Exploratory Trial to Evaluate Premature Endothelial Dysfunction in Early Rheumatoid Arthritis(RA)Compared to Patients With Established RA, and Normal Subjects

Inclusion Criteria:

Group 1

1. Subjects currently experiencing active early RA (duration of symptoms ≤ 2 years)
according to the 2010 ACR/EULAR criteria for the diagnosis of RA at screening.

2. Subjects with early RA must be drug naïve (no prior treatment with traditional
disease-modifying antirheumatic drugs (DMARDs), or biologic response modifying
agents).

Group 2

3. Subjects currently experiencing active established RA (duration of symptoms ≥ 2
years) according to the 2010 ACR/EULAR criteria for the diagnosis of RA at screening.

4. Subjects with active established RA currently receiving methotrexate (MTX), must have
received it for at least 12 weeks, and at a stable dose (≥15mg/week) for at least 6
weeks prior to screening. They must be biologic drug naïve. These subjects must
receive at least 5 mg oral folic acid weekly.

5. Subjects diagnosed with RA must be seropositive with documented rheumatoid factor
(RF) or anti-cyclic citrullinated peptide (anti CCP) positivity. If a documented
history of RF or anti CCP positivity is not available, RF and anti CCP titers will be
obtained at screening Group 3

6. Healthy subjects without RA.

7. All subjects must have sitting diastolic BP ≤90 mm Hg and/or sitting systolic BP ≤
140 at screening

8. Subjects must have fasting plasma glucose (FPG) of ≤ 100 mg/dL.

9. If subjects with established RA are receiving an oral corticosteroid, the dose must
be ≤7 mg/day prednisone (or equivalent) and stable for at least 28 days prior to
screening.

10. Subjects able and willing to give written informed consent and comply with the
requirements of the study protocol. Informed consent must be obtained prior to any
study-related procedures.

A copy of the signed informed consent form must be given to the subject

11. Patients must have a BMI of less than 42

Exclusion Criteria:

1. Major surgery (including joint surgery) within 8 weeks prior to screening.

2. Rheumatic autoimmune disease other than RA, including systemic lupus erythematosus
(SLE), mixed connective tissue disease (MCTD), scleroderma, polymyositis, or
significant systemic involvement secondary to RA (vasculitis, pulmonary fibrosis or
Felty's syndrome). Prior history of or current inflammatory joint disease other than
RA (gout, Lyme disease, seronegative spondyloarthropathy including reactive arthritis
and psoriatic arthritis)

3. Functional class IV as defined by ACR Classification of Functional Status in RA

4. Current treatment with any traditional DMARDs other than MTX within 4 weeks before
the screening visit (For subjects with established RA). Current or prior use of
Leflunomide will be exclusionary.

5. Treatment with any investigational agent within 4 weeks (or 5 half-lives of
investigational agent, whichever is longer) before screening

6. Exposure to any Biologic Response Modifying Agent for RA

7. Intraarticular or parenteral corticosteroids within 6 weeks prior to screening (For
subjects with established RA)

8. Exclusionary laboratory: Serum creatinine >2 mg/dL, ALT or AST > 2.0 x ULN, total
bilirubin > 2.0 x ULN, platelet count <100 x 10⁹ /L, hemoglobin < 8.5 g/dL, WBC count
< 1,000/mm³ , absolute neutrophil count < 1,000/ mm³, absolute lymphocyte count <
500/mm³, triglycerides >400 mg/dL, Serum potassium <3.5 or >5.5 mEq /L without
medication, serum albumin <2.5 g/dL, Gamma GT 3.0 x UNL

9. Smokers (use of tobacco products in the recent past < 6 months). Urine cotinine
levels will be measured during screening for all subjects. Smokers will be defined
as any subject who reports cigarette use or has a urine cotinine greater than 200
ng/mL.

10. Pregnant women or nursing mothers

11. Females of child bearing potential who are not using reliable means of contraception

12. Evidence of serious uncontrolled concomitant cardiovascular (including known CAD,
HTN, or hyperlipidemia), nervous system, pulmonary, renal, hepatic, endocrine or GI
disease.

13. Uncontrolled disease states, such as asthma, psoriasis, or inflammatory bowel
syndrome, where flares are commonly treated with corticosteroids.

14. History or presence of severe bronchospastic disease (including asthma and chronic
obstructive pulmonary disease, treated or not treated).

15. History of cardiovascular abnormalities including myocardial infarction, angina
pectoris, hypertensive encephalopathy, stroke, transient ischemic attack, valvular
heart disease, ventricular arrhythmia A-V block, atrial fibrillation or cardiac
revascularization/angioplasty. Symptoms or clinical evidence of congestive heart
failure or known left ventricular ejection fraction < 40%.

16. Medical history of clinically significant ECG abnormalities, including history of a
prolonged QT-interval syndrome.

17. History of autonomic dysfunction

18. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial,
or other infections such as atypical mycobacterial disease, hepatitis B and C, HIV,
herpes zoster, or any major episode of infection requiring hospitalization or
treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within
2 weeks prior to screening.

19. Any malignancy except for skin cancer (basal cell or squamous cell) diagnosed within
the previous 5 years