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Relapsing-remitting multiple sclerosis (RRMS) is characterized by neuroaxonal damage, astrogliosis and inflammation. These mechanisms may already be active from early disease stages, underscoring the need for sensitive biomarkers capable of capturing treatment-related biological effects beyond conventional clinical measures. In this multicenter, ambispective, observational real-world study, the longitudinal effects of ozanimod on serum biomarkers were evaluated, during the first year of treatment in patients with low-to-moderate activity RRMS. Serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP) and cytokines associated with immune activity (IFN-γ, IL-17, IL-6, IL-10, and IL-1β) were quantified at baseline, 6 months, and 12 months using an ultrasensitive single-molecule array (SIMOA). Ozanimod was associated with significant reductions in sNfLs and sGFAP at 12 months. Concomitantly, significant decreases in IFN-γ and IL-1β were observed. IL-17 levels remained unchanged in the overall cohort but decreased in patients with higher baseline IL-17 levels. These findings demonstrate coordinated modulation of biomarkers reflecting neuroaxonal damage, astroglial activation, and inflammatory activity under ozanimod treatment in early RRMS in real-world conditions. These results highlight the biological relevance of early intervention within a therapeutic window of opportunity and support the potential utility of serum biomarkers for monitoring biological treatment effects in clinical practice.

Background Dimethyl fumarate (DMF) tolerability and safety in multiple sclerosis (MS) has been analyzed in randomized clinical trials. Real-life studies are needed to assess possible harms of this therapy in a wider MS population. Objective To evaluate DMF tolerability, safety and persistence in MS in a real-world setting. Methods We conducted a multicenter prospective study of patients who started DMF, attended in 16 public hospitals of Spain. A specific database was elaborated to collect data on most frequent adverse events (AE). Regression models were used to analyze the effect of demographic and clinical characteristics on risk of AEs and DMF discontinuation. Results We collected data of 886 patients (2681 patients/years-exposition) with median 39.5 (IQR 23, 51.5) months on DMF exposure; 25.3% were treatment naïve and 74.7% switched to DMF from other disease-modifying therapies. DMF was discontinued in 29.9% of patients, in 13.2% due to AEs and in 13.5% to inefficacy. AEs were experienced by 71.2%, being flushing the most frequent (44.1%), 5.4% developed grade III lymphopenia, without cases of grade IV. Females showed a higher risk of flushing and gastroenteric symptoms (OR 1.49, p  = 0.011; OR 1.69, p  = 0.001, respectively); lymphopenia was associated with older age (OR 1.04, p  < 0.001), and a higher EDSS with lymphopenia (OR 1.10, p  = 0.035) and DMF withdrawal (HR 1.43, p  = 0.012). No safety problems were reported. Conclusions Our findings confirm good tolerability and safety of DMF in real-world setting and suggest that women have an increased risk of AEs and higher baseline disability involves greater risk of drug discontinuation.

This study evaluated perceived workplace difficulties in 128 individuals with early-stage relapsing-remitting multiple sclerosis and low physical disability. Significant workplace challenges were reported by 40.6% of participants. External barriers, including workplace inflexibility and professional-domestic life imbalance (median 23-item multiple sclerosis (MS) Work Difficulties Questionnaire-MSWDQ-23 score: 31.3, interquartile range 6.3–56.3), represented the highest burden. Women reported higher difficulty scores than men (mean MSWDQ-23 total scores: 29.9 vs. 21.2, p = 0.010). Multivariable analysis identified fatigue (OR 1.37, 95% CI 1.17–1.61) and anxiety (OR 1.21, 95% CI 1.05–1.38) as the only independent predictors of significant workplace difficulty (p < 0.001). These findings demonstrate a significant dissociation between physical disability and functional outcomes. Vocational vulnerability is driven by non-motor symptoms rather than overt neurological impairment. Proactive clinical screening for these factors is essential to mitigate work instability and preserve long-term professional trajectories.

Shared decision-making is critical in multiple sclerosis (MS) due to the uncertainty of the disease trajectory over time and the large number of treatment options with differing efficacy, safety and administration characteristics. The aim of this study was to assess patients' decisional conflict regarding the choice of a disease-modifying therapy and its associated factors in patients with mid-stage relapsing-remitting multiple sclerosis (RRMS). A multicenter, non-interventional study was conducted. Adult patients with a diagnosis of RRMS (2017 revised McDonald criteria) and disease duration of 3 to 8 years were included. The level of uncertainty experienced by a patient when faced with making a treatment choice was assessed using the 4-item Decisional Conflict Scale. A battery of patient-reported and clinician-rated measures was administered to obtain information on symptom severity, illness perception, illness-related uncertainty, regret, MS knowledge, risk taking behavior, preferred role in the decision-making process, cognition, and self-management. Patients were recruited during routine follow-up visits and completed all questionnaires online using electronic tablets at the hospital. A multivariate logistic regression analysis was conducted. A total of 201 patients were studied. Mean age (Standard deviation) was 38.7 (8.4) years and 74.1% were female. Median disease duration (Interquartile range) was 6.0 (4.0-7.0) years. Median EDSS score was 1.0 (0-2.0). Sixty-seven (33.3%) patients reported a decisional conflict. These patients had lower MS knowledge and more illness uncertainty, anxiety, depressive symptoms, fatigue, subjective symptom severity, a threatening illness perception, and poorer quality of life than their counterparts. Lack of decisional conflict was associated with MS knowledge (Odds ratio [OR]=1.195, 95% CI 1.045, 1.383, p=0.013), self-management (OR=1.049, 95% CI 1.013, 1.093, p=0.018), and regret after a healthcare decision (OR=0.860, 95% CI 0.756, 0.973, p=0.018) in the multivariate analysis. Decisional conflict regarding the selection of a disease-modifying therapy was a common phenomenon in patients with mid-stage RRMS. Identifying factors associated with decisional conflict may be useful to implement preventive strategies that help patients better understand their condition and strengthen their self-management resources.

A multicenter study involving 204 adults with relapsing-remitting multiple sclerosis (RRMS) assessed the dimensionality and item characteristics of the Mishel-Uncertainty of Illness Scale (MUIS), a generic self-assessment tool. Mokken analysis identified two dimensions in the MUIS with an appropriate item and overall scale scalability after excluding nonclassifiable items. A refined 12-item MUIS, employing a grade response model, effectively discriminated uncertainty levels among RRMS patients (likelihood ratio test p-value = .03). These findings suggest the potential value of the 12-item MUIS as a reliable measure for assessing uncertainty associated with the course of illness in RRMS.

[This corrects the article DOI: 10.3389/fimmu.2024.1480676.].

Background: Serum neurofilament light chain (sNfL) is an established biomarker of neuroaxonal damage in multiple sclerosis (MS). Despite its prognostic utility, patient awareness of its clinical application remains poorly characterized. The objective of this study was to assess the acceptance of sNfL monitoring among patients with early-stage relapsing–remitting MS (RRMS) and identify factors predicting their willingness to adopt this tool. Methods: This non-interventional, cross-sectional study was conducted across 16 neuroimmunology clinics. We included RRMS patients with a disease duration of ≤3 years receiving disease-modifying therapy. Acceptance was assessed following a standardized educational tutorial. Multivariable logistic regression was employed to identify predictors of patient acceptance. Results: The study included 144 patients (mean age 37.6 [SD 10.3] years, 69.4% female). Only 19.4% (n = 28) had prior awareness of sNfL. However, after the tutorial, 84.0% (n = 121) expressed willingness to adopt sNfL testing. Furthermore, 62.5% (n = 90) indicated that normal sNfL levels would provide emotional reassurance between clinical visits. Patients willing to undergo testing showed higher disease knowledge, less treatment regret, and better physical quality of life and cognitive performance. In the multivariable analysis, higher disease knowledge (OR = 1.52, 95%CI 1.16–1.99; p = 0.002) and lower symptom burden (OR = 0.96, 95%CI 0.93–0.99; p = 0.038) were associated with greater acceptance. Conclusions: Patients demonstrate high receptivity to sNfL monitoring when provided with adequate clinical context. Because disease knowledge is a primary driver of acceptance, personalized educational initiatives may be a complementary strategy to facilitate the integration of precision biomarkers into MS management.

Disability accrual is mainly driven by progression independent of relapse activity, which is present even in early stages of relapsing-remitting multiple sclerosis (RRMS) and sometimes overlooked. This multicenter, non-interventional study evaluated whether patient-reported outcomes measures (PROMs) could capture disability in 189 early-stage RRMS patients (mean age: 36.1 ± 9.4 years, 71.4% female, mean disease duration: 1.4 ± 0.8 years, median EDSS: 1.0). The 9-Hole Peg Test (9-HPT), NeuroQoL Upper Extremity (NeuroQoL-UE), Timed 25-Foot Walk (T25-FW), Multiple Sclerosis Walking Scale (MSWS-12), Symbol Digit Modalities Test (SDMT), and Perceived Deficits Questionnaire (PDQ-5) were used to assess hand function, gait, and cognition, respectively. These functions were at least mildly affected in this early-stage population, finding significant correlations between PROMs and clinical assessments. PROMs could enable early-stage RRMS patients to communicate their perceived disability in different domains, assisting clinicians in disease monitoring and decision making.

Relapsing–remitting multiple sclerosis (RRMS) is characterized by neuroaxonal damage, astrogliosis and inflammation. These mechanisms may already be active from early disease stages, underscoring the need for sensitive biomarkers capable of capturing treatment-related biological effects beyond conventional clinical measures. In this multicenter, ambispective, observational real-world study, the longitudinal effects of ozanimod on serum biomarkers were evaluated, during the first year of treatment in patients with low-to-moderate activity RRMS. Serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP) and cytokines associated with immune activity (IFN-γ, IL-17, IL-6, IL-10, and IL-1β) were quantified at baseline, 6 months, and 12 months using an ultrasensitive single-molecule array (SIMOA). Ozanimod was associated with significant reductions in sNfLs and sGFAP at 12 months. Concomitantly, significant decreases in IFN-γ and IL-1β were observed. IL-17 levels remained unchanged in the overall cohort but decreased in patients with higher baseline IL-17 levels. These findings demonstrate coordinated modulation of biomarkers reflecting neuroaxonal damage, astroglial activation, and inflammatory activity under ozanimod treatment in early RRMS in real-world conditions. These results highlight the biological relevance of early intervention within a therapeutic window of opportunity and support the potential utility of serum biomarkers for monitoring biological treatment effects in clinical practice.

To ascertain the changes of serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) values in relapsing-remitting multiple sclerosis (RRMS) patients treated with ocrelizumab and their association with treatment response. Multicenter prospective study including 115 RRMS patients initiating ocrelizumab treatment between February 2020 and March 2022 followed during a year. Serum samples were collected at baseline and every 3 months to measure sNfL and sGFAP levels using single-molecule array (SIMOA) technology. Based on age and body mass index, sNfL values were standardized using z-score. NEDA (non-evidence of disease activity)-3 status was defined for patients free of disease activity after a year of follow-up. Inflammation (INFL) was considered when new relapses occurred during follow-up or new MRI lesions were found at 1-year exploration. PIRA (progression independent of relapse activity) was defined as disability progression occurring in the absence of relapses or new MRI activity. After a year on ocrelizumab, 85 patients (73.9%) achieved NEDA-3. Thirty patients did not achieve NEDA: 20 (17.4%) because of INFL and 10 (8.7%) because of PIRA. Of INFL patients, 6 (30.0%) had relapses, and 17 (85.0%) had at least one new MRI lesion at the 12-month examination. At baseline, INFL patients had higher sNfL (p = 0.0003) and sGFAP (p = 0.03) than the NEDA-3 group. PIRA patients mostly exhibited low sNfL and heterogeneous sGFAP levels. After a year, NEDA-3 and INFL patients showed similar decreases in sNfL (p < 0.0001) and sGFAP (p < 0.0001 for NEDA-3 and p = 0.001 for INFL ones). However, the decrease occurred earlier in NEDA-3 patients. Accordingly, sNfL > 1.5 z-score 3 months after ocrelizumab initiation indicated a higher risk of inflammation (OR = 13.6; p < 0.0001). Decrease in sGFAP values occurred later in both groups, with significant reductions observed at 12 months for INFL and 6 and 12 months for NEDA-3. No significant changes in sNfL or sGFAP were observed in PIRA patients. Ocrelizumab induced normalization of sNfL and sGFAP in the majority of NEDA-3 and inflammatory patients but did not cause changes in the PIRA group. Our data suggest that normalization of sNfL and sGFAP is associated with the lack of inflammatory-associated disease progression but it may not affect non-inflammatory PIRA.