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Introduction: On the basis of the French and British (FB) MS Trial, Mitoxantrone (MITOX) was approved by the AFSAPPS in October 2003 in patients with aggressive multiple sclerosis (MS), given as induction therapy monthly for 6 months (ELSEP). We report an observational study of 100 aggressive relapsing remitting (RR) MS patients treated by induction therapy with MITOX and followed up to 5 years., Methods: One hundred patients with aggressive RR MS received an induction therapy with MITOX 20 mg monthly combined with methylprednisolone 1 g for 6 months. MRI data within 12 months before and 6 months after MITOX induction were collected (mean cumulative dose 65 mg/m2). Clinical evaluation was performed every 6 months and data (relapses and EDSS scores) were prospectively recorded in the EDMUS Database. After MITOX, a maintenance therapy was given to 57 patients (MITOX every 3 months: 21; Interferon beta: 13; Azathioprine: 14; Methotrexate: 7; Glatiramer acetate: 2). The mean follow-up period was of 3.8 years., Results: Patients were treated at a mean age of 27 +/- 9 years after 5 +/- 3 years of MS duration. Within the 12 months preceding MITOX onset, the annual relapse rate (ARR) was 3.2, the mean EDSS increased by 2.2 +/- 1 points (to a score of 4 at M0), 87 patients worsened by 1 point EDSS or more and 85 percent of patients had Gd enhancing lesions on MRI. During the 12 months following MITOX onset, the inflammatory activity of the disease dropped dramatically with a reduction of the ARR by 91 percent whereas 76 percent of patients were free of new relapse and MRI activity was reduced by 89 percent. In addition, the mean EDSS decreased by 1.2 points (p<10-6) and 60 percent of patients improved by 1 point EDSS or more. At a longer term, the reduction of the ARR was confirmed (0.28-0.37 up to 5 years) and the median time to the first relapse was 2.8 years. A significant improvement of disability was maintained until 4 years and got back to the initial level at year 5. The ARR was significantly lower (0.09) for patients treated with MITOX every 3 months as maintenance therapy than for patients treated by other disease modifying therapies (0.33-0.39) or not (0.43) after the induction. Three patients presented an asymptomatic decrease of the left ventricular ejection fraction under 50 percent, reversible in one case., Conclusion: MITOX as induction therapy monthly for 6 months was safe and had a rapid and strong impact on the inflammatory process and on the evolution of disability. The drug might be a good candidate as induction therapy followed by a maintenance therapy in patients with aggressive MS.

Although in previous studies no clear demonstration was found of the efficacy of azathioprine, cyclophosphamide and methotrexate as immunoprophylactic agents in cases of multiple sclerosis (MS), over the past five years a number of well-designed clinical trials utilizing immunosuppressive and immunomodulatory agents have shown partial efficacy regarding the drugs involved, but they have not been able to determine in what way these drugs can modify the natural course of this disease. Among the immunosuppressors, mitoxantrone is of particular interest as during the past two years three controlled trials have taken place in Europe and have demonstrated its efficacy both as regards clinical (frequency of symptoms, progression of the disease) and magnetic resonance imaging (MRI) criteria. Due to its potentially severe cardiotoxicity related to total cumulative dose, mitoxantrone is only prescribed for a limited period, and its use is limited to selected patients with a high relapse rate and incomplete remission, or to those who do not respond to beta-interferon treatment. The immunomodulatory agents have less immediate efficacy, but because they are well tolerated they can be used early in the course of the disease and over a prolonged period of time. The beta-interferons (1a or 1b) have been given market approval for use in the treatment of MS: three large, randomized, double-blind studies have demonstrated their capacity to reduce by 30% the frequency of symptoms and the appearance of disabilities associated with relapse and with the progression of the disease. Glatirameracetate or copolymer 1, which is available in France (ATU), has been found to reduce the frequency of relapse by 30%. It constitutes an alternative immunomodulatory treatment for relapsing-remitting patients without major functional disabilities and who suffer from severe side effects with beta-interferon treatment. In the future, the early use of immunomodulatory agents and therapeutic drug combinations may be introduced. Therapeutic trials are currently in progress to determine the viability of this approach.

Multiple sclerosis is a highly complex disease due to the great diversity of symptoms and signs from disseminated demyelinating CNS lesions which lead to different levels of handicap, and to the different types of evolution (exacerbations or slow progression). Most of the patients with multiple sclerosis have a normal longevity. The main concern is the accumulation of disabilities. In order to follow accurately the progression of these disabilities, specific scales, especially EDSS, have been validated allowing more uniformity in method of collecting data from multiple sclerosis.