATOID ARTHRITIS patients that are directed against GAMMA-CHAIN IMMUNOGLOBULINS.
Cytokine Tumour Necrosis Factor (TNF)
TNF is a compound that is classified as a cytokine which plays a central role in the cellular mechanisms of apoptosis or cell death. However, there are a number of different kinds of TNF, just under twenty, but the family of molecules have very similar a...
Arthritis is by definition the inflammation of one or more joints, characterized by swelling, pain, warmth, redness and diminished range of joint movement (Oxford Medical Dictionary). There are many different types; Noninflammatory; Osteoarthritis, N...
Arthritis Fibromyalgia Gout Lupus Rheumatic Rheumatology is the medical specialty concerned with the diagnosis and management of disease involving joints, tendons, muscles, ligaments and associated structures (Oxford Medical Diction...