Rituximab May Be Effective in Relapsing Multiple Sclerosis
Abstract & Commentary
By Brian R. Apatoff, MD, PhD, Department of Neurology and Neuroscience, NewYork- Presbyterian Hospital, Cornell Campus Dr. Apatoff reports that he is on the speaker's bureau for Biogen Idec, Serono-Pfizer, and Teva Pharmaceuticals.
Synopsis: This phase II placebo-controlled trial showed a dramatic benefit from rituximab in preventing clinical relapses, as well as new MRI lesions, in patients with multiple sclerosis (MS).
Source: Hauser SL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008; 358:676-688.
This phase II, double-blind, placebo-controlled, 48-week trial enrolled 104 patients with relapsing-remitting multiple sclerosis (RRMS). Of these, 69 patients received IV rituximab 1000 mg on days 1 and 15, and 35 patients received placebo. The groups had an average disease duration of 6 years, median annualized relapse rate of 1, and a median EDSS (Expanded Disability Status Scale) of 2.5. More than three-fourths had been on prior immunotherapy with interferon-beta, glatiramer, or natalizumab. The primary end point was the total number of gadolinium-enhancing lesions on brain MRIs at weeks 12, 16, 20, and 24. Secondary clinical outcome measures were the proportion of relapses and annualized relapse rate.
The number of total and new gadolinium-enhancing lesions was significantly reduced at week 24 by 91% in the rituximab group compared to placebo controls (p<0.001). The proportion of patients with relapses was reduced by over 50% at week 24 (14.5% vs. 34.3%, p=0.02) and week 48 (20.3% vs. 40.0%, p=0.04). Examining safety measures, 50 patients (92.6%) of rituximab-treated patients had mild to moderate infusion-associated adverse events, and 4 patients (7.4%) reported severe infusion reactions, which included headache, back pain, limb pain, pruritus, and rash. At week 48, 16 patients (24.6%) tested positive for human antichimeric antibodies against rituximab.
Commentary
Rituximab is a human-mouse chimeric monoclonal antibody against CD20, a cell surface protein expressed on B-cells (but not on mature antibody secreting plasma cells), and was the first monoclonal antibody to be FDA-approved for the treatment of malignancy in non-Hodgkin B-cell lymphoma. Rituximab also has been used in treatment of refractory rheumatoid arthritis and systemic lupus erythematosus.
MS is an inflammatory, demyelinating pathology of the central nervous system that is thought to be largely T-cell mediated. Thus, the significant reduction in MRI activity and clinical relapses by selective B-cell depletion with rituximab was surprising, and provides evidence of an important role of B-cells in disease pathogenesis. Since reduction of MS disease activity occurs within 4 weeks of rituximab treatment, it does not appear to correlate with the slow reduction of serum antibody levels. The primary mechanism of action may relate to effects on the memory pre-B cells, interfering with antigen presentation to T-cells, or reduction in pro-inflammatory B-cell cytokines.
A significant obstacle for rituximab, however, in the treatment of a chronic condition like MS, is the frequency of severe infusion reactions. Another major concern is that 1 in every 4 patients developed antichimeric antibodies after only two infusions of rituximab, which would certainly reduce effective retreatment after 48 weeks. The testing of a fully humanized version of rituximab now developed may prove to be a less immunogenic monoclonal antibody for more optimal long-term disease management.
Overall, there were significant reductions in contrast-enhancing lesions and clinical relapses in the rituximab-treated patients compared to placebo controls. The relative long-term safety and efficacy of this selective immune intervention, especially compared to other monoclonal antibody therapies such as natalizumab and daclizumab, remain to be defined in a larger phase III trial. Other clinical trials investigating the use of rituximab in demyelinating disease are ongoing, including a phase III trial in 435 patients with primary-progressive MS and a smaller study in neuromyelitis optica.
This phase II placebo-controlled trial showed a dramatic benefit from rituximab in preventing clinical relapses, as well as new MRI lesions, in patients with multiple sclerosis (MS).You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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