Multiple Sclerosis: New Therapeutic Concepts or Better Use of Old Drugs?

Multiple Sclerosis: New Therapeutic Concepts or Better Use of Old Drugs? Prof. Michel Clanet, Services de Neurologie, Association pour la Recherche sur la Sclérose en Plaques, CHU Purpan, F-31059 Toulouse Cedex (France) In the last few months new exciting advances have been reported in the treatment of multiple sclerosis (MS): P interferon decreases the rate of exacerbations in relapsing remitting (RR) MS patients [1,2] and oral tolerization with myelin antigens might be an original procedure of treatment which is under investigation [3]. These two examples emphasize the efficacy of a strict methodological approach in the therapeutic trials and the growing knowledge in the fundamental mechanisms of demyelin-ating lesions. Gamma interferon was the first drug used as a therapeutic agent which demonstrated a harmful effect in RR MS patients [4]. After several negative trials with a or (3 natural interferons [5], the recombinant (3 interferon Beta-seron was the first drug which showed an actual therapeutic effect in RR MS patients. Interferons are a heterogeneous group of cytokines. Alpha and beta interferons are produced by macrophages and fibroblasts under viral activation. Their pharmacological properties are similar because they share the same receptor. Gamma interferon is secreted by activated lymphocytes as an enhancing factor of the immune responses [6]. Experimentally beta interferon suppresses the synthesis of gamma interferon and activates some subpopulations of lymphocytes which down-regulate the immune responses. From June 1988 to May 1990, 372 patients with RR MS of a disease duration less than 5 years were randomized into three groups: group 1 (123 patients) was treated with placebo, group 2 (125 patients) and group 3 (124 patients) were treated with Betaseron, 1.6 and 8 MIU, respectively. Placebo and Betaseron were administered subcutaneously every 2 days. After 2 years the two major end points were significantly different between patients treated with Betaseron compared to placebo controls: annual exacerbation rates were lower and more patients on high-dose Betaseron were exacerbation-free. However there was no difference in the disability scores after 2 years, only a tendency to be less severe in the high-dose group after 3 years. MRI scans of the brain of patients showed significant reduction in disease activity in the highdose group, measured by total lesion area or appearance of new lesions. The treatment was well tolerated: major side effects, more frequently observed in the high-dose group, a flu-like syndrome and inflammation at the injection site, decreased after 3 months. The general impression given by these results is a great consistency: beta interferon reduces the activity of the disease without suppressing its evolutivity. Two findings must be outlined. Firstly, in the low-dose group, the therapeutic results were intermediate between placebo and the high-dose group, but the local inflammation at the injection site was identical in the highand low-dose groups: the beneficial effect appears to be dose-dependent and not related to any placebo effect. Secondly, this is the first trial in which the monitoring of the disease activity by MRI strengthens the clinical data. This monitoring must be included in future therapeutic trials. However reducing the disease activity on MRI cannot yet be considered as a major end point because of the uncertainty about its clinical significance [7]. The main problem raised is the inefficacy of Betaseron to modify the disability score: either follow-up duration can be too short to observe any modification or disability © 1993 S. Karger AG, Basel