The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics of ISIS CRP Rx and its effects on CRP and other pharmacodynamic measures, versus placebo, in subjects with active rheumatoid arthritis.

Inclusion Criteria:

• Male or female; age 18 to 75 years
• Active RA for at least 6 months
• Active disease defined by having equal to or greater than 6 swollen joints and 6 tender joints, based on a 28 joint count
• On stable doses and regimen of allowed RA medications
• Currently receiving at least 10 mg of methotrexate a week. Patients unable to tolerate doses greater than 10 mg may also be eligible for enrollment.

Exclusion Criteria:

• Diagnosis of Felty's syndrome, psoriatic arthritis, gout, or auto-immune rheumatic disease
• Any surgical procedure within 30 days of Screening or likely to need joint or tendon surgery or other surgical procedure during the study
• Intra-articular or intra-muscular corticosteroids within 60 days prior to dosing
• Previous treatment with any biologic response modifying agent for RA within 90 days or 5 half-lives, whichever is greater, prior to screening
• Previous treatment with rituximab at any time
• Use of corticosteroid therapy equivalent to an average daily dose of >10 mg of prednisone
• Any Screening laboratory values that are out of allowed reference ranges
• Inability to comply with protocol or study procedures
• Any other significant illness or condition that may adversely affect the subjects participation in the study