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Contrast that with the use of teriflunomide, both an immunomodulator and mild cell-depleting agent, together with IFN- , a combination shown to be both safe and synergistic.Reference Freedman, Wolinsky and Wamil 29 However, if the mechanism of action of an agent like GA is to produce regulatory cells that need to reach the CNS in order to work, then concomitant use of an anti-trafficking drug might counteract that ability.Reference Farina, Weber, Meinl, Wekerle and Hohlfeld 30 - Reference Lalive, Neuhaus and Benkhoucha 32 On the other hand, based on their unique mechanisms of action, one could speculate that fingolimod followed by GA might be an ideal sequence. Fingolimod might act first to round up all disease-causing cells and sequester them in lymph nodes,Reference Cohen and Chun 33 , Reference Chun and Hartung 34 where GA has its greatest action and shifts T cells from a mostly pro-inflammatory T helper (Th) 1 pattern of cytokine secretion to a mostly anti-inflammatory Th2 pattern.Reference Comi, Amato and Bertolotto 35 Induction Therapies: Cell-Depleting Agents and their Impact on Sequential Therapeutic Approaches Induction therapy refers to the use of powerful cell-depleting therapy capable of eliminating disease-causing autoimmune cells up front in patients presenting with early active aggressive disease(~10 % of MS patients).Reference Lazibat, Nevajda, Grahovac and Brinar 36 Evidence from experimental models of MS and other immune-mediated diseases suggests that this type of approach might reset the immune system to prevent epitope spreading and control inflammatory disease activity more effectively than immunomodulation, thus preventing early structural damage, controlling disease progression, and preserving brain function.Reference Cornaby, Gibbons and Mayhew 37 However, the duration of the induction treatment is often limited by specific toxicity and by cumulative doses.Reference Morrissey, Le Page and Edan 38 Serious side effects related to potent immunosuppressants such as mitoxantrone and cyclophosphamide are dose related, which is often a limiting factor.Reference Morrissey, Le Page and Edan 38 In the case of mitoxantrone, the risk of cardiotoxicity appears proportional to the total lifetime cumulative dose and it is increased in patients with a history of cardiac disease

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