Natalizumab (NAT), a specific a4-integrin antagonist blocking lymphocytes transmigration across the blood–brain barrier, is a second-line treatment of active relapsing-remitting (RR) multiple sclerosis (MS). The benefit of reduction in relapse rate, disability progression and Magnetic Resonance Imaging (MRI) lesions load has to be weighed against the risks of adverse events [
1]. Which is mainly related to the rare but serious progressive multifocal leukoencephalopathy (PML); longer treatment duration increases the risk of this adverse event [
2,
3]. After NAT discontinuation, MRI and clinical disease activity gradually return to the pre-treatment levels [
2], sometimes even a rebound with a flare-up to a level beyond the pre-NAT treatment level was reported [
4‐
6]. There are no available randomized controlled trials or established guidelines on “what to do after NAT therapy”. The RESTORE study showed that disease activity began 12-weeks after NAT-discontinuation and occurred regardless of following “drug holiday”, “bridge” therapy or “switch” to an alternative treatment with either glatimarer acetate or interferons [
7]. On the contrary, those who continued NAT did not show MRI evidence of new disease activity, suggesting that only NAT can stop the rebound due to NAT-interruption. However, in that study [
7], new switching options which are available either currently or in the near future, such as fingolimod, dimethyl-fumarate (DMF), teriflunomide and alemtuzumab were not included. Furthermore, other observational studies were conducted to investigate the effect of fingolimod in preventing disease reactivation after NAT discontinuation [
8‐
12]. Among them, five studies showed clearly that early initiation of fingolimod (less than 2 or 3 months after discontinuing NAT) decreases the probability of disease re-activation [
8,
10‐
13], highlighting the importance of an early treatment after NAT withdrawal. Iaffaldano et al. showed a superiority of fingolimod in comparison to interferon beta/glatiramer acetate in controlling disease reactivation after NAT discontinuation in a large sample of real life setting [
13]. Preliminary evidences showed both positive [
14,
15], and negative effect of DMF on minimizing disease activity in persons with MS switching from NAT [
16].
To summarize, data about MS rebound occurrences in patients treated with DMF after NAT-discontinuation are not available in literature.