This study characterized the relationship between clinical response, serum
rituximab concentrations, and peripheral B-cell levels in patients with
rheumatoid arthritis treated with
rituximab. Data were analyzed from a double-blind, phase IIa trial in which 161 patients with active
rheumatoid arthritis despite continuing
methotrexate were randomized to
methotrexate alone (10-25 mg/wk),
rituximab alone (single course: 1000 mg administered intravenously on days 1 and 15),
rituximab plus
cyclophosphamide (750 mg administered intravenously on days 3 and 17), or
rituximab plus
methotrexate. Serum samples for pharmacokinetic analysis were collected through 24 weeks, and peripheral circulating CD19+ B-cell levels were measured through 48 weeks. All treatments were generally well tolerated, with no clinically relevant excess of adverse events leading to withdrawal among patients who received
rituximab compared with those who received
methotrexate alone. The proportions of patients who achieved an American College of Rheumatology score of 50 at week 24 were 13% (
methotrexate alone), 33% (
rituximab alone), 41% (
rituximab plus
cyclophosphamide), and 43% (
rituximab plus
methotrexate). Peripheral B-cell depletion occurred by day 15 in all patients treated with
rituximab. There was no relationship between B-cell depletion and clinical response. Recovery of peripheral B cells was variable and showed no relationship with return of disease activity in patients who responded to
rituximab. The mean terminal half-life of
rituximab was 19 to 22 days; pharmacokinetic parameters were similar whether
rituximab was administered alone or with
methotrexate or
cyclophosphamide. Because the level of peripherally circulating B cells does not appear to correlate with a maintained clinical response in patients with
rheumatoid arthritis, the timing of
rituximab retreatment should be based on clinical symptoms rather than peripheral B-cell levels.