Several in vivo and in vitro studies showed that mitoxantrone (MTX), a novel anthracendione antineoplastic agent, had an immunomodulatory effect that suppressed humoral immunity, reduced T-cell numbers, lessened helper activity, enhanced suppressor function and had some positive effect on acute and chronic experimental allergic encephalomyelitis in rats. Up to now, several trials of therapy with MTX have been performed in patients with multiple sclerosis (MS). MTX has been recently shown to reduce disease activity, as expressed by reducing relapse rate and decreasing new, active MRI lesions, in a selected group of patients with active relapsing-remitting (RR) MS. Furthermore, more recently, it has been demonstrated that MTX reduce neurological disability in secondary progressive MS. We designed the open-label clinical trial involving 35 MS patients with active disease in order to evaluate the long-term clinical effects of 6-months MTX treatment during a follow-up period of 20-46 months (mean, 30 months). The study comprised 35 patients, who met the Poser criteria for clinically definite MS. All patients were clinically treated at the Institute of Neurology, Clinical Centre of Serbia, Belgrade, during the period from March 1996 to August 2000. The neurological disability state was evaluated at the entry, every month until completion of the therapy and every six months until August 2000, by means of Kurtzke Expanded Disability Status Scale (EDSS) score. All patients had active MS. The criteria for disease activity were: 1) at least 2 relapses within the previous 2 years, or 2) progression of at least 1.0 point on EDSS scale during the same period. The included patients did not receive immunosuppressive therapy six months prior to the entry. The patients were assigned to receive MTX 20 mg intravenously (iv) per month and methylprednisolone 1g iv per month, over six months. The clinical characteristics and demographic data of patients included in the study were shown in table 1. The parameters monitored during the trial were shown in table 2. Clinical assessment showed a significant improvement of the final mean EDSS score after 6 months of the therapy as compared to the value at entry in the total MS group (p=0.00001). Although EDSS value showed an increasing tendency during the follow-up period (20-46 months), the mean EDSS value was still significantly lower at the end of the follow-up comparing to the value at entry (p=0.013) (Figure 1). Overall, MTX was well tolerated and only minor side effects occurred. Cardiotoxicity was not registered. Our findings further support the notion that mitoxantrone reduces neurological disability in active relapsing and secondary progressive multiple sclerosis patients. However, follow-up suggests that this effect slowly subsides after discontinuation of therapy, implying the need for prolongation of such treatment (up to 120 mg/m2) for a period as long as possible.
