• Changes in circulating and synovial cell populations; changes in immunoglobulin (Ig) and autoantibody levels; changes in indicators of inflammation; changes in disease activity [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  

• Relationships between mechanistic and disease activity endpoints and HLA alleles and FCGR3A polymorphisms; levels of cellular apoptosis assessed by changes in percentage of nucleated cells present in synovial tissue [ Time Frame: Through Week 12 ] [ Designated as safety issue: No ]
  

RA is characterized by persistent inflammation of peripheral joints, causing pain, stiffness, swelling, and warmth. RA is commonly managed by DMARDs initiated early in the disease process, before irreversible joint damage occurs. The most common DMARD prescribed in the United States is MTX; this drug is well tolerated and has better efficacy compared to other DMARDs, but is inadequate in providing lasting improvement in people with RA. In patients with an inadequate response to MTX alone, the use of biologic agents, including TNF-blocking agents in combination with MTX, has become a standard therapeutic approach.

Rituximab is a man-made antibody used to treat certain types of cancer. The drug blocks the CD20 antigen found on the surface of B cells and is known to deplete B cells when administered intravenously. Previous research suggests B-cell activity is important in pathogenesis of RA, so B-cell depletion may decrease inflammation and other symptoms of RA. Rituximab has recently been approved by the FDA for use in combination with MTX for treatment of patients with moderately to severely active RA who have had an inadequate response to TNF-blocking agents. This study will examine the effects of rituximab on the immune response and disease activity in participants with early RA who have not been treated with any disease-modifying agent. Levels of B and T cells and other markers of disease activity will be monitored during the study. The safety and tolerability of rituximab in this DMARD-naive population will be examined.

This study will last about 2.5 years. All study participants will receive two intravenous infusions of rituximab given in an outpatient setting at study entry and Week 2. Throughout the study, participants will receive MTX, systemic corticosteroids, and folic acid. MTX dosing will be re-evaluated with disease activity scores every month until Month 6 and again at Months 8, 10, and 12. Systemic corticosteroid doses will be modified based on the participant's health while in the study. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) is permitted, but NSAID doses should not be changed during the study if at all possible. NSAIDs will not be provided by this study.

There will be a maximum of 2 screening visits before study treatment, a baseline visit, and 11 study visits. A physical exam, assessment for adverse events, and blood collection will occur at all study visits. Kidney and liver function tests and rheumatologic evaluations will occur at most study visits; participants will also be asked to complete a questionnaire on their health at most study visits. Arthroscopy (knee biopsy) on the more inflamed knee will occur at baseline and Month 3. Participants will be contacted by telephone the day after each arthroscopy and rituximab infusion.

Inclusion Criteria:

• Diagnosis of RA, as defined by fulfilling at least four of seven American College of Rheumatology (ACR) criteria
• Positive for rheumatoid factor (RF) and/or anticyclic citrullinated peptide (CCP)
• Have had arthritis symptoms for more than 6 weeks but less than 1 year
• Active RA, as defined by at least four swollen joints, at least four tender joints, and either an erythrocyte sedimentation rate (ESR) of greater than 30 mm/hr OR C-reactive protein level greater than 1.0 mg/dl (normal less than 0.4)
• Willing to follow the study protocol
• Willing to use acceptable forms of contraception

Exclusion Criteria:

• Allergy to MTX
• Previous exposure to anti-CD20 monoclonal antibody (mAb) or other type of mAb therapy
• Previous DMARD therapy
• Previous use of a biologic agent
• Currently taking daily oral steroid doses of greater than 7.5 mg
• Intra-articular injections within 4 weeks prior to study entry
• Current peptic ulcer disease
• Unwilling to stop drinking alcohol
• History of alcohol or substance abuse
• Active infection, or chronic or persistent infection that might worsen with immunosuppressive treatment (e.g., HIV, hepatitis B virus, hepatitis C virus, tuberculosis [TB])
• Interstitial lung disease observed on chest x-ray
• Known coronary artery disease or significant cardiac arrhythmias or severe congestive heart failure (New York Heart Association [NYHA] classes III or IV)
• Definitive diagnosis of another autoimmune rheumatologic disease (e.g., systemic lupus erythematosus [SLE], scleroderma, primary Sjogren's syndrome, primary vasculitis)
• History of immunoglobulin E (IgE)-mediated or non-IgE-mediated hypersensitivity or known anaphylaxis to mouse proteins
• History of cancer. Participants with previous resected basal or squamous cell carcinoma, treated cervical dysplasia, or treated in situ Grade I cervical cancer within 5 years prior to study entry are not excluded.
• History of positive purified protein derivative (PPD) test (positive TB test) without treatment for TB infection or chemoprophylaxis for TB exposure
• History of inflamed pancreas
• Live vaccine within 3 months of study entry
• Certain abnormal laboratory values
• Require certain medications
• Any psychiatric disorder that would prevent a participant from providing informed consent
• Any condition or treatment (including biologic therapies) that, in the opinion of the investigator, may place the participant at unacceptable risk during the study
• Pregnancy