After Natalizumab: Real-World Study Pits Two B-Cell Drugs Head to Head in Multiple Sclerosis

For thousands of people with multiple sclerosis, the drug natalizumab has been a lifeline, suppressing the relentless immune attacks that mark the disease. But the therapy carries a shadow: a small but serious risk of progressive multifocal leukoencephalopathy, a rare brain infection caused by the JC virus that can be disabling and sometimes fatal. When patients reach an elevated risk of this infection, clinicians face one of the most delicate decisions in modern neurology, namely how to stop natalizumab safely and what to switch to without triggering a dangerous rebound of disease activity. A new retrospective study from one of Europe’s leading multiple sclerosis centers now offers fresh evidence on that question, comparing the two most prominent anti-CD20 therapies as successor treatments.

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