Title: Quantitative MRI in rheumatoid arthritis from hand to heart
Funder: Health Education England

Abstract: Background Rheumatoid arthritis (RA) affects approximately 400,000 people with costs of around 6 billion per year (6). It is an independent risk factor for heart disease constituting up to 40% mortality in RA patients (7). There is evidence that the use of biologic drugs achieves earlier functional improvement (2) than standard therapy. The ongoing VEDERA study compares standard therapy with early biologic therapy in treatment nave patients to assess which treatment achieves a higher level of clinical remission. In parallel the CADERA study assesses the differences between these two therapies in the heart. Clinical remission in VEDERA is assessed using a subjective disease activity score. Quantitative dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) provides more sensitive and objective measurements of functional changes to biological tissues (811). As VEDERA is a longitudinal study, quantitative DCE-MRI analysis will allow the depth and rate of remission from RA to be compared. The hypothesis is that biologic therapy will be associated with a greater depth and rate of remission than standard therapy. In CADERA quantitative DCE-MRI will measure tissue changes in the myocardium. The hypotheses are that RA causes changes relative to healthy normals and that biologic therapy will be associated with a greater level of recovery from these changes. The above two hypotheses cannot be tested at the functional tissue level without a sensitive quantitative measure of disease activity. An aim of this study is to analyse the VEDERA and CADERA datasets using quantitative DCE-MRI. Quantitative DCE-MRI remains a prohibitively complex technique outside of dedicated research centres. One of the inflammation sensitive measurements made available by quantitative DCE-MRI is the extracellular volume (ECV) (12). It is possible to measure ECV using two MRI acquisitions known as T1-maps. An aim of this study is to assess the reliability of ECV as a measure of RA disease activity in the hand. Research Questions 1. Is early biologic therapy associated with a greater rate and depth of remission than standard therapy? 2. Are there changes in the myocardium in early RA patients relative to normal controls? Is early biologic therapy associated with a greater amount of recovery from these changes than standard therapy? 3. Do hand ECV measurements correlate with quantitative DCE-MRI? What is the reproducibility of ECV measurement in the hand? Plan of Investigation VEDERA has recruited 60 patients to standard therapy treatment and 60 to early biologic therapy. Quantitative DCE-MRI of the hand will be performed at 0, 12, 24 and 48 weeks post therapy. The depth and rate of remission between the two groups will be compared using multivariable multilevel modelling. CADERA has recruited 20 normal volunteers and 83 patients from the VEDERA study. Quantitative DCE-MRI of the myocardium will be performed at 0 and 1 year post therapy. The difference between the pre-treatment RA and control group, and the difference between the 1 year post-treatment biologics and standard therapy groups will be assessed using multivariable linear regression analysis. Thirty patients with RA disease activity ranging from low to high will undergo DCE-MRI twice over 7 days. The correlation between quantitative DCE-MRI and ECV measurements and the reproducibility of the measurements will be assessed. Summary of Potential Benefits to Patients VEDERA and CADERA have the potential to quantify previously unrealised benefits of biologic therapy. If, based on this evidence, earlier biologic therapy is introduced into national guidelines patients will experience increased depth and rate of remission from RA and/or reduced cardiovascular comorbidity. If simple ECV measurements are a reliable measurement of RA disease activity the benefits of quantitative MRI will become more accessible to researchers, increasing the power of future research.

Lay abstract: Background Rheumatoid arthritis (RA) affects about 600,000 people in the UK, costing the NHS 6 billion per year. In addition to causing painful joint damage RA increases the risk of death from heart disease. Recently new types of drugs, known as biologics, have improved outcomes for RA patients. Current treatment guidelines recommend that biologics are reserved for patients that have not responded well to standard treatment. However, some researchers think that using biologics earlier could yield greater benefits, potentially decreasing the chances of joint damage and heart disease.To see how severe a patient's disease is, doctors look at how tender and swollen their joints are. This joint scoring is not a good measure of how much active disease (inflammation) there actually is in the joints and it's not good at picking up early RA. However, inflammation in the joint can be measured using a technique called quantitative dynamic contrast enhanced magnetic resonance imaging (qDCE-MRI). This technique has the potential to detect the earliest changes in response to treatment of RA in both the hand and the heart.qDCE-MRI measures a number of properties of human tissue, one of which is known as the extracellular volume (ECV). qDCE-MRI is extremely complex to carry out and so ECV measurements are not available outside of research centres that specialise in qDCE-MRI. However, a simpler way of measuring ECV with MRI, using a technique called T1-mapping, has recently proven to be useful in the heart and may be applicable in the hand as well.Aims This study will use qDCE-MRI to measure tissue changes in two ongoing studies:- In the VEDERA study qDCE-MRI will be used in the hands of patients that have been newly diagnosed with RA. We will see if we can measure a difference in tissue recovery between patients treated with biologics and those treated with standard therapy. - In the CADERA study qDCE-MRI will be used to look for differences in the heart between newly diagnosed RA patients and healthy volunteers. If a difference is found we will then look at whether those changes can be reversed and whether standard or biologic therapy is better at achieving this. - Finally, we will look at whether simpler methods of measuring ECV could be useful in the hands of RA patients. If this is possible it would provide a simpler, more accessible alternative to qDCE-MRI.Design and MethodsVEDERA (study 1) The VEDERA study has recruited 120 patients with newly diagnosed RA. Sixty patients were randomly chosen to receive standard therapy, and 60 to receive biologic therapy. All patients had their hands imaged at 0, 12, 24, 48 and 96 weeks after starting treatment. Using qDCE-MRI measurements taken from these scans we will look for differences between the two treatment groups, and how these differences change over time.CADERA (study 2) 83 patients from VEDERA also had their hearts scanned before, and 48 weeks after, beginning their treatment. An additional 20 healthy volunteers were also scanned. Using qDCE-MRI we will see if there is a difference between the hearts of the healthy volunteer group and the RA group. We will then compare standard and biologic therapy groups at one year after treatment to see if either treatment is better at reversing changes in the heart. ECV (study 3) Thirty patients with different severities of RA will be scanned and analysed with both qDCE-MRI and ECV techniques twice within a seven day interval. We will look for an agreement between the ECV and qDCE-MRI measurements. We will then compare the day 0 and day 7 scans to see how reliable the measurements are.Patient Benefit Both the VEDERA and CADERA studies will tell us whether patients will do better if biologic therapy is used earlier. This study aims to apply qDCE-MRI to both these studies. This will improve the ability of these studies to detect subtle, early changes in the amount of active disease. The benefits to patients are: - Potential evidence supporting earlier use of biologics. - This evidence could contribute to a review of national guidelines on RA treatment. - This would improve outcomes for patients with RA. - Study 3 has the potential to make quantitative MRI more accessible to RA researchers. - This could increase the power of future research studies in RA.Dissemination The results will be disseminated through publications in leading journals and presented at National and International conferences. The study's patient public involvement group will provide advice for dissemination of results to patient groups.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM