WÜRZBURG, Germany?A memory B-cell subset that could be readily monitored in peripheral blood samples might help clinicians identify rheumatoid arthritis (RA) patients who need early re-treatment or higher than usual doses of rituximab (Rituxan^®) to prevent relapse. German researchers led by Petra Roll, MD, from the University of Würzburg, report in Arthritis & Rheumatism that response to anti-CD20 treatment with rituximab is lower in patients who have high numbers of IgD +, CD27+ memory B-cells during the early phase of B-cell recovery.

“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 RA,” said coauthor Hans Peter Tony, MD, also from the University of Würzburg. Thomas Dorner, MD, from the University of Berlin, Germany, also collaborated on the research.

The finding may have clinical importance because it might help identify patients who have responded to rituximab but who are on the brink of relapse. About half of RA patients respond to rituximab, but most relapse and require re-treatment. Complete remission lasting >1 year rarely occurs after a single infusion of rituximab. The researchers hoped to find reliable predictors of response or relapse to rituximab. Their data highlight the critical role of memory B-cells in the compromised immune reaction of RA and the short-term gains of rituximab therapy.
 
The B-cell investigation began with an open-label trial of one cycle of rituximab in 17 RA patients?14 women and 3 men. The participants had a median age of 51 years, a median disease duration of 14 years, and a history of failure to respond to disease-modifying drugs and/or anti-TNFα therapy. Sixteen patients received two infusions rituximab 1000 mg each, 2 weeks apart, and one patient received 4 weekly infusions of rituximab 375 mg. Blood samples were obtained at baseline, on day 15, and at a 3-month follow-up and were analyzed for B-cell repopulation.

After one cycle of rituximab, 12 of 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 nonresponder group had a significantly larger IgD +, CD27+ memory B-cell subset. Six of the 12 responders had early relapse of RA activity, between 24 and 40 weeks after drug treatment; they also had had a significantly higher proportion of overall CD27+ memory B-cells before therapy.

Eleven patients were re-treated and again achieved a good clinical response. The pattern of B-cell recovery was similar after the second cycle of rituximab. 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. The researchers note that this indicates an unimpaired capacity of B-cell regeneration after repeated B-cell depletion.

While revealing a potentially important target for rituximab therapy in RA, the study calls for further research into whether patients with a high level of particular memory B-cells might benefit from early re-treatment or might even require higher doses of this anti-CD20 antibody.

Translating research into practice

Daniel E. Furst, MD, the Carl M. Pearson professor of rheumatology at the University of California at Los Angeles, thinks that the discovery could significantly change RA therapy by helping clinicians predict who will not respond to conventional treatment with rituximab and who is at high risk of relapse despite initial response. Dr. Roll and colleagues suggested also that “targeting memory B-cells is a key to [rituximab's] mechanism of action.

“B-cells as a whole in the periphery do not correlate with response, although there is a correlation between B-cells in the tissues and response. That is obviously not something that can be sampled on a routine basis in patient care. With the new highly sensitive B-cell tests, we are now looking at subsets,” Dr. Furst said. “Rituximab is supposed to kill all B-cells but not plasma cells. The cells in this subset are not quite plasma cells yet.”

“This approach is a good idea. A potential way forward would be a larger, prospective study,” he proposed. “This has the potential to identify who will not respond to rituximab, which could be very useful if the predictive ability is high enough. A negative predictive ability of 60% would not be useful, but a negative predictive value of 85% to 90% would change therapy.”
 
Reference

1. Roll P, Dörner T, Tony H-P. Anti-CD20 therapy in patients with rheumatoid arthritis: predictors of response and B-cell subset regeneration after repeated treatment. Arthritis Rheum. 2008;58:1566-1575.