Ofatumumab (OFA) is a fully human anti-CD20 monoclonal antibody approved for the treatment of relapsing multiple sclerosis (RMS). Real-world data on its effectiveness and safety remain limited. To assess the effectiveness and safety of OFA in a large Italian RMS cohort and to examine the impact of prior treatment exposure on clinical, radiological, and safety outcomes in routine clinical practice. This retrospective, multicenter study included adults with RMS who initiated OFA and had at least one follow-up visit. Patients were classified as treatment-naïve, switching from moderate-efficacy therapies (MET), or switching from high-efficacy therapies (HET). Outcomes included annualized relapse rate (ARR), magnetic resonance imaging (MRI) activity, disability measures (including confirmed disability worsening and improvement), no evidence of disease activity (NEDA-3), and adverse events (AEs). A total of 424 patients were analyzed, with a mean follow-up of 1.32 (± 0.61) years: 101 (23.8

No evidence of disease activity-3 (NEDA-3) constitutes a crucial target for relapsing-remitting multiple sclerosis (RRMS). Long-term predictors of its attainment remain insufficiently characterized. This study aimed to assess the prevalence and the predictors of long-term NEDA-3 status in a large real-world RRMS cohort. This retrospective monocentric study analyzed RRMS patients strictly followed for up to six years. Treatment exposure was classified based on the efficacy of the first therapy in moderate (ME) and high efficacy (HE) disease modifying treatments (DMTs). Percentages of patients exposed to ME and HE DMTs reaching NEDA-3 were compared. Logistic regression models were applied to identify predictors of NEDA-3 achievement at 2 and 5 years. EBNA-1 IgG and VCA IgG from Epstein-Barr virus (EBV) were also analyzed in a small sub-cohort. 485 RRMS patients were included. Subjects starting treatment with HE DMTs were associated with significantly higher rates of NEDA-3 across all time-points. Significant risk factors for not achieving NEDA-3 included multifocal onset, delayed treatment initiation and spinal cord lesions. Conversely, treatment initiation with HE DMT was a significant protective factor for NEDA-3 status achievement at 2 and 5 years of follow-up. Early initiation of HE DMTs significantly improves long-term control of disease activity. Multifocal onset, delayed treatment initiation, presence of spinal cord lesions and oligoclonal bands were identified as risk factors of not achieving NEDA-3 status.

BackgroundSecondary progressive multiple sclerosis (SPMS) encompasses heterogeneous phenotypes that may or may not exhibit disease activity.ObjectivesTo characterize a cohort of non-relapsing SPMS (nrSPMS) identified through a data-driven definition adapted from the HERCULES trial criteria, compared with neurologist-defined (ND) SPMS.MethodsRelapsing MS patients were retrospectively extracted from the Italian Multiple Sclerosis Register (RISM). ND was defined according to clinical criteria for SPMS and the HERCULES cohort adapting the trial inclusion criteria. Progression independent from relapse activity (PIRA) and relapse-associated worsening (RAW) events were assessed. Diagnostic performances of SPMS definitions were evaluated.ResultsAmong 20,306 patients, 866 (4.26%) were classified as SPMS by ND and 1603 (7.89%) by HERCULES criteria. The HERCULES group included older patients, less likely to relapse post-conversion. PIRA occurred in 88.8% of ND and 88.5% of HERCULES-defined cases, with a shorter median time to first PIRA in the latter. The HERCULES definition showed high specificity (93.4%) and low sensitivity (37.6%).ConclusionsHERCULES-adapted criteria identified a subgroup of 7.9% nrSPMS patients in the real-world cohort of RISM, characterized by fewer post-conversion relapses and earlier PIRA onset. These findings reinforce the value of applying standardized algorithmic definitions of SPMS in registry-based studies.

Abstract Effective social decision-making requires understanding interpersonal dynamics involving moral content, a process supported by social cognition. When this ability is impaired, as in Mild Cognitive Impairment (MCI), individuals may struggle to act appropriately, reducing social engagement and accelerating decline. The study investigated moral decision-making and social cognition in individuals with MCI and healthy controls ( N = 40; 20 per group). Participants completed tasks assessing Theory of Mind (ToM), emotion attribution, social situation understanding, and moral/conventional distinctions. Moral decisions were measured using interactive scenarios (sacrificial, real-life moral, and neutral), recording choices and response times (RTs). Additional measures included cognitive reserve, social engagement, and perceived social isolation. Results showed that individuals with MCI performed significantly worse than controls in identifying normative behaviours, with no group differences in other social cognition domains. Both groups made similar choices in moral decision-making tasks. However, individuals with MCI exhibited longer response times in morally salient scenarios, while no group differences emerged in neutral scenarios. This pattern may tentatively suggest greater processing demands in morally relevant contexts. Additionally, individuals with MCI reported lower levels of cognitive reserve and social engagement. These findings underscore the importance of assessing moral decision-making in clinical populations to support autonomy and social inclusion in ageing.

BackgroundCladribine tablets are an oral short-course disease-modifying therapy (DMT) approved for the treatment of highly active relapsing multiple sclerosis (MS). While their efficacy has been demonstrated in clinical trials, limited real-world evidence is available on their impact on patient-reported outcomes (PROs) and the potential added value of wearable devices for continuous functional monitoring.ObjectivesTo evaluate the association between cladribine tablets use and PROs related to physical functioning and quality of life, and to explore the relationship between PROs and biometric data collected through wearable devices over 52 weeks in a real-world cohort of patients with highly active MS after therapeutic switch.MethodsCLADFIT-MS is a prospective, multicenter, observational phase IV study conducted in Italy. This interim analysis includes 190 patients with highly active MS who initiated cladribine tablets and had data available up to Week 52. PROs included the Multiple Sclerosis Impact Scale (MSIS-29), EuroQoL-5D-5L, and PROMIS-29 physical function and fatigue scores. Biometric data (e.g., range of movement, walking distance, sleep time) were collected using Fitbit® devices. Associations between PROs and wearable-derived data were analyzed using univariate mixed models and correlation matrices.ResultsMSIS-29 physical scores and EQ-5D-5L remained stable over 52 weeks. PROMIS-29 fatigue scores showed slight improvement [from 54.6 (9.59) to 51.8 (10.30)], while PROMIS-29 physical function scores remained stable. An exploratory association was observed between baseline range of movement and changes in MSIS-29 scores (p = 0.0425), and between walking distance and PROMIS-29 fatigue (p = 0.0345). Biometric variables demonstrated moderate to strong inter-correlations, suggesting internal consistency of the wearable-derived data.ConclusionIn this real-world cohort of patients with highly active MS, cladribine tablets treatment was associated with the maintenance of PROs over one year. The integration of wearable technology provided objective metrics that were consistent with patient perceptions, supporting the feasibility of combining digital tools with PROs to monitor functional outcomes in MS clinical practice.

Migraine is common in people with multiple sclerosis (PwMS) and substantially contributes to disability and impaired quality of life. Although (CGRP)–targeting therapies have reshaped migraine prevention, evidence on their use in PwMS remains scarce, particularly in people receiving concomitant disease-modifying therapies (DMTs). We retrospectively collected data from 17 Italian multiple sclerosis (MS) centers on adult PwMS with comorbid migraine treated with anti-CGRP monoclonal antibodies or gepants in addition to stable DMTs. Monthly headache days (MHDs) and total number of analgesics per month were compared between treatment initiation and last follow-up. MS activity was assessed through clinical relapses, Expanded Disability Status Scale (EDSS), and MRI findings. A ≥ 50

BACKGROUND AND OBJECTIVES:Although anti-CD20 monoclonal antibodies (anti-CD20s) theoretically represent an ideal treatment option for women with multiple sclerosis (wwMS) planning a pregnancy, the paucity of real-world data still limits their use in this context. Through our Italian registry "CD20-PREGNANCY," we aim to report pregnancy, infant, and maternal outcomes in wwMS treated with anti-CD20s. METHODS:In this observational study, wwMS having received rituximab (RTX), ocrelizumab (OCR), or ofatumumab (OFA) before and/or during pregnancy (≤12 months for RTX/OCR, ≤6 months for OFA) were included. Considering drug pharmacokinetics and timings of immunoglobulin placental transfer, pregnancies were classified as "exposed" (last administration pre-pregnancy ≤2.3 months for RTX, ≤3 for OCR, ≤1.8 for OFA) and "not-exposed" (last administration beyond these intervals) for comparative analysis. RESULTS:A total of 153 pregnancies (85 "not-exposed," 68 "exposed") across 27 Italian MS centers were collected. The median age at conception was 33.9 years (interquartile range 30.0-37.6) with 39.9% of women older than 35 years. Most pregnancies occurred in patients treated with OCR (77.1%). 80.4% of pregnancies ended in livebirth and 13.1% in spontaneous abortions (SA), without stillbirths/neonatal deaths. There was a significantly higher percentage of SA in "exposed" pregnancies than "not-exposed" (20.6% vs 7.1%, p = 0.014), but with values similar to those reported in general population. One serious perinatal infection ("exposed" group) and 2 major congenital anomalies (MCA) (one per group) were reported. Compared with the 12 months pre-pregnancy, annualized relapse rate remained stable during pregnancy but slightly increased postpregnancy (0.00 vs +0.09) in "not-exposed." Conversely, it decreased in both periods (-0.02 vs -0.13) among "exposed". Compared with pre-pregnancy, postpregnancy combined unique active lesions decreased in both groups (-0.15 in "not-exposed", -0.38 in "exposed"), while 2 confirmed disability worsening were observed ("not-exposed"). DISCUSSION:In conclusion, a good control of disease activity was observed without an increased risk of MCA or perinatal infections. Percentages of SA were overall in line with those of general population, although with a higher proportion in the "exposed" group. These findings support the use of anti-CD20 therapies in wwMS planning pregnancy, although further data are needed to better define their safety profile in this setting.

BACKGROUND:In multiple sclerosis (MS), real-world evidence supports early intensive treatment (EIT) with high-efficacy therapies (HET) over escalation (ESC), although comparative data on long-term safety across sequences remain limited. OBJECTIVE:To compare the incidence of infections and neoplasms in patients treated with different treatment sequences. METHODS:Data were extracted from the Italian MS and Related Disorders Register. DMTs were classified as moderate-efficacy treatment (MET), continuous HET (C-HET) or pulsed HET (P-HET). Six therapeutic sequences were reconstructed: MET-only, C-HET-only, P-HET-only, MET→C-HET, MET→P-HET and P-HET→MET. Incidence rates (IRs; per 1000 person-years) and incidence rate ratios (IRRs) were estimated using multivariable Poisson regression, adjusting for age, sex, Expanded Disability Status Scale (EDSS), disease duration, MS phenotype and prior relapse activity. RESULTS:A total of 37,375 patients were included in the analysis, with a median duration of treatment exposure of 8.8 years. Infection risk was significantly higher with C-HET-only (IR, 24.82; IRR, 3.12), P-HET-only (IR, 13.43; IRR, 1.69), MET→C-HET (IR, 10.46; IRR, 1.32) and MET→P-HET (IR, 12.30; IRR, 1.55) versus MET-only (IR, 7.94), while P-HET→MET showed no significant difference from MET-only (IR, 7.67; IRR, 0.97). Regarding neoplasm incidence, P-HET-only showed the lowest rates (IR, 0.18; IRR, 0.24), whereas it was significantly higher in C-HET-only (IR, 1.33; IRR, 1.79) and MET→C-HET (IR, 1.01; IRR, 1.36) versus MET-only (IR, 0.74). CONCLUSIONS:This is the first real-world study to compare the safety of different sequences in a national registry. ESC strategies did not confer a long-term safety advantage over EIT. Among HET regimens, C-HET was associated with the greatest risk of both serious infections and neoplasms, whereas P-HET showed the lowest neoplasm incidence.

The Migraine Interictal Burden Scale (MIBS-4) is a brief validated patient-reported measure of migraine interictal impact; however, an official Italian translation is not currently available. The MIBS-4 was translated and culturally adapted into Italian language and psychometrically evaluated in adults with episodic or chronic migraine enrolled in the Italian Headache Registry (RICe). In a 4-week test–retest design, participants completed the Italian version of MIBS-4 and the Migraine Disability Assessment (MIDAS) at baseline (T0) and at follow up (T1). We assessed internal consistency, dimensionality, test–retest reliability, convergent validity, and known-groups validity across MIDAS disability grades. A total of 191 patients with migraine were included in test–retest analyses. Internal consistency was good to excellent (Cronbach’s α = 0.86 at T0; 0.90 at T1; ordinal α = 0.91–0.94; McDonald’s ω = 0.88–0.91). Parallel analysis supported a stable one-factor solution at both timepoints. Item-level agreement was moderate (weighted κ = 0.45–0.60; all p < 0.001), as was the total-score stability (ICC[A,1] = 0.62, 95

OBJECTIVE:To evaluate the long-term impact of early intensive treatment (EIT) versus escalation (ESC) strategies using high-efficacy disease-modifying therapies (HE-DMTs) on disability progression in relapsing multiple sclerosis (RMS). METHODS:This observational study included 4878 RMS patients from the Italian Multiple Sclerosis Register. Eligible participants initiated their first disease-modifying therapy (DMT) within 3 years of disease onset and had ≥ 5 years of follow-up with at least three Expanded Disability Status Scale (EDSS) evaluations. Patients were categorized into the EIT group if they started with HE-DMTs and into the ESC group if HE-DMTs were initiated after ≥ 1 year of moderate-efficacy therapy. Propensity score matching was performed to balance baseline characteristics. Outcomes included disability trajectories assessed using linear mixed models for repeated measures and risks of confirmed disability accrual (CDA), progression independent of relapse activity (PIRA), and relapse-associated worsening (RAW) evaluated using Cox proportional hazards models. RESULTS:Post-matching analysis of 908 pairs revealed significantly slower disability progression in the EIT group compared to the ESC group. At 10 years, the delta-EDSS difference between groups was -0.63 (95% CI: -0.83 to -0.43; p < 0.0001). ESC was associated with higher risks of CDA (HR 1.36, 95% CI: 1.20-1.54; p < 0.0001), PIRA (HR 1.22, 95% CI: 1.05-1.40; p = 0.0074), and RAW (HR 1.55, 95% CI: 1.17-2.05; p = 0.0021). INTERPRETATION:EIT significantly reduces long-term disability progression in RMS compared to ESC. These findings underscore the potential of EIT to optimize long-term outcomes in RMS patients.

Creutzfeldt–Jakob disease (CJD) is the most common human prion disease, with genetic forms linked to PRNP gene mutations accounting for 10–15

Cladribine is an immune reconstitution therapy approved for relapsing multiple sclerosis (RMS). This multicentric retrospective study of the Italian Multiple Sclerosis Register (RISM) aimed to assess the effect of cladribine on the annualized relapse rate (ARR) and progression independent of relapse activity (PIRA) phenomena, also evaluating the strategies of disease-modifying treatment (DMT) continuation after cladribine termination. Patients with RMS treated with at least one cycle of cladribine recorded in RISM after 2018 were retrospectively included in the analysis. Patients previously treated with other DMTs were stratified into moderately and highly effective DMTs. Adjusted ARR and PIRA events were calculated in the overall cohort and stratified by age at cladribine start (<50 vs ≥ 50 years) and by previous DMT. ARRs were compared between groups using negative binomial models. PIRA was analyzed using the Ghosh-Lin Cox-type regression for the marginal mean. DMTs prescribed after cladribine cycles were analyzed. A total of 2,329 patients treated with cladribine were identified in RISM, with a median (IQR) age of 36.5 (29.2-45.2) years at treatment start. 1,488 patients (63.9%) received 2 courses of cladribine. ARR decreased (p < 0.0001) from 0.96 (95% CI 0.91-1.02) in the 2 years preceding cladribine start to 0.09 (0.08-0.11) during the 2 years after in the overall cohort. One hundred thirty-three PIRA events were reported during the noncladribine treatment period and 54 during cladribine therapy (HR 0.711, 95% CI 0.531-0.952, p = 0.0219) in the entire cohort. All the analyses stratified by age and previous treatment confirmed the significant reduction in PIRA events and the suppression of relapse activity. After cladribine, most DMTs prescribed were ocrelizumab, ofatumumab, and natalizumab. Eight patients re-treated with an additional cycle of cladribine were also identified. For patients with RMS, both naïve and switchers, as well as younger and older patients, cladribine is an effective treatment in reducing relapses and PIRA. Different therapeutic strategies after cladribine are currently reported. This study provides Class IV evidence that for patients with relapsing multiple sclerosis, cladribine treatment is associated with a reduction in ARR and PIRA events.

Exosomes are small, membrane-bound vesicles secreted by most cell types into the extracellular environment. They play a crucial role in intercellular communication by transporting bioactive molecules, including proteins, lipids, and RNAs, thereby influencing the phenotype and potentially the genotype in recipient cells. In recent years, exosomes have gained increasing attention in the study of pathophysiological conditions and numerous diseases, including multiple sclerosis (MS), an autoimmune disorder with myelin sheath and neuroaxonal damage in the central nervous system. In this study, we isolated and purified serum-derived exosomes from patients with relapsing remitting MS (RR-MS) and characterized their lipid profiles using matrix-assisted laser desorption ionization-time-of-flight/mass spectrometry (MALDI-TOF/MS). Lipid analysis was performed in both negative and positive ion modes on intact exosomes, bypassing lipid extraction steps and significantly reducing sample-processing time. The lipid profiles of RR-MS exosomes were compared to those of exosomes isolated from the serum of healthy subjects (HS), and statistical analysis was applied to mass spectra to identify potential lipid biomarkers. The specific phospholipid marker of exosomal membranes, bis(monoacylglycero)phosphate (BMP), was clearly detected in both MALDI lipid profiles, with no significant differences in its content between the two sample groups. However, RR-MS exosomes exhibited significantly lower levels of phosphatidic acid (PA) compared to HS exosomes, despite PA being a key structural component of extracellular vesicles. Notably, comparative analysis revealed an enrichment of several lysophosphatidylcholine (LPC) species in RR-MS exosome membranes, aligning with their known proinflammatory role in MS pathology. Our most significant finding was a markedly lower phosphatidylcholine (PC) to LPC ratio in the pathological group indicating potential alterations in membrane lipid homeostasis. To the best of our knowledge, this study is the first to report a distinct lipid signature in serum-derived exosomes from RR-MS patients using direct MALDI-TOF/MS analysis.

BACKGROUND AND OBJECTIVES:Cladribine is an immune reconstitution therapy approved for relapsing multiple sclerosis (RMS). This multicentric retrospective study of the Italian Multiple Sclerosis Register (RISM) aimed to assess the effect of cladribine on the annualized relapse rate (ARR) and progression independent of relapse activity (PIRA) phenomena, also evaluating the strategies of disease-modifying treatment (DMT) continuation after cladribine termination. METHODS:Patients with RMS treated with at least one cycle of cladribine recorded in RISM after 2018 were retrospectively included in the analysis. Patients previously treated with other DMTs were stratified into moderately and highly effective DMTs. Adjusted ARR and PIRA events were calculated in the overall cohort and stratified by age at cladribine start (<50 vs ≥ 50 years) and by previous DMT. ARRs were compared between groups using negative binomial models. PIRA was analyzed using the Ghosh-Lin Cox-type regression for the marginal mean. DMTs prescribed after cladribine cycles were analyzed. RESULTS:A total of 2,329 patients treated with cladribine were identified in RISM, with a median (IQR) age of 36.5 (29.2-45.2) years at treatment start. 1,488 patients (63.9%) received 2 courses of cladribine. ARR decreased (p < 0.0001) from 0.96 (95% CI 0.91-1.02) in the 2 years preceding cladribine start to 0.09 (0.08-0.11) during the 2 years after in the overall cohort. One hundred thirty-three PIRA events were reported during the noncladribine treatment period and 54 during cladribine therapy (HR 0.711, 95% CI 0.531-0.952, p = 0.0219) in the entire cohort. All the analyses stratified by age and previous treatment confirmed the significant reduction in PIRA events and the suppression of relapse activity. After cladribine, most DMTs prescribed were ocrelizumab, ofatumumab, and natalizumab. Eight patients re-treated with an additional cycle of cladribine were also identified. DISCUSSION:For patients with RMS, both naïve and switchers, as well as younger and older patients, cladribine is an effective treatment in reducing relapses and PIRA. Different therapeutic strategies after cladribine are currently reported. CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that for patients with relapsing multiple sclerosis, cladribine treatment is associated with a reduction in ARR and PIRA events.

Multiple sclerosis (MS) is a chronic central nervous system disease characterized by neurodegeneration and inflammation. Neurofilament light chain (NfL), a protein released during axonal injury, has gained recognition as a potential biomarker for monitoring MS progression and treatment response. Evidence indicates that blood NfL (bNfL) offers a minimally invasive, cost-effective tool for tracking neuroaxonal damage. Regular bNfL assessments can identify subclinical disease activity, guide treatment intensification, and support individualized care. However, bNfL level evaluation is currently not optimized in Italian clinical practice. This work examines the utility of bNfL monitoring in clinical practice, focusing on optimizing its use within specific patient profiles, especially in resource-limited settings. bNfL testing, particularly in targeted MS patient profiles, including stable patients exhibiting subclinical signs of disease activity, such as fatigue, and patients off-treatment, represents a promising adjunct for personalized disease management. Its integration into clinical practice, alongside MRI and clinical assessments, can enhance decision-making and improve care efficiency, especially in settings with limited MRI resources. Further research is needed to standardize testing protocols and establish disease-specific cutoffs.

Ublituximab, a newly launched anti-CD20 monoclonal antibody, represents a substantial advancement in the treatment landscape for relapsing multiple sclerosis (RMS). Its unique glycoengineered design enhances antibody-dependent cellular cytotoxicity, enabling rapid and effective B-cell depletion. Phase III randomized controlled trials ULTIMATE I and II confirmed superior efficacy of ublituximab over teriflunomide, achieving substantial reductions in annualized relapse rates, near-complete suppression of gadolinium-enhancing T1 lesions and new/enlarging T2-hyperintense white matter lesions, as well as higher rates of no evidence of disease activity 3. Safety data indicate that ublituximab is generally well tolerated, with mild, manageable infusion-related reactions as the most common adverse event. Its streamlined infusion protocol, requiring maintenance doses administered in just 1 h twice a year, provides a practical solution to the clinical and logistical challenges of MS management. Its rapid B-cell depletion, high efficacy, and convenient twice-yearly short infusion regimen make it particularly suitable for treatment-naïve patients with high disease activity who may benefit from early and robust disease control as well as for those who have experienced suboptimal responses, poor tolerability, or safety concerns with prior disease-modifying therapies. Although ublituximab shows great promise and five-year data are already available, further research is required to fully explore its potential in limiting disability progression and neurodegeneration, as well as to confirm its long-term safety. Real-world evidence, extended follow-ups, and comprehensive biomarker assessment specific to MS-related pathology will be essential to confirm its efficacy and optimize RMS patients’ management. This review synthesizes discussions from two meetings of Italian Neurologists held in 2024 and 2025, focusing on efficacy and safety data of ublituximab, and providing a comprehensive and in-depth analysis of its current and future role in RMS treatment.

Background and Objectives: In multiple sclerosis (MS), the Risk of Ambulatory Disability (RoAD) score is a validated prognostic tool based on demographic, clinical, and MRI variables assessed at treatment initiation and after one year. We aimed to assess the predictive value of the RoAD score for long-term irreversible disability in a large real-world MS cohort. Materials and Methods: A retrospective analysis was performed on relapsing–remitting MS patients (RRMS) followed for ≥5 years at the Bari MS Center. The RoAD score (0–8) was calculated and dichotomized (<4 vs. ≥4). Cox proportional hazards models were used to evaluate the risk of irreversible Expanded Disability Status Scale (EDSS) 6.0. Results: A total of 1051 RRMS patients (67.1% female) were included, with a median follow-up of 18.0 years. Most patients (97.5%) received moderate-efficacy DMTs as first-line therapy. During follow-up, 123 (11.7%) patients reached irreversible EDSS 6.0 after a median of 9.5 years. Patients with RoAD score ≥4 (16.8%) showed a threefold higher risk of irreversible disability (HR 3.16, 95% CI 2.19–4.56, p < 0.001). The predictive value of RoAD ≥4 was confirmed both in the adjusted multivariable model and in sensitivity analyses treating RoAD as a continuous variable. Conclusions: In this real-world cohort, the RoAD score demonstrated solid predictive validity for long-term ambulatory disability, supporting its role as a practical tool for early risk stratification in MS management.

Background Physical activity (PA) has been recommended in multiple sclerosis (MS) to maintain good physical fitness and mental health, reduce the severity of symptoms and risk of relapse, and improve quality of life. Pilates has been suggested as an ideal PA to manage physical, cognitive, and psychological symptoms of MS and a useful method to maintain and improve balance and gait. Objective This paper presents the protocol for a study that aims to evaluate the efficacy on the physical domain (specifically balance and gait) of a home-based, self-managed PA intervention delivered through the MS-FIT exergame (HELAGLOBE Società a responsabilità limitata). In addition, measures of cognitive performance, quality of life, and well-being will be considered. Methods This is a 2-arm, multicenter, randomized controlled trial with 3 assessment points (baseline, 12 weeks postintervention, and 6 weeks follow-up). People with MS with mild disability, low risk of falling, preserved cognitive functions, and low anxiety and depression are potential eligible participants. The experimental group (MS-FIT) will self-administer the MS-FIT exergame at home in addition to their leisure-time physical activities. MS-FIT is an internet- and Pilates-based tool that uses the Microsoft Kinect Sensor V2. Participants in the control group will only have access to their leisure-time physical activities. Participants in the MS-FIT group will train at home with MS-FIT for 12 weeks and will be required to perform the exercises for a total of 30 minutes/day for at least 3 days/week. The primary outcome is the Timed Up and Go, a test designed to assess walking. We will also administer additional tests for motor function (visual analog scale 0-10, Timed 25-Foot Walk, Ambulation Index, 2-minute walk test, Twelve Item Multiple Sclerosis Walking Scale, Nine-Hole Peg Test), cognition (Brief International Cognitive Assessment for Multiple Sclerosis), fatigue (Modified Fatigue Impact Scale), quality of life (Multiple Sclerosis Quality of Life-54), well-being (Psychological Well-Being Scales), and PA (International Physical Activity Questionnaire and Minnesota Leisure Time Physical Activity Questionnaire). Acceptance and satisfaction with the intervention received (Client Satisfaction Questionnaire and an adapted version of the Tele-healthcare Satisfaction Questionnaire – Wearable Technology) and subjective impressions of changes in performance (Patients’ Global Impression of Change) will also be assessed. Results Recruitment for the trial started on March 16, 2022, and the first participant was randomized the same day. Data analysis and results are expected to be published in 2025. Conclusions Pilates has proven beneficial in several neurological diseases such as MS. With this study, we will provide evidence for the use in clinical practice of a digital tool for self-administered Pilates exercises at home as a complement to rehabilitation and for the continuity of care in MS. Trial Registration ClinicalTrials.gov NCT04011579; https://tinyurl.com/2p9n4d2t International Registered Report Identifier (IRRID) DERR1-10.2196/58026