RHYTHM (Formerly Escape II Myocardium)

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, we
found 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 we don't know 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 Rheumatoid Arthritis 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.. However when these medications
were used in trials for the treatment of advanced heart failure in patients without RA they
were not helpful and it was thought that they may be harmful. Although the effect of these
drugs has not been directly studied in the hearts of RA patients, 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.

In this study the investigators propose to investigate whether TNF inhibitors are beneficial
or not in terms of heart disease risk and heart function in patients with RA. We are going
to only enroll patients with RA who do not have any prior heart disease. Specifically we are
going to enroll 25 patients who have active joint disease and have not responded adequately
to treatment with methotrexate or DMARD combination therapy. These patients will be
evaluated at baseline and 6 months later after escalation to a TNF inhibitor. Normally, even
if these patients did not participate in this (or any) study, they would have to take an
additional medication along with methotrexate. The addition of a TNF inhibitor is one of the
options for treatment of patients with inadequate response to MTX and other oral DMARDs. 25
patients will be enrolled and prescribed a TNF inhibitor in addition to their current
treatment.

All these patients will come to our research facilities at Columbia university and will
undergo a series of tests at baseline and 6 months later. These will include imaging of the
heart with PET scanning and echocardiography. The latter will tell us the size of the heart
muscle. The former will tell us how strongly the heart muscle pumps the blood. PET scanning
can also quantify the degree of inflammation within the heart. Patients will complete
questionnaires about their RA their other diseases, their quality of life. Their joints will
be examined by a rheumatologist and patients will provide some blood for research and
clinical tests.

These will allow the investigators to see whether TNF inhibitors have anyl effect on the
heart function. This will allow us to understand how heart disease starts in RA, what is the
role of inflammation and which inflammatory pathways are responsible for heart disease in
patients with RA.

In between the two study visits the patients participating in the study will return every
6-8 weeks for what we call safety visits. During these visits they will be evaluated for the
need to increase the dose of their medications or switched to a different but similar drug,
they will be asked whether they can tolerate their drugs and in summary we will ensure their
well-being and improvement of their joint inflammation. Overall this study will
parallel/mirror what would happen even if the patients did not participate in research. The
only difference from "real life clinical practice" is that the patients will have to undergo
imaging and other research tests.

Other assessments pertinent to heart function evaluations will take place during this study
such as weight measurement , blood pressure, heart rate, and a walk test.

In addition to the above: our previous studies have shown that RA patients have more fat
than non RA individuals and that fat accumulates in the body in a different way than non RA
people. This differential fat amount and distribution is thought to increase the amount of
inflammation in the body and is thought to further increase the risk of heart disease in RA.
In order to measure the amount of fat and how it is distributed across the body, patients
will undergo whole body DEXA scans and three CT slices (two abdominal and one thigh), which
will be obtained concurrently with the PET-CT imaging. Then these data will be analyzed in
order to find out the effect of TNF inhibitors on fat distribution.

In order to be certain that the results of this study will not be the result of what is
called random variation we are going to enroll 15 healthy subjects. These subjects will also
be evaluated 6 months apart with the same evaluations mentioned above. Obviously the 15
healthy enrolled individuals will not receive any treatment. The results of heart imaging
for these healthy participants will allow us to "standardize" the results for the RA
patients enrolled.

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 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 (tuberculosis skin test) PPD 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 control participation (15 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