RHYTHM (Formerly Escape II Myocardium) (RHYTHM)

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

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).

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: TNF inhibitors; Drug: DMARDs

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 149
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Patients - DMARDs + TNF Inhibitors; 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; 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.; Other Names: Anti-TNF drugs; Drug: DMARDs; Standard of care treatment for RA, such as Methotrexate or other disease-modifying antirheumatic drugs.; Other Names: Disease-modifying antirheumatic drugs
Active Comparator: Patients - DMARDs only; Patients will receive their current treatment in an open label protocol in the context of standard of care.	Drug: DMARDs; Standard of care treatment for RA, such as Methotrexate or other disease-modifying antirheumatic drugs.; Other Names: Disease-modifying antirheumatic drugs
No Intervention: Healthy Volunteers; Subjects without RA who will function as controls.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
• Investigators: Principal Investigator: Joan M Bathon, MD, Columbia University

Publications and helpful links

General Publications

• Amigues I, Tugcu A, Russo C, Giles JT, Morgenstein R, Zartoshti A, Schulze C, Flores R, Bokhari S, Bathon JM. Myocardial Inflammation, Measured Using 18-Fluorodeoxyglucose Positron Emission Tomography With Computed Tomography, Is Associated With Disease Activity in Rheumatoid Arthritis. Arthritis Rheumatol. 2019 Apr;71(4):496-506. doi: 10.1002/art.40771. Epub 2019 Feb 28.

Helpful Links

• Click here for information about this study

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2011
• Primary Completion (Actual): September 1, 2019
• Study Completion (Actual): September 1, 2019

Study Registration Dates

• First Submitted: March 6, 2012
• First Submitted That Met QC Criteria: March 7, 2012
• First Posted (Estimate): March 8, 2012

Study Record Updates

• Last Update Posted (Actual): November 27, 2020
• Last Update Submitted That Met QC Criteria: November 4, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Cardiovascular disease; Rheumatoid Arthritis; Co-morbidities; Myocardium; TNF-alpha inhibitors; ESCAPE; RHYTHM
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Anti-Inflammatory Agents; Tumor Necrosis Factor Inhibitors; Antirheumatic Agents
• Other Study ID Numbers: AAAI1026; 7R01AR050026-07 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No