The study, published in Annals of Clinical and Translational Neurology, drew on participants from DAYBREAK, a phase 3 open-label extension trial that followed adults with relapsing forms of multiple sclerosis who had previously completed earlier ozanimod trials. Across the parent trials and the extension, participants accumulated up to 117.2 months, nearly a decade, of cumulative exposure to the drug. Of the 2,494 people who entered DAYBREAK, nearly 80 percent completed the study. The researchers focused on 1,679 participants who had at least one day of post-treatment safety follow-up and who did not transition to commercial ozanimod within 14 days of stopping the study drug, creating a window in which any returning disease activity could be observed.

The headline finding is striking in its simplicity: only 55 participants, or 3.3 percent of the analysis population, experienced an objectively confirmed relapse after permanently discontinuing ozanimod. When suspected relapses that failed to meet strict objective criteria were included, the figure rose only slightly, to 4.1 percent. Given that multiple sclerosis is, by its nature, a relapsing disease in these patients, the question the investigators set out to answer was not merely whether relapses occurred, but whether they occurred at a rate and severity beyond what would be expected from the underlying disease simply reasserting itself.

The timing of the relapses tells a story written in pharmacology. Ozanimod works by selectively modulating sphingosine 1-phosphate receptors 1 and 5, trapping lymphocytes inside lymphoid tissues and preventing them from migrating into the central nervous system, where they drive the inflammatory attacks that characterize multiple sclerosis. The drug itself has an elimination half-life of about 21 hours, but its major active metabolite lingers far longer, with a half-life of approximately 11 days. After discontinuation, blood lymphocyte counts return to normal after a median of 30 days, with 80 to 90 percent of patients back in the normal range within three months. True to that pharmacokinetic profile, relapses clustered at two to three months after stopping the drug, with a median onset of 61 days and a range of 3 to 141 days.

The granular breakdown is equally informative. Only five participants, 0.3 percent, relapsed within the first 28 days after discontinuation. Another 22 relapsed between days 29 and 60, representing 1.7 percent of those followed that long, and 26 more relapsed between days 61 and 90, or 2.2 percent of participants with follow-up beyond 60 days. Just two participants relapsed after 90 days, one of whom fell within the protocol’s permitted 10-day follow-up window and the other of whom had been nonadherent to follow-up because of COVID-19 travel restrictions. The pattern mirrors the waning of the drug’s immunological grip rather than any paradoxical overshoot.

Severity is where the rebound question is truly decided, and here the data lean strongly toward reassurance. Nearly all post-treatment relapses were judged mild or moderate by the treating investigators: 20 were mild and 34 were moderate, while only a single participant, 1.8 percent, had a relapse classified as severe. Even that case, the investigators concluded, did not represent higher-than-expected disease activity. The participant, a 44-year-old woman with a heavy pre-treatment disease burden, including 70 T2 lesions on MRI and substantial prior relapse activity, had already experienced a severe relapse while still taking ozanimod roughly a year before the post-treatment episode. Her disability worsened from an Expanded Disability Status Scale score of 7.5 to 8.0, she was not hospitalized, and she achieved partial recovery within 36 days.

Recovery outcomes across the relapsing group were similarly encouraging. Among the 55 participants with confirmed post-treatment relapse, 76.4 percent had completely recovered by their last safety follow-up, 20 percent had partially recovered, and only two participants had not recovered. Median relapse duration was 22 days, and the median increase in EDSS score at relapse was just one point. Four of the seven participants whose EDSS scores rose by two or more points went on to make complete recoveries. Notably, no MRI scans were performed at the time of relapse, and no tumefactive demyelinating lesions, the dramatic, mass-like brain lesions sometimes seen after fingolimod cessation, were ever reported during or after ozanimod treatment in the entire trial program.

The investigators went further, stress-testing their data against definitions of rebound used in earlier studies. Applying the criteria from the fingolimod FREEDOMS trials, where higher-than-expected disease activity rates of 4.0 and 3.5 percent were recorded but were matched by 4.4 and 4.1 percent in placebo groups, 1.4 percent of the ozanimod analysis population met the threshold. Of the 24 participants qualifying, 14 were hospitalized during relapse, but 11 of those hospitalizations occurred in Eastern Europe, where intravenous steroid treatment for relapses is routinely delivered on an inpatient basis regardless of severity, a practice pattern that inflates hospitalization counts compared with settings like the United States. An informal comparison of EDSS changes during relapse against historical data from untreated patients found no statistically significant difference, further supporting the conclusion that these episodes reflect ordinary disease reactivation, not rebound.

Who relapsed matters as much as how many. Participants who experienced post-treatment relapse were younger, diagnosed with multiple sclerosis at a younger age, and carried greater clinical and radiological disease burden, with more gadolinium-enhancing and T2 lesions at baseline and more relapses both during the trials and in the year before discontinuation. A multivariable logistic regression model identified three nominally significant predictors: younger age at diagnosis, a higher number of relapses during the extension trial, and a higher T2 lesion count at parent-trial baseline. This aligns with a consistent theme in the literature, that patients with more active disease before or during treatment face greater risk of relapse after stopping any disease-modifying therapy, and with the well-documented observation that relapse rates in multiple sclerosis peak in the twenties and thirties before declining with age.

The study’s limitations deserve honest acknowledgment. DAYBREAK was not designed to assess post-treatment relapse, the analysis is exploratory and post hoc, and the reported P values are nominal rather than confirmatory. Roughly one-fifth of the overall population lacked safety follow-up and was excluded, though their characteristics resembled those analyzed. About a quarter of the analysis population had fewer than 29 days of follow-up, meaning some relapses may have occurred after observation ended, and the strict requirement for objective neurological worsening may have undercounted milder episodes. The absence of MRI data limits conclusions to clinical activity. Still, the authors’ conclusion stands on a large, systematically assessed dataset: no case showed a pattern suggestive of rebound, and the return of disease activity after stopping ozanimod appears milder and less frequent than that reported after discontinuing natalizumab, where rebound rates of 8 to 22 percent have been reported, or fingolimod, where observational studies have ranged as high as 42.8 percent under varying definitions. For clinicians and patients weighing discontinuation, whether for family planning, side effects, or waning benefit, the message is clear: relapses cluster two to three months after the last dose, are usually mild to moderate, and usually resolve completely, which argues for prompt switching to another therapy and careful monitoring rather than fear of a pharmacological storm.

Subject of Research: Relapse activity and rebound risk after discontinuation of the multiple sclerosis therapy ozanimod in the DAYBREAK open-label extension trial

Article Title: Multiple Sclerosis Relapse Activity After Ozanimod Discontinuation in DAYBREAK Trial Participants

Article References: Gold, R., Selmaj, K. W., Berkovich, R., Cohen, J. A., Comi, G., Havrdová, E. K., Sheffield, J. K., Desai, H., Cheng, C.-Y., Riolo, J. V., Thorpe, A., DeBoer, E., & Cree, B. A. C. (2026). Multiple Sclerosis Relapse Activity After Ozanimod Discontinuation in DAYBREAK Trial Participants. Annals of Clinical and Translational Neurology, 13(10), 2017-2026. https://doi.org/10.1002/acn3.70366

Image Credits: AI Generated

DOI: 10.1002/acn3.70366

Keywords: multiple sclerosis, ozanimod, DAYBREAK trial, rebound, disease-modifying therapy, S1P receptor modulator, relapse, fingolimod, natalizumab, lymphocytes, pharmacokinetics, neurology

The study, published as a letter to the editors in the Journal of Neurology, comes from the Neurology Unit and Multiple Sclerosis Center at IRCCS Ospedale San Raffaele in Milan, with co-first authors Veronica Marino and Lucia Moiola and co-senior authors Simone Guerrieri and Massimo Filippi. The team conducted a retrospective, real-world comparison of patients with multiple sclerosis who discontinued natalizumab and were subsequently switched either to ocrelizumab, an intravenous anti-CD20 monoclonal antibody, or to ofatumumab, a subcutaneously injected antibody of the same class. The work was approved by the institutional ethics committee at San Raffaele and conducted in accordance with the Helsinki Declaration, with patients providing dedicated informed consent for inclusion in the Italian Multiple Sclerosis and Related Disorders Register.

To understand why this comparison matters, it helps to look at the biology. Both ocrelizumab and ofatumumab belong to a class of drugs that target the CD20 molecule, a protein found on the surface of most B cells, the immune cells that are central players in the inflammatory attacks of relapsing multiple sclerosis. By binding CD20, these antibodies deplete circulating B cells, quieting the autoimmune storm. Yet the two drugs are not identical twins. Ocrelizumab is delivered by intravenous infusion every six months and is approved for both relapsing and primary progressive forms of the disease. Ofatumumab is self-injected under the skin once a month and binds a slightly different region of the CD20 molecule, a difference in epitope that influences how the antibody interacts with its target and with the immune system more broadly.

Those pharmacological distinctions translate into different clinical profiles. Ofatumumab’s subcutaneous route produces rapid and sustained B-cell depletion with a more continuous exposure, while ocrelizumab’s intermittent infusions create a pulsatile pattern of depletion and repopulation. Previous research, including pharmacokinetic and pharmacodynamic analyses of the pivotal OPERA and ORATORIO trials for ocrelizumab and the phase 2 APLIOS study of subcutaneous ofatumumab, has documented these characteristics. A recent comparative analysis published in Annals of Neurology in 2025 suggested that treatment outcomes can differ between patients receiving the two agents, adding urgency to the question of which drug is the better landing spot for patients stepping down from natalizumab.

The natalizumab discontinuation problem is well known to specialists. Natalizumab works by blocking the trafficking of immune cells across the blood-brain barrier, and when it is stopped, that barrier traffic resumes, sometimes with a vengeance. Systematic reviews and meta-analyses have documented post-natalizumab disease reactivation, including severe rebound phenomena in which patients experience bursts of new relapses and magnetic resonance imaging activity within weeks to months of the last infusion. Risk factors for reactivation after cessation have been identified in large cohort studies, and the timing of the switch is critical. A prolonged gap between stopping natalizumab and starting the next therapy leaves a window in which the disease can flare, while certain successor drugs, particularly those with slower onset, may not close that window quickly enough.

Against that backdrop, anti-CD20 agents have emerged as favored switch options, because they act on a different arm of the immune response and can maintain disease control across the transition. Several earlier studies, including pilot work on switching to ocrelizumab from natalizumab given at extended interval dosing in patients at high risk of progressive multifocal leukoencephalopathy, have reported favorable outcomes over follow-up periods as long as 96 weeks. But head-to-head real-world data comparing ocrelizumab and ofatumumab specifically in the post-natalizumab setting had been lacking, leaving clinicians to extrapolate from trials that enrolled different populations. The Milan study was designed to fill that gap using the kind of messy, unselected patient data that randomized trials rarely capture.

The retrospective design has both strengths and limits that readers should keep in mind. On the strength side, real-world cohorts reflect the full spectrum of patients seen in clinic, including those with comorbidities, atypical disease courses, and prior treatment histories that trial populations often exclude. The San Raffaele center is one of the largest multiple sclerosis referral hubs in Italy, and its registry-based approach allows researchers to track outcomes such as relapse rates, magnetic resonance imaging activity, and safety events under routine clinical conditions. On the limit side, retrospective comparisons cannot fully control for why clinicians chose one drug over the other, and such selection bias can color the results. The authors acknowledge the inherent constraints of this design, and the findings should be read as hypothesis-generating evidence that complements, rather than replaces, randomized trials.

Safety is a central concern in any switch strategy. Anti-CD20 therapies deplete B cells broadly, and while they have accumulated a substantial safety record since ocrelizumab’s approval, questions remain about infection risk, hypogammaglobulinemia over the long term, and the theoretical concern that B-cell depletion could modulate the immune response to the JC virus itself. The risk stratification for progressive multifocal leukoencephalopathy relies on anti-JC virus antibody testing using second-generation assays such as the STRATIFY JCV DxSelect, which supports clinical decisions about when natalizumab must be abandoned. The Milan team evaluated safety alongside efficacy in both switch groups, providing clinicians with a side-by-side view of how patients tolerate each transition in everyday practice.

The broader significance of the study lies in the evolution of multiple sclerosis treatment. The field has moved decisively toward high-efficacy therapies earlier in the disease course, and natalizumab, once a flagship of that movement, is increasingly managed with extended interval dosing to reduce infection risk before ultimately being withdrawn in patients who accumulate risk factors. As the population of patients needing a post-natalizumab home grows, the choice between intravenous ocrelizumab and subcutaneous ofatumumab becomes a practical fork in the road, influenced by efficacy signals, safety profiles, dosing convenience, patient preference, and health system logistics. Real-world comparisons like this one give neurologists evidence grounded in clinical reality rather than idealized trial conditions.

For patients and clinicians alike, the message from Milan is one of cautious reassurance paired with continued vigilance. Switching from natalizumab to either anti-CD20 agent appears to be a viable strategy for maintaining disease control, but the details of timing, monitoring, and individual risk profiling remain decisive. The study’s data are held at IRCCS Ospedale San Raffaele and are available upon reasonable request to the corresponding author, an approach that supports transparency and further analysis by the research community. As longer follow-up accumulates and more centers contribute their own switch cohorts, the evidence base will mature, helping to convert one of neurology’s trickiest transitions from an act of clinical judgment into an evidence-based protocol.

Subject of Research: Comparison of ocrelizumab and ofatumumab as post-natalizumab switch therapies in multiple sclerosis

Article Title: Ocrelizumab versus ofatumumab efficacy and safety after natalizumab discontinuation in multiple sclerosis: a retrospective real-world comparison

Article References: Marino, V., Moiola, L., Zanetta, C., Rubin, M., Rossi, L., Margoni, M., Nozzolillo, A., Gattuso, I., Viti, V., Petza, E., Rocca, M. A., Guerrieri, S., & Filippi, M. (2026). Ocrelizumab versus ofatumumab efficacy and safety after natalizumab discontinuation in multiple sclerosis: a retrospective real-world comparison. Journal of Neurology, 273(10), Article 577. https://doi.org/10.1007/s00415-026-14124-1

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14124-1

Keywords: multiple sclerosis, natalizumab, ocrelizumab, ofatumumab, anti-CD20 therapy, B-cell depletion, progressive multifocal leukoencephalopathy, JC virus, drug switching, real-world evidence, disease reactivation, neuroimmunology