Therapeutic approaches to secondary progressive multiple sclerosis

characterized by an initial relapsing-remitting (RR) disease course followed by progression with or without occasional relapses, minor remissions and plateaus. SPMS may be seen as a long-term outcome of RR-MS, in that most SP patients initially begin with RR disease as defined here. However, once the baseline between relapses begins to progressively worsen, the patient has switched from RR-MS to SP-MS. Even a single remote initial exacerbation followed many years later by a gradual progressive course falls within this definition. Approximately 50% or more of RR patients will progress to SP. SP-MS patients tend to have greater disability than RR patients and the disability develops from both incomplete recovery from exacerbations (step-wise worsening) as well as gradual progression. In the past, there have been a number of clinical trials of chronic progressive MS. These were done prior to the publication of the disease course denitions listed above. Therefore, they tended to include a mixture of patient types that could potentially obscure a benecial effect of a therapy on a particular disease type. This is most important in considering trials that mix both primary and secondary progressive patients, as the later may be more amenable to therapy than the former. Further, some patients with RR-MS with step-wise worsening might have been included in these trials. The molecular basis for the disability/impairment in SP-MS is not yet known. Either inammatory demyelination or axonal damage could lead to permanent disability. While it is speculated that current therapies affect primarily the inammatory aspects of MS, this is not yet proven. As technology improves, we would hope to be able to target the specic mechanisms underlying the pathophysiologic cause(s) of progressive disease. Most past clinical trials of progressive MS have utilized chemotherapeutic (cytostatic) agents. These all have the disadvantage of producing generalized immunosuppression and have considerable potential systemic toxicity. Further, the toxic and long-term residual effects of these agents tend to limit or preclude long term or repetitive dosing, further restricting their usefulness. More recently, there have been several trials of SP-MS utilizing interferon beta and one recent successful trial of a cytostatic agent. Interferon b-1b: A European multicenter controlled trial of interferon b-1b in SP-MS was reported. This study involved 718 patients with SP-MS treated with either interferon, 8 MIU subcutaneously every other day, or placebo. The study was planned for 3 years, but was stopped after an interim analysis when all patients had completed 2 years because of demonstrated efcacy. The analysis of this study reveals that patients treated with interferon b-1b had signicant delays in progression of disability, as measured by sustained worsening of EDSS. On average this delay amounted to 9–12 months. Similarly, patients receiving interferon b-1b had a delay in time to becoming wheelchair bound of about 9 months, compared to placebo patients. Similar results were seen for relapse rate reduction, MRI analyses, hospitalizations and steroid use. A second study of interferon b-1b, performed in North America has been reported, but not yet published. In this study, SP-MS patients were treated with either placebo, interferon b-1b, 8 MIU every other day or interferon b-1b 5 MIU/m2 every other day (this group had an average dose of 9.6 MIU). As opposed to the European study, in this study there was no effect on the primary outcome assessment of reduction in time to worsening disability, as measured by the EDSS. Other outcome measures, such as reduction in relapse rate, MRI activity and lesion load, favored the treated groups. A European/Canadian study of high doses of interferon b-1a (Rebif) also failed to achieve their primary outcome measure (time to confirmed worsening of EDSS). Other outcome measures such as relapse rate and MRI measures were favorable. These data have not yet been published. The Rebif study and the North American study had patients with similar levels of disability as the European interferon b-1b patients, but the former studies included patients with a lower relapse rate, more relapse free patients in the prior 2 years and less active MRI scans, evidence of less inammatory disease than seen in the European study. However, relapse status prior to and during the study was not a determinant of response in the European interferon b-1b study; both groups responded similarly. At the American Academy of Neurology meeting in Philadelphia, May 2001, the data from the recently completed IMPACT study of interferon b-1a (Avonex) in patients with secondary progressive MS was presented. The study design was multi-center, randomized, placebocontrolled, double blind. Patients received either placebo or IFN b-1a, 60 mcg (a double dose) IM once weekly for 2 years. There were 436 patients enrolled, with EDSS 3.5–6.5 at entry. The mean EDSS at baseline was 5.2, similar to the other IFN secondary progressive studies. Therapeutic approaches to secondary progressive multiple sclerosis