Safety and Tolerability of Rituxan With Methotrexate and Etanercept or Methotrexate and Adalimumab in Patients With Active Rheumatoid Arthritis

Inclusion Criteria: 1. Must give written informed consent. If required by local law, candidates must also authorize the release and use of protected health information (PHI). 2. Male or female participants, between 18 and 65 years of age, who have a diagnosis of active RA for at least 6 months, diagnosed according to the revised 1987 American College of Rheumatology (ACR) criteria for the classification of rheumatoid arthritis (RA). 3. Must have at least 5 tender and 5 swollen joints at Screening and Day 1. 4. Must have been treated with etanercept at 50 mg per week (25 mg twice per week or 50 mg once per week) or adalimumab at 40 mg every other week for at least 12 weeks immediately prior to Day 1. 5. Must have been treated with methotrexate (MTX) greater than or equal to 15 mg per week and less than or equal to 25 mg per week (dose may be as low as 10 mg if unable to tolerate higher dose) for at least 12 weeks immediately prior to Day 1, at a stable dose for at least 4 weeks. 6. Must be willing to receive oral folate. 7. Oral glucocorticoids must not exceed 10 mg per day of prednisone (or equivalent dose) and must have been administered at a stable dose for at least 4 weeks prior to Day 1. 8. Any concomitant non-steroidal antiinflammatory drugs (NSAIDs) must be stable for at least 2 weeks prior to Day 1. 9. For participants of reproductive potential (males and females), use of a reliable means of contraception (e.g., hormonal contraceptive, patch, intrauterine device, physical barrier) throughout study participation. Exclusion Criteria: Exclusions Related to RA 10. Rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis, or Felty's syndrome). Secondary Sjögren's syndrome or secondary limited cutaneous vasculitis with RA is permitted. 11. Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis. 12. History of, or current, inflammatory joint disease other than RA (e.g., gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease) or other systemic autoimmune disorder (e.g., systemic lupus erythematosus \[SLE\], inflammatory bowel disease, scleroderma, inflammatory myopathy, mixed connective tissue disease, or any overlap syndrome). 13. Diagnosis of juvenile idiopathic arthritis, also known as juvenile RA, and/or RA before age 16. Exclusions Related to General Health 14. Any surgical procedure, including bone/joint surgery/synovectomy (including joint fusion or replacement) within 12 weeks prior to baseline or planned within 24 weeks of randomization. 15. Lack of peripheral venous access. 16. Pregnancy or breast feeding. 17. Significant cardiac or pulmonary disease (including obstructive pulmonary disease). 18. History of chronic heart failure (CHF), SLE-like syndrome, neuropathy or myelitis, optic neuritis, or pancytopenia while on etanercept or adalimumab. 19. Evidence of significant uncontrolled concomitant disease such as, but not limited to, nervous system, renal, hepatic, endocrine, or gastrointestinal disorders which, in the investigator's opinion, would preclude subject participation. 20. Primary or secondary immunodeficiency (history of, or currently active), including known history of human immunodeficiency virus (HIV) infection. 21. Known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with IV anti infectives within 4 weeks of Day 1 or completion of oral anti infectives within 2 weeks of Day 1. 22. History of positive purified protein derivative (PPD) not adequately treated. 23. History of deep space/tissue infection (e.g., fasciitis, abscess, osteomyelitis) within 52 weeks of Day 1. 24. History of serious infection or opportunistic infection in the last 2 years (to screen for a chest infection, a chest radiograph will be performed at Screening if one was not performed within 12 weeks prior to Screening). 25. History of seizures. 26. History of cancer, including solid tumors, hematologic malignancies, and carcinoma in situ (except basal cell and squamous cell carcinoma of the skin that have been excised and cured). 27. Any neurological (congenital or acquired), vascular, or systemic disorder that might affect any of the efficacy assessments, in particular, joint pain and swelling (e.g., Parkinsons disease, cerebral palsy, diabetic neuropathy). 28. Currently active alcohol or drug abuse or history of alcohol or drug abuse (as determined by the Investigator) within 1 year prior to Day 1. Exclusions Related to Medications 29. History of a severe allergic or anaphylactic reaction to a biologic agent or known hypersensitivity to any component of rituximab or to murine proteins. 30. Previous treatment with an anti alpha 4 integrin agent or costimulation modulator. 31. Concurrent treatment with any biologic agent other than etanercept or adalimumab, or disease-modifying anti-rheumatic drug (DMARD) other than MTX. Treatment with any biologic or DMARD except etanercept or adalimumab, and MTX must be discontinued 14 days prior to baseline, except for the following: azathioprine for 28 days; leflunomide for 8 weeks (or 14 days after 11 days of standard cholestyramine or activated charcoal washout). 32. Previous treatment with any cell depleting therapies, including investigational agents (e.g., Campath \[alemtuzumab\], anti-CD4, anti-CD5, anti-CD3, anti-CD19, anti CD11a, anti-CD22, B lymphocyte stimulator/B-cell activating factor \[BLys/BAFF\], and anti-CD20). 33. Treatment with another investigational drug within 4 weeks prior to Day 1 or 5 half lives of the investigational drug (whichever is the longer). 34. Receipt of a live/attenuated vaccine within 4 weeks prior to Day 1. 35. Intra-articular or parenteral glucocorticoids within 4 weeks prior to Day 1. 36. Intolerance or contraindications to IV glucocorticoids. Exclusions Related to Laboratory Findings 37. For women of childbearing potential, a positive serum pregnancy test at screening and/or a positive urine pregnancy test on Day 1. 38. Positive hepatitis B surface antigen (HBsAg). 39. Positive hepatitis B core antibody (HBcAb) associated with positive hepatitis B viral DNA (HBV DNA). 40. Positive hepatitis C antibody. 41. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>2.5 times upper limit of normal. 42. Hemoglobin \<8.0 g/dL. 43. Levels of immunoglobulin G (IgG) and/or immunoglobulin M (IgM) below 5.0 and 0.4 mg/mL, respectively. 44. Absolute neutrophil count (ANC) \<1500/mL. Miscellaneous Exclusions 45. Current enrollment in any other investigational or other drug study. 46. Treatment with IV Gamma Globulin or the Prosorba® Column within 6 months of the Screening visit.