Inclusion Criteria (Stage I):

• Male or female subjects, between 18 and 80 years of age, who have a documented diagnosis of active RA for ≥ 6 months
• Receiving treatment for RA on an outpatient basis
• Have had an inadequate response to at least one non-biologic DMARD and have been receiving this DMARD(s) for ≥ 12 weeks prior to baseline, with stable dose greater than or equal to 4 weeks prior to baseline
• Demonstrated tolerability to currently prescribed DMARDs
• If taking a background corticosteroid, use of the corticosteroid must be at a stable dose during the 4 weeks prior to Day 1
• Use of one nonsteroidal anti-inflammatory drug (NSAID) is permitted if the dose is stable for ≥ 2 weeks prior to Day 1

Exclusion Criteria (Stage I):

• Rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA (including but not limited to vasculitis, pulmonary fibrosis, or Felty's syndrome)
• Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis
• History of or current inflammatory joint disease other than RA or other systemic autoimmune disorder
• Diagnosis of juvenile idiopathic arthritis, or juvenile RA, and/or RA before age 16 years
• 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 enrollment
• Lack of peripheral venous access
• Significant cardiac or pulmonary disease (including obstructive pulmonary disease)
• Evidence of significant uncontrolled concomitant disease such as, but not limited to, nervous system, renal, hepatic, endocrine, or gastrointestinal disorders that, in the investigator's opinion, would preclude subject participation
• Primary or secondary immunodeficiency (history of or currently active), including known history of HIV infection
• Known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of baseline or completion of oral antibiotics within 2 weeks prior to baseline
• History of medically significant opportunistic infection
• History of serious recurrent or chronic infection
• History of deep space/tissue infection within 52 weeks prior to baseline
• 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)
• History of significant cytopenias or other bone marrow disorders
• History of alcohol, drug, or chemical abuse within 24 weeks prior to baseline
• Pregnancy or lactation
• Neuropathies and neurovasculopathies that might interfere with pain evaluation
• MTX monotherapy at the time of screening
• Concurrent treatment with MTX and leflunomide in combination
• Concurrent treatment with any biologic agent
• Prior to Day 1, subjects will be discontinued from all DMARDs/combinations that are prohibited in the protocol
• History of a severe allergic or anaphylactic reaction to a biologic agent, or known hypersensitivity to any component of rituximab or to murine proteins
• Previous treatment with an anti-α4 integrin agent
• Previous treatment with any cell-depleting therapies, including investigational agents
• Receipt of any vaccine within 28 days prior to baseline
• Intolerance or contraindications to IV corticosteroids
• Receipt of IV immunoglobulin (IVIG) or Prosorba<TM> column within 6 months prior to baseline
• Any previous treatment with rituximab
• Positive hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C antibody

Inclusion Criteria (Stage II):

• Male or female subjects, between 18 and 80 years of age, who have a documented diagnosis of active RA for ≥ 6 months, diagnosed according to the revised 1987 ACR criteria for the classification of RA
• Receiving treatment for RA on an outpatient basis
• Have had an inadequate response to at least one biologic DMARD and have been receiving this agent at screening and for ≥ 12 weeks prior to baseline, with stable dose greater than or equal to 4 weeks prior to baseline
• Have demonstrated tolerability to currently prescribed DMARDs/biologics
• If taking a background corticosteroid, use of the corticosteroid must be at a stable dose during the 4 weeks prior to baseline
• Use of one NSAID is permitted if the dose is stable for ≥ 2 weeks prior to baseline

Exclusion Criteria (Stage II):

• Rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA (including but not limited to vasculitis, pulmonary fibrosis, or Felty's syndrome)
• Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis
• History of, or current, inflammatory joint disease other than RA or other systemic autoimmune disorder
• Diagnosis of juvenile idiopathic arthritis, or juvenile RA, and/or RA before age 16 years
• 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
• Lack of peripheral venous access
• Significant cardiac or pulmonary disease (including obstructive pulmonary disease)
• Evidence of significant uncontrolled concomitant disease such as, but not limited to, nervous system, renal, hepatic, endocrine or gastrointestinal disorders that, in the investigator's opinion, would preclude subject participation
• Primary or secondary immunodeficiency (history of or currently active), including known history of HIV infection
• Known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of baseline or completion of oral antibiotics within 2 weeks prior to baseline
• History of medically significant opportunistic infection
• History of serious recurrent or chronic infection
• History of deep space/tissue infection within 52 weeks prior to baseline
• 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)
• History of significant cytopenias or other bone marrow disorders
• History of alcohol, drug, or chemical abuse within 24 weeks prior to baseline
• Pregnancy or lactation
• Neuropathies and neurovasculopathies that might interfere with pain evaluation
• Infliximab monotherapy at the time of screening (infliximab should be in combination with MTX)
• Concurrent treatment with MTX and leflunomide in combination
• Concurrent treatment with more than one biologic agent
• Prior to Day 1, subjects will be discontinued from all DMARDs/combinations that are prohibited in the protocol
• History of a severe allergic or anaphylactic reaction to a biologic agent, or known hypersensitivity to any component of rituximab or to murine proteins
• Previous treatment with an anti-α4 integrin agent
• Previous treatment with any cell-depleting therapies
• Treatment with any investigational agent within 28 days of baseline or 5 half-lives of the investigational drug (whichever is the longer)
• Receipt of any vaccine within 28 days prior to baseline
• Intolerance or contraindications to IV corticosteroids
• Receipt of IVIG or Prosorba<TM> column within 6 months prior to baseline
• Any previous treatment with rituximab
• Positive hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C antibody
• Positive purified protein derivative (PPD) skin test not adequately treated according to Center for Disease Control (CDC) guidelines