RHYTHM (Formerly Escape II Myocardium)

Study Overview
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Brief Summary
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For aim 1, the proposed studies will be performed in 150 patients with RA and 25 subjects without RA (healthy volunteers) who will function as controls. For aim 2, 25 of the patients enrolled in aim 1 (who are in need for further treatment due to increased RA activity despite their current treatment) will be recruited to continue in the study for an additional 24 (+/- 2) weeks (or 6 months). These patient will receive a TNF inhibitor in addition to their current treatment in an open label protocol for increased disease activity and in the context of standard of care. The investigators hypothesize that anti-TNF agents in RA patients without heart disease will not adversely affect the heart (will not cause a detrimental change in heart structure or its function).

Detailed Description
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Patients with Rheumatoid Arthritis (RA) have a shortened life expectancy compared to the general population. Cardiovascular disease (CVD), including heart failure (HF), is the primary cause of the extra deaths in RA. HF, in general, results from failure of the heart muscle to pump adequately. In other words the heart muscle in HF becomes weak. In patients without RA, the heart muscle gets larger before symptoms of HF appear. Contrary to that, patients with RA have reduced heart size and reduced heart strength. This may mean that in RA the pathway to heart failure may be different compared to what happens in patients without RA. It is possible - for example - that in RA the heart muscle becomes smaller before it becomes weak (while in non-RA patients the heart muscle becomes larger before it becomes weak). It is possible that cells that create inflammation in the joints may also do the same in the heart muscle making it smaller, thinner and eventually weaker. Patients with RA nowadays can be treated with a variety of medications for their joint inflammation. These medications are powerful and have reduced the risk of permanent joint damage and disability. However it is unknown what is the effect of these medications on the heart size and strength and whether they increase or decrease the risk for cardiovascular disease and heart failure. Among the medications used for RA are medications called TNF inhibitors. They are usually prescribed to patients who have joint inflammation that has not responded to treatment with the first line medication Methotrexate. Data in non-RA patients with advanced heart failure suggest that anti-TNF agents may not help heart failure and may even be harmful. However, the effect of these agents on the hearts of RA patients has never been directly studied. Some observational studies suggest that RA patients treated with TNF inhibitors have a lower risk of developing heart disease. Overall the knowledge regarding the effect of TNF inhibitors on RA patients heart function is limited.

Official Title
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RHYTHM (RHeumatoid Arthritis studY of THe Myocardium): How Rheumatoid Arthritis (RA) and Tumor Necrosis Factor (TNF) Inhibitors Affect the Myocardial Structure and Function.

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: TNF inhibitors
* Drug: DMARDs


Participation Criteria
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Eligibility Criteria
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For RA patients (150 patients): INCLUSION CRITERIA Diagnosis of Rheumatoid Arthritis by 2010 American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) diagnostic criteria Age>18 years old Moderate to high RA disease activity defined by a Clinical Disease Activity Index (CDAI) of >10 Stable dose of Methotrexate for 6 weeks prior to enrollment Stable doses of Nonsteroidal anti-inflammatory drug (NSAID) and prednisone (if already taking these medications) for 2 weeks prior to study EXCLUSION CRITERIA Prior self reported or physician diagnosed CV event (MI; angina; stroke or Transient Ischemic Attach (TIA); Heart Failure (HF); prior CV procedure (e.g., coronary artery bypass graft, angioplasty, valve replacement, pacemaker) Contraindications to having a PET-CT scan or receive adenosine or Fludeoxyglucose (FDG) Active treatment for Cancer Uncontrolled hypertension Diabetes Smoking Treatment with a TNF inhibitor or other biologic currently or within the last 6 months Current treatment with Triple Therapy or within the last 2 months Untreated positive purified protein derivative (PPD) tuberculosis skin test or active tuberculosis History of Lymphoma and Melanoma Ejection Fraction (EF) < 40% (if not known in advance then the Study Visit I Echocardiogram results will be used to exclude the patient from randomization and follow up) Change in NSAID/Prednisone dosage in last 2 weeks Participation in other research studies involving imaging/radiation exposure For non-RA subjects (25 controls): INCLUSION CRITERIA Age>18 years old Absence of diagnosis of RA EXCLUSION CRITERIA Prior self reported or physician diagnosed CV event (MI; angina; stroke or Transient Ischemic Attach (TIA); Heart Failure (HF); prior CV procedure (e.g., coronary artery bypass graft, angioplasty, valve replacement, pacemaker) Contraindications to having a PET-CT scan or receive adenosine or FDG Uncontrolled hypertension Participation in other research studies involving imaging/radiation exposure

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients - DMARDs + TNF Inhibitors<br>Patients will receive a TNF inhibitor in addition to their current treatment in an open label protocol for increased disease activity and in the context of standard of care. | Drug: TNF inhibitors<br>* TNF inhibitors are an FDA approved class of medications indicated for the treatment of RA when initial treatment (usually with methotrexate) has failed to achieve remission of RA disease activity. TNF inhibitors are part of the standard of care management of RA. The possible TNF inhibitors are: Remicade, Humira, Enbrel, Cimzia, Simponi.<br>* Other names: Anti-TNF drugs;Drug: DMARDs<br>* Standard of care treatment for RA, such as Methotrexate or other disease-modifying antirheumatic drugs.<br>* Other names: Disease-modifying antirheumatic drugs;|
| Active Comparator: Patients - DMARDs only<br>Patients will receive their current treatment in an open label protocol in the context of standard of care. | Drug: DMARDs<br>* Standard of care treatment for RA, such as Methotrexate or other disease-modifying antirheumatic drugs.<br>* Other names: Disease-modifying antirheumatic drugs;|
| No Intervention: Healthy Volunteers<br>Subjects without RA who will function as controls. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Myocardial FDG Uptake | This is designed to evaluate the baseline characteristics of the cross sectional RA cohort to understand the correlation of disease activity measured by the Clinical Disease Activity Index (CDAI) with myocardial inflammation measured by fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) scan at the baseline visit. Myocardial FDG uptake is classified as diffuse or focal. | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Myocardial FDG Uptake After Escalation of RA Pharmacotherapy | This is designed to measure the myocardial inflammation, and its association with change in CDAI, after ramp-up of RA therapy over 6 months. Measurements are taken at baseline and 6-months post treatment escalation. Myocardial FDG uptake is classified as diffuse or focal. | Baseline, 6-Month Follow-up | 
| LV Structure (Mean EDVI) in Association With Myocardial FDG Uptake | This is designed to evaluate the baseline characteristics of the entire RA cohort to understand the association of myocardial inflammation measure by FDG uptake with measures of left ventricular (LV) structure measured by 2D/3D echocardiogram at the baseline visit. | Baseline | 
| LV Function (Mean Stroke Volume Index) in Association With Myocardial FDG Uptake | This is designed to evaluate the baseline characteristics of the entire RA cohort to understand the association of myocardial inflammation measure by FDG uptake with measures of left ventricular (LV) function measured by 2D/3D echocardiogram at the baseline visit. | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid Arthritis, Cardiovascular disease, Myocardium, TNF-alpha inhibitors, ESCAPE, Co-morbidities, RHYTHM