A Study of the Safety of Rituximab in Combination With Other Anti-Rheumatic Drugs in Subjects With Active Rheumatoid Arthritis

Inclusion Criteria (Stage I): * Male or female subjects, between 18 and 80 years of age, who have a documented diagnosis of active rheumatoid arthritis (RA) for ≥ 6 months * Receiving treatment for RA on an outpatient basis * Have had an inadequate response to at least one non-biological disease-modifying anti-rheumatic drug (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 the first day of treatment with rituximab (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 American College of Rheumatology (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 human immunodeficiency virus (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 intravenous (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 * Methotrexate (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