ISIS 104838 is an antisense oligonucleotide drug that reduces the production of a specific protein called tumor necrosis factor (TNF-alpha), a substance that contributes to joint pain and swelling in rheumatoid arthritis. ISIS 104838 works by blocking TNF-alpha messenger RNA, the "instruction" molecule that is required for the production of TNF-alpha protein. This trial will assess the safety and efficacy of ISIS 1048383 by subcutaneous injection, administered by 3 different dosing regimens for 3 months, versus placebo. Approximately 160 TNF-alpha inhibitor-naïve rheumatoid arthritis patients will be evaluated at 32 sites in the U.S. and Canada.

Inclusion Criteria

1. Age >/= 18 years.
2. Rheumatoid arthritis for >/= 6 months.
3. Active disease as defined by >/= 6 swollen and >/= 9 tender joints, AND an abnormal C-reactive protein or Westergren Erythrocyte Sedimentation Rate lab test, OR Morning Stiffness >/= 1 hour.
4. Use of at least one DMARD, and ability to discontinue any current DMARD.

Exclusion Criteria

1. Onset of rheumatoid arthritis before the 16th birthday.
2. Wheelchair or bed-bound functional level.
3. No previous infliximab or etanercept treatment, or investigational therapy (not placebo) with other TNF-alpha inhibitors.
4. Prednisone > 10 mg per day or more than one nonsteroidal anti-inflammatory drug.
5. Patients with an active infection, a history of tuberculosis, multiple sclerosis, other poorly controlled medical illness, or a malignancy within the last 5 years.
6. Patients who require intravenous heparin therapy or with a history of a bleeding problem.