Treatment That Targets the Root Cause of Multiple Sclerosis

What new therapies for multiple sclerosis are on the horizon?

Young adults are usually not considered to be susceptible to debilitating neurological disease, unless of course the brain injury is incurred as a result of trauma. However, the second leading cause of neurological pathology in this age group is multiple sclerosis (MS). About 400,000 persons in the United States have this disease; in one-third of these patients, a fully progressive form of MS develops, eventuating in severe disability. A substantial number of these patients are young adults.

THE CURRENT MS ARMAMENTARIUM
Previous advances in the treatment of MS have been made by targeting CD4 helper cells. In fact, 2 agents that were developed as a result of the CD4 theory-interferon beta and glatiramer acetate-reduce the relapse rate in patients with MS. Unfortunately, neither agent alone or in combination completely prevents recurrences or irreversible injury to myelin.

A more recent addition to the MS treatment armamentarium, natalizumab, is an antibody to a lymphocyte receptor, a4-integrin, that prevents the movement of inflammatory, myelin-destroying cells past the blood-brain barrier. However, despite treatment with this agent, MS can still progress and cause serious disability. Is it time for a shift in the MS disease paradigm and as a result in the treatment program?

B CELLS: A NEW TREATMENT TARGET
For years, spinal fluid obtained in the diagnostic workup of MS has been sent for measurement of oligoclonal bands. The bands are antibodies that are produced locally by B cells in the CNS. These B cells secrete antibodies that irreversibly damage the myelin of patients with MS; in addition, the B cells can present myelin antigen to T cells, thereby stimulating their inflammatory response. An antibody against CD20 B cells called rituximab has already been used to successfully treat diverse diseases including B-cell lymphomas, immune thrombocytopenic purpura, and hairy cell leukemia. Investigators recently completed a promising phase 2 trial with rituximab as a treatment for MS.^1,2 Sixty-nine patients with relapsing-remitting MS received rituximab (1 dose) and 35 others received placebo. Both groups were monitored by MRI with gadolinium to detect the development of the "enhancing" lesions of MS over a 48-week period. Compared with patients who received placebo, the rituximab group had fewer enhancing lesions caused by MS at 12, 16, 20, and 24 weeks. The results were sustained for the 48 weeks of follow-up.

Since this was a phase 2 trial, no one knows how long the effect of rituximab will persist after 48 weeks. However, an important door to discovery has been opened. The data suggest that B cells are important contributors to the damage done in patients with MS. Rituximab may be the first of many anti B-cell agents that target the cells that directly cause the disability and inflammation of MS.

 

References:

REFERENCES:

1. Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing remitting multiple sclerosis. N Engl J Med. 2008;358:676-688.
2. McFarland HF. The B-cell-old player, new position on the team. N Engl J Med. 2008;358:664-665.