Dimethyl fumarate (DMF) is among the over 20 disease-modifying therapies (DMTs) approved for treatment of multiple sclerosis (MS) by Health Canada. Lymphopenia is a well-known side effect of DMF ^{Reference Longbrake, Naismith, Parks, Wu and Cross1} with absolute lymphocyte count (ALC) below 0.5 x 10⁹/L for six months or longer typically prompting a switch to a different DMT due to concerns about infection risk, the most concerning being progressive multifocal leukoencephalopathy. ^{Reference Jordan, Yang, Fisher, Racke and Mao-Draayer2} When switching from DMF to another DMT, the question arises of whether a washout period is needed, weighing out the risks of insufficient time for ALC reconstitution versus development of new disease activity with a prolonged washout period.

In this issue, Zubkow et al. aimed to answer important questions of whether a washout period is needed when switching off DMF to another DMT, and if a washout period is pursued, what the optimal timing of this is to prevent new disease activity. ^{Reference Zubkow, Kim and Kahovec3} This single-center retrospective cohort study from the Saskatoon MS Clinic included 109 persons with MS (pwMS) who had discontinued DMF due to lack of efficacy, adverse events, lymphopenia or family planning. ^{Reference Zubkow, Kim and Kahovec3}

After DMF discontinuation, 35 pwMS had new clinical and/or MRI disease activity: 14 with clinical relapses, 11 with MRI activity and 10 with both clinical relapse and MRI activity. ^{Reference Zubkow, Kim and Kahovec3} For those experiencing a clinical relapse between stopping DMF and starting a different DMT, the median time to relapse was six months with half having a relapse within the first six months off DMF. ^{Reference Zubkow, Kim and Kahovec3} They did not find any association between ALC at the time of DMF discontinuation or the interval between DMF discontinuation and starting a new DMT and subsequent disease activity, with only 10 of 35 pwMS with new disease activity having lymphopenia. ^{Reference Zubkow, Kim and Kahovec3} Interestingly, others have shown that those discontinuing DMF specifically due to lymphopenia will have ALC reconstitution within 2–4 months after discontinuing DMF, ^{Reference Chan, Rose and Alvarez4,Reference de Seze, Labauge and Liblau5} leading one to wonder if after ALC reconstitution there is an increased risk of disease activity, which could align with a study demonstrating less new MRI activity in those with lymphopenia on DMF. ^{Reference Chu, Balusha, Casserly, Berger and Morrow6} However, this would be less relevant for the Zubkow et al. study, with most developing new disease activity not having lymphopenia at the time of DMF discontinuation.

Overall, this study by Zubkow et al. provides valuable guidance to start a different DMT within six months of discontinuing DMF, regardless of the presence of lymphopenia, to avoid development of new disease activity in pwMS. ^{Reference Zubkow, Kim and Kahovec3}