Information on the safety profile of disease-modifying therapies (DMTs) in multiple sclerosis (MS) is often lacking in routine clinical practice. Real-world data sources, such as patient registries, support pharmacovigilance to characterise safety signals, as recently recognised by regulatory agencies. In Italy, the "Italian Multiple Sclerosis and Related Disorders Register" (RISM) was officially launched in 2015 to collect demographic and clinical data from patients with MS. To describe the main characteristics of RISM as a research platform supporting the safety evaluation of MS therapies. RISM enables the systematic characterisation of clinical events occurring in treated patients and, over the years, has implemented procedures to ensure high-quality data collection. A study cohort including subjects who initiated a DMT between 2016 and 2025 is analysed using descriptive statistics. Clinical events recorded during the study period are reported as absolute numbers and frequencies. Between 2016 and 2025, a total of 24 259 subjects received at least one DMT, and 4419 of them (18.2%) experienced one or multiple clinical events. For descriptive purposes, the occurrence of infections and malignancies, which accounted for 29.4% and 3.7% of all the clinical events collected in RISM respectively, are reported and categorised. This article outlines the strengths and limitations of RISM in conducting safety studies and highlights the methodological and legal challenges associated with such platforms. Routinely collected healthcare data within RISM provide a comprehensive, patient-centred perspective for the long-term evaluation of DMT safety and can address relevant questions on drug policies and public health. Multiple sclerosis (MS) is a chronic condition that often requires long‐term treatment with therapies that are specific for MS. However, information about the safety of MS therapies in everyday clinical practice is still limited. The Italian Multiple Sclerosis and Related Disorders Register (RISM) was created in 2015 to collect information from clinical practice about people with MS across Italy. By gathering data from specialised MS centres, RISM helps better understand how MS therapies work and what side effects may occur over time. Data quality controls have been implemented with the aim to collect complete and accurate information. Between 2016 and 2025, RISM recorded 24 259 people who received at least one MS treatment. About 18% of them reported at least one clinical event, most often infections (29.4% of all events) or, less frequently, cancers (3.7%). This work describes how RISM can be used to monitor the safety of available MS therapies by analysing data collected in routine clinical practice, as well as the challenges of managing such large data collections. Information from RISM can guide clinicians, researchers, and relevant stakeholders in improving treatment safety and supporting better healthcare decisions for people living with MS.
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Multiple sclerosis (MS) is a severe neuroinflammatory disease causing substantial long-term disability. Strong epidemiologic evidence links Epstein-Barr virus (EBV) exposure with MS risk, but genetic evidence for immune target prioritization in EBV-related phenotypes remains limited. We integrated single-cell cis-eQTL data from 14 immune cell types with GWASs of an EBV-related clinical phenotype and MS using a single-cell Mendelian randomization framework with colocalization analyses. Candidate eGenes were evaluated in independent cohorts. For multi-SNP instruments, we performed heterogeneity, pleiotropy, MR-Egger, weighted median, mode-based, and MR-PRESSO sensitivity analyses. We also conducted phenome-wide association analyses and queried DrugBank to annotate candidate compounds targeting prioritized genes. We prioritized 43 immune-cell-specific candidate eGenes with convergent genetic support, including 6 for the EBV-related phenotype and 37 for MS. SERPINB1 in NK cells was associated with increased risk of the EBV-related phenotype, whereas HLA-G was associated with decreased risk. For MS, APOM and MSH5 showed protective associations, while AHI1 showed cell-type-dependent, bidirectional associations across immune lineages. Colocalization and independent cohort evaluation supported these findings. Among FDR-significant multi-SNP associations, MR-Egger intercept tests did not indicate directional pleiotropy, although a small subset showed heterogeneity or MR-PRESSO signals. Phenome-wide analyses identified no significant adverse phenotypic associations among evaluable genes at the prespecified threshold. DrugBank annotation nominated sodium nitroprusside, fasudil, artenimol, and choline as hypothesis-generating compounds for experimental follow-up. This study provides a single-cell genetic framework for prioritizing immune-cell-specific candidate targets for EBV-related phenotypes and MS, and nominates genetically supported targets and pharmacologic hypotheses for experimental investigation.
The relationship between social participation and health-related outcomes remains underexplored among individuals with multiple sclerosis (MS). This study aimed to examine associations between social participation and self-reported outcomes, and to explore whether these relationships varied by age and sex. A total of 1162 adults with MS (mean age: 52.3 years, 80.6% female) completed an online survey. Social participation was assessed using the short form of the ability to participate in social roles and activities of the Quality of Life in Neurological Disorders. Outcomes included self-reported ambulation difficulty (Multiple Sclerosis Walking Scale-12), cognitive deficit (Perceived Deficits Questionnaire), fatigue (Modified Fatigue Impact Scale), dual-task difficulty (Dual-Task Impact on Daily Living Questionnaire), fear of falling (Fall Efficacy Scale-International), and recurrent falls (>1 fall). Linear and logistic regression models were used to examine the associations between social participation and self-reported outcomes. Greater social participation is associated with reduced fatigue (B [95% CI] = -2.04 [-2.38, -1.70]), ambulation difficulty (-1.79 [-2.19, -1.38]), cognitive deficit (-0.40 [-0.50, -0.30]), dual-task difficulty (-1.30 [-1.59, -1.01]), fear of falling (-0.75 [-0.91, -0.60]), and recurrent falls (OR [95% CI] = 0.89 [0.83, 0.95]). Significant age and social participation interactions were observed for cognition, ambulation, and fatigue, with older adults showing smaller magnitudes of benefits from social participation. Only cognition showed significant sex and social participation interaction, with a stronger association among females than males with MS. This study supports the clinical relevance of social participation as a factor associated with health-related outcomes in people with MS.
Early impairments in Multiple Sclerosis, such as reduced hand dexterity, worsen as disability progresses. Rehabilitation is essential, yet evidence on the efficacy of upper limb (UL) interventions remains limited. This study investigates the effects of UL rehabilitation on fine and gross motor function in a large cohort of people with multiple sclerosis (pwMS). We examined data from 237 pwMS enrolled in studies on arm function interventions. Demographic characteristics and hand dominance were recorded; manual dexterity was assessed by blinded therapists using the Box and Block Test (BBT) and the Nine Hole Peg Test (NHPT). Statistical analyses evaluated dominant and non-dominant hands, stratified results by MS type and EDSS disability levels and tested pre-post differences using Wilcoxon or paired-t tests. Rehabilitation led to statistically significant improvements in fine and gross hand function, with median gains of 2.5-3 s on the NHPT and 7-8 cubes on the BBT, and moderate effect sizes. Approximately 20% of participants reached a 20% improvement on NHPT and one-third on BBT. Mild and moderate EDSS groups showed gains on NHPT and BBT, while severe groups improved more on BBT. Relapsing-Remitting and Primary Progressive types exhibited consistent improvements on both tests, whereas Secondary Progressive showed smaller NHPT changes. UL rehabilitation in pwMS appears more effective for individuals with milder disability and a relapsing-remitting course. Interventions were more successful in improving gross motor function, while fine hand function showed limited improvement in higher disability levels or progressive MS.
Myelin enables rapid action potential conduction and axonal support, and its disruption underlies diverse neurological disorders. Its assessment is essential for studying development, plasticity, and repair of the nervous system (NS), and for diagnosing demyelinating diseases and evaluating remyelination therapies. Multiple histological methods detect myelin, each with trade-offs in sensitivity, cost, and reproducibility. Among them, Eriochrome Cyanine R (EC-R) is a simple, affordable myelin stain widely used in thin sections, but remains poorly standardized, and underexplored in thick vibratome sections. Here we describe and validate a simple, inexpensive, solvent-free EC-R protocol for central and peripheral nervous system tissue across seven vertebrate species and multiple demyelinating conditions. The method replaces subjective microscopic differentiation with fixed, time-controlled incubations scaled to section thickness, improving reproducibility. Using perfusion and immersion-fixed samples, we show that the protocol yields homogeneous myelin labeling with sharp white/gray matter contrast in whole brains, cortical slabs, spinal cord, and peripheral nerves. Thick sections stained with EC-R preserve 3-dimensional tissue architecture, resolve single myelinated axons and intracortical bands, and can be combined with Nissl-like counterstains and immunohistochemistry. Developmental series in neonatal rats reveal expected PNS-CNS myelination gradients, while experimental demyelination models and naturally occurring diseases (canine distemper and human multiple sclerosis) illustrate the method's ability to delineate lesion cores, perilesional gradients, and associated glial and immune activation. This standardized EC-R approach provides a robust and versatile tool for comparative neuroanatomy, experimental neuropathology, and translational studies of myelination, demyelination, and remyelination, as well as for the clinical diagnosis of myelin-related disorders.
Relapsing-remitting multiple sclerosis (RRMS) is frequently associated with anxiety, depression, and emotion regulation difficulties, which may foster maladaptive coping strategies such as emotional eating and contribute to comorbid overweight/obesity. Transdiagnostic, emotion-focused interventions may be especially relevant for this population. To evaluate the effectiveness of an adapted group-based Unified Protocol (UP) on emotion regulation, eating behaviors, and medical outcomes in adults with RRMS and overweight/obesity. A pre-registered single-blind randomized controlled trial (OSF: https://osf.io/sr4bx) compared a 14-session group-based adapted UP (n = 47) against standard medical care (n = 33). Complete pre-post medical data (body mass index (BMI), weight, Expanded Disability Status Scale (EDSS), Symbol Digit Modalities Test (SDMT), magnetic resonance imaging (MRI) brain metrics, T2 lesions) were available for both arms; complete psychological self-report data were available only for the intervention arm. Medical outcomes were analyzed with two-way mixed ANOVAs (Group × Time); psychological outcomes were analyzed within-arm with linear mixed-effects models. Within the intervention arm, significant pre-post improvements were observed in emotion regulation difficulties, emotional eating, and psychosocial impairment, with longitudinal reductions in anxiety and depressive symptoms. Between-group analyses revealed significant Group × Time interactions for BMI (p=.030, ηp²=.07), weight (p=.024, ηp²=.07), and EDSS (p<.001, ηp²=.31), favoring the intervention. No interactions emerged for SDMT, MRI brain volumes, or T2 lesions. Within the intervention arm, the group-based UP was associated with within-group improvements in emotion regulation and disordered eating, and with between-group anthropometric and EDSS outcomes relative to standard care. Because the psychological outcomes were assessed within the intervention arm only, these within-group changes should not be interpreted as treatment effects relative to standard care. EDSS findings should be interpreted as preliminary, as they were not corroborated by confirmed disability improvement criteria or concurrent MRI changes.
Psychological resilience predicts better outcomes in persons with multiple sclerosis (pwMS), yet factors which sustain it over time remain poorly understood, particularly in diverse populations. Personality traits may represent stable determinants of resilience. To examine the influence of personality on resilience in Black and Non-Hispanic White pwMS (BpwMS/WpwMS) and their healthy counterparts (BHCs/WHCs). Psychological resilience and personality were assessed in a matched cohort of 120 pwMS and 80 HCs using the Connor-Davidson Resilience Scale and NEO-Five Factor Inventory-3. Personality and resilience were compared across groups. In pwMS, cross-sectional regression and longitudinal mixed-effects models evaluated personality-resilience associations; sensitivity analyses adjusted separately for depressive symptoms, psychiatric history, and subjective social status to evaluate the robustness of these associations. PwMS and HCs reported similar levels of Neuroticism, Agreeableness, and Conscientiousness; Extraversion and Openness were lower in pwMS. PwMS had worse resilience compared to HCs at follow-up. Higher Neuroticism predicted lower resilience, with a stronger association observed in BpwMS; higher Extraversion and Conscientiousness predicted better resilience. Higher Conscientiousness was associated with less longitudinal decline in resilience. Adjustment for depression attenuated the Conscientiousness and Neuroticism × Race associations, whereas Neuroticism and Extraversion associations remained significant. In prospective models, Conscientiousness continued to predict follow-up resilience independent of baseline depression. Personality traits may identify pwMS susceptible to reduced psychological resilience; Conscientiousness in particular may help sustain it over time. Although depression contributes to personality-resilience relationships, Neuroticism and Extraversion remain independently associated with resilience. Our findings support personality-informed approaches to strengthen psychological resilience in pwMS and identify depression as a clinically actionable target for future intervention.
Multiple sclerosis (MS) is a demyelinating disease in which chronic inflammation is predominant in nerve tissue, characterized by neurodegeneration and variable neurological impairment, as well as immune system-induced damage. MS, which is particularly common in young adults, causes significant disability and drastically reduces the quality of life. We aimed to determine the predictive value of integrating serum albumin, lymphocyte, and C-reactive protein (CALLY index) for assessing the disability status of MS patients, as determined by the EDSS (Expanded Disability Status Scale). This retrospective study included 290 patients with MS and a 290-member healthy control group matched for BMI (body mass index), gender, and age. The MS group had significantly higher neutrophil count and NLR, whereas it had significantly lower CALLY index, albumin, and lymphocyte count. The CALLY index demonstrated a significant negative (inverse) correlation with the EDSS, EDSS severity, disease duration, BMI, and NLR in Spearman's correlation analysis. The multivariable logistic regression analysis demonstrated that the CALLY index and disease duration were independent predictors of MS severity (the EDSS ≤3.5 vs. ≥4). The Receiver Operating Characteristic (ROC) analysis for the CALLY index with a cut-off level of 0.71 predicted the EDSS severity with a specificity of 72.1%; and a sensitivity of 67.3% (the area under curve analysis was 0.719, p < 0.001). The CALLY index is a reliable, robust, inexpensive, and simple biomarker for predicting the disability and severity of MS patient), with implications for both inflammation and immunonutrition.
Spinal cord lesions are common in Multiple Sclerosis (MS) and contribute to disability, but the frequency of new asymptomatic lesions during follow-up is uncertain. To review new asymptomatic spinal cord lesions (aSCLe), estimate the patient-level proportion developing at least one lesion, and assess isolated spinal cord activity without concomitant brain Magnetic Resonance Imaging (MRI) activity. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. PubMed, Scopus, and Web of Science were searched through May 1st, 2026 for studies reporting new aSCLe on follow-up MRI in clinically stable patients with MS (pwMS). According to the criteria used in original papers, MS stability was clinically defined most commonly as the absence of relapses, new neurological symptoms, and/or disability progression during the interval assessed; however, operational definitions varied across studies. The primary outcome was the patient-level proportion developing at least one new lesion. Comparable studies were pooled using a random-effects generalized linear mixed model (GLMM). Nine studies were included in the qualitative synthesis and three in the meta-analysis (1637 patients). The pooled proportion developing at least one new asymptomatic spinal cord lesion was 13.0% (95% confidence interval 6.2-25.1; I² = 96.5%). In relapsing-remitting multiple sclerosis, the pooled estimate was 19.1% (95% confidence interval 13.2-26.7; I² = 79.1%). Isolated spinal cord activity was reported across studies but could not be pooled because of heterogeneous definitions and analytic units. Available evidence suggests that new asymptomatic spinal cord lesions may occur during clinically stable follow-up in a meaningful proportion of pwMS. Clinicians should recognize that spinal cord activity may be missed when surveillance relies on brain MRI alone. Standardized whole-cord protocols and patient-level reporting are needed to determine prognostic value and implications for treatment escalation.
Ponesimod demonstrated efficacy and safety in relapsing-remitting multiple sclerosis (RRMS) in 24-week phase-2 core study, further confirmed by an interim combined analysis of the core and open-label long-term extension (LTE) studies (NCT01093326; up to 8 years). Current study evaluated safety and efficacy of ponesimod using combined core and LTE studies data for up to 13 years. Of 393 participants completing the core study, 353 (90%) entered LTE, having 3 treatment periods (TP). In TP1 (∼1.85 years), participants continued core treatment (ponesimod: 10, 20, or 40 mg QD) whereas placebo-treated participants were re-randomized (1:1:1) to respective ponesimod doses. In TP2 (TP2 and TP3 combined duration: ∼10.4 years), participants on 40 mg were re-randomized (1:1) to 10/20 mg, while others continued same dose; in TP3 all participants received 20 mg. Study outcomes included safety and efficacy (ARR, time-to 24-week confirmed-disability-accumulation [24-week CDA], total T1-weighted Gadolinium-enhanced (T1 Gd+) lesions, new/enlarging T2 lesions and Combined Unique Active Lesions [CUALs]). For 20 mg dose, total 92.4% participants experienced ≥1 TEAEs (73.1% mild/moderate severity) and 19 (13%) participants discontinued study. Mean (95% CI) ARR=0.14 (0.10-0.20); Kaplan-Meier estimate (95% CI) of confirmed relapse and 24-week CDA=52.5% (42.3-63.5) and 31.3% (22.6-42.3). Mean [SD] T1 Gd+ lesions decreased from ponesimod baseline (2.62 [7.06]) to 12.4 years (0.26 [1.48]), mean (95% CI) CUALs per participant/year=3.97 (2.75-5.73). Ponesimod treatment for up to 13 years was not associated with new safety concerns. Participants continued to experience low levels of disease activity consistently across clinical and MRI outcomes.
Cognitive fatigability is a decline in performance over the course of a sustained cognitive task. Objective, time-efficient, and reliable measures of cognitive fatigability remain limited. The Psychomotor Vigilance Task (PVT) has been utilized to quantify sustained attention deficits, but its psychometric properties for MS populations are not well established. To evaluate the reliability and validity of a 10-minute PVT of cognitive fatigability in MS patients. Twenty-two MS patients completed the 10-minute PVT on three occasions, 7-10 days apart. Cognitive fatigability was quantified as performance decline across five consecutive 2-minute blocks using reaction time (RT) and cognitive lapses. Cognitive lapses were analyzed using a ≥ 500-ms and ≥300-ms thresholds. Test-retest reliability was assessed using intraclass correlation coefficients (ICC). Convergent validity was assessed by associations between PVT indices (RT and cognitive lapses) and general cognitive fatigue, and current fatigue. Divergent validity was assessed by associations between PVT indices and global cognition and cardiorespiratory fitness. Across all sessions, participants demonstrated slowing of RT, indicating cognitive fatigability. Cognitive lapses increased over time when the ≥300-ms was applied. Test-retest reliability was excellent for mean RT (ICC=0.934), median RT (ICC=0.928), and cognitive lapses (≥500-ms [ICC=0.925] and ≥300-ms [ICC=0.829]). RT (r = 0.621) and cognitive lapses using the 500-ms (r = 0.477) and 300-ms (r = 0.560) were associated with cognitive fatigue. Neither RT nor cognitive lapse was associated with current fatigue, global cognition, or cardiorespiratory fitness. The 10-minute PVT, using RT and cognitive lapses, is a brief measure of cognitive fatigability in MS for clinical evaluation in MS fatigue.
Relapsing-remitting multiple sclerosis is a chronic inflammatory disease of the central nervous system and the leading cause of disability in young adults. In Germany, 90% of relapses are treated with high-dose intravenous glucocorticoids, despite limited evidence for long-term benefit and international preference for oral administration. Time constraints often hinder informed decision-making. The multicentre Randomized Controlled Trial (RCT) POWER@MS2 (N = 160, 2020-2023), conducted at 18 German MS-centres, aimed to promote self-determined relapse management through a complex intervention (dialogue-based decision aid, nurse-led webinar, online-chat). While RCTs demonstrate effectiveness, process evaluations are essential to understand implementation, mechanisms of impact and contextual factors. This study explored healthcare professionals' experiences and attitudes toward implementing relapse self-management and self-medication in clinical practice. A mixed-methods process evaluation followed the UK Medical Research Council- framework. Quantitative data were collected via validated questionnaires at up to three time points and analysed descriptively. Interview guides were developed based on these results. Qualitative data from neurologist and study nurse interviews were thematically analysed. Results were triangulated using a joint display. Data were collected from 55 neurologists and 17 study nurses (quantitative) and from 7 neurologists and 4 nurses (qualitative) (2020-2024). Most neurologists opposed routine steroid use, reserving it for severe relapses. Some voiced concerns about self-management, but informed patients were generally viewed as capable of safe self-medication. Study nurses gave mixed feedback on the intervention, citing overload and improved guidance. Clinicians showed openness toward implementing the intervention. Enhancing accessibility and addressing specific concerns may support broader adoption.
Adolescents and young adults (AYAs) with multiple sclerosis (MS) navigate their disease during a critical developmental window. Whilst physical disability is typically low, the impact on age-appropriate educational and vocational milestones is often underestimated. This study characterises clinical care and health-related quality of life (HRQoL) outcomes in an AYA MS cohort, focusing on the cognitive and fatigue burden and its link to vocational stability. This cross-sectional survey recruited people diagnosed with MS aged 25 years or younger at a Queensland tertiary service. Data covered demographics, clinical characteristics, symptom burden, and changes in education or employment since diagnosis. Symptom items, adapted from PedsQL™-analogous frameworks, were scored 0-100 and benchmarked against Australian Bureau of Statistics (ABS) 2025 data. A human capital model estimated the economic impact of reduced employment. Of 25 eligible patients, 21 responded (84%; 81.8% female). Mean age at diagnosis was 20.3 years; six (28.6%) were diagnosed before age 18. Fatigue (90.5%) and self-reported cognitive dysfunction (81.0%) were most prevalent. Eleven participants (52.4%) reported MS-driven change to work or study-five (23.8%) ceased and six (28.6%) reduced to part-time-with eight (38.1%) reporting increased sick days. Those not in work or study (23.8%) numbered nearly triple the 8% national benchmark. Estimated annual productivity loss for these eleven approached AUD 572,000. Substantial fatigue, cognitive, and emotional burden coexisted with marked vocational instability, despite widespread high-efficacy disease-modifying therapy use. Although the cross-sectional design precludes causal inference, the findings support broadening care to include cognitive screening, fatigue and sleep assessment, and vocational support in AYA MS management.
While the multiple sclerosis (MS) prodrome may be prolonged, healthcare use by sex >5 years pre-onset remains underexplored. We examined healthcare use up to 29 years pre-MS onset, stratified by sex. Using administrative data from Ontario, Canada (1991-2020), we compared annual physician visit rates by diagnostic chapter between MS and matched non-MS cohorts, stratified by sex. Quasi Poisson models estimated rate ratios (RRs) with 95% confidence intervals (CI). Included were 35,018 MS and 136,007 matched non-MS individuals (mean onset age ∼43 years; standard deviation ∼14 years; ∼69% female in both cohorts). Sex differences were observed for nervous system-related visits; males exhibited higher RRs from 10 years pre-onset ('year -10'), peaking in year -1 for both sexes (RRs: males=28.60;95%CI:24.10-34.00, females=13.60;95%CI:12.56-14.70). This was followed by mental disorders, being higher for males from year -4, peaking in year -1 (RRs: males=2.98;95%CI:2.73-3.25; females=2.09;95%CI:1.99-2.21), then ill-defined signs/symptoms and injury-related visits from year -3 to -1 (e.g., ill-defined signs/symptoms, RRs range: males=1.85-4.26 and females=1.67-3.27). Additionally, males had higher RRs in the 1-2 years pre-onset for respiratory, genitourinary, musculoskeletal, circulatory, digestive, and infection-related visits. Sex differences in healthcare use were evident up to 10 years pre-MS onset across multiple diagnostic chapters. Findings suggest that prodromal MS patterns differ by sex, potentially reflecting differences in symptom presentation, health-seeking behaviour, or diagnostic recognition before MS onset.
Overweight and obesity (OW/OB) are prevalent in patients with multiple sclerosis (PwMS) from disease onset and are associated with faster disease progression. While gait impairment is one of the most disabling symptoms of MS, the impact of OW/OB on gait in PwMS remains poorly understood. To investigate the impact of OW/OB on gait parameters in PwMS with low disability. In this exploratory prospective study, PwMS with low disability (EDSS < 4) were recruited during routine MS follow-up consultations between 2021 and 2025. Participants underwent a clinical assessment and three-dimensional gait analysis. Based on body mass index (BMI), participants were divided into two groups (BMI < 25 kg/m² or BMI ≥ 25 kg/m²). Spatiotemporal parameters were compared between groups. Kinematic and kinetic analyses used statistical parametric mapping. Among 29 PwMS ultimately included (mean age: 40.1 years, median EDSS: 2, 27 females), 17 were allocated to the overweight/obesity group (BMI ≥ 25 kg/m²). No statistically significant differences were between groups in terms of clinical assessment, except for body mass. Gait speed, cadence, and step length did not differ between groups. However, PwMS with OW/OB exhibited increased step width and significant reorganization of the gait cycle. Kinematic and kinetic analyses revealed a more extended hip posture and altered hip and knee joint moments in PwMS with OW/OB, while ankle biomechanics remained unchanged. OW/OB is associated with specific gait alterations in PwMS, which may potentially amplify functional vulnerability in early MS. Addressing this modifiable comorbidity may represent an important component of early, comprehensive MS care.
The role of childhood trauma (CT) and its impact on therapeutic adherence in patients with multiple sclerosis (MS) has been poorly explored. The aim of this study was to investigate the association between CT and treatment adherence, and to test the potential mediating role of the physician-patient rapport in this association. Two hundred and five patients with MS were enrolled and completed self-report measures assessing the main study variables. Mediation models analyzing the direct and indirect effects of CT on treatment adherence through the physician-patient rapport were performed while controlling for socio-demographic and clinical confounding factors. The models showed that the total effect of CT on treatment adherence was significant (B = -0.050, p < .001) and that this association was mediated by lower interpersonal physician-patient connection (B = -0.014, p = .019). These findings suggest that CT may negatively affect treatment adherence in patients with MS and that this association is significantly mediated by difficulties in the physician-patient interpersonal connection, highlighting the importance of targeted psychological interventions to improve disease management and patient care.
Biomarkers are crucial in multiple sclerosis (MS) to improve diagnosis, prognosis, and disease monitoring in this heterogeneous immune-mediated disorder. Vasoactive intestinal peptide (VIP) is an immunomodulatory and neuroprotective neuropeptide with established effects in preclinical models, but its biomarker utility remains uncertain. This review evaluated VIP expression as an MS biomarker. A systematic search of PubMed, Embase, and Cochrane databases was conducted according to PRISMA guidelines. Eligible studies included original clinical research measuring VIP levels, genetic variants, or expression of VIP and its receptors in MS patients. Reviews, non-clinical, animal or in vitro studies, and non-English publications were excluded. Study selection and data extraction were performed independently by several reviewers. Due to methodological heterogeneity, qualitative synthesis was conducted, and risk of bias was assessed using the QUADAS-2 tool. Seven studies published between 1984 and 2024 met inclusion criteria. Most studies reported reduced VIP concentrations in cerebrospinal fluid or blood compared with healthy donors, although statistical significance was inconsistent and methodological differences limited direct comparisons. One recent study suggested moderate diagnostic performance of serum VIP and subtype-specific differences. Genetic studies showed no association between VIP variants and MS susceptibility. Tissue analyses revealed heterogeneous, subtype-dependent alterations in VIP and its receptors expression. Clinical evidence supporting VIP as a biomarker in MS remains limited since most available evidence is cross-sectional and lacks prognostic utility. Substantial heterogeneity, small sample sizes, and moderate-to-high bias preclude firm conclusions. Larger studies, standardized quantification methods, and longitudinal designs are needed to clarify its biomarker value.
Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) demonstrate anti-inflammatory and neuroprotective properties in preclinical models. No formal synthesis of this evidence existed prior to this review. We conducted a PROSPERO-registered systematic review (CRD420261385854) following PRISMA 2020 guidelines. PubMed/MEDLINE and Scopus were systematically searched to June 12, 2026. Google Scholar was used as a supplementary source for grey literature. Studies examining GLP-1RAs in confirmed MS patients, EAE animal models, or case reports were eligible. Risk of bias was assessed using SYRCLE (preclinical) and Newcastle-Ottawa Scale (human studies). Narrative synthesis followed SWiM guidelines. Fifteen studies met inclusion criteria: eight preclinical animal studies (six EAE, two cuprizone models), four human observational studies, and three narrative-context studies. GLP-1RAs consistently reduced clinical severity in EAE models through multiple mechanisms (AMPK/SIRT1 activation, NLRP3 suppression, Th1/Th17 modulation, microglial deactivation). In humans, GLP-1RA use was associated with BMI reduction and vitamin D augmentation without change in EDSS or relapse rate (two cohorts; n = 109). A NARCOMS survey (n = 4181) documented 7.4% ever-use. Pharmacovigilance showed inverse reporting odds ratios with semaglutide (ROR 0.238), dulaglutide (ROR 0.165), and liraglutide (ROR 0.161). Mendelian randomization found no causal association between GLP-1R activation and MS susceptibility. Most preclinical studies were high risk of bias; human studies moderate to high. GLP-1RAs demonstrate consistent preclinical efficacy through diverse neuroprotective mechanisms. Human evidence shows metabolic benefit without neurological harm. Randomized controlled trials are urgently needed. This is the first registered, PRISMA-compliant synthesis of GLP-1RA evidence in MS.