With more choices for multiple sclerosis (MS) disease-modifying therapies, data are urgently required to support clinical decisions regarding safe transitioning and sequencing of therapies. With more than 7 years of clinical experience, natalizumab has been confirmed as highly effective in reducing MS disease activity. However, natalizumab carries a risk of progressive multifocal leukoencephalopathy (PML),(1) with more than 400 cases of natalizumab-related PML to date.(2) Because 2 of the 3 initial natalizumab-associated PML cases were on the combination natalizumab plus interferon, the concern was that combining agents led to a heightened risk of infectious complications. In these early times, uncertainty revolved around 2 points: the theoretical risk of PML if natalizumab was transiently combined with another immune-altering agent and the value of transiently "reconstituting" CNS immune surveillance by washout of natalizumab in an effort to clear theoretical subclinical JC virus within the CNS.(3) The optimal length of natalizumab washout became the subject of intense consternation and debate, with no clear guidelines to inform practice. However, upon withdrawing natalizumab, resumption of disease activity was soon observed, beginning 3-4 months after the last dose of natalizumab.(4-10) Postnatalizumab return of disease raised concern that the washout may harm the patient by a severe relapse with incomplete recovery.