Trial Information

ESCAPE II MYOCARDIUM: How Rheumatoid Arthritis (RA) and Tumor Necrosis Factor (TNF) Inhibitors Affect the Myocardial Structure and Function.

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. We have observed in few patients
with RA that when they received treatment with medications called TNF inhibitors (in order
to control the joint inflammation) their heart size and strength improved along with the
improvement in their joint inflammation. 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. Some studies have shown 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 expand on the evidence suggesting that TNF
inhibitors may be beneficial in terms of heart disease risk and heart function. We are going
to only enroll patients with RA who do not have any prior heart disease. Specifically we are
going to enroll 50 patients who have active joint disease and have not responded to
treatment with methotrexate. These patients will be evaluated at baseline and 6 months later
after randomization to different therapies. Normally, even if these patients did not
participate in this ( or any) study, would have to take an additional medication along with
methotrexate. Among the FDA approved options most rheumatologists would choose to add a TNF
inhibitor to Methotrexate or proceed with what is called triple therapy (Methotrexate,
Sulfasalazine, Plaquenil) . Both options are considered equivalent in terms of their ability
to control joint inflammation. However nobody knows whether one or the other has a more
beneficial influence on heart size function and degree of inflammation. We believe that TNF
inhibitors will be more beneficial compared to triple therapy in terms of heart function.

In order to prove that the investigators are going randomly split the aforementioned 50
patients to receive one of the two treatments (TNF inhibitor vs triple therapy).

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 later 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 compare the two treatments and see whether TNF
inhibitors truly have a beneficial effect on the heart function and how much more beneficial
it is compared to triple therapy. A different effect of the two regimens 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 and also that the treatment will be randomly assigned.

Other 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 whether there is any differential effect between treatment with TNF
inhibitors and triple therapy 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.