A drug therapy currently used to treat non-Hodgkin’s lymphoma and rheumatoid arthritis had a significant effect in treating the most common form of multiple sclerosis in a small, short-term clinical trial.

Because the drug targets the immune system’s B-cells, rather than the immune system’s traditionally targeted T-cells, the finding provides a new insight into the cause of the relapsing-remitting multiple sclerosis.

The study, published in the New England Journal of Medicine, showed that the drug, Rituximab ( MabThera, Rituxan ), dramatically reduced the number of inflammatory lesions that form along nerve fibers in patients’ brains, the hallmark of the disease. It also significantly decreased the clinical symptom of the disease: sporadic, temporary disruptions in certain neurological functions, such as mobility in a limb or vision in an eye.

“ The magnitude and rapidity of the drug’s effect suggest that therapies targeting B-cells may provide an important treatment strategy if proven effective and safe in larger and longer-term clinical trials,” said the principal investigator of the multi-center study, Stephen L. Hauser, at University of California, San Francisco ( UCSF ). “ These findings shift the perspective on the cause of multiple sclerosis and open up a new frontier for investigation.”

Multiple sclerosis is thought to be an autoimmune disease, a condition in which one or more types of cells of the immune system turn against a tissue of the body.
Multiple sclerosis occurs when the immune system attacks myelin, the protective insulating sheath that surrounds nerve fibers in the central nervous system, leaving scars of hardened sclerotic patches called plaques in multiple places within the brain and spinal cord. Nerve fibers allow the transmission of electrical impulses between the nerve cells and damage to the myelin disrupts this transmission, affecting neurological function.

Since the early 1970s, researchers have focused on the role of T-cells in multiple sclerosis, and all currently available therapies target these cells, some quite successfully. Rituximab targets B-cells, specifically, those with a protein on their surface known as CD20.

Hauser and his team, including Emmanuelle Waubant, proposed the clinical trial based on accumulating evidence by UCSF researchers and a handful of other teams during the last decade that CD20+ B-cells and related pathways played a central role in damaging the myelin sheath.

The trial was conducted at 32 medical centers in the U.S. and Canada, and involved 104 patients, 69 of whom received Rituximab and 35 of whom received a placebo.

The trial focused on patients with relapsing-remitting multiple sclerosis, the most common form of the disease. Patients with this condition have acute flare-ups of inflammation in the myelin sheath that lead to temporary neurological malfunctions. Once the attacks pass ( usually within days or weeks ), patients regain most, if not all of their previous function. However, residual damage ( permanent scarring, loss of myelin, and injury to neurons’ axons that together can result in the progressive loss of neurological function ) remains and accrues with each attack, ultimately leading to a progression of disability.

Participants in the study received one course of Rituximab, intravenously, and were examined regularly with brain scans and clinical evaluations. At the primary endpoint, week 24, those receiving the drug had a 91 percent reduction in inflammatory lesions and a 58 percent reduction in the number of relapses, compared to patients receiving placebo.
Results were comparable at week 48.
Adverse events were comparable between both groups.

While the mechanism by which the rogue CD20+ B cells exact their toll is unknown, their depletion had such a quick impact on the disease that they could not be acting by calling up their key ammunition – antibodies – says Hauser.
B-cells circulating in the blood, probably in conjunction with T-cells, must be driving the inflammation causing the demyelination and scarring in the myelin sheath by some yet to be determined means.

Source: University of California - San Francisco, 2008

XagenaMedicine2008



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