Antibodies Against B Cells
B cells are critical to the pathogenesis of RA. Mature B cells may evolve into antibody producing plasma cells. Although the precise role of B-cell-producing autoantibodies in RA remains unclear, B cell and plasma cell infiltration into synovium has consistently been found. In addition to their role as precursors to antibody producing plasma cells, B cells may function as antigen-presenting cells and may also produce inflammatory cytokines and may costimulatory molecules important for T-cell function.
As rituximab is a B-cell-depleting agent, chimeric/IgG1 monoclonal antibody which binds to the CD20 cell surface marker found on several maturation stages of B lymphocytes. It gained FDA/EMA approval in 2006 for the treatment of moderate-to-severe RA in combination with MTX in patients with inadequate response to anti-TNF. Rituximab is given via the intravenous route at a dose of 1000 mg for two doses 2 weeks apart for each cycle. The first study evaluated rituximab in RA was reported by Edwards et al. Four treatment groups consisting of MTX monotherapy, rituximab monotherapy, rituximab plus cyclophosphamide and rituximab plus MTX were compared, and all rituximab groups had a better ACR20 response compared with MTX monotherapy, with a comparable safety profile. In the DANCER study, the efficacy of 500 and 1000 mg of rituximab versus placebo infused 15 days apart with pretreatment methylprednisolone was evaluated in RA patients who remained on MTX despite an incomplete response. There were no differences between the two doses in primary clinical outcomes with both doses significantly more efficacious than placebo, but more stringent outcome measures, such as remission, favored the higher dose. Radiographic inhibition was also superior at the higher dose. The corticosteroids did not seem to contribute to efficacy, but significantly reduced the frequency of acute infusion reactions at the first infusion; 35% in the placebo group versus 25% of the glucocorticosteroid-treated group.
In the REFLEX trial, rituximab was efficacious in patients with RA who had an incomplete response to one or more TNF inhibitors. Significantly more patients treated with rituximab plus MTX achieved an ACR50 response rate compared with placebo plus MTX, 27 versus 5%. All primary outcome measures were achieved in the rituximab group, which also demonstrated less radiographic progression and improved patient reported outcomes. Rituximab has also demonstrated efficacy in patients with early RA in the IMAGE trial, in incomplete MTX responders who were biologic-treatment naive in the SERENE trial, and as monotherapy with some success. Retreatment with rituximab is successful, but the optimal interval for such retreatment is not clearly established. A number of treatment schedules have been used including a fixed retreatment schedule every 6 months, an as-need schedule and a treat-to-target approach, all with some success.[56,57] The fixed dose schedule appeared to be superior to retreatment at the time of flares. The efficacy of repeated courses of rituximab seems about the same as the original course with some increase in the proportion of patients achieving remission over time. The retreatment of initial nonresponders (all seropositive) has been less successful. Rituximab is significantly more efficacious in trials in seropositive patients compared with those that are seronegative.
Rituximab has been used in patients failing prior biologics without an increase in serious infections, compared with other biologics. Moreover, other biologics have been used in rituximab-inadequate responders without an increase in serious infections. Rituximab may be particularly helpful in patients who might have another connective tissue disease other than RA and in patients with lymphoma and those with multiple sclerosis.
Int J Clin Rheumatol. 2013;8(5):541-556. © 2013 Future Medicine Ltd.