Background. Mitoxantrone (MTX) and Rituximab (RTX) are successfully used for treatment of multiple sclerosis (MS) and can be combined to increase efficacy. Objective. We used MTX, RTX, and methylprednisolone in a single combined regiment and observed patients prospectively. Methods. We present results of observational pilot study of combined therapy of RTX and MTX in 28 patients with active MS. Therapeutic protocol consisted of two infusions within 14 days. First infusion was 1000？mg methylprednisolone (MP) IV, 1000？mg RTX IV, and 20？mg MTX IV. On day 14, 1000？mg MP IV and 1000？mg RTX IV were given. Patients were followed prospectively from 12 to 48 months. Results and Conclusion. There were no relapses among all 28 patients during the observation period. B-cell depletion of CD19+ and CD19+/CD27+ memory B-cell subpopulation in both compartments was confirmed in all patients at 6 months. We found a more rapid reconstitution of B cells in the CSF than in the peripheral blood and longstanding depression of CD19+CD27+ memory B-cell. Conclusion. Effectiveness of combined regimen of RTX and MTX could be related to longstanding depletion of CD19+CD27+ memory B-cell subset. 1. Introduction Multiple sclerosis (MS) is an autoimmune inflammatory disease of the CNS, characterized by focal demyelination, loss of axons, and gliosis that result in neurological symptoms. While our understanding of MS immunopathology continues to improve, the underlying etiology of the disorder remains unclear. The overall efficacy of traditional MS treatments (beta-interferon, glatiramer acetate) is limited, and these drugs are widely accepted to have a relatively small effect on disease activity [1, 2]. More powerful approaches to disease modification in MS include the so-called “biological therapies” or monoclonal antibodies (natalizumab, alemtuzumab, daclizumab, rituximab, and ocrelizumab) and cytotoxic drugs (cladribine and mitoxantrone) [3–6]. The use of these therapies is limited by concerns regarding potential side effects, including an increased risk of infection and a theoretical increase in the lifetime risk of malignancy. It is thought that at least some of these risks increase as the cumulative dose of the drug increases [7]. Clinical trials of the anti-CD20 monoclonal antibody rituximab (RTX) in rheumatoid arthritis, systemic connective tissue diseases, and ANCA-associated vasculitides have reinforced its position as one of the leading potential therapeutic options in a range of autoimmune diseases [3, 8–11]. In MS, CD20+ B cells are rapidly becoming recognized as a valid
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