Top 5 Most-Read Multiple Sclerosis Articles of 2025

The past year brought forth critical developments in multiple sclerosis (MS) research, focusing heavily on optimizing current treatments and advancing novel mechanisms to address the progressive forms of the disease. From definitive data confirming the optimal dose of a leading therapy to the revolutionary understanding of the Epstein-Barr virus (EBV) as a necessary trigger for MS, researchers and clinicians are rapidly reshaping the MS treatment landscape.

MS is a chronic, immune-mediated condition of the central nervous system that permanently damages the protective myelin covering of nerves, primarily affecting the brain, spinal cord, and optic nerves. Although more than 20 FDA-approved disease-modifying therapies (DMTs) are currently available, significant research continues into treatments for progressive disease forms and potential preventive strategies.

These are the top 5 MS articles covering critical advances and clinical insights.

5. 5 Ongoing Clinical Trials Evaluating Treatment for MS

Researchers are actively investigating numerous therapeutic agents for multiple sclerosis, aiming to enhance the management and understanding of the chronic condition. A search of active trials revealed 28 ongoing clinical trials investigating DMTs such as ocrelizumab, fingolimod, and ublituximab. Five notable trials currently underway highlight key areas of focus:

1. Tolebrutinib (NCT04742400): This phase 2 trial is investigating the Bruton tyrosine kinase (BTK) inhibitor in adult patients already on anti-CD20 therapy, with the primary goal of assessing its effectiveness in ameliorating chronically inflamed white matter lesions. Its estimated completion date is December 31, 2025.
2. Fingolimod (NCT01892722): This phase 3, multicenter, randomized trial is comparing the safety and efficacy of daily oral fingolimod vs weekly intramuscular interferon β-1a in pediatric patients aged 10 to 17 years. This trial, which includes a 5-year extension phase, is estimated to be completed by February 26, 2030.
3. Ocrelizumab (NCT04377555): This phase 4, open-label, single-arm study focuses on Black or African American and Hispanic/Latino patients with relapsing MS, who are either treatment-naïve or switching from certain DMTs. The study aims to assess disease activity and biomarkers and is estimated to be complete in December 2025.
4. Ublituximab (NCT04130997): An open-label extension of the ULTIMATE I and II trials, this phase 3 study is evaluating the long-term safety and efficacy of the monoclonal antibody ublituximab in adults with relapsing MS. The primary outcome is annualized relapse rate, with an estimated completion date of February 1, 2030.
5. Fenebrutinib (NCT04544449): The phase 3 FENtrepid trial is evaluating the oral BTK inhibitor fenebrutinib for efficacy and safety against an ocrelizumab-matching placebo in adult patients with primary progressive MS. This trial, which focuses on the time to onset of 12-week confirmed disability progression, is estimated to be completed on December 18, 2026.

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4. Higher-Dose Ocrelizumab Shows No Added Benefit vs Approved Dose in MS

The intravenous (IV) formulation of ocrelizumab (Ocrevus; Genentech), a B-cell therapy approved for relapsing MS (RMS) and primary progressive MS (PPMS), is the most-prescribed disease-modifying therapy in the US, having treated more than 400,000 people globally. Recent findings from the phase 3 MUSETTE trial (NCT04544436) confirmed the optimal dosing strategy for this established treatment.

The MUSETTE trial investigated whether administering a higher dose of IV ocrelizumab—specifically 1200 mg or 1800 mg, depending on patient weight—would provide additional benefit compared to the currently approved 600 mg dose in patients with RMS. The trial failed to meet its primary end point, which was demonstrating added benefits in slowing disability progression.

Results demonstrated that rates of disability progression were low and consistent with the established efficacy seen in pivotal studies of the standard 600-mg dose. The study reinforced that the current 600-mg dose of IV ocrelizumab is optimal for significantly slowing disability progression in RMS. Furthermore, the higher dose was well-tolerated and showed no new safety signals compared with the standard dose, supporting the strong safety and efficacy profile of ocrelizumab.

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3. Real-World Discontinuations of Ocrelizumab in MS Comparable to Pivotal Trials

A systematic review of real-world data provided reassuring evidence about patient adherence to ocrelizumab, suggesting that discontinuation rates remain low and are similar to those observed in pivotal clinical trials. The analysis included 30 studies and found that discontinuation rates ranged from 3.2% to 4.1% for patients with relapsing-remitting MS (RRMS) and PPMS.

This stability in persistence suggests high tolerability outside of controlled clinical environments. The most frequent reason reported for discontinuing treatment was side effects (noted in 11 studies), followed by concerns regarding efficacy (8 studies) and pregnancy or family planning (6 studies). Discontinuation typically occurred after a median of 0.6 to 1.8 years in studies that reported median time to discontinuation.

In comparisons with other disease-modifying therapies (DMTs), ocrelizumab generally yielded higher adherence and lower discontinuations compared with other oral, injectable, and intravenous treatments. Although one study noted that significantly more patients discontinued ocrelizumab than rituximab due to side effects, the overall first-year discontinuation rates between the 2 treatments were not statistically different. The consistency between real-world use and clinical trial data reinforces ocrelizumab’s role as a cornerstone therapy for MS.

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2. Emerging MS Treatments Offer New Hope for Progressive Disease

Current MS therapies have significantly improved outcomes for relapsing forms, but the progressive forms of the disease remain challenging to treat. A comprehensive review of emerging therapies highlights innovative strategies focused on myelin repair, neuroprotection, and targeting central nervous system (CNS)–resident immune cells, moving beyond traditional immunomodulation.

One of the most promising classes of drugs is Bruton tyrosine kinase inhibitors (BTKis). Tolebrutinib, a BTKi capable of crossing the blood-brain barrier, showed a substantial effect in slowing confirmed disability progression in individuals with nonrelapsing secondary progressive MS. BTKis are believed to act on B cells, macrophages, and microglia within the CNS, suggesting a mechanism that addresses progression independent of relapses. Other BTKis, such as fenebrutinib and remibrutinib, are also showing potential in limiting lesion activity.

Beyond BTKis, research is advancing remyelination and neuroprotective strategies, including investigating compounds like clemastine fumarate and metformin, which are being studied in combination to stimulate myelin repair. Cell therapies are also being explored; autologous hematopoietic stem cell transplantation shows promise for inducing remission in relapsing MS by resetting the immune system, and mesenchymal stem cells are being investigated for their regenerative capabilities. These efforts signify hope that the next generation of treatments may finally slow or halt disease progression and restore neurological function.

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1. Future Therapies Targeting Epstein-Barr Virus Could Help Combat MS

A growing body of evidence strongly links the EBV, a common herpesvirus that causes mononucleosis, to multiple sclerosis, suggesting that EBV acts as a necessary trigger for the disease. Epidemiological studies show that people who have never been infected with EBV have a near-zero risk of developing MS.

A recent review built a compelling argument for prioritizing therapeutic strategies that directly target EBV to treat or prevent MS. The review supports the "driver hypothesis," which suggests that ongoing EBV replication and cycles of latent and lytic infection continuously expose the immune system to viral antigens, thereby fueling the inflammatory disease activity seen in MS.

Further supporting this targeted approach is the observation that HIV-positive individuals who received highly active antiretroviral therapy (HAART) demonstrated a lower risk of developing MS, potentially because some antivirals in HAART are effective against EBV. Consequently, researchers are calling for a new effort in drug development focused on EBV. Proposed strategies include CNS-penetrant small molecule antiviral agents, therapeutic EBV vaccines, and higher-dose B-cell depleting therapies to target B-cells in the CNS. The authors recommend future large-scale, long-term studies to monitor EBV-negative individuals to uncover the exact mechanisms by which EBV triggers MS and autoimmunity.

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