B-cell depletion with rituximab in relapsing-remitting multiple sclerosis.
BACKGROUND
There is increasing evidence that B lymphocytes are involved in the pathogenesis of multiple sclerosis, and they may be a therapeutic target. Rituximab, a monoclonal antibody, selectively targets and depletes CD20+ B lymphocytes.


METHODS
In a phase 2, double-blind, 48-week trial involving 104 patients with relapsing-remitting multiple sclerosis, we assigned 69 patients to receive 1000 mg of intravenous rituximab and 35 patients to receive placebo on days 1 and 15. The primary end point was the total count of gadolinium-enhancing lesions detected on magnetic resonance imaging scans of the brain at weeks 12, 16, 20, and 24. Clinical outcomes included safety, the proportion of patients who had relapses, and the annualized rate of relapse.


RESULTS
As compared with patients who received placebo, patients who received rituximab had reduced counts of total gadolinium-enhancing lesions at weeks 12, 16, 20, and 24 (P<0.001) and of total new gadolinium-enhancing lesions over the same period (P<0.001); these results were sustained for 48 weeks (P<0.001). As compared with patients in the placebo group, the proportion of patients in the rituximab group with relapses was significantly reduced at week 24 (14.5% vs. 34.3%, P=0.02) and week 48 (20.3% vs. 40.0%, P=0.04). More patients in the rituximab group than in the placebo group had adverse events within 24 hours after the first infusion, most of which were mild-to-moderate events; after the second infusion, the numbers of events were similar in the two groups.


CONCLUSIONS
A single course of rituximab reduced inflammatory brain lesions and clinical relapses for 48 weeks. This trial was not designed to assess long-term safety or to detect uncommon adverse events. The data provide evidence of B-cell involvement in the pathophysiology of relapsing-remitting multiple sclerosis. (ClinicalTrials.gov number, NCT00097188 [ClinicalTrials.gov].).
Hauser
Stephen L
SL
Department of Neurology, University of California at San Francisco, San Francisco, CA 94143-0114, USA. hausers@neurology.ucsf.edu
Waubant
Emmanuelle
E
Arnold
Douglas L
DL
Vollmer
Timothy
T
Antel
Jack
J
Fox
Robert J
RJ
Bar-Or
Amit
A
Panzara
Michael
M
Sarkar
Neena
N
Agarwal
Sunil
S
Langer-Gould
Annette
A
Smith
Craig H
CH
D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D001921:Brain / Q000473:pathology; D004311:Double-Blind Method; D005260:Female; D005682:Gadolinium; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D007155:Immunologic Factors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D012074:Remission Induction; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D007136:Immunoglobulins; D007155:Immunologic Factors; D000069283:Rituximab; D005682:Gadolinium