Reason for hope: the advent of disease-modifying therapies in multiple sclerosis.

Technology: Cytokineand antigen-based immunosuppressive therapies for multiple sclerosis. Use: In the last decade partially effective disease-modifying drugs for multiple sclerosis (MS) have finally emerged. All require self-injection and include interferon-β (Betaseron, Avonex and Rebif) and glatiramer acetate (Copaxone). In general, these agents reduce the frequency of MS relapses by onethird and slow progression of disability, at least as shown in relatively short-term (2–3 years) clinical trials. History: MS is the commonest disabling neurologic disorder of young Canadian adults, exacting a heavy toll on patients and their families. Pathophysiologically, inflammatory demyelination and axonal degeneration occur, with attendant neurologic symptoms and signs. Quality of life tends to be lowered, unemployment frequent and the condition chronic, with median survival of about 30 years. The prevalence of MS in Canada is particularly high, estimated at 1 in 1000 to 1 in 500. In 85% of cases patients begin with the relapsingremitting form of the disease, although half of such patients enter the debilitating secondary-progressive phase within 10 to 15 years. Until the interferons appeared, treatment was purely symptomatic and largely empiric. Interferon-β has a wide range of biologic effects that are both immunomodulatory and antiviral. Beta-interferon comes in 2 types: interferon beta-1a (Avonex and Rebif), which is identical to the human protein, and interferon beta-1b (Betaseron), which differs from the human protein by one serine residue. Glatiramer acetate is thought to induce immune tolerance for myelin basic protein, the presumed autoantigen in MS.The decision to try interferon-β in MS patients was largely inspired by their effectiveness in animal MS models. Interferon-β was first administered intrathecally by Jacobs in 1981. There were many subsequent small trials using interferon-β, but not until 1993 was a large appropriately designed multicentre trial involving patients with relapsing-remitting MS completed and published. Further trials of interferon-β in this patient population included the Multiple Sclerosis Clinical Research Group Trial, published in 1996, and the PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study, published in 1998. In late 1998 a mildly positive trial of Betaseron in the treatment of secondary-progressive MS was published, although results from a negative trial of Rebif in the same condition were presented in early 1999. Positive results from a major multicentre trial of glatiramer acetate appeared in 1995. Promise: The advent of these disease-modifying therapies is a boon to patients and their physicians — gone is the therapeutic nihilism of the past. In relapsing-remitting MS, the early phase of the disease, these agents reduce the frequency of relapse and the progression of disability by about one-third (Fig. 1). Interestingly, they show much stronger effects in controlling the progression of disease as seen on brain MRI, particularly at higher doses. The recent Betaseron results in the treatment of the more challenging secondary-progressive form of the disease are also encouraging, although the observed treatment effect of slowing one-fifth of patients from progressing one disability level over 3 years is very modest indeed. For example, a 36-year-old woman with secondaryprogressive MS who walks with a cane has a disability level of 6.0. With treatment for 3 years, her likelihood of progressing to the next disability level of 6.5 (requires 2 canes or a walker) falls from about 50% to 40%. With an observed absolute risk reduction for progression of about 10%, the number needed Reason for hope: the advent of disease-modifying therapies in multiple sclerosis