Sun exposure may influence MS susceptibility, but evidence in pediatric-onset MS (PedMS) is limited. We examined whether reduced early-childhood outdoor time (a proxy for lower sun exposure) is associated with PedMS risk. In the Italian multicenter PEDIGREE Study, environmental data were collected using the PEQ-IT questionnaire. We enrolled individuals < 18 years with PedMS and disease duration ≤ 5 years and controls without CNS inflammatory disorders. Outdoor time was reported by season and age (0–1, 1–2, 3–5 years); reduced activity was defined as < 60 min/week. We included 114 PedMS cases and 121 controls. Cases were 77.2

BACKGROUND AND OBJECTIVES:Multiple sclerosis (MS) affects not only individuals but also family dynamics. Scalable, digitally delivered assessments may support routine screening of psychosocial and relational needs across the household. This study aimed to investigate perceived family functioning in families living with MS, using a web-based, multi-informant approach, focusing on relationship quality and psychosocial factors. METHODS:This Italian multicenter, cross-sectional study recruited families with a member diagnosed with MS. Participants included individuals with MS (PwMS), partners, adolescent children, and other adult relatives. Families without self-reported chronic illness were included as a comparison group. Participants completed anonymous, validated online questionnaires. Standardized instruments included: Hospital Anxiety and Depression Scale (HADS), Family Assessment Measure-III (FAM-III), Multidimensional Scale of Perceived Social Support (MSPSS), Toronto Alexithymia Scale (TAS-20), Dyadic Adjustment Scale (DAS), and Inventory of Parent and Peer Attachment (IPPA). RESULTS:The final sample consisted of 50 families: 50 PwMS (mean age: 42.6 ± 11.4 years), 34 partners (mean age: 45.2 ± 10.6 years), 25 adolescent children (mean age: 16.2 ± 3.6 years), 25 adult relatives (mean age: 47.2 ± 17.7 years). Compared with controls, PwMS reported lower anxiety (median HADS-A: 6.5 vs. 9; p = 0.002), higher dyadic adjustment (median DAS: 109.5 vs. 104.5; p = 0.024) and greater perceived support from significant others (median MSPSS: 27 vs. 24; p = 0.047). Adolescent children showed stronger attachment to parents (IPPA total mother: 94 vs. 83; father: 92.5 vs. 76.5; both p < 0.001) and peers (IPPA total peers: 98 vs. 90; p = 0.016). In PwMS, higher disability correlated with more severe depressive symptoms (ρ = 0.55, p < 0.001) and poorer family functioning (ρ = 0.37, p = 0.009). DISCUSSION:A web-based, standardized, multi-informant assessment can capture family functioning and key psychosocial correlates in MS, supporting the design of digitally enabled screening pathways to identify families who may benefit from early psychological or relational interventions.

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.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and a leading cause of disability in young adults. Traditional measures of MS-related disability primarily rely on objective clinical evaluations, often neglecting patients’ subjective experiences, which are affected by physical, cognitive, and emotional factors. This study aimed to validate the Italian Perceived Disability Scale (IPDS), a 20-item self-report tool designed to assess perceived disability across physical, psychological, and social domains. A cohort of 100 individuals with MS underwent the IPDS and a comprehensive clinical and neuropsychological assessment, including the Expanded Disability Status Scale (EDSS), Fatigue Severity Scale (FSS), Hamilton Depression and Anxiety Rating Scales (HAM-D and HAM-A), and the Brief Repeatable Battery of Neuropsychological Tests (BRB-N). Factor analysis confirmed the five-factor structure of the IPDS, accounting for 75

Cognitive impairment (CI) is a frequent and disabling manifestation of multiple sclerosis (MS), yet its molecular underpinnings remain poorly understood. This study aimed to identify microRNA (miRNA) signatures and related gene expression changes associated with CI in MS. Forty-six people with MS underwent clinical, radiological, and cognitive assessment. Peripheral blood mononuclear cells were collected for miRNA profiling using the miRCURY LNA miRNA Focus PCR Panel and validated through RT-qPCR. Experimentally validated miRNA target genes were retrieved using miRWalk with miRTarBase filtering. Target networks were constructed in Cytoscape, followed by protein–protein interaction analysis using STRING and functional enrichment analysis with database for annotation, visualization, and integrated discovery (DAVID) ( https://davidbioinformatics.nih.gov/ ). Selected target genes were further evaluated by gene expression analysis. The results showed that three miRNAs (i.e., miR-146a-5p, miR-let-7a-5p, and miR-21-5p) were significantly dysregulated in patients with MS with CI compared to those with preserved cognition. Gene expression analysis identified differential regulations of IL-1B, IL-6, SLC16A10, and NEFL, supporting the involvement of inflammatory and neurodegenerative pathways. Correlation analyses indicated specific miRNA–mRNA relationships underlying these alterations. These findings suggest that the combined dysregulation of miR-146a-5p and miR-21-5p, together with their target genes, constitutes a molecular signature associated with CI in MS. This profile could contribute to the development of miRNA-based biomarkers for early detection and monitoring of cognitive dysfunction in MS.

Air pollution is linked to an increased risk of multiple sclerosis (MS) in adults. To investigate the link between air pollutant exposure and pediatric MS (pedMS) in an Italian cohort. PEDIGREE (Pediatric Italian Genetic and Environment Exposure) is a multicenter case–control study investigating genetic and environmental factors in MS before the age of 18. Information on environmental and perinatal exposures was collected through the PEQ-IT questionnaire. Air pollution data during the first, second, and third years prior to MS onset (PM2.5, PM10, O3, NO2, SO2, and CO levels) were obtained from the European Monitoring and Evaluation Program database. Data were available for 113 pedMS cases and 117 controls. We found statistically significant associations between pedMS and higher exposure to ozone (O3) in the first (OR = 1.11; 95

Evidence directly comparing ocrelizumab (OCR) and ofatumumab (OFA) after sphingosine-1-phosphate receptor modulators (S1PRMs) withdrawal is limited, even though this transition period carries an increased risk of disease reactivation and the two anti-CD20 agents differ in molecular properties that may influence post-S1PRM outcomes. We compared effectiveness, safety, and tolerability of OFA versus OCR in relapsing–remitting multiple sclerosis (RRMS) after S1PRM therapy. We retrospectively analyzed adult (> 18 years) patients with RRMS from 23 Italian centers who switched from S1PRMs to OCR or OFA (October 2016 to July 2024). Clinical outcomes included annualized relapse rate (ARR), cumulative relapse incidence, confirmed disability progression (CDP), progression independent of relapse activity (PIRA), confirmed disability improvement (CDI), and variation in the expanded disability status scale score (ΔEDSS) from baseline to last follow-up. Magnetic resonance imaging (MRI) outcomes included time to overall MRI activity, new/enlarging T2 lesions, and new T1 Gd-enhancing lesions. Persistence on anti-CD20 and safety were also assessed. We applied inverse probability of treatment weighting (IPTW) to balance baseline covariates, and used Cox, Andersen–Gill, and regression models, further adjusted for variables with residual imbalance, to compare outcomes. We included 225 subjects (mean age 43.3 ± 10.6 years; OCR = 131, OFA = 94), with a median follow-up of 33 months. After IPTW, groups were well balanced. Compared with OCR, OFA was associated with lower ARR (adjusted relative risk [aRR] 0.22, 95

EASIER 2 is a multicenter, observational, cross-sectional study conducted in 14 Italian multiple sclerosis (MS) centers to evaluate patient and healthcare professional (HCP) time, healthcare resource consumption, costs, and patient quality of life (QoL) associated with subcutaneous (SC) administration of natalizumab compared to intravenous (IV) administration as measured in the earlier EASIER study. The study included: (1) time-and-motion analysis using a mobile application to collect real-world data during SC administration; (2) structured HCP questionnaire assessing organizational impacts; (3) patient survey capturing experience, preferences, and QoL. The comparison between SC and IV was conducted using a random-intercept regression model adjusted for patient history. A total of 265 SC procedures were analyzed. Compared to IV administration, SC reduced patient center time by 77

Effective management of multiple sclerosis requires precise monitoring to detect disease progression, yet conventional episodic assessments often fail to capture subtle functional decline. This systematic review aimed to synthesize current evidence on passive digital phenotyping via smartphones and wearable sensors as a tool for continuous and ecological evaluation. Following PRISMA guidelines, fourteen studies meeting strict eligibility criteria were included. These investigations analyzed raw data collected unobtrusively from smartphone touchscreens, inertial sensors, and photoplethysmography. The signals were processed to extract digital features, including keystroke dynamics, gait metrics, physiological markers, and behavioral patterns, to test their associations with standard clinical scales. The results demonstrated robust, significant correlations between these objective digital biomarkers and established clinical scores across motor, cognitive, and symptomatic domains. Specifically, processed typing kinematics and gait parameters significantly aligned with upper limb dexterity and walking ability respectively, while specific keystroke latency metrics proved sensitive to cognitive processing speed. Furthermore, multimodal physiological and behavioral markers successfully tracked complex symptoms such as fatigue, depression, and sleep quality. Overall, the findings highlighted that the integration of these multimodal biomarkers into clinical practice offers a scalable, non-invasive solution for personalized management. This approach could facilitate the early detection of “silent” symptoms and optimize therapeutic strategies, effectively bridging the critical gap between sporadic clinical visits and real-world functioning in multiple sclerosis.

BACKGROUND AND OBJECTIVES:Fc gamma receptor 3A (FCGR3A) V158F polymorphism has been shown to modify the response to anti-CD20 therapy across several autoimmune diseases. Ocrelizumab (OCR), an anti-CD20 agent, suppresses inflammatory activity in multiple sclerosis (MS), yet whether FCGR3A V158F polymorphism affects its efficacy in MS remains unclear. Here, we tested whether this genetic variant influences B-cell repopulation and disease activity in MS participants treated with OCR and assessed genotype-dependent differences in OCR binding to FcγRIIIa-expressing natural killer (NK) cells. METHODS:In this observational cohort study, we enrolled people with MS treated with OCR consecutively between May 2022 and August 2025. FCGR3A V158F genotyping was performed by pyrosequencing. The primary outcome was preinfusion CD19+ B-cell repopulation, defined as CD19+ B cells ≥1%. Secondary outcomes included clinical and MRI inflammatory activity and composite disease activity/disability-worsening measures. In a parallel mechanistic ex vivo substudy, OCR or rituximab (RTX) binding to NK cells was evaluated in genotype-selected donors by flow cytometry. Cycle-based repeated measures were analyzed using mixed-effects logistic regression. RESULTS:In 101 participants, 500 interinfusion intervals were analyzed. The odds of B-cell repopulation decreased with higher cycle number (odds ratio [OR] per cycle 0.77; 95% CI 0.65-0.91; p = 0.002) and increased with longer infusion intervals (OR per +30 days, 2.02; 95% CI 1.27-3.21; p = 0.0029). FCGR3A F-carrier status significantly modified the effect of interval length (interaction OR, 2.47; 95% CI 1.04-5.89; p = 0.042). Specifically, the odds of B-cell repopulation increased with longer intervals in MS participants carrying the FCGR3A-F allele (OR, 3.67; 95% CI 1.84-7.34; p = 0.00023) but not in FCGR3A-VV individuals (OR, 1.49; 95% CI 0.87-2.54; p = 0.146). FCGR3A genotype was not associated with clinical or MRI activity outcomes. In ex vivo assays, NK cells from FCGR3A-FF donors exhibited significantly lower binding of OCR (p = 4.34 × 10-4) and RTX (p = 0.00172) as compared with VV donors. DISCUSSION:Longer OCR infusion intervals were associated with higher odds of B-cell repopulation. The FCGR3A V158F polymorphism modified this interval-dependent repopulation, possibly by affecting OCR binding to NK cells. Prospective studies are needed to determine whether FCGR3A V158F polymorphism and B-cell repletion kinetics can inform optimized interval-based OCR dosing in MS.

INTRODUCTION AND OBJECTIVE:The introduction of follow-on formulations of glatiramer acetate (GA) has raised questions regarding their equivalence to the originator in real-world practice. This study aimed to evaluate the clinical effectiveness and safety of switching from originator GA to its follow-on product, Copemyl® (CO), in people with multiple sclerosis (MS). METHODS:A multicenter, retrospective observational study was conducted, including patients with MS treated for at least two years with GA followed by at least two years with CO. The primary outcome was the annualized relapse rate (ARR), whereas secondary outcomes included disability progression assessed by the Expanded Disability Status Scale (EDSS), MRI activity, and adverse events (AEs). RESULTS:A total of 138 patients were included. The ARR was very low and comparable across treatments (GA: 0.028; CO: 0.019), with a mean paired difference of -0.009 (95 % CI -0.028 to 0.010; p = 0.38), falling within the predefined equivalence margin. Disability progression over six months occurred in 6.0 % of GA and 7.3 % of CO periods (HR 1.53; 95 % CI 0.74-3.16; p = 0.26). No significant difference was found in MRI activity (52.2 % vs 60.1 %, p = 0.14). Safety profiles were comparable, with mostly mild to moderate AEs; four serious AEs occurred under CO, two of them possibly treatment-related. CONCLUSIONS:Switching from originator GA to CO did not influence clinical outcomes or safety. These findings support the therapeutic equivalence of the two formulations in real-world clinical practice, by supporting previous evidence from randomized trials.

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.

Background: Siponimod, a selective sphingosine-1-phosphate receptor modulator was approved for patients with Secondary progressive Multiple Sclerosis (SPMS) with ongoing disease activity. However, its real-world positioning and management after discontinuation remain challenging.Objectives: To evaluate the real-world use of siponimod in Italian real world setting, focusing on discontinuation rates, possible predictors, and post-treatment management.Methods: A retrospective, multicenter study on patients treated with siponimod across six Italian MS centers. Demographics, prior disease modifying therapy (DMTs), reasons for discontinuation, adverse events, and subsequent therapies were collected. Statistical analyses included propensity-adjusted Cox model.Results: A total cohort of 188 patients (63.8% female, median age 52 years) was enrolled, out of them 76(40.4%) discontinued siponimod, with a median treatment duration of 26 months. The main reason for discontinuation was safety concerns (72.4%), particularly persistent lymphopenia (43.6%) and recurrent infections (27.3%). Disease activity accounted for 27.6% of discontinuations. No significant demographic or clinical predictors of discontinuation were identified. After discontinuation, 49 patients (64%) started a new DMT, most commonly ocrelizumab (n = 22) or cladribine (n = 15), while 25 (32.9%) received no further therapy.Conclusion: High discontinuation rates, mainly due to safety, and frequent post-treatment gaps highlight the need for improved, individualized management strategies for SPMS after siponimod.

Assessing the environmental impact on multiple sclerosis (MS) is complex because of long disease latency and potential recall bias, especially for perinatal exposures. This study aimed to investigate the association between parental smoking and the development of pediatric MS (PedMS). As part of the Italian multicenter PEDIGREE study, the PEQ-IT questionnaire was used for prospective data collection. We enrolled subjects under 18 years with PedMS (2013 Krupp criteria) and disease duration ≤ 5 years from onset, along with matched controls. The study included 114 PedMS cases and 121 controls. Female participants represented 77.2

Objective Theory of Mind (ToM) deficits are common in people with Multiple Sclerosis (PwMS). This pilot study evaluated the feasibility of an ecologically valid ToM training in PwMS and examined whether experimental transcranial direct current stimulation (tDCS) intervention targeting the prefrontal cortex could enhance its effects on cognitive and affective ToM components across verbal and nonverbal modalities. Methods Two studies were conducted. Study 1 employed a single-case design with three PwMS undergoing a 16-week video-based ToM training. ToM performance was assessed at baseline, post-intervention, and 3-month follow-up. Study 2 included 12 PwMS randomly assigned to receive ToM training with either active tDCS (dlPFC or vmPFC) or sham stimulation. tDCS was delivered twice weekly (2mA, 20 minutes) over 16 weeks. Results In Study 1, participants showed improvements in cognitive ToM (verbal and nonverbal), and selective improvement in verbal affective ToM. In Study 2, both active tDCS groups exhibited improvements in cognitive and affective ToM compared to the sham group. Conclusions ToM training seems to be useful in improving cognitive and verbal affective ToM in PwMS, especially when combined with prefrontal tDCS. However, nonverbal affective ToM appears resistant to intervention, suggesting the need for targeted strategies. These preliminary findings support a personalized, multimodal approach to social cognitive rehabilitation in MS.

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.

CD4+CD25hiFoxP3+ regulatory T cells (Treg cells) are key controllers of immune self-tolerance, and their suppressive function is impaired in people with relapsing-remitting multiple sclerosis (pwRR-MS). Because the mechanisms underlying this condition are still ill-defined, we investigated the role of Treg cell-derived extracellular vesicles (Treg-EVs) in Treg cell dysfunction observed in pwRR-MS. We found that Treg-EVs from healthy individuals inhibit CD4+ conventional T (Tconv) cells by shuttling miR-142-3p from the Treg cell to the Tconv cell. There, miR-142-3p down-regulated mRNAs necessary for Tconv cell growth and effector functions, such as the redox controller cystine carrier SLC7A11. However, Treg cells from pwRR-MS released EVs containing reduced amounts of miR-142-3p, resulting in impaired suppressive function. Furthermore, Treg-EV miR-142-3p inversely correlated with the disability score and gadolinium-enhancing lesions in pwRR-MS. Together, our results elucidate a molecular mechanism involving miR-142-3p shuttled by Treg-EVs in the control of immune self-tolerance and unveil its pathogenetic implications in human autoimmunity.

Apathy is a common neuropsychiatric symptom in people with Multiple Sclerosis (PwMS), and is significantly associated with increased dependency on caregivers, intensifying their emotional and physical burden. The present study aims to evaluate apathy from the perspectives of both PwMS and caregivers, considering the MS clinical phenotype; and to explore the impact of caregiver-reported patient apathy on their distress, particularly in relation to their coping strategies and resilience. Eighty dyads of PwMS and caregivers completed the self-evaluation or caregiver version of the Apathy-Motivation Index, which assesses apathy in terms of behavioral activation, social motivation, and emotional sensitivity. Caregivers also completed the Zarit Burden Interview and the Caregiver Burden Inventory to assess burden, the Coping Orientation to Problems Experienced to evaluate coping strategies, and the Connor-Davidson Resilience Scale to measure resilience. Caregivers consistently reported higher levels of perceived patient apathy than PwMS, particularly in terms of behavioral apathy. Notably, higher levels of emotional apathy in PwMS, as perceived by caregivers, were strongly associated with increased psychological distress and burden. Furthermore, caregivers relying on maladaptive coping strategies experienced significantly greater levels of emotional exhaustion and role strain related to caregiver-reported patient apathy. These findings highlight the need to comprehensively assess all dimensions of apathy and integrate the caregiver’s perspective in its assessment. Tailored interventions should focus on reinforcing adaptive coping mechanisms to mitigate caregiver distress, associated with caregiver-reported patient apathy, ultimately improving the well-being of both PwMS and their caregivers.

Importance:Early treatment choice in relapsing-remitting multiple sclerosis (RRMS) is prognostically crucial, yet robust comparative data on cladribine vs sphingosine-1-phosphate receptor modulators (S1PRMs) in treatment-naive patients with RRMS are limited. Objective:To compare the clinical effectiveness of cladribine vs S1PRMs in treatment-naive individuals with RRMS. Design, Setting, and Participants:This comparative effectiveness research study used data from 108 Italian multiple sclerosis (MS) centers affiliated with the Italian Multiple Sclerosis and Related Disorders Register. All treatment-naive patients with RRMS who initiated cladribine or an S1PRM (fingolimod, ozanimod, or ponesimod) between January 2011 and October 2021 and had at least 12 months of follow-up were included. Propensity score matching and pairwise censoring were used to balance baseline differences and follow-up duration. Patient data were extracted from the register in September 2024. Exposure:Initiation of cladribine or an S1PRM, with duration reflecting clinical practice. Main Outcomes and Measures:The primary outcome was no evidence of disease activity (NEDA-3) and its subcomponents. Secondary analyses evaluated disability accrual subdivided into progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW), plus variables associated with treatment response. Cox proportional hazards models, adjusted for visit and magnetic resonance imaging (MRI) frequency, were used to compare outcomes. Results:Of the 1587 patients (485 taking cladribine and 1102 taking S1PRMs), matching yielded 475 pairs (950 individuals; mean [SD] age, 34.7 [10.7] years; 686 female [72.2%]), with a median (IQR) follow-up period of 25 (12-60) months. For the cladribine vs S1PRM groups, no significant differences were observed in relapse rates (72 patients [15.2%] vs 76 patients [16.0%]), MRI activity (137 patients [31.3%] vs 145 patients [34.8%]), or NEDA-3 loss (194 patients [44.4% vs 219 patients [52.2%]). Cladribine was associated with a lower risk of disability worsening vs S1PRM (54 patients [11.4%] vs 70 patients [14.7%]; hazard ratio [HR], 0.64; 95% CI, 0.42-0.96; P = .03), a finding that was confirmed in sensitivity analyses for patients younger than 40 years, those whose diagnoses were made according to the 2017 McDonald Criteria, and those with Expanded Disability Status Scale score less than or equal to 3.0. This was mainly driven by reduced PIRA risk with cladribine (HR, 0.40; 95% CI, 0.20-0.79; P = .009), with no RAW difference. After 36 months, patients treated with cladribine showed higher relapse risk (HR, 1.81; 95% CI, 1.02-3.20; P = .04) and increased NEDA-3 loss (HR, 2.08; 95% CI, 1.18-3.67; P = .01). Discontinuation rates were similar (HR, 0.92; 95% CI, 0.67-1.15; P = .58). Conclusions and Relevance:These findings suggest cladribine was associated with superior effectiveness in reducing disability progression over 25 months, likely due to reduced PIRA, despite comparable short-term NEDA-3 outcomes. However, relapse prevention declined after 36 months, suggesting retreatment or therapy modification within 3 years may be needed to maintain long-term disease control.

Multiple sclerosis is an autoimmune neurodegenerative disease and one of the most significant challenges in modern neurology, impacting approximately 2.8 million people globally. As a multifactorial condition, susceptibility to MS can result from a combination of genetic and environmental factors. Current treatment strategies aim to prevent acute attacks, slow disease progression, and alleviate symptoms. Ocrelizumab, a monoclonal antibody targeting CD20, has demonstrated efficacy in clinical trials by reducing both disease activity and frequency of relapses.Given the recent approval of this treatment, we investigated whether Ocrelizumab alters the expression of key miRNAs and genes involved in neuroinflammation, such as let-7a-5p, miR-14a-5p, miR-21a-5p, miR-338-3p, IL-1, IL-6, NEAT1, NEFL, NESTIN, SLC16A10 and TNF-alpha, by comparing their expression in patients’ blood before and after one year of treatment with Ocrelizumab. Additionally, we explored potential inverse correlations and direct or indirect interactions among the genes and miRNAs that showed significant changes in expression. Lastly, we conducted a pathway analysis to understand the overall effects potentially exerted by the drug.Results revealed a significant decrease in the expression of TNF-alpha, SLC16A10, NEFL and IL-6, and an increase in let-7a-5p expression. There was an inverse correlation between let-7a-5p and the four genes, while the genes positively correlated with each other, suggesting let-7a-5p as a common modulator. These findings indicate that further investigation is needed to determine if the drug directly upregulates let-7a-5p, thereby downregulating the four genes, or if these expression changes are an indication of an overall reduction in inflammation.