B cells, precursors of autoantibody-secreting cells, have emerged as promising new therapeutic targets in autoimmune diseases, including rheumatoid arthritis ( RA ). In particular, B cell depletion with the anti-CD20 antibody Rituximab ( MabThera, Rituxan ) seems to work for RA patients resistant to standard disease-modifying antirheumatic drugs ( DMARDs ) and tumor necrosis factor alfa ( TNF-alpha ) blockers.
In large trials, about half of these hard-to-treat patients respond to Rituximab, achieving at least a 20 percent improvement in disease activity based on the American College of Rheumatology ( ACR ) criteria. However, in the majority of responders, the disease relapses over time. After a single treatment with Rituximab, complete remission of rheumatoid arthritis symptoms for longer than a year is very rare.
With the goal of identifying reliable predictors of response or relapse to Rituximab, researchers focused on the recovery response of different B cell subsets to repeated B cell depletion. Their analysis reveals the critical role of memory B cells in the compromised immune reaction of rheumatoid arthritis and the short-term gains of Rituximab therapy.
The B cell investigation began with an open-label trial of one cycle of Rituximab on 17 RA patients. The participants, 14 women and 3 men, had a median age of 51 years, a median disease duration of 14 years, and a history of failure to respond to DMARD and/or anti-TNF-alpha therapy; 16 of the patients received 2 infusions Rituximab, 1,000 milligrams each, 2 weeks apart, and one patient received 4 weekly infusions of Rituximab at a dose of 375 milligrams. Blood samples from all participants were obtained at baseline, on day 15, and at a 3-month follow-up, and analyzed for B cell repopulation.
After receiving one cycle of Rituximab, 12 of the 17 patients showed a good clinical response, with significant improvement in the Disease Activity Score in 28 joints ( DAS28 ). At the time of B cell recovery, the IgD +, CD27+ memory B cell subset was significantly larger in the nonresponder group. Within the group of 12 responders, 6 patients experienced an early relapse of rheumatoid arthritis activity, between 24 and 40 weeks after Rituximab treatment.
The relapsers were characterized by a significantly higher proportion of overall CD27+ memory B cells before therapy. 11 patients were re-treated and again achieved a good clinical response. After the second cycle of Rituximab, the pattern of B cell reconstitution was repeated. The number of B cells was still reduced at the time of second depletion but recovered to levels similar to those following the first cycle of therapy. This indicates an unimpaired capacity of B cell regeneration after repeated B cell depletion.
Based on statistical analysis, the researchers found a significant correlation between the size of the IgD +, CD27+ memory B cell subset during the early phase of B cell repletion and the response to anti-CD20 treatment. Patients with lower numbers of IgD memory cells at the beginning of peripheral B cell repopulation had a much more favorable clinical response. Therefore, the extent of memory B cell repletion seems to be a key factor influencing the pathophysiology of rheumatoid arthritis.
While revealing a potentially important target for Rituximab therapy in rheumatoid arthritis, this study calls for further research into whether patients with a high level of particular memory B cells may benefit from early re-treatment or may even require higher doses of this anti-CD20 antibody.
Source: Arthritis & Rheumatism, 2008
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