Approximately 50% diagnosed with relapsing-remitting multiple sclerosis (RRMS) transition to secondary progressive multiple sclerosis (SPMS) within 20 years following disease onset. However, early diagnosis of SPMS and effective treatment remain important clinical challenges. The lack of established diagnostic criteria often leads to delays in identifying SPMS. Also, there are limited disease-modifying therapies (DMTs) available for progressive forms of MS, and these therapies require evidence of disease activity to be initiated. This review examines the challenges in diagnosing SPMS at an early stage and summarizes the current and potential use of biomarkers of disease progression in clinical practice. We also discuss the difficulties in initiating the DMTs indicated for active SPMS (aSPMS), particularly in patients already undergoing treatment with DMTs that suppress disease activity, which may mask the presence of inflammatory activity required for the therapy switch. The article also addresses the DMTs available for both active and non-active SPMS, along with the clinical trials that supported the approval of DMTs indicated for aSPMS or relapsing MS in Europe, which includes aSPMS. We also offer insights on when discontinuing these treatments may be appropriate.

To estimate the socioeconomic burden of people with secondary progressive multiple sclerosis (pwSPMS), considering direct health care, direct non-health care, and indirect costs, and to evaluate the relationship between costs and patients’ functional outcomes. Observational, cross-sectional, multicenter study with retrospective real-life clinical practice data collection from pwSPMS visiting the neurology services of 34 hospitals during 2019–2020. Clinical data included Expanded Disability Status Scale scores, number of relapses, magnetic resonance imaging, disease-modifying treatment (DMT), symptoms, and comorbidities from 24 months before the study visit. Resource use and allied costs were collected 12 months before the study visit. Patient-reported outcomes, functional and cognitive scales were also collected. 70

The development of disease-modifying therapies (DMTs) for the treatment of multiple sclerosis (MS) has been highly successful in recent decades. It is now widely accepted that early initiation of DMTs after disease onset is associated with a better long-term prognosis. However, the question of when and how to de-escalate or discontinue DMTs remains open and critical. This topic was discussed during an international focused workshop organized by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in 2023. The aim was to review the current evidence on the rationale for, and the potential pitfalls of, treatment de-escalation in MS. Several clinical scenarios emerged, mainly driven by a change in the benefit-risk ratio of DMTs over the course of the disease and with ageing. The workshop also addressed the issue of de-escalation by the type of DMT used and in specific situations, including pregnancy and paediatric onset MS. Finally, we provide practical guidelines for selecting appropriate patients, defining de-escalation and monitoring modalities and outlining unmet needs in this field.

Ofatumumab demonstrated superior efficacy and similar safety versus teriflunomide in ASCLEPIOS I/II in people with relapsing multiple sclerosis; no new safety concerns and sustained efficacy were observed up to 4 years in the open-label extension study ALITHIOS. Here, we further characterise the safety and efficacy of ofatumumab up to 5 years by discussing infection outcomes in the COVID-19 era and providing a comprehensive overview of participant disability outcomes. Safety (N = 1969; participants who received ≥ 1 dose of ofatumumab in ASCLEPIOS I/II, APLIOS, APOLITOS, or ALITHIOS) and efficacy sets (N = 1882; participants randomised to ofatumumab [OMB-OMB] or teriflunomide [TER-OMB] in ASCLEPIOS I/II, regardless of whether they entered ALITHIOS) were analysed. Data cutoff: 25 September 2022. The exposure-adjusted incidence rates (per 100 patient-years) of adverse events (AEs, 124.65), serious AEs (4.68), serious infections (1.63), and malignancies (0.32) remained consistent with previous findings up to 5 years of follow-up, with no new safety signals identified. With ofatumumab treatment up to 5 years, > 80 https://clinicaltrials.gov/ct2/show/NCT03650114

Background:Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system (CNS), characterized by inflammation and neurodegeneration. The pathophysiology of MS, especially its progressive forms, involves various cellular components, including microglia, the primary resident immune cells of the CNS. This review discusses the role of microglia in neuroinflammation, tissue repair, and neural homeostasis, as well as their involvement in MS and explores potential therapeutic strategies targeting microglial function. Methods:A literature search conducted in August 2023 and updated in March 2025, using the PubMed database, focused on articles relating to microglia and MS published in 2018-2025. Additionally, ongoing clinical trials of Bruton's tyrosine kinase (BTK) inhibitors were identified through the ClinicalTrials.gov website in November 2023 and updated in March 2025. Results:Microglia are highly adaptive and exhibit various functional states throughout different life stages and play critical roles in neuroinflammation, tissue repair, and neural homeostasis. Their altered activity is a prominent feature of MS, contributing to its pathogenesis. Imaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) provide insights into microglial activity in MS. BTK inhibitors and other novel treatments for MS, including masitinib and frexalimab, show promise in modulating microglial function and influencing the disease progression rate. Conclusions:The multifaceted roles of microglia in CNS development, immune surveillance, and particularly in the pathogenesis of MS highlight the potential of targeting microglial functions in MS treatment. Emerging research on the involvement of microglia in MS pathophysiology offers promising avenues for developing novel therapies, especially for progressive MS, potentially improving patient outcomes in this debilitating disease.

Twenty years on from its initial approval as the first monoclonal antibody for the treatment of multiple sclerosis (MS), natalizumab remains a valuable high-efficacy treatment option for people with relapsing-remitting MS, with robust real-world evidence supporting its long-term efficacy and well-characterized safety profile, provided that the risk of progressive multifocal leukoencephalopathy (PML) is monitored and mitigated. This review explores the long-term clinical impact of natalizumab. It draws on two decades of experience to guide treatment strategies with natalizumab, including its use early in the disease course, switching to natalizumab, its use during vaccination, and PML risk management and exit strategies. Guidance on the use of natalizumab in pregnant and breastfeeding women with MS, children with MS, and people with comorbidities is discussed, along with reflections on what has been learned from 20 years with natalizumab, and what the future holds for this impactful treatment in MS and beyond.

BACKGROUND:Multiple sclerosis (MS) places substantial socioeconomic burden on patients due to its early onset and progressive nature, but healthcare systems are also impacted by the high costs of disease-modifying treatments (DMTs). The use of generics (for conventional drugs), biosimilars (for biologics) or follow-on versions of non-biologic complex drugs (NBCDs) can help to reduce the cost of MS care and improve patient access. This review describes the European regulatory processes for these DMT 'copies' and the available data in people with MS. METHODS:A PubMed literature search was undertaken in March 2024, using the terms 'biosimilar', 'generic', 'non-biologic complex drug', 'NBCD' and 'follow-on' in association with 'multiple sclerosis'. RESULTS:Our literature search identified three clinical studies with generic treatments for MS (two with generic fingolimod and one with generic dimethyl fumarate), 11 studies with biosimilars (eight with biosimilar interferon formulations, one with natalizumab and two with rituximab biosimilars) and six studies with follow-on glatiramer acetate. The data showed that the generics, biosimilars and follow-on NBCDs had similar clinical efficacy and tolerability profiles to the originator drugs, although the quality and quantity of the research varied between DMTs. CONCLUSIONS:In Europe, there are robust regulatory processes for generics, biosimilars and follow-on NBCDs, in order to ensure that these agents can be considered equally effective and safe as the originator DMT. Physicians caring for people with MS should familiarise themselves with the evidence so that they can have informed conversations about the potential use of these agents.

BACKGROUND:Throughout the course of multiple sclerosis, gradually progressive neurologic impairment can occur, which has been called disability accrual. Current disease-modifying therapies for multiple sclerosis have limited effects on disability accrual unrelated to relapses, which is thought to be partially caused by chronic, nonresolving neuroinflammation within the central nervous system. Tolebrutinib is an oral, brain-penetrant Bruton's tyrosine kinase inhibitor that targets myeloid cells (including microglia) and B cells in both the periphery and central nervous system. There are no approved treatments for nonrelapsing secondary progressive multiple sclerosis. METHODS:In a phase 3, double-blind, placebo-controlled, event-driven trial, we randomly assigned participants with nonrelapsing secondary progressive multiple sclerosis, in a 2:1 ratio, to receive tolebrutinib (60 mg once daily) or matching placebo. The primary end point was confirmed disability progression that was sustained for at least 6 months, assessed in a time-to-event analysis. RESULTS:A total of 1131 participants underwent randomization: 754 were assigned to receive tolebrutinib and 377 to receive placebo. The median follow-up was 133 weeks. A smaller percentage of participants in the tolebrutinib group than in the placebo group had confirmed disability progression sustained for at least 6 months (22.6% vs. 30.7%; hazard ratio, 0.69; 95% confidence interval, 0.55 to 0.88; P = 0.003). Serious adverse events occurred in 15.0% of the participants in the tolebrutinib group and in 10.4% of those in the placebo group. A total of 4.0% of the participants in the tolebrutinib group and 1.6% of those in the placebo group had increases in alanine aminotransferase levels to more than 3 times the upper limit of the normal range. CONCLUSIONS:In participants with nonrelapsing secondary progressive multiple sclerosis, the risk of disability progression was lower among those who received treatment with tolebrutinib than among those who received placebo. (Funded by Sanofi; HERCULES ClinicalTrials.gov number, NCT04411641.).

BACKGROUND:The severity of relapses is lower in patients treated with DMTs compared to untreated patients. Although Disease-modifying treatments (DMTs) differ considerably in their efficacy for relapse prevention, the specific impact of different DMTs on relapse severity has not yet been thoroughly investigated. OBJECTIVE:To study the relationship between DMT use, relapse severity and recovery outcomes in relapsing-remitting multiple sclerosis (RRMS). METHODS:A restrospective cohort study analyzed 85 RRMS patients treated with either moderate-efficacy DMTs (interferons, glatiramer acetate, teriflunomide, dimethyl fumarate; n = 48) or high-efficacy DMTs (fingolimod, natalizumab, ocrelizumab, alemtuzumab, cladribine; n = 37). Regular EDSS assessments were used to evaluate relapse severity and subsequent recovery. RESULTS:Although patients on high-efficacy DMTs tended to experience less severe relapses (ΔEDSS = 0.49 ± 0.59 vs 0.71 ± 0.68 with moderate-efficacy DMTs; p = 0.12), multivariable analysis did not confirm a significant influence of high-efficacy treatment on relapse severity (OR = 0.46; 95 % CI: 0.13-1.61; p = 0.22). Relapse recovery showed a similar gradual improvement in both groups, with a slightly lower increase in disability among patients on high-efficacy DMTs at 6 months (0.26 ± 0.89 vs 0.39 ± 0.73; p = 0.46) and 12 months (0.27 ± 0.83 vs 0.31 ± 0.78; p = 0.98), though without statistically significant differences. Baseline EDSS emerged as the main determinant of relapse severity (OR=0.40; 95 % CI: 0.21-0.77; p = 0.006). CONCLUSIONS:These findings indicate that, among the DMTs analyzed (both moderate- and high-efficacy), the level of preventive efficacy does not substantially modify relapse severity or recovery once a relapse occurs.

Importance:Progression independent of relapse activity (PIRA) is a significant contributor to long-term disability accumulation in relapsing-remitting multiple sclerosis (MS). Prior studies have used varying PIRA definitions, hampering the comparability of study results. Objective:To compare various definitions of PIRA. Design, Setting, and Participants:This cohort study involved a retrospective analysis of prospectively collected data from the MSBase registry from July 2004 to July 2023. The participants were patients with MS from 186 centers across 43 countries who had clinically definite relapsing-remitting MS, a complete minimal dataset, and 3 or more documented Expanded Disability Status Scale (EDSS) assessments. Exposure:Three-hundred sixty definitions of PIRA as combinations of the following criteria: baseline disability (fixed baseline with re-baselining after PIRA, or plus re-baselining after relapses, or plus re-baselining after improvements), minimum confirmation period (6, 12, or 24 months), confirmation magnitude (EDSS score at/above worsening score or at/above threshold compared with baseline), freedom from relapse at EDSS score worsening (90 days prior, 90 days prior and 30 days after, 180 days prior and after, since previous EDSS assessment, or since baseline), and freedom from relapse at confirmation (30 days prior, 90 days prior, 30 days before and after, or between worsening and confirmation). Main Outcome and Measure:For each definition, we quantified PIRA incidence and persistence (ie, absence of a 3-month confirmed EDSS improvement over ≥5 years). Results:Among 87 239 patients with MS, 33 303 patients fulfilled the inclusion criteria; 24 152 (72.5%) were female and 9151 (27.5%) were male. At the first visits, the mean (SD) age was 36.4 (10.9) years; 28 052 patients (84.2%) had relapsing-remitting MS, and the median (IQR) EDSS score was 2.0 (1.0-3.0). Participants had a mean (SD) 15.1 (11.9) visits over 8.9 (5.2) years. PIRA incidence ranged from 0.141 to 0.658 events per decade and persistence from 0.753 to 0.919, depending on the definition. In particular, the baseline and confirmation period influenced PIRA detection. The following definition yielded balanced incidence and persistence: a significant disability worsening compared with a baseline (reset after each PIRA event, relapse, and EDSS score improvement), in absence of relapses since the last EDSS assessment, confirmed with EDSS scores (not preceded by relapses within 30 days) that remained above the worsening threshold for at least 12 months. Conclusion and Relevance:Incidence and persistence of PIRA are determined by the definition used. The proposed standardized definition aims to enhance comparability among studies.

Background Pregnancy is not discouraged in multiple sclerosis (MS) patients. However, MS patients tend to delay motherhood since they must wait for a low clinical and radiological activity before considering pregnancy, which impacts their fertility and their need for assisted reproductive technology (ART). This review aimed to cover, from a multidisciplinary perspective, the most critical aspects revolving around pregnancy in MS patients. Methods A group of seven experts (four neurologists and three gynaecologists) met for three discussion sessions to review current knowledge on ART in patients with MS. PubMed searches for journal articles published in English or Spanish between 2000 and 2024 were undertaken. 354 articles were revised at the title level. Results We reviewed current evidence on fertility in women and men with MS, on the effects of pregnancy on MS, the disease's pharmacological treatment during pregnancy, MS during delivery and breastfeeding, ART (intrauterine insemination, in vitro fertilisation, intracytoplasmic sperm injection, and oocyte cryopreservation) in patients with MS. Conclusion Early family planning, supported by good coordination between neurology and gynaecology departments, is paramount to managing MS women with motherhood desire. Besides, although a well-planned, early pregnancy is always the most desirable outcome, ART is considered safe and valuable for MS patients. Finally, multidisciplinary units are deemed pivotal to guide MS patients with parenthood desire through pregnancy.