Natalizumab (
NAT) was the first
monoclonal antibody to be approved for the treatment of
relapsing-remitting multiple sclerosis (RRMS). While pivotal and postmarketing studies have showed considerable and sustained efficacy of
NAT in RRMS, the increasing incidence of
therapy-associated
progressive multifocal leukoencephalopathy (PML), a brain
infection caused by the John Cunningham virus (JCV), is a risk associated with long-term
therapy. The risk for
therapy-associated PML is highest in so-called "triple risk" patients. Therefore, long-term
NAT-treated, immunosuppressive-pretreated, and JCV antibody-positive patients often discontinue
NAT therapy. However, until now, it is not known which treatment strategy should be followed after
NAT cessation. Since disease activity returns to pretreatment levels, or even above, within 4-7 months from the last infusion of
NAT, patients who stop
NAT are at considerable risk of relapse and worsening of
multiple sclerosis (MS)-related disability. Several strategies have been applied to prevent the recurrence of disease activity after discontinuation of
NAT. Of these, bridging with intravenous
methylprednisolone, and switching to
glatiramer acetate or
interferon beta (IFN-beta) do not seem to be effective enough. More promising results have been obtained in retrospective studies and case series with
fingolimod (FTY), an alternative escalation
therapy for RRMS, although some patients have showed a severe disease rebound after starting FTY treatment. The time interval between the discontinuation of
NAT and the start of FTY might affect the recurrence of disease activity. Long-term data about the efficacy and safety of FTY treatment after cessation of
NAT are urgently needed and should be further investigated. Prospective studies are warranted, to optimize treatment strategies for RRMS patients who discontinue
NAT, especially because new
therapies will be available in the very near future.