INTRODUCTION:Multiple Sclerosis (MS) affects several social determinants of health (SDH), but research remains limited and fragmented. We examined four SDH (education, work, financial resources and social life) to study the impact of MS and explore interrelationships, identify risk factors, and study the association with social support. METHODS:SocialMS is a cross-sectional Italian questionnaire-based study including adults with MS. The number of SDH affected by MS was the primary endpoint and risk factors were identified using Poisson regression. RESULTS:We included 1039 participants (mean age: 43.82 years (sd: 11.53); 68.82% females; 86.53% relapsing remitting; median Patient Determined Disease Steps (PDDS): 1 (iqr: 0-3)). Median number of SDH affected by MS was 1 (iqr: 0-3), with social life (51.20%) and work (48.22%) most impacted; high interrelationships among domains were observed. Relevant risk factors included socioeconomic factors (education incomplete at diagnosis: incidence-rate ratio (IRR)=1.19 [95% CI: 1.06; 1.35]; non-working or early retired: IRR=1.18 [1.05; 1.34]; economic strain: IRR=1.47, [1.31; 1.64]), comorbidities (IRR=1.23 [1.11; 1.37]) and PDDS (IRR=1.17 [1.13; 1.20]). Almost 90% received tangible (64.29%) or intangible (85.18%) social support, and number of SDH impacted by MS was positively associated with both (p < 0.05). CONCLUSION:MS substantially affects multiple SDH, with greater burden among individuals with socioeconomic and health-related vulnerabilities.

BACKGROUND:Strong evidence links Epstein-Barr virus (EBV) infection to Multiple Sclerosis (MS). Peginterferon beta-1a (peg-IFN), currently the most used interferon formulation among first-line treatments in MS, displays immunomodulatory, anti-inflammatory, and antiviral properties and remains also an important therapeutic option in conditions such as pregnancy, lactation and aging patients. OBJECTIVES:In this study we evaluated the ability of peg-IFN to restore a homeostatic EBV-host interaction in MS by regulating antiviral and immunometabolic responses. METHODS:In people with MS (pwMS), peripheral blood mononuclear cells (PBMCs) were analyzed before (T0) and after six months (T6mos) of peg-IFN administration: IFN-stimulated gene (ISG) levels, EBV DNA load, Epstein-Barr nuclear antigen 2 (EBNA2) allele distribution, and T-lymphocyte phenotyping with glycolytic metabolism were assessed. RESULTS:Peg-IFN increased ISG transcription and glycolysis in CD4+ T lymphocytes, and reduced EBV DNA load without altering EBNA2 allele distribution. Notably, ISG expression increase at T6mos in pwMS infected by the non-risk 1.3B EBNA2 allele, correlating with a better long-term response to peg-IFN after 2-years. Lower T-cell glycolytic capacity at T0 predicted higher peg-IFN responsiveness in pwMS carrying the 1.3B allele, suggesting that EBNA2 variants might be predictive of response to peg-IFN. CONCLUSION:Here, we found that infection with MS-associated EBNA2 variants might be involved in the clinical response to peg-IFN therapy. The predictive model developed, which integrates immunological and viral parameters, may help clinicians in a finer selection of first-line therapies tailored to patient profiles, supporting personalized medicine approaches.

Background:Cladribine (CLAD) stands as an oral disease modifying treatment (DMT) for multiple sclerosis (MS) patients, distinguished by its unique dosing regimen and mechanism of action. However, real-world data on its effectiveness remain limited, particularly regarding the clinical and therapeutical management beyond the 2-year treatment schedule. Objectives:The aim of our study was to explore the effectiveness profile of CLAD in individuals with MS (pwMS). We assessed the proportion of patients achieving no evidence of disease activity (NEDA-3) status and identified variables associated with better outcomes. Design:In this retrospective study, we collected clinical and magnetic resonance imaging (MRI) data of MS patients across 10 MS Clinics in Central Italy who started CLAD between 2018 and 2023. Methods:We evaluated the annualized relapse rate (ARR) during treatment, and the proportion of patients who experienced relapses, radiological activity, and confirmed disability progression. Additionally, we estimated the proportion of patients achieving NEDA-3 among those with a minimum follow-up of 3 months and explored baseline variables associated with NEDA status. Results:We collected data from 1094 patients with a mean follow-up of 25.1 months, of whom 79% completed the second CLAD cycle. The mean age was 37.7 years (SD 9.7), and the mean disease duration was 6.5 years, with 40.5% being treatment naïve. Despite a significant reduction of the ARR from 0.91 to 0.04 (p < 0.01) following CLAD treatment, 8.9% of patients presented at least one relapse, while 22.0% and 7.9% of patients experienced radiological activity or disability progression, respectively. Across the entire study cohort, 70.2% of patients maintained the NEDA-3 status. Younger age (HR = 0.98, p < 0.001) and higher expanded disability status scale score (HR = 1.11, p = 0.049) were associated with a higher risk of not achieving the NEDA-3 status. Additionally, we included 131 patients who were older than 50 years at the time of CLAD initiation. Among the cohort, 116 patients switched to another DMT after CLAD, primarily anti-CD20 monoclonal antibodies following disease reactivation. Conclusion:This postmarketing experience confirms the effectiveness of CLAD in the treatment of pwMS, with a significant reduction in ARR and a high proportion of patients remaining free from disease activity. By contrast, some patients required an escalation strategy mainly with anti-CD20 monoclonal antibodies because of persisting disease activity.

Ofatumumab (OFA) is a highly effective therapeutic option for multiple sclerosis (MS), but real-world data on its efficacy and safety remain limited. We evaluated the real-world efficacy and safety of OFA in patients with MS and explored the predictive value of frailty. We retrospectively collected clinical and MRI data from 12 MS centers in Central Italy, including patients who initiated OFA between April 2022 and January 2024. We assessed annualized relapse rate (ARR), clinical relapses, radiological activity, and safety. Frailty, defined as increased vulnerability due to age-related health deficits, was measured using a frailty index (FI). The study was approved by the local Ethics Committee (No. 6357). A total of 242 patients with MS were included (66.8

Recent research on the impact of gut microbiota on multiple sclerosis (MS) has been extensive; however, the role of microbial composition in other body interfaces, such as the mouth and the skin, has received much less attention. In a first step towards addressing this gap, we used Mendelian Randomization (MR), an analytical approach using genetic variants as proxies for environmental exposures to estimate the causal relationship between a risk factor and an outcome. Here, we performed a two-sample MR analysis to assess the link between oral and skin microbiome composition and both MS risk and severity. Exposure data were extracted from summary statistics of two large genome-wide association studies (GWAS) assessing the influence of host genetics on the microbiome composition of the oral cavity and skin. Outcome data derived from the largest GWAS on MS susceptibility and the recent GWAS on MS severity. After stringent instrumental variant selection, we applied inverse-variance-weighted (IVW) and Wald's ratio as primary MR methods, MR EGGER to control for horizontal pleiotropy, and checked directionality through Steiger's test. We found that the relative abundance of Veillonella genus in the skin may enhance MS risk, while no significant association between oral composition and MS susceptibility emerged. Furthermore, we found the Gammaproteobacteria class in the skin is associated with MS severity. We also identified suggestive, protective signals from different oral microbial strains (Bacilli class, Porphyromonas genus, Proteobacteria phylum and Veillonella dispar species). Overall, our findings provide preliminary evidence supporting the hypothesis that skin microbiota might contribute to MS risk, and both oral and skin microbial composition could affect disease severity, broadening the relevance of dysbiosis beyond the gut in MS etiopathogenesis.

INTRODUCTION:Safety concerns have been raised regarding fingolimod to siponimod transition in people with Secondary Progressive Multiple Sclerosis (SPMS). OBJECTIVE:To explore factors associated with the choice of switching from fingolimod to siponimod and the safety of this sequencing. METHODS:We conducted a prospective observational study that included patients who had a confirmed diagnosis of SPMS at the time of study entry and had been treated with fingolimod for at least two years. Upon enrollment, patients either continued fingolimod (comparator group) or transitioned to siponimod (switch group) and were followed up for six months to assess disease activity and changes in laboratory parameters. RESULTS:Out of 95 SPMS subjects, 42 (44.2 %) switched to siponimod at study entry. The switch group was younger and had more prior treatments than the comparator group (p = 0.042 and p = 0.015, respectively). Five subjects experienced disease activity (three in the switch group, two in the comparator). Patients switching to siponimod experienced a greater increase in GPT (p = 0.015) and GOT levels (p = 0.041) at 6 months. Four adverse events were reported: melanoma and grade IV lymphopenia in the comparator group, and grade IV lymphopenia and dizziness in the switch group. CONCLUSION:During the 6-month observation period, switching from fingolimod to siponimod was safe in terms of disease reactivation and tolerability.

Background Despite advances in multiple sclerosis (MS) management, the need for more accurate biomarkers remains critical. Conventional MRI, while essential for diagnosis, prognosis and disease monitoring, has limitations in capturing the full complexity of disease progression. This paper aims to identify biomarkers likely to be available in clinical practice by 2028, define a prospective organisational follow-up model for patients with MS, explore organisational requirements and propose solutions to facilitate their implementation. These insights aim to inform and anticipate future discussions among policymakers regarding the adoption of prospective biomarkers into clinical practice.Methods A multimethod qualitative design was employed, including a systematic literature review of 82 studies, two modified Delphi consensus processes and semistructured interviews with nine neurologists and three healthcare programming experts, applying the Structural, Technological, Organisational and Professional (STOP) framework. The STOP framework was used to assess structural, technological, organisational and professional requirements and to explore solutions.Results The research identified a prospective organisational follow-up model that integrates the most probable prospective biomarkers into clinical practice. The prospective organisational follow-up model defined an optimal testing frequency of Serum Neurofilament Light Chain and Glial Fibrillar Acidic Protein every 6 months, as well as Cognitive Tests and Optical Coherence Tomography every 12 months. Combining biomarkers and aligning them with MRI was seen as beneficial. Despite the validation of the model through a modified Delphi consensus process based on organisational feasibility and economic sustainability, structural and organisational challenges need to be addressed to ensure smoother integration into clinical practice.Conclusions This article aims to define an organisational model for the integration of prospective biomarkers into clinical follow-up in MS. It also explores potential strategies to facilitate their transition from research settings to routine clinical practice. The proposed approach provides a framework with potential for replication across various care pathways.

BACKGROUND:The study aims to examine the age and disability levels at diagnosis in people with multiple sclerosis (PwMS), with and without autoimmune comorbidities (AC), and the effect of AC on NEDA-3 status and to characterize AC associated with MS, comparing also therapeutic approaches between MS patients with and without other AC. METHODS:This population-based, multicentric study enrolled patients with relapsing-remitting MS (RRMS) with AC (AC group) or without AC (reference group) from 14 MS centers. Demographical, clinical features, treatment information, MRI activity, EDSS, and no evidence of disease activity (NEDA-3) status were assessed at T36 (enrollment time) and T0 (36 months prior). RESULTS:Eight hundred seventy-three RRMS patients were included; 215 (24.7%) presented with at least one AC. The AC group was characterized by higher proportion of female patients than reference group (p = 0.008). Patients with AC, compared to reference group, exhibited older age at MS onset and MS diagnosis, and higher EDSS score at diagnosis, at T0 (all p < 0.001), and T36 (p = 0.03). The proportion of patients reaching EDSS 4 was higher in reference group than AC group (p = 0.03). People in AC group were more often treated with glatiramer acetate, natalizumab, and rituximab, whereas PwMS from reference group with interferon-beta and fingolimod at T0 and T36. The risk of losing NEDA-3 was lower in AC group (OR = 0.61, 95% CI 0.43-0.86, p = 0.005). CONCLUSIONS:AC are common in PwMS and can be related to a delay in onset, diagnosis and higher disability at MS presentation. However, the coexistence of AC is not associated with a worse prognosis.

Despite its widespread use in clinical practice, the effectiveness of natalizumab extended interval dosing (EID) adopted from treatment start across different treatment intervals and individual modifiers (body mass index - BMI) is still under-investigated. Here, seven-hundred and forty-five multiple sclerosis (MS) patients, exposed to natalizumab for 3.30 ​± ​1.34 years, were retrospectively enrolled in an observational multicenter study. After stratifying patients in EID or standard interval dosing (SID), we assessed differences in time to relapse, MRI activity and Expanded Disability Status Scale (EDSS) progression. The primary analysis was conducted on patients exposed to EID interval from 5 weeks and 1 day to 7 weeks, while a secondary analysis included also EID periods up to 8 weeks. An additional analysis explored the impact of BMI. No differences in time to first relapse, time to radiological activity, time to EDSS progression or time to EDA (evidence of disease activity) were detected between SID and EID group (EID interval from 5 weeks to 1 day to 7 weeks). When including EID periods from 7 weeks and 1 day to 8 weeks, the EID group showed a trend towards higher risk of experience clinical relapses than the SID group. A higher EDA risk was also identified in EID patients with BMI above median. In conclusion, a higher risk of relapses seems to occur for EID above 7 weeks. Independently from the EID scheme adopted, higher BMI increases the risk of EDA in these patients.

Background: The increasing knowledge about multiple sclerosis (MS) pathophysiology has reinforced the need for an improved description of disease phenotypes, connected to disease biology. Growing evidence indicates that complex diseases constitute phenotypical and genetic continuums with "simple," monogenic disorders, suggesting shared pathomechanisms. Objectives: The objective of this study was to depict a novel MS phenotypical framework leveraging shared physiopathology with Mendelian diseases and to identify phenotype-specific candidate drugs. Methods: We performed an enrichment testing of MS-associated variants with Mendelian disorders genes. We defined a "MS-Mendelian network," further analyzed to define enriched phenotypic subnetworks and biological processes. Finally, a network-based drug screening was implemented. Results: Starting from 617 MS-associated loci, we showed a significant enrichment of monogenic diseases (p < 0.001). We defined an MS-Mendelian molecular network based on 331 genes and 486 related disorders, enriched in four phenotypic classes: neurologic, immunologic, metabolic, and visual. We prioritized a total of 503 drugs, of which 27 molecules active in 3/4 phenotypical subnetworks and 140 in subnetwork pairs. Conclusion: The genetic architecture of MS contains the seeds of pathobiological multiplicities shared with immune, neurologic, metabolic and visual monogenic disorders. This result may inform future classifications of MS endophenotypes and support the development of new therapies in both MS and rare diseases.

Ocrelizumab (OCR), an anti-CD20 monoclonal antibody, is approved for treating relapsing remitting (RR) and primary progressive (PP) multiple sclerosis (MS). The standard interval dosing (SID) regimen requires intravenous infusions every six months. Experience of extended dosing due to COVID-19 pandemic-related issues suggests that this strategy may provide comparable efficacy while reducing treatment burden and healthcare costs. This study aimed to evaluate clinical effectiveness, changes in B- and T-cell count, and immunoglobulin dynamics associated with extended interval dosing (EID) of ocrelizumab in a real-world setting. We retrospectively included RRMS or PPMS patients treated with OCR that had already received two OCR cycles and with at least 6 months of follow up after the last infusion. EID was defined as a ≥4 weeks delay compared to SID. Clinical outcomes were occurrence of relapses, MRI activity, 6-months confirmed disability progression (CDP) and their combination (No Evidence of Disease Activity, NEDA-3). We also evaluated changes in CD19+ B cell count, CD4+ and CD8+ T cell count, immunoglobulin titers, and occurrence of hypogammaglobulinemia (hypo-Ig). Frequency tests, multivariate regression models, and survival analysis were applied as appropriate. We analyzed data on 93 subjects (75.3% RRMS) for a total of 389 infusions (272 SID, 117 EID). Clinical and MRI activity, CDP, and NEDA 3 did not significantly differ between EID and SID. EID was associated with lower rates of B-cell depletion. T-cell dynamics and incidence of hypo-Ig were comparable following EID and SID. Hypo-IgG at index infusion was associated with further occurrence of hypo-IgG; male sex and hypo-IgM at index infusion were independently associated with hypo-IgM. In conclusion, OCR EID does not impact MS clinical and radiological outcomes, although it interferes with B-cell dynamics. These findings provide support for a tailored schedule of OCR in MS.