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Background: Studies have reported an association between socioeconomic status and disability progression in multiple sclerosis (MS), but findings using the pre-MS individual socioeconomic status are missing. Objective: The objective was to investigate the association between education level and disability progression. Methods: All Observatoire Français de la Sclérose en Plaques (OFSEP) patients with MS clinical onset over 1960–2014, and aged ⩾25 years at MS onset were included. Education level was classified into four categories from low (primary/secondary school) to very high (master/doctoral degree). Time from MS onset to EDSS 4.0 was studied using flexible parametric survival models adjusted for age, period, and center, and stratified by phenotype (relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS)) and sex. Results: A total of 11,586 patients were included (women/men ratio = 2.5; age = 36.7 ± 8.6 years; follow-up duration 16.7 ± 9.3 years; 86.4% RMS). For women with RMS, the risk of reaching the outcome at 5 years was inversely associated with the education level (Hazard Ratio medium: 0.74 (0.63–0.87), high: 0.51 (0.43–0.62), very high: 0.39 (0.30–0.50) vs low). Results were similar for men. In PPMS, the risk was significantly different between the extreme groups (very high vs low) for women (0.45 (0.28–0.75)) and men (0.54 (0.32–0.91)), but no gradient was evident. Conclusion: Our study showed a strong association between education level and disability progression, regardless of sex and phenotype. [ABSTRACT FROM AUTHOR]

BackgroundSiponimod is a sphingosine 1-phosphate receptor modulator approved for active secondary progressive multiple sclerosis (aSPMS) in most countries; however, phase 3 EXPAND study data are from an SPMS population with/without disease activity. A need exists to characterize efficacy/safety of siponimod in aSPMS.MethodsPost hoc analysis of participants with aSPMS (≥ 1 relapse in 2 years before study and/or ≥ 1 T1 gadolinium-enhancing [Gd +] magnetic resonance imaging [MRI] lesions at baseline) receiving oral siponimod (2 mg/day) or placebo for up to 3 years in EXPAND.Endpoints3-month/6-month confirmed disability progression (3mCDP/6mCDP); 3-month confirmed ≥ 20% worsening in Timed 25-Foot Walk (T25FW); 6-month confirmed improvement/worsening in Symbol Digit Modalities Test (SDMT) scores (≥ 4-point change); T2 lesion volume (T2LV) change from baseline; number of T1 Gd + lesions baseline-month 24; number of new/enlarging (N/E) T2 lesions over all visits.ResultsData from 779 participants with aSPMS were analysed. Siponimod reduced risk of 3mCDP/6mCDP vs placebo (by 31%/37%, respectively; p

Background: While obesity has been shown to elevate the risk of developing multiple sclerosis (MS), there is a lack of strong evidence regarding its role in the disability progression and status of MS patients. Methods: This systematic review and meta-analysis aimed to provide comparative estimates of WC and BMI in patients with MS (PwMS) and to investigate potential associations between the waist circumference (WC) and body mass index (BMI) and demographic and specific MS characteristics. Adhering to PRISMA guidelines, a detailed search of the MEDLINE PubMed, Cochrane Library, and Scopus databases was conducted. Results: A total of 16 studies were included. The pooled mean WC and BMI among PwMS was estimated to be 87.27 cm (95%CI [84.07; 90.47]) and 25.73 (95%CI [25.15; 26.31]), respectively. Meta-regression models established a significant bidirectional relationship between WC and the Expanded Disability Scale (EDSS) (p < 0.001) but not between BMI and EDSS (p = 0.45). Sensitivity analyses showed no association between WC and age (p = 0.48) and a tendency between WC and disease duration (p = 0.08). Conclusions: Although WC measurements classify PwMS as normal weight, BMI measurements classify them as overweight. Therefore, WC should complement BMI evaluations in clinical practice. Additionally, our findings highlight the significant association between abdominal fat, as indicated by WC, and disease progression. Considering the heightened risk of cardiovascular comorbidity and mortality among PwMS, we recommend integrating both WC and BMI as standard anthropometric measurements in routine clinical examinations and targeted prevention strategies for PwMS. [ABSTRACT FROM AUTHOR]

Treatment options for secondary progressive MS (SPMS) are limited, especially considering that the new drugs recently approved are licensed for actively relapsing patients. We aimed to compare the disability progression in a real-world cohort of SPMS patients treated with natalizumab (NTZ) or interferon beta-1b (IFNb-1b). This multicenter retrospective enrolled patients with a diagnosis of SPMS according to 2014 Lublin criteria, who received NTZ or IFNb-1b for at least 48 months between the 1st June 2012 and the 15th May 2018 ​at 33 Italian MS centers contributing to the Italian MS Registry NTZ or IFNb-1b. Confirmed Expanded Disability Status Scale worsening (CEW) and progression independent of relapse (PIRA) were evaluated. In order to correct for non-randomization, a propensity score matching of the groups was performed. Out of 5206 MS patients identified at the time of data extraction, 421 SPMS patients treated with NTZ (224 [53.2%] females, mean age 45.3 ​± ​25.4 years) and 353 with IFNb-1b (133 [37.8%] females, mean age 48.5 ​± ​19.8 years) were enrolled. After applying the matching procedure, 102 patients were retained in the NTZ group and 98 in the IFNb-2b group. The proportion of patients who reached the 48-month 1-point CEW was significantly higher in IFNb-1b compared to NTZ group (58.2% versus 30.4%, p ​= ​0.01). The proportion of patients who developed PIRA at 48 months were significantly higher in IFNb-1b compared to NTZ (72.4% versus 40.2%, p ​= ​0.01). EDSS before treatment initiation and SPMS duration were risk factors for disability progression in terms of PIRA (HR 2.54, 25%CI 1.67–5.7; p ​= ​0.006 and HR 2.04, 25%CI 1.22–3.35; p ​= ​0.01, respectively). Patients treated with IFNb-1b were 1.64 times more to likely to develop PIRA (HR 1.64, 25%CI 1.04–4.87; p ​= ​0.001). Treatment with NTZ in SPMS patients showed more favorable disability outcomes compared to IFNb-1b with beneficial effects over 48 months.

Abstract Introduction Much of the current literature on treatment patterns and disability progression in multiple sclerosis (MS) does not distinguish between the relapsing–remitting and progressive subtypes (including primary [PPMS] and secondary progressive MS [SPMS]), or between active/nonactive disease. Current treatment options for progressive MS are limited, with only one approved product for PPMS and none specifically for nonactive SPMS. Here we report treatment patterns, disability progression, and unmet needs among patients with active and nonactive PPMS and SPMS. Methods The annual, cross-sectional survey from the Adelphi Disease Specific Program was used to collect physician-reported data on US adult patients with PPMS and SPMS, including active and nonactive disease. Treatment patterns (including the proportion of patients who were untreated with a disease-modifying therapy [DMT]), disability progression, and unmet need are described from 2016 to 2021. Results Data were collected for 2067 patients with progressive MS (PPMS, 1583; SPMS, 484). A substantial proportion of patients were untreated across all groups, and this was highest for nonactive PPMS (~ 43%). The proportion of untreated patients generally declined over time but remained high in 2018–2021 (~ 10–38%). Among treated patients, the proportion receiving infusions increased over time to ~ 34–46%, largely driven by ocrelizumab use after approval. Disability progression was reported for most patients (> 50%), including many who were receiving a DMT. Across all disease subtypes, when physicians were asked about the greatest unmet need with current DMTs, they most frequently cited effectiveness (~ 63–87%), and specifically slowing disease progression (~ 32–59%). Conclusions This analysis of physician-reported data reveals that patients with progressive MS, particularly those with nonactive disease, frequently remain untreated or continue to decline despite treatment with available DMTs. Thus there is an enduring need for safe and effective treatments for this underserved population.

While magnetic resonance imaging (MRI) is established in diagnosing and monitoring disease activity in multiple sclerosis (MS), its utility in predicting and monitoring disease progression is less clear. The authors consider changing concepts in the phenotypic classification of MS, including progression independent of relapses; pathological processes underpinning progression; advances in MRI measures to assess them; how well MRI features explain and predict clinical outcomes, including models that assess disease effects on neural networks, and the potential role for machine learning. Relapsing-remitting and progressive MS have evolved from being viewed as mutually exclusive to having considerable overlap. Progression is likely the consequence of several pathological elements, each important in building more holistic prognostic models beyond conventional phenotypes. MRI is well placed to assess pathogenic processes underpinning progression, but we need to bridge the gap between MRI measures and clinical outcomes. Mapping pathological effects on specific neural networks may help and machine learning methods may be able to optimize predictive markers while identifying new, or previously overlooked, clinically relevant features. The ever-increasing ability to measure features on MRI raises the dilemma of what to measure and when, and the challenge of translating research methods into clinically useable tools. [ABSTRACT FROM AUTHOR]

Introduction: Much of the current literature on treatment patterns and disability progression in multiple sclerosis (MS) does not distinguish between the relapsing–remitting and progressive subtypes (including primary [PPMS] and secondary progressive MS [SPMS]), or between active/nonactive disease. Current treatment options for progressive MS are limited, with only one approved product for PPMS and none specifically for nonactive SPMS. Here we report treatment patterns, disability progression, and unmet needs among patients with active and nonactive PPMS and SPMS. Methods: The annual, cross-sectional survey from the Adelphi Disease Specific Program was used to collect physician-reported data on US adult patients with PPMS and SPMS, including active and nonactive disease. Treatment patterns (including the proportion of patients who were untreated with a disease-modifying therapy [DMT]), disability progression, and unmet need are described from 2016 to 2021. Results: Data were collected for 2067 patients with progressive MS (PPMS, 1583; SPMS, 484). A substantial proportion of patients were untreated across all groups, and this was highest for nonactive PPMS (~ 43%). The proportion of untreated patients generally declined over time but remained high in 2018–2021 (~ 10–38%). Among treated patients, the proportion receiving infusions increased over time to ~ 34–46%, largely driven by ocrelizumab use after approval. Disability progression was reported for most patients (> 50%), including many who were receiving a DMT. Across all disease subtypes, when physicians were asked about the greatest unmet need with current DMTs, they most frequently cited effectiveness (~ 63–87%), and specifically slowing disease progression (~ 32–59%). Conclusions: This analysis of physician-reported data reveals that patients with progressive MS, particularly those with nonactive disease, frequently remain untreated or continue to decline despite treatment with available DMTs. Thus there is an enduring need for safe and effective treatments for this underserved population. [ABSTRACT FROM AUTHOR]

Vitamin D deficiency is involved in the pathogenesis of multiple sclerosis (MS), a severe autoimmune demyelinating disease of the central nervous system. The gene polymorphism Cdx-2 (rs11568820, G/A) seriously influences the trancriptional activity of the vitamin D receptor (VDR) that binds the vitamin D responsive elements of target genes including HLA-DRB1*15. The aim of the present study in Slovaks was to analyse the association of Cdx-2 variants with the risk of MS and disability progression, and to assess the DRB1*15:01 allele as a possible confounding factor. In total, 493 MS patients and 417 healthy controls were involved in this study. The genotyping of Cdx-2 was performed using restriction analysis; DRB1*15:01 positivity was determined by a high-resolution melting analysis of its surrogate marker rs3135388 (G/A). Our results did not prove any allelic association between Cdx-2 and a risk of MS (minor allele A − 0.181 in patients vs. 0.161 in controls, OR = 1.15,.95 CI = 0.90–1.47, p = 0.289). The logistic regression analysis, adjusted for sex and age, showed no differences in Cdx-2 genotype counts when using an additive, dominant or recessive genetic model (p = 0.351, 0.150, 0.240 respectively). The Cdx-2 variants were also not associated with disease disability progression, evaluated using the Multiple Sclerosis Severity Score. The HLA-DRB1*15:01 allele was found to strongly increase the risk of MS in our study (0.300 in patients vs. 0.101 in controls, OR = 3.83,.95 CI = 2.94–4.99, p = 1.016 × 10−26, dominant genetic model OR = 4.62,.95 CI = 3.40–6.26, p = 9.1 × 10−23). In summary, we found the Cdx-2 as a single genetic marker not to be associated with MS development or progression in Slovaks, independently of HLA-DRB1*15:01 status. [ABSTRACT FROM AUTHOR]

Background: The clinical relevance of serum glial fibrillary acidic protein (sGFAP) concentration as a biomarker of MS disability progression independent of acute inflammation has yet to be quantified. Objective: To test whether baseline values and longitudinal changes in sGFAP concentration are associated with disability progression without detectable relapse of magnetic resonance imaging (MRI) inflammatory activity in participants with secondary-progressive multiple sclerosis (SPMS). Methods: We retrospectively analyzed longitudinal sGFAP concentration and clinical outcome data from the Phase 3 ASCEND trial of participants with SPMS, with no detectable relapse or MRI signs of inflammatory activity at baseline nor during the study (n = 264). Serum neurofilament (sNfL), sGFAP, T2 lesion volume, Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), and composite confirmed disability progression (CDP) were measured. Linear and logistic regressions and generalized estimating equations were used in the prognostic and dynamic analyses. Results: We found a significant cross-sectional association between baseline sGFAP and sNfL concentrations and T2 lesion volume. No or weak correlations between sGFAP concentration and changes in EDSS, T25FW, and 9HPT, or CDP were observed. Conclusion: Without inflammatory activity, changes in sGFAP concentration in participants with SPMS were neither associated with current nor predictive of future disability progression. [ABSTRACT FROM AUTHOR]

This study aimed to determine whether peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell–inner plexiform layer (GCIPL) thickness thresholds for single-time-point swept-source optical coherence tomography (SS-OCT) measures can differentiate the clinical outcomes of treatment-naïve people with multiple sclerosis (pwMS). A total of 275 patients with the clinically isolated syndrome (n = 23), benign MS (n = 8), relapsing–remitting MS (n = 185), secondary progressive MS (n = 28), primary progressive MS (n = 31), and with no history of optic neuritis were included. The mean Expanded Disability Status Scale (EDSS) score was 3.0 ± 1.6. The cut-off values of pRNFL (87 µm and 88 µm) and GCIPL (70 µm) thicknesses have been adopted from previous studies using spectral-domain OCT. PwMS with pRNFL ≤87 µm and ≤88 µm had a longer disease duration, more advanced disability, and more frequently progressive MS variants compared to those with greater pRNFL thicknesses. In distinguishing pwMS with disability greater than or equal to the mean EDSS score (EDSS ≥ 3) from those with less severe disability, GCIPL thickness <70 µm had the highest sensitivity, while pRNFL thickness ≤87 µm had the greatest specificity. The optimal cut-off values differentiating patients with EDSS ≥ 3 from those with less severe disability was 63 µm for GCIPL thickness and 93.5 µm for pRNFL thickness. In conclusion, pRNFL and GCIPL thickness thresholds for single-time-point SS-OCT measurements may be helpful in differentiating the disability status of treatment-naïve pwMS. [ABSTRACT FROM AUTHOR]

Background: The current standard endpoint to assess disability accumulation in multiple sclerosis (MS) clinical trials is the time to the first confirmed disability progression, which excludes subsequent progression events. Including recurrent progression events may permit a more comprehensive assessment of treatment effects on disability progression. Objective: To propose a definition of recurrent disability progression events and to compare time-to-first and recurrent event analysis. Methods: Recurrent disability progression events were defined by expanding the recommended first event definition. Marginal recurrent event methods (negative binomial model, Lin–Wei–Yang–Ying model) were compared with Cox regression in data from three randomized controlled trials in relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS), and in simulated randomized controlled trial data. Results: The recurrent event analyses included a substantially larger number of progression events compared with the time-to-first-event analyses (+7.5% and +9.9% in the RMS trials and +22.7% in the PPMS trial). The increase in the number of events resulted in more precise treatment effect estimates and a corresponding gain in statistical power. Conclusion: Our results support the use of recurrent event data analysis, especially in progressive MS trials, to improve estimates of treatment effects, increase statistical power, and better capture the clinically meaningful long-term disability progression experience. [ABSTRACT FROM AUTHOR]

Background: Upper and lower limb disabilities are hypothesized to have partially independent underlying (network) disturbances in multiple sclerosis (MS). Objective: This study investigated functional network predictors and longitudinal network changes related to upper and lower limb progression in MS. Methods: Two-hundred fourteen MS patients and 58 controls underwent functional magnetic resonance imaging (fMRI), dexterity (9-Hole Peg Test) and mobility (Timed 25-Foot Walk) measurements (baseline and 5 years). Patients were stratified into progressors (>20% decline) or non-progressors. Functional network efficiency was calculated using static (over entire scan) and dynamic (fluctuations during scan) approaches. Baseline measurements were used to predict progression; significant predictors were explored over time. Results: In both limbs, progression was related to supplementary motor area and caudate efficiency (dynamic and static, respectively). Upper limb progression showed additional specific predictors; cortical grey matter volume, putamen static efficiency and posterior associative sensory (PAS) cortex, putamen, primary somatosensory cortex and thalamus dynamic efficiency. Additional lower limb predictors included motor network grey matter volume, caudate (dynamic) and PAS (static). Only the caudate showed a decline in efficiency over time in one group (non-progressors). Conclusion: Disability progression can be predicted using sensorimotor network measures. Upper and lower limb progression showed unique predictors, possibly indicating different network disturbances underlying these types of progression in MS. [ABSTRACT FROM AUTHOR]

Background: Overall Disability Response Score (ODRS) is a composite endpoint including Expanded Disability Status Scale, Timed 25-foot Walk, and 9-Hole Peg Test, designed to quantify both disability improvement and worsening in multiple sclerosis (MS). Objective: To assess the sensitivity and clinical meaningfulness of ODRS using natalizumab Phase 3 data sets (AFFIRM in relapsing-remitting MS and ASCEND in secondary progressive MS). Methods: Differences in ODRS over 96 weeks, ODRS at Week 96, and slope of ODRS change per year between natalizumab and placebo groups were analyzed. Correlation between ODRS and changes in patient-reported outcomes was also analyzed. Results: The difference (95% confidence interval (CI)) in the ODRS over 96 weeks between natalizumab and placebo groups was 0.34 (0.21–0.46) in AFFIRM (p < 0.001), and 0.18 (0.03–0.34) in ASCEND (p = 0.021). Significant differences between treatment arms were also observed in ODRS at Week 96 and in the slope of change per year in both studies. There was a significant linear correlation between ODRS at Week 96 and the change from baseline in both the physical and mental components of the 36-item Short Form Survey (SF-36) in both studies. Conclusion: This analysis supports ODRS as a sensitive and potentially clinically meaningful disability outcome measure in MS. [ABSTRACT FROM AUTHOR]

Background: Smoking and obesity interact to exacerbate the risk of hypertension, diabetes, and cardiovascular disease, but their potential synergistic effects on outcomes in multiple sclerosis (MS) have not been well studied. We aimed to study whether smoking and obesity interact to affect disease progression and cognitive function in patients with MS., Methods: Incident cases from the population-based case-control study Epidemiological Investigation of MS (EIMS) were categorized by smoking and obesity status at diagnosis and followed up to 15 years postdiagnosis through the Swedish MS registry (n = 3336). Cox regression was used to analyze outcomes, including clinical disease worsening (CDW), progression to Expanded Disability Status Scale (EDSS) levels 3 and 4, physical worsening as measured by a 7.5-point increase in the MS Impact Scale (MSIS) physical score, and cognitive decline, defined as an 8-point or greater reduction on the Symbol Digit Modalities Test (SDMT). Interaction effects on the additive scale were assessed by combining dichotomous variables for smoking (nonsmoker = 0, smoker = 1) and obesity (nonobese = 0, obese = 1), yielding four categories: 0/0 (reference category), 0/1, 1/0, and 1/1., Results: Additive interactions between smoking and obesity were identified for CDW (attributable proportion due to interaction [AP] 0.18, 95% CI 0.03-0.30), progression to EDSS 4 (AP 0.18, 95% CI 0.08-0.26), MSIS-Physical score worsening (AP 0.32, 95% CI 0.21-0.42), and cognitive decline (AP 0.27, 95% CI 0.19-0.35)., Conclusions: Smoking and obesity appear to synergistically worsen MS progression and cognitive functioning, with the observed additive interactions across most outcomes suggesting that these factors partly share common biological pathways contributing to disease progression., (© 2025 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: We re-examined the per-region response amplitudes and delays obtained from multifocal pupillographic objective perimetry (mfPOP) after 10 years in 44 persons living with multiple sclerosis (PwMS), both to examine which parts of the visual field had progressed in terms of response properties and to examine if the baseline data could predict the overall progression of disease. Methods: Expanded Disability Status Scale (EDSS) scores were assessed in 2009 and 2019. Both eyes of each participant were concurrently tested at 44 locations/eye on both occasions. Several measures of clinical progression were examined, using logistic regression to determine the odds of progression. Results: At the second examination the 44 PwMS (31 females) were aged 61.0 ± 12.2 y. Mean EDSS had not changed significantly (3.69 ± 1.23 in 2009, 3.81 ± 2.00 in 2019). mfPOP delay increased progressively from inferior to superior regions of the visual fields while amplitudes demonstrated a temporal to nasal gradient. The mean of the 3 most delayed visual field regions was correlated with progression of MS by 2019 (p = 0.023). Logistic regression indicated a significant association between delay and odds of progression (p = 0.045): an individual with 3 regions at least 1 SD (40 ms) slower than the mean in 2009 had 2.05× (±SE: 1.43× to 2.95×) the odds of progression by 2019. A 1 SD shorter delay was associated with 2.05× lower odds of progression. Amplitude changes were not predictive of progression. Significance: mfPOP may provide a rapid, convenient method of monitoring and predicting MS progression.

Objective: The objective of this study was to explore the potential causal associations of body mass index, height, weight, fat mass, fat percentage and non-fat mass in the whole body, arms, legs and trunk (henceforth, 'anthropometric measures') with multiple sclerosis (MS) risk and severity. We also investigated the potential for reverse causation between anthropometric measures and MS risk. Methods: We conducted a two-sample univariable, multivariable and bidirectional Mendelian randomisation (MR) analysis. Results: A range of features linked to obesity (body mass index, weight, fat mass and fat percentage) were risk factors for MS development and worsened the disease's severity in MS patients. Interestingly, we were able to demonstrate that height and non-fat mass have no association with MS risk or MS severity. We demonstrated that the association between anthropometric measures and MS is not subject to bias from reverse causation. Conclusions: Our findings provide evidence from human genetics that a range of features linked to obesity is an important contributor to MS development and MS severity, but height and non-fat mass are not. Importantly, these findings also identify a potentially modifiable factor that may reduce the accumulation of further disability and ameliorate MS severity. [ABSTRACT FROM AUTHOR]

Background: It is unclear whether drugs approved for the treatment of progressive multiple sclerosis (PMS) are effective in disability progression only because of their effect on the inflammatory component of the disease. Objective: This meta-analysis aimed to evaluate whether the benefits of PMS treatments are mediated by its effect on the active component of the disease. Methods: We conducted a systematic search to identify randomised, double-blind, placebo-controlled trials evaluating the efficacy of disease-modifying therapies on disability progression for primary or secondary PMS. The primary endpoint of the analysis was disability progression based on the expanded disability status scale. A subgroup meta-analysis evaluated the effects of treatment according to disease activity at baseline. Results: Twelve trials (a total of 8659 PMS cases) were selected. Analysis of the included trials demonstrated that treatment benefit appears to be mainly confined to the group with active disease (hazard ratio (HR) = 0.67; 95% confidence interval (CI): 0.58–0.79) as compared to the group with inactive disease (HR = 0.90; 95% CI: 0.79–1.02, interaction test: p = 0.005). Conclusions: This study showed that the benefit of treating patients with PMS was mostly confined to those with the more active disease. Drugs targeting specific pathological processes leading to disability progression remain necessary. [ABSTRACT FROM AUTHOR]

Background and purpose: Therapeutic management of relapsing–remitting multiple sclerosis (RRMS) has evolved towards early treatment. The objective was to assess the impact of early treatment initiation on disability progression amongst RRMS first‐line‐treated patients. Methods: This study included all incident RRMS cases starting interferon or glatiramer acetate for the first time from 1 January 1996 to 31 December 2012 (N = 5279) from 10 MS expert Observatoire Français de la Sclérose en Plaques centres. The delay from treatment start to attaining an irreversible Expanded Disability Status Scale (EDSS) score of 3.0 was compared between the early group (N = 1882; treated within 12 months following MS clinical onset) and the later group using propensity score weighted Kaplan–Meier methods, overall and stratified by age. Results: Overall, the restricted mean time before reaching EDSS 3.0 from treatment start was 11 years and 2 months for patients treated within the year following MS clinical onset and 10 years and 7 months for patients treated later. Thus, early treated patients gained 7 months (95% confidence interval [CI] 4–11 months) in the time to reach EDSS 3.0 compared to patients treated later (treatment start delayed by 28 months). The difference in restricted mean time was respectively 6 months (95% CI 1–10 months) and 14 months (95% CI 4–24 months) in the ≤40 years age group and in the >40 years age group, in favour of the early group. Conclusions: Early treatment initiation resulted in a significant reduction of disability progression amongst patients with RRMS, and also amongst older patients. [ABSTRACT FROM AUTHOR]

BackgroundNo evidence of disease activity (NEDA; defined as no 12-week confirmed disability progression, no protocol-defined relapses, no new/enlarging T2 lesions and no T1 gadolinium-enhancing lesions) using a fixed-study entry baseline is commonly used as a treatment outcome in multiple sclerosis (MS).ObjectiveThe objective of this paper is to assess the effect of ocrelizumab on NEDA using re-baselining analysis, and the predictive value of NEDA status.MethodsNEDA was assessed in a modified intent-to-treat population (n = 1520) from the pooled OPERA I and OPERA II studies over various epochs in patients with relapsing MS receiving ocrelizumab (600 mg) or interferon beta-1a (IFN β-1a; 44 μg).ResultsNEDA was increased with ocrelizumab vs IFN β-1a over 96 weeks by 75% (p

Background: Very little is known regarding the impact of post traumatic stress disorder (PTSD) on the course of multiple sclerosis (MS). Objectives: To explore the impact of pre-existing PTSD on MS relapses, magnetic resonance imaging (MRI) activity, and disability in a large population-based cohort. Methods: Military Veterans with MS and PTSD prior to symptom onset (MSPTSD, n = 96) were identified using the Department of Veterans Affairs MS databases. MSPTSD cases were matched to MS controls without PTSD (n = 95). Number of relapses, number of new T2 lesions and new gadolinium lesions on brain MRI, and neurological disability were abstracted between 2015 and 2019. Results: The mean annualized relapse rate was greater in the MSPTSD group versus controls (0.23 vs 0.06, respectively; p < 0.05), as was the annualized mean number of new T2 and gadolinium-enhancing lesions on brain MRI (0.52 vs 0.16 and 0.29 vs 0.08, respectively; p < 0.05). Disability accrual (time to Disability Status Scale 6.0) was more rapid (23.7 vs 29.5 years, p < 0.05) in relapsing MS patients with PTSD. Conclusion: Patients with MSPTSD have higher disease activity and reach disability endpoints more rapidly than controls. This is the first study to show PTSD as a potentially modifiable risk factor for MS relapses, MRI activity, and disability. [ABSTRACT FROM AUTHOR]

Background and purpose: Effectiveness of autologous haematopoietic stem cell transplantation (AHSCT) in relapsing–remitting multiple sclerosis (MS) is well known, but in secondary–progressive (SP)‐MS it is still controversial. Therefore, AHSCT activity was evaluated in SP‐MS using low‐dose immunosuppression with cyclophosphamide (Cy) as a comparative treatment. Methods: In this retrospective monocentric 1:2 matched study, SP‐MS patients were treated with intermediate‐intensity AHSCT (cases) or intravenous pulses of Cy (controls) at a single academic centre in Florence. Controls were selected according to baseline characteristics adopting cardinality matching after trimming on the estimated propensity score. Kaplan–Meier and Cox analyses were used to estimate survival free from relapses (R‐FS), survival free from disability progression (P‐FS), and no evidence of disease activity 2 (NEDA‐2). Results: A total of 93 SP‐MS patients were included: 31 AHSCT, 62 Cy. Mean follow‐up was 99 months in the AHSCT group and 91 months in the Cy group. R‐FS was higher in AHSCT compared to Cy patients: at Year 5, 100% versus 52%, respectively (p < 0.0001). P‐FS did not differ between the groups (at Year 5: 70% in AHSCT and 81% in Cy, p = 0.572), nor did NEDA‐2 (p = 0.379). A sensitivity analysis including only the 31 "best‐matched" controls confirmed these results. Three neoplasms (2 Cy, 1 AHSCT) and two fatalities (2 Cy) occurred. Conclusions: This study provides Class III evidence, in SP‐MS, on the superior effectiveness of AHSCT compared to Cy on relapse activity, without differences on disability accrual. Although the suppression of relapses was observed in the AHSCT group only, AHSCT did not show advantages over Cy on disability, suggesting that in SP‐MS disability progression becomes based more on noninflammatory neurodegeneration than on inflammation. [ABSTRACT FROM AUTHOR]

Background: Interventions targeting the adaptive immune response are needed in multiple sclerosis (MS). Objective: Evaluate laquinimod's efficacy, safety, and tolerability in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: CONCERTO was a randomized, double-blind, placebo-controlled, phase-3 study. RRMS patients were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 or 1.2 mg or placebo for ⩽24 months (n = 727, n = 732, and n = 740, respectively). Primary endpoint was time to 3-month confirmed disability progression (CDP). The laquinimod 1.2-mg dose arm was discontinued (1 January 2016) due to cardiovascular events at high doses. Safety was monitored throughout the study. Results: CONCERTO did not meet the primary endpoint of significant effect with laquinimod 0.6-mg versus placebo on 3-month CDP (hazard ratio: 0.94; 95% confidence interval: 0.67–1.31; p = 0.706). Secondary endpoint p values were nominal and non-inferential. Laquinimod 0.6 mg demonstrated 40% reduction in percent brain volume change from baseline to Month 15 versus placebo (p < 0.0001). The other secondary endpoint, time to first relapse, and annualized relapse rate (an exploratory endpoint) were numerically lower (both, p = 0.0001). No unexpected safety findings were reported with laquinimod 0.6 mg. Conclusion: Laquinimod 0.6 mg demonstrated only nominally significant effects on clinical relapses and magnetic resonance imaging (MRI) outcomes and was generally well tolerated. Clinical trial registration number: ClinicalTrials.gov (NCT01707992). [ABSTRACT FROM AUTHOR]

Background: Evidence suggests that early highly efficacious therapy in relapsing multiple sclerosis is superior to escalation strategies. Objective: A cost-consequence analysis simulated different treatment scenarios with ofatumumab (OMB), dimethyl fumarate (DMF) and glatiramer acetate (GA): immediate OMB initiation as first treatment, early switch to OMB after 1 year on DMF/GA, late switch after 5 years or no switch. Methods: An EDSS-based Markov model with a 10-year time horizon was applied. Cycle transitions included EDSS progression, improvement or stabilization, treatment discontinuation, relapse or death. Input data were extracted from OMB trials, a network meta-analysis, published literature, and publicly available sources. Results: The late switch compared to the immediate OMB scenario resulted in a lower proportion of patients with EDSS 0–3 (Δ − 7.5% DMF; Δ − 10.3% GA), more relapses (Δ + 0.72 DMF; Δ + 1.23 GA) and lower employment rates (Δ − 4.0% DMF; Δ − 5.6% GA). The same applies to late versus early switches. No switch scenarios resulted in worse outcomes. Higher drug acquisition costs in the immediate OMB and early switch scenarios were almost compensated by lower costs for patient care and productivity loss. Conclusion: Immediate OMB treatment and an early switch improves clinical and productivity outcomes while remaining almost cost neutral compared to late or no switches. [ABSTRACT FROM AUTHOR]

Abstract Background Women are more susceptible to multiple sclerosis (MS) than men by a ratio of approximately 3:1. However, being male is a risk factor for worse disability progression. Inflammatory genes have been linked to susceptibility, while neurodegeneration underlies disability progression. Thus, there appears to be a differential effect of sex on inflammation versus neurodegeneration. Further, gray matter (GM) atrophy is not uniform across the brain in MS, but instead shows regional variation. Here, we study sex differences in neurodegeneration by comparing regional GM atrophy in a cohort of men and women with MS versus their respective age- and sex-matched healthy controls. Methods Voxel-based morphometry (VBM), deep GM substructure volumetry, and cortical thinning were used to examine regional GM atrophy. Results VBM analysis showed deep GM atrophy in the thalamic area in both men and women with MS, whereas men had additional atrophy in the putamen as well as in localized cortical regions. Volumetry confirmed deep GM loss, while localized cortical thinning confirmed GM loss in the cerebral cortex. Further, MS males exhibited worse performance on the 9-hole peg test (9HPT) than MS females. We observed a strong correlation between thalamic volume and 9HPT performance in MS males, but not in MS females. Conclusion More regional GM atrophy was observed in men with MS than women with MS, consistent with previous observations that male sex is a risk factor for worse disease progression.

Abstract Background Multiple sclerosis (MS) is a chronic immune mediated disease and the progressive phase appears to have significant neurodegenerative mechanisms. The classification of the course of progressive MS (PMS) has been re-organized into categories of active vs. not active inflammatory disease and the presence vs. absence of gradual disease progression. Clinical trial experience to date in PMS with anti-inflammatory medications has shown limited effect. Andrographolide is a new class of anti-inflammatory agent, that has been proposed as a potential drug for autoimmune disorders, including MS. In the present trial, we perform an exploratory pilot study on the efficacy and safety of andrographolide (AP) compared to placebo in not active PMS. Methods A pilot clinical trial using 140 mg oral AP or placebo twice daily for 24 months in patients with not active primary or secondary progressive MS was conducted. The primary efficacy endpoint was the mean percentage brain volume change (mPBVC). Secondary efficacy endpoints included 3-month confirmed disability progression (3-CDP) and mean EDSS change. Results Forty-four patients were randomized: 23 were assigned to the AP group, and 21 were assigned to the placebo group. The median baseline EDSS of both groups was 6.0. Annualized mPBVC was − 0.679% for the AP group and − 1.069% for the placebo group (mean difference: -0.39; 95% CI [− 0.836–0.055], p = 0.08, relative reduction: 36.5%). In the AP group, 30% had 3-CDP compared to 41% in the placebo group (HR: 0.596; 95% CI [0.200–1.777], p = 0.06). The mean EDSS change was − 0.025 in the AP group and + 0.352 in the placebo group (mean difference: 0.63, p = 0.042). Adverse events related to AP were mild rash and dysgeusia. Conclusions AP was well tolerated and showed a potential effect in reducing brain atrophy and disability progression, that need to be further evaluated in a larger clinical trial. Trial registration ClinicalTrials.gov NCT02273635 retrospectively registered on October 24th, 2014.

BACKGROUND: Ozanimod treatment was associated with significantly fewer relapses than interferon beta-1a (IFN) in phase 3 relapsing multiple sclerosis (RMS) trials and provided sustained control of disability progression for up to 5 years in an open-label study. OBJECTIVES: To determine the incidence and predictors of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) in participants in the RADIANCE and DAYBREAK trials. METHODS: Participants in phase 3 RADIANCE (NCT02047734) were randomly assigned oral ozanimod 0.46 mg/day or 0.92 mg/day or intramuscular IFN 30 μg/week for 24 months, and completers were eligible to enroll in an ozanimod 0.92-mg open-label extension trial (DAYBREAK [phase 3; NCT02576717]; data cutoff: February 1, 2022). In participants continuously treated with ozanimod 0.92 mg or those who initially received IFN, we assessed 6-month confirmed disability progression (CDP; ≥ 1-point increase in Expanded Disability Status Scale [EDSS] score from baseline, confirmed after 6 months), and participants were considered to have RAW if CDP onset occurred ≤ 90 days of a relapse or PIRA if CDP onset occurred without relapse or > 90 days after a relapse. For relapse with incomplete recovery, baseline EDSS was reset > 90 days after relapse onset to identify the next PIRA event. Kaplan-Meier analysis and univariable Cox proportional hazards regression assessed incidence over time and predictors, respectively. P values were determined via Wald χ2 test. RESULTS: A total of 363 participants who received continuous ozanimod 0.92 mg and 346 who switched from IFN were included. In up to 8 years of follow-up, 75.9% of participants were free of 6-month CDP. Among participants with CDP, 44.3% and 54.5% of those treated with continuous ozanimod had RAW or PIRA, respectively; 8% had both. Of the participants who switched from IFN to ozanimod, 57.8% and 43.4% had RAW or PIRA, respectively; 4.8% had both. RAW was observed in 10.7% of participants treated with continuous ozanimod and 13.9% of those who switched from IFN to ozanimod; PIRA was observed in 13.2% of participants treated with continuous ozanimod and 10.4% of those who switched from IFN to ozanimod. In both treatment groups, predictors of RAW with nominal P < .05 included RADIANCE baseline EDSS score (positive association) and whole brain, cortical gray matter, and thalamic volumes (negative associations); these variables were not predictors of PIRA. CONCLUSIONS: In ozanimod-treated participants with RMS, RAW and PIRA contributed similarly to disability progression over 8 years. Higher baseline EDSS scores and lower baseline whole brain, cortical gray matter, and thalamic volumes were predictive of RAW. FUNDING: Bristol Myers Squibb. Writing and editorial assistance was provided by Noud van Helmond, MD, PhD, of Peloton Advantage, LLC, an OPEN Health company, and was funded by Bristol Myers Squibb. [ABSTRACT FROM AUTHOR]

Objectives: Investigation of the comorbidity burden in persons with multiple sclerosis (PwMS) has become increasingly important. The aim of this study was to investigate the relationships of cardiovascular disease (CVD) comorbidities and type 2 diabetes with the disability progression. Materials & Methods: The retrospective cohort study was conducted at the Clinic of Neurology, Belgrade. The Belgrade MS population Registry, which comprises 2725 active MS cases, was used as the source of data. The mean duration of the disease was 21.6 ± 12.5 years. Expanded Disability Status Scale (EDSS) was followed in all PwMS in the Registry. In the statistical analysis, the Cox proportional hazard regression analysis and Kaplan‐Meier curve were performed. Results: Hypertension statistically significantly contributed to more rapid reaching investigated levels of irreversible disability (EDSS 4.0, 6.0, and 7.0), while the presence of any of the investigated CVD comorbidities and type 2 diabetes significantly contributed to faster reaching EDSS 4.0 and EDSS 6.0. In a multivariable model, progression index (PI) was singled out (HR = 3.171, p <.001), indicating that higher progression index (PI) was an independent predictor of CVD occurrence in MS patients. In the case of type 2 diabetes, PI (p <.001) and MS phenotype (p =.015) were statistically significant in multivariable Cox regression analysis. Conclusions: Our study confirms the impact of CVD comorbidities and type 2 diabetes in MS on the progression of disability as measured by EDSS in the large cohort of PwMS from the population Registry. [ABSTRACT FROM AUTHOR]

Background and purpose: Modifiable lifestyle factors, including diet, may affect clinical outcomes in multiple sclerosis (MS). This study assessed the relationships between diet, and disability, fatigue, and depression risk in people with MS. Methods: Participants from the Health Outcomes and Lifestyle In a Sample of people with Multiple sclerosis (HOLISM) international cohort were assessed over 2.5 years. Dietary data were obtained using a modified Diet Habits Questionnaire (DHQ), disability using the calculated Patient‐determined MS Severity Score (P‐MSSS), fatigue using the Fatigue Severity Scale, and depression risk using the Patient Health Questionnaire‐2. Participants reported whether they were experiencing symptoms due to a recent relapse. Cross‐sectional and prospective relationships of diet and disease outcomes were explored, adjusted for relevant confounders. Results: Among 1,346 participants, higher DHQ scores showed significant dose‐dependent associations with lower frequencies of severe disability, fatigue, and depression risk, cross‐sectionally. Prospectively, higher baseline DHQ scores were associated with a lower risk of increasing disability, those above the median having 41% and 36% lower risk of increasing disability, and 0.30 P‐MSSS points less disability progression, but were not associated with fatigue or depression risk. Meat consumption was associated with 0.22 P‐MSSS points higher disability cross‐sectionally, while prospectively, baseline meat consumption was associated with 76% higher risk of increasing disability and 0.18 P‐MSSS points higher disability progression. Dairy consumption showed mixed associations cross‐sectionally and prospectively. Conclusions: These results show that better quality of diet, as well as not consuming meat, were associated with reduced disability progression in people with MS. Substantiation of these findings in other settings may inform opportunities to manage disability progression in people with MS using dietary modifications. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), with variable prognosis, and significant social impact. The prevalence in Colombia was 7.52 per 100,000 inhabitants during 2013 and has increased by 60% from 2009 to 2013. Objective: identify the sociodemographic and clinical factors related to disability progression in MS. Methodology: A descriptive study with a cross- sectional analytical component was carried out using disability progression as the dependent variable. The medical records of 216 patients living within the Metropolitan Area of Valle de Aburrá, Antioquia, Colombia. Results: In the multivariate mod- el, by adjusting the MS phenotype for the other variables, the following factors were associated with a greater likelihood of having disability progression: primary progressive (OR 3.246, 95% CI 1.294 - 8.145, P-value = 0.012); cerebellar complications (OR 2.498, 95% CI 1.186 - 5.265, P-value = 0.016); anti- depressant drugs (OR 2.336, 95% CI 1.054 - 5.176, P-value = 0.037); the presence of other neurological diseases (OR 3.392, 95% CI 1.139 - 10.102, P-value = 0.028); and active lesions on magnetic resonance imaging (OR 2.162, 95% CI 1.042 - 4.485, -P = 0.038). Those with pathologies other than cardiovascular, metabolic, mental, autoimmune, or infectious diseases had a lower likelihood of disability progression (OR 0.138, 95% CI 0.024 - 0.799, P-value = 0.028). Conclusions: The results of the present work can serve as a starting point for monitoring patients, contributing to problem-solving, and improving the quality of life for people with this disease. [ABSTRACT FROM AUTHOR]

Background: Neuroactive steroids (NASs) exert multiple biological effects on development and inflammation. The effects of NASs on disease progression in multiple sclerosis (MS) are uncertain, prompting analyses of NAS profiles during the transition from clinically isolated syndrome (CIS) to relapsing-remitting (RR) MS. Methods: Subjects with CIS or RRMS and healthy controls (HCs) were recruited; demographic and clinical data as well as disability scores measured by the Expanded Disability Status Scale (EDSS) were recorded. Matched plasma NAS and amino acid (AA) concentrations were measured. Results: HC (n = 17), CIS (n = 31), and RRMS (n = 33) groups showed similar ages and sex distribution although disability scores were higher in the RRMS group. The conversion rate of CIS to RRMS group was 51.6% (n = 16) during a mean follow-up period of 1.85 years. The RRMS group showed significantly higher mean allopregnanolone, aspartate, and taurine concentrations with lower epiallopregnanolone concentrations than CIS patients, and higher L-serine-O-phosphate and lower alanine, arginine, and glutamine concentrations than the HC group. Among CIS and RRMS groups, multivariate hierarchical regressions revealed that higher concentrations of plasma tetrahydrodeoxycorticosterone (THDOC) may predict disability worsening. Conclusions: RRMS and CIS patients exhibited differing concentrations of both NASs and AAs in plasma while both THDOC and pregnanolone might serve as biomarkers of disability worsening. [ABSTRACT FROM AUTHOR]

Background and purpose: Studies reporting the baseline determinants of cognitive performance and treatment effect on cognition in patients with multiple sclerosis (MS) are limited. We investigated the baseline correlates of cognition and the long‐term treatment effects of fingolimod 0.5 mg once daily on cognitive processing speed and attention in patients with relapsing‐remitting MS. Methods: This post hoc analysis pooled data from the phase 3 FREEDOMS and FREEDOMS II trials (N = 1556). We assessed the correlation between baseline patient demographic and disease characteristics and baseline 3‐second Paced Auditory Serial Addition Test (PASAT‐3) scores (Spearman's rank test) and the changes from baseline in PASAT‐3 (mixed model repeated measures model) in the fingolimod and placebo (up to 24 months) or placebo‐fingolimod switched (from Month 24 up to 120 months) groups. Additionally, the predictive value of PASAT‐3 score for future disease outcomes was assessed (Cox or logistic regression models). Results: Among the variables assessed, lower PASAT‐3 score at baseline correlated with higher disease burden (total brain volume, T2 lesion volume, and Expanded Disability Status Scale score), longer disease duration and older age (p < 0.0001 for all). Fingolimod significantly improved PASAT‐3 scores from baseline versus placebo at 6 (1.3; p = 0.0007), 12 (1.1; p = 0.0044) and 24 months (1.1; p = 0.0028), with a sustained effect (overall treatment effect p = 0.0012) up to 120 months. Improvements were seen regardless of baseline cognitive status (PASAT quartile). Baseline PASAT‐3 score was predictive of both clinical and magnetic resonance imaging measures of disease activity at Month 24 (p < 0.001 for all). Conclusion: Early fingolimod treatment may offer long‐term cognitive benefit in patients with relapsing‐remitting MS. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the accuracy of a data-driven approach, such as machine learning classification, in predicting disability progression in MS. Methods: We analyzed structural brain images of 163 subjects diagnosed with MS acquired at two different sites. Participants were followed up for 2–6 years, with disability progression defined according to the expanded disability status scale (EDSS) increment at follow-up. T2-weighted lesion load (T2LL), thalamic and cerebellar gray matter (GM) volumes, fractional anisotropy of the normal appearing white matter were calculated at baseline and included in supervised machine learning classifiers. Age, sex, phenotype, EDSS at baseline, therapy and time to follow-up period were also included. Classes were labeled as stable or progressed disability. Participants were randomly chosen from both sites to build a sample including 50% patients showing disability progression and 50% patients being stable. One-thousand machine learning classifiers were applied to the resulting sample, and after testing for overfitting, classifier confusion matrix, relative metrics and feature importance were evaluated. Results: At follow-up, 36% of participants showed disability progression. The classifier with the highest resulting metrics had accuracy of 0.79, area under the true positive versus false positive rates curve of 0.81, sensitivity of 0.90 and specificity of 0.71. T2LL, thalamic volume, disability at baseline and administered therapy were identified as important features in predicting disability progression. Classifiers built on radiological features had higher accuracy than those built on clinical features. Conclusions: Disability progression in MS may be predicted via machine learning classifiers, mostly evaluating neuroradiological features. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate long-term effectiveness of natalizumab (NTZ) and to determine demographic, clinical, and radiological predictors regarding long-term disease activity (≥ 7 years) in a nationwide observational cohort, using data collected prospectively in a real-life setting. Materials and methods: We analysed data from 230 patients from the Austrian Multiple Sclerosis Treatment Registry (AMSTR), who had started treatment with NTZ at any time since 2006 and stayed on NTZ for at least 7 years without treatment gap of more than three months. Results: Estimated mean annualised relapse rates (ARR) over a mean treatment period of 9.3 years were 0.07 for NTZ. Sustained EDSS progression for 12 weeks was observed in 36 (19%) patients and for 24 weeks in 31 (16.3%) cases. Sustained EDSS regression for 12 and 24 weeks was seen in 45 (23.7%) and 42 (22.1%) cases. The baseline parameters ≥ 1 Gadolinium-enhancing MRI lesion(s) [incidence rate ratio (IRR) of 0.409 (95% CI 0.283–0.593), p = 0.001], ARR ≤ 1 in the prior 12 month before treatment initiation with NTZ [IRR of 0.353 (95% CI 0.200–0.623), p = 0.001] and EDSS ≤ 1 [incidence rate ratio (IRR) of 0.081 (95% CI 0.011–0.581), p = 0.012] were significantly associated with a reduced relapse risk, whereas a disease duration ≤ 5 years increased significantly the ARR [IRR of 1.851 (95% CI 1.249–2.743), p = 0.002]. The only predictive baseline parameter for experiencing EDSS progression (sustained for 12 and 24 weeks) was age > 35 years [HR of 2.482 (95% CI 1.110–5.549), p = 0.027, and HR of 2.492 (95% CI 1.039–5.978), p = 0.041, respectively]. Conclusions: These real-life data show a stable disease course regarding relapse activity and disease progression under NTZ treatment for more than 7 years. The main predictors for disease activity were higher relapse rate before treatment initiation, higher disability, shorter disease duration and absence of Gadolinium-enhancing MRI lesions at baseline. Older age at NTZ start was the only significant risk factor for disease progression over long-term. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is a disease continuum from a clinically isolated syndrome through relapsing remitting MS to secondary progressive MS (SPMS). There are numerous therapeutic approaches with proven efficacy on relapse and focal inflammatory disease aspects, whereas treatment of secondary progression and associated neuropathological aspects continues to be a challenge. Objective: Overview of the current options for disease-modifying treatment of SPMS. Material and methods: Results of randomized clinical trials are presented and evaluated on a substance-specific basis. Results: Randomized SPMS trials showed inconsistent results regarding disability progression for beta interferons and negative results for natalizumab. Oral cladribine and ocrelizumab reduced disability progression in relapsing MS but have not been specifically studied in an SPMS population. Positive results for mitoxantrone are only partially applicable to current SPMS patients. For siponimod, a substance that crosses the blood-brain barrier, the EXPAND trial demonstrated a significant reduction in the risk of disability progression in typical SPMS. Subgroup analyses suggest a higher efficacy of siponimod in younger patients with active SPMS. Conclusion: There is limited evidence for the use of previously available disease-modifying treatment in SPMS. Siponimod represents a new therapeutic option for active SPMS, defined by relapses or focal inflammatory MRI activity. To establish the therapeutic indications for siponimod, early detection of relapse-independent progression as well as differentiation of active SPMS from inactive disease are of critical importance. [ABSTRACT FROM AUTHOR]

• No significant sex differences in time-to-relapse or disability progression in early multiple sclerosis. • Minimal or no sex-related differences in other clinical outcomes, including cognitive function, quality of life, fatigue, and depression in early multiple sclerosis. • Only minor disease progression in MS during early stage. • Findings suggest that neither being male, nor female is a relevant factor influencing disease outcomes in early-stage RRMS. Previous evidence suggests sex differences in the clinical course of relapsing remitting multiple sclerosis (RRMS), but comprehensive early-stage prospective studies are lacking. We aim to quantify the impact of sex on clinical outcomes in early-stage RRMS. Utilizing prospective cohort data, we assessed the impact of biological sex on time-to-relapse, disability progression (Expanded Disability Status Scale [EDSS]), extremity function (Nine-Hole Peg Test, Timed-25-food walk test), cognition (Paced Auditory Serial Addition Test , Symbol Digit Modalities Test), quality-of-life (Hamburg Quality of Life Questionnaire in Multiple Sclerosis , Short-Form-36), fatigue (Fatigue Severity Scale, Fatigue Scale for Motor and Cognitive functions), and depression (Beck Depression Inventory-II) in clinically isolated syndrome (CIS) or RRMS patients. Inclusion was within 12 months of symptom onset. Linear, negative binomial, mixed, and Cox models estimated male vs. female effects at the four-year follow-up including baseline-to-follow-up course. We included 149 patients (65.1 % female). Eighty-five completed four-year follow-up. No sex differences in time-to-relapse emerged (HR = 0.91;95 %CI = 0.53–1.58). Males had no increased risk of EDSS worsening (OR = 0.75;95 %CI = 0.21–2.35) compared to females. Similarly, minor/no sex differences emerged in other outcomes. Four years after first manifestation, neither disease activity (disability progression and relapse rate) nor patient-reported outcomes showed sex-related disparities in this early-MS-cohort. : NCT01371071 [ABSTRACT FROM AUTHOR]

Abstract Background No longitudinal, long-term, follow-up studies have explored the association between presence and severity of variations in extracranial venous anatomy, and clinical outcomes in patients with multiple sclerosis (MS). Objective This prospective 5-year follow-up study assessed the relationship of variations in extracranial venous anatomy, indicative of chronic cerebrospinal venous insufficiency (CCSVI) on Doppler sonography, according to the International Society for Neurovascular Disease (ISNVD) proposed consensus criteria, with clinical outcomes and disease progression in MS patients. Methods 90 MS patients (52 relapsing-remitting, RRMS and 38 secondary-progressive, SPMS) and 38 age- and sex-matched HIs were prospectively followed for 5.5 years. Extracranial and transcranial Doppler-based venous hemodynamic assessment was conducted at baseline and follow-up to determine the extent of variations in extracranial venous anatomy. Change in Expanded Disability Status Scale (∆EDSS), development of disability progression (DP) and annualized relapse rate (ARR) were assessed. Results No significant differences were observed in MS patients, based on their presence of variations in extracranial venous anatomy at baseline or at the follow-up, in ∆EDSS, development of DP or ARR. While more MS patients had ISNVD CCSVI criteria fulfilled at baseline compared to HIs (58% vs. 37%, p = 0.03), no differences were found at the 5-year follow-up (61% vs. 56%, p = 0.486). Discussion This is the longest follow-up study assessing the longitudinal relationship between the presence of variations in extracranial venous anatomy and clinical outcomes in MS patients. Conclusion: The presence of variations in extracranial venous anatomy does not influence clinical outcomes over the 5-year follow-up in MS patients.

Abstract Background and purpose Evidence on regional changes resulting from neurodegenerative processes underlying primary progressive multiple sclerosis (PPMS) is still limited. We assessed brain region volumes and their relationship with disability progression and cognitive function in PPMS patients. Methods This was an MRI analysis of 43 patients from the prospective Understanding Primary Progressive Multiple Sclerosis (UPPMS) cohort study. MRI scans were performed within 3 months before enrollment and at month 12. Results Gray matter volume of declive and white matter volumes adjacent to left straight gyrus, right calcarine sulcus, and right inferior occipital gyrus significantly decreased from baseline to month 12. Baseline white matter volumes adjacent to right amygdala and left cuneus significantly differed between patients with and without disability progression, as well as baseline gray matter volumes of left cuneus, right parahippocampal gyrus, right insula, left superior frontal gyrus, declive, right inferior temporal gyrus, right superior temporal gyrus (pole), and right calcarine sulcus. Baseline gray matter volumes of right cuneus and right superior temporal gyrus positively correlated with 12‐month Selective Reminding Test and Word List Generation performance, respectively. Gray matter changes in right superior semilunar lobe and white matter adjacent to left declive and right cerebellar tonsil also positively correlated with Word List Generation scores, while white matter change in left inferior semilunar lobe positively correlated with Symbol Digit Modalities Test performance after 12 months. Conclusions White and gray matter volumes of specific brain regions could predict disability progression and cognitive performance of PPMS patients after one year.

Background: Longitudinal evolution of cortical thickness (CTh) in different MS phenotypes has been rarely studied. Aim: To investigate the regional pattern and 1-year progression of cortical thinning in relapsing-remitting (RR) and progressive (P) MS. Methods: 3T high-resolution T1-weighted magnetic resonance imaging (MRI) was obtained from 86 patients (75 RRMS, 11 PMS) and 34 healthy controls (HC) at three European sites at baseline and 1-year follow-up. Using FreeSurfer, baseline CTh between-group differences, longitudinal CTh changes and their correlations with clinical and MRI variables were assessed. Results: Baseline frontal, parietal and sensorimotor atrophy was found in MS versus HC. Such pattern was driven by RRMS, while PMS showed additional parietal, insular and sensorimotor cortical atrophy versus RRMS. At 1-year versus baseline, additional frontal and temporal cortical thinning was detected in RRMS patients, while a widespread CTh reduction was found in PMS patients (significant at time-by-group interaction vs RRMS). In MS, baseline fronto-parietal atrophy correlated with more severe disability and higher lesion volume. Baseline inferior parietal CTh decrease and 1-year temporal cortical thinning correlated with more severe disability. Conclusion: Parieto-temporal baseline CTh abnormalities and thinning pattern over time characterized the main MS clinical phenotypes and were associated with 1-year disability worsening. [ABSTRACT FROM AUTHOR]

Background: Although confirmed disability progression (CDP) is a common outcome in multiple sclerosis (MS) clinical trials, its predictive value for long-term outcomes is uncertain. Objective: To investigate whether CDP at month 24 predicts subsequent disability accumulation in MS. Methods: The Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital includes participants with relapsing-remitting MS or clinically isolated syndrome with Expanded Disability Status Scale (EDSS) scores ≤5 (N = 1214). CDP was assessed as a predictor of time to EDSS score 6 (EDSS 6) and to secondary progressive MS (SPMS) using a Cox proportional hazards model; adjusted models included additional clinical/participant characteristics. Models were compared using Akaike's An Information Criterion. Results: CDP was directionally associated with faster time to EDSS 6 in univariate analysis (HR = 1.61 [95% CI: 0.83, 3.13]). After adjusting for month 24 EDSS, CDP was directionally associated with slower time to EDSS 6 (adjusted HR = 0.65 [0.32, 1.28]). Models including CDP had worse fit statistics than those using EDSS scores without CDP. When models included clinical and magnetic resonance imaging measures, T2 lesion volume improved fit statistics. Results were similar for time to SPMS. Conclusions: CDP was less predictive of time to subsequent events than other MS clinical features. [ABSTRACT FROM AUTHOR]

Background: Disability progression independent of relapses (PIRA) has been described as a frequent phenomenon in relapsing-remitting multiple sclerosis (RRMS). Objective: To compare the occurrence of disability progression in relapse-free RRMS patients on interferon-beta/glatiramer acetate (IFN/GA) versus fingolimod. Methods: This study is based on data from the Swiss association for joint tasks of health insurers. Time to relapse and 12-month confirmed disability progression were compared between treatment groups using multivariable Cox regression analysis with confounder adjustment. Inverse-probability weighting was applied to correct for the bias that patients on fingolimod have a higher chance to remain relapse-free than patients on IFN/GA. Results: We included 1640 patients (64% IFN/GA, 36% fingolimod, median total follow-up time = 4–5 years). Disease-modifying treatment (DMT) groups were well balanced with regard to potential confounders. Disability progression was observed in 155 patients (8.8%) on IFN/GA and 51 (7.6%) on fingolimod, of which 44 and 23 were relapse-free during the initial DMT, respectively. Adjusted standard regression analysis on all patients indicated that those on fingolimod experience less frequently disability progression compared with IFN/GA (hazard ratio = 0.53 (95% confidence interval = 0.37–0.76)). After bias correction, this was also true for patients without relapses (hazard ratio=0.56 (95% confidence interval = 0.32–0.98). Conclusion: Our analysis indicates that fingolimod is superior to IFN/GA in preventing disability progression in both relapsing and relapse-free, young, newly diagnosed RRMS patients. [ABSTRACT FROM AUTHOR]

Background: Greater brain atrophy is associated with disability progression (DP) in patients with multiple sclerosis (PwMS). However, methodological challenges limit its routine clinical use. Objective: To determine the feasibility of atrophy measures as markers of DP in PwMS scanned across different MRI field strengths. Methods: A total of 980 PwMS were scanned on either 1.5 T or 3.0 T MRI scanners. Demographic and clinical data were retrospectively collected, and the presence of DP was determined according to standard clinical trial criteria. Lateral ventricular volume (LVV) change was measured with the NeuroSTREAM technique on clinical routine T2-FLAIR images. Percent brain volume change (PBVC) was measured using SIENA and ventricular cerebrospinal fluid (vCSF) % change was measured using VIENA and SIENAX algorithms on 3D T1-weighted images (WI). Stable vs. DP PwMS were compared using analysis of covariance (ANCOVA). Mixed modeling determined the effect of MRI scanner change on MRI-derived atrophy measures. Results: Longitudinal LVV analysis was successful in all PwMS. SIENA-based PBVC and VIENA-based changes failed in 37.6% of cases, while SIENAX-based vCSF failed in 12.9% of cases. PwMS with DP (n = 241) had significantly greater absolute (20.9% vs. 8.7%, d = 0.66, p

Background: Although quantitative measures from research-quality MRI provide a means to study multiple sclerosis (MS) pathology in vivo, these metrics are often unavailable in legacy clinical datasets. Objective: To determine how well an automatically-generated quantitative snapshot of brain pathology, measured only on clinical routine T2-FLAIR MRI, can substitute for more conventional measures on research MRI in terms of capturing multi-factorial disease pathology and providing similar clinical relevance. Methods: MRI with both research-quality sequences and conventional clinical T2-FLAIR was acquired for 172 MS patients at baseline, and neurologic disability was assessed at baseline and five-years later. Five measures (thalamus volume, lateral ventricle volume, medulla oblongata volume, lesion volume, and network efficiency) for quantifying disparate aspects of neuropathology from low-resolution T2-FLAIR were applied to predict standard research-quality MRI measures. They were compared in regard to association with future neurologic disability and disease progression over five years. Results: The combination of the five T2-FLAIR measures explained most of the variance in standard research-quality MRI. T2-FLAIR measures were associated with neurologic disability and cognitive function five-years later (R2 = 0.279, p

Background: Fractal geometry measures the morphology of the brain and detects CNS damage. We aimed to assess the longitudinal changes on brain’s fractal geometry and its predictive value for disease worsening in patients with Multiple Sclerosis (MS). Methods: We prospectively analyzed 146 consecutive patients with relapsing-remitting MS with up to 5 years of clinical and brain MRI (3 T) assessments. The fractal dimension and lacunarity were calculated for brain regions using box-counting methods. Longitudinal changes were analyzed in mixed-effect models and the risk of disability accumulation were assessed using Cox Proportional Hazard regression analysis. Results: There was a significant decrease in the fractal dimension and increases of lacunarity in different brain regions over the 5-year follow-up. Lower cortical fractal dimension increased the risk of disability accumulation for the Expanded Disability Status Scale [HR 0.9734, CI 0.8420–0.9125; Harrell C 0.59; Wald p 0.038], 9-hole peg test [HR 0.9734, CI 0.8420–0.9125; Harrell C 0.59; Wald p 0.0083], 2.5% low contrast vision [HR 0.4311, CI 0.2035–0.9133; Harrell C 0.58; Wald p 0.0403], symbol digit modality test [HR 2.215, CI 1.043–4.705; Harrell C 0.65; Wald p 0.0384] and MS Functional Composite-4 [HR 0.55, CI 0.317–0.955; Harrell C 0.59; Wald p 0.0029]. Conclusions: Fractal geometry analysis of brain MRI identified patients at risk of increasing their disability in the next five years.

Background: Methodological challenges limit the use of brain atrophy and lesion burden measures in the follow-up of multiple sclerosis (MS) patients on clinical routine datasets. Objective: To determine the feasibility of T2-FLAIR-only measures of lateral ventricular volume (LVV) and salient central lesion volume (SCLV), as markers of disability progression (DP) in MS. Methods: A total of 3,228 MS patients from 9 MSBase centers in 5 countries were enrolled. Of those, 2,875 (218 with clinically isolated syndrome, 2,231 with relapsing-remitting and 426 with progressive disease subtype) fulfilled inclusion and exclusion criteria. Patients were scanned on either 1.5 T or 3 T MRI scanners, and 5,750 brain scans were collected at index and on average after 42.3 months at post-index. Demographic and clinical data were collected from the MSBase registry. LVV and SCLV were measured on clinical routine T2-FLAIR images. Results: Longitudinal LVV and SCLV analyses were successful in 96% of the scans. 57% of patients had scanner-related changes over the follow-up. After correcting for age, sex, disease duration, disability, disease-modifying therapy and LVV at index, and follow-up time, MS patients with DP (n = 671) had significantly greater absolute LVV change compared to stable (n = 1,501) or disability improved (DI, n = 248) MS patients (2.0 mL vs. 1.4 mL vs. 1.1 mL, respectively, ANCOVA p

Abstract Background In the PRISMS study, interferon beta-1a subcutaneously (IFN β-1a SC) reduced clinical and radiological disease burden at 2 years in patients with relapsing–remitting multiple sclerosis. The study aimed to characterize efficacy of IFN β-1a SC 44 μg and 22 μg three times weekly (tiw) at Year 1. Methods Exploratory endpoints included annualized relapse rate (ARR), 3-month confirmed disability progression (1-point Expanded Disability Status Scale increase if baseline was