Effect of repurposed simvastatin on disability progression in secondary progressive multiple sclerosis (MS-STAT2): a phase 3, randomised, double-blind, placebo-controlled trial.

Uncontrolled evidence suggests that autologous hematopoietic stem cell transplantation (AHSCT) can be effective in people with active secondary progressive multiple sclerosis (SPMS). In this study, we compared the effect of AHSCT with that of other anti-inflammatory disease-modifying therapies (DMTs) on long-term disability worsening in active SPMS. We collected data from the Italian Bone Marrow Transplantation Study Group and the Italian Multiple Sclerosis Register. Patients were considered eligible if treatment had been started after the diagnosis of SPMS. Disability worsening was assessed by the cumulative proportion of patients with a 6-month confirmed disability progression (CDP) according to the Expanded Disability Status Scale (EDSS) score. Key secondary endpoints were the EDSS time trend after treatment start and the prevalence of disability improvement over time. Time to first CDP was assessed by means of proportional hazard Cox regression models. A linear mixed model with a time × treatment group interaction was used to assess the longitudinal EDSS time trends. Prevalence of improvement was estimated using a modified Kaplan-Meier estimator and compared between groups by bootstrapping the area under the curve. Seventy-nine AHSCT-treated patients and 1975 patients treated with other DMTs (beta interferons, azathioprine, glatiramer-acetate, mitoxantrone, fingolimod, natalizumab, methotrexate, teriflunomide, cyclophosphamide, dimethyl fumarate, and alemtuzumab) were matched to reduce treatment selection bias using propensity score and overlap weighting approaches. Time to first CDP was significantly longer in transplanted patients (hazard ratio [HR] = 0.50; 95% CI = 0.31-0.81; p = 0.005), with 61.7% of transplanted patients free from CPD at 5 years. Accordingly, EDSS time trend over 10 years was higher in patients treated with other DMTs than in AHSCT-treated patients (+0.157 EDSS points per year compared with -0.013 EDSS points per year; interaction p < 0.001). Patients who underwent AHSCT were more likely to experience a sustained disability improvement: 34.7% of patients maintained an improvement (a lower EDSS than baseline) 3 years after transplant vs 4.6% of patients treated by other DMTs (p < 0.001). The use of AHSCT in people with active SPMS is associated with a slowing of disability progression and a higher likelihood of disability improvement compared with standard immunotherapy. This study provides Class III evidence that autologous hematopoietic stem cell transplants prolonged the time to CDP compared with other DMTs.

SummaryBackgroundNeurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource.MethodsWe did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25–65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0–6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259.FindingsBetween Jan 29, 2015, and June 22, 2016, 445 patients were randomly allocated amiloride (n=111), fluoxetine (n=111), riluzole (n=111), or placebo (n=112). The primary analysis included 393 patients who were allocated amiloride (n=99), fluoxetine (n=96), riluzole (n=99), and placebo (n=99). No difference was noted between any active treatment and placebo in PBVC (amiloride vs placebo, 0·0% [95% CI −0·4 to 0·5; p=0·99]; fluoxetine vs placebo −0·1% [–0·5 to 0·3; p=0·86]; riluzole vs placebo −0·1% [–0·6 to 0·3; p=0·77]). No emergent safety issues were reported. The incidence of serious adverse events was low and similar across study groups (ten [9%] patients in the amiloride group, seven [6%] in the fluoxetine group, 12 [11%] in the riluzole group, and 13 [12%] in the placebo group). The most common serious adverse events were infections and infestations. Three patients died during the study, from causes judged unrelated to active treatment; one patient assigned amiloride died from metastatic lung cancer, one patient assigned riluzole died from ischaemic heart disease and coronary artery thrombosis, and one patient assigned fluoxetine had a sudden death (primary cause) with multiple sclerosis and obesity listed as secondary causes.InterpretationThe absence of evidence for neuroprotection in this adequately powered trial indicates that exclusively targeting these aspects of axonal pathobiology in patients with secondary progressive multiple sclerosis is insufficient to mitigate neuroaxonal loss. These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials. This trial provides a template for future simultaneous testing of multiple disease-modifying medicines in neurological medicine.FundingEfficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership, UK Multiple Sclerosis Society, and US National Multiple Sclerosis Society.

Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study

Therapeutic options for patients with secondary progressive multiple sclerosis (SPMS) are limited. To analyze disability progression in patients with SPMS treated with rituximab compared with matched control patients never treated with rituximab. This retrospective cohort study analyzed data obtained from patients with SPMS at 3 multiple sclerosis centers located in Basel and Lugano, Switzerland, and Amsterdam, the Netherlands, from 2004 to 2017. Patients were included for analysis if they had received a diagnosis of SPMS, were treated (57 eligible; 54 included) or never treated (504 eligible; 59 included) with rituximab, and had at least 1 follow-up visit. The variables used for propensity score matching were sex, age, Expanded Disability Status Scale (EDSS) score, and disease duration. Follow-up duration was up to 10 years, with a mean (SD) of 3.5 (2.6) years for rituximab-treated patients and 5.4 (2.4) years for controls in the total cohort and a mean (SD) of 3.5 (2.7) years for rituximab-treated patients and 4.8 (2.2) years for controls in the matched cohort. Comparing EDSS score progression in patients with SPMS (treated with rituximab vs not treated with rituximab) using propensity score matching. The primary end point was progression of EDSS score after baseline, and the secondary end point was time to confirmed disability progression. After 1:1 propensity score matching, 44 matched pairs (88 patients) were included in the analysis. At baseline, patients treated with rituximab had a mean (SD) age of 49.7 (10.0) years, mean (SD) disease duration of 18.2 (9.4) years, and mean (SD) EDSS score of 5.9 (1.4), and 26 (59%) were women, whereas controls had a mean (SD) age of 51.3 (7.4) years, mean (SD) disease duration of 19.4 (8.7) years, and mean (SD) EDSS score of 5.70 (1.29), and 27 (61%) were women. In the covariate-adjusted analysis of the matched set, patients with SPMS who were treated with rituximab had a significantly lower EDSS score during a mean (SD) follow-up of 3.5 (2.7) years (mean difference, -0.52; 95% CI, -0.79 to -0.26; P < .001). Time to confirmed disability progression was significantly delayed in the rituximab-treated group (hazard ratio, 0.49; 95% CI, 0.26-0.93; P = .03). In this study, patients with SPMS treated with rituximab had a significantly lower EDSS score for up to 10 years of follow-up and a significantly delayed confirmed progression compared with matched controls, suggesting that B-cell depletion by rituximab may be therapeutically beneficial in these patients. A prospective randomized clinical trial with a better level of evidence is needed to confirm the efficacy of rituximab in such patients.

Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension

To study the relationship between retinal nerve fiber layer (RNFL) thickness and brain atrophy using magnetic resonance imaging (MRI) with bicaudate ratio (BCR) in patients with multiple sclerosis (MS) with different levels of disease severity. We also assessed whether RNFL thickness correlated with Expanded Disability Status Scale (EDSS) score. The participants consisted of 88 patients with MS and 59 age- and sex-matched healthy control subjects. Eleven patients had clinically isolated syndrome (CIS), 68 patients had relapsing-remitting MS (RR-MS), and 9 patients had secondary progressive MS. Patients and controls were evaluated using optical coherence tomography (OCT, Cirrus) and scanning laser polarimetry with variable corneal compensation (GDx VCC). Patients underwent the same brain MRI scanning protocol. Disability was evaluated according to the EDSS. The BCR was calculated by dividing the minimum intercaudate distance by brain width along the same level. The BCR was higher in patients with MS (0.12 ± 0.03) than in controls (0.08 ± 0.009) (P < 0.001). OCT average RNFL thickness in patients with MS was significantly lower (84.51 ± 14.27 μm) than in control subjects (98.44 ± 6.83 μm). BCR was correlated with OCT average RNFL thickness (r = -0.48, P = 0.002) in patients with MS without optic neuritis. Significant correlations were found between average RNFL thickness and EDSS (r = -0.43, P = 0.003). Additionally, there were correlations between BCR with GDx parameters in patients with MS without optic neuritis. This study shows that RNFL thickness correlates with BCR and with MS subtypes. Additionally, our study indicates that OCT is better suited for MS assessment than GDx. We conclude that the damage of retinal axons appears related to brain damage in patients with MS.

BackgroundAlthough confirmed disability progression (CDP) is a common outcome in multiple sclerosis (MS) clinical trials, its predictive value for long-term outcomes is uncertain.ObjectiveTo investigate whether CDP at month 24 predicts subsequent disability accumulation in MS.MethodsThe 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.ResultsCDP 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.ConclusionsCDP was less predictive of time to subsequent events than other MS clinical features.

In a retrospective multicentre cohort study, we explored the association between brain atrophy and multiple sclerosis (MS) disability using different MRI scanners and protocols at multiple sites. Relapse-onset MS patients were included if they had two clinical MRIs 12 months apart and ≥2 Expanded Disability Status Scale (EDSS) scores. Percentage brain volume change (PBVC), percentage grey matter change (PGMC), fluid-attenuated inversion recovery (FLAIR) lesion volume change, whole brain volume (BV), grey matter volume (GMV), FLAIR lesion volume and T1 hypointense lesion volume were assessed by icobrain. Disability was measured by EDSS scores and 6-month confirmed disability progression (CDP). Of the 260 relapse-onset MS patients included, 204 (78%) MRI pairs were performed in the same scanner and 56 (22%) pairs were from different scanners. 93% of patients were on treatment and mean PBVC was -0.26% (±0.52). During the median follow-up of 2.8 years from the second MRI, median EDSS change was 0.0 and 12% patients experienced 6-month CDP. Cross-sectional BV and GMV at the later MRI showed a trend for association with CDP (HR 0.99; 95% CI 0.98 to 1.00; p=0.06). Only BV at the later MRI was associated with EDSS score (β -0.03, SE 0.01, p<0.001) and the rate of EDSS change over time (β -0.001, SE 0.0003, p=0.02). There was no association between longitudinal PBVC or PGMC and CDP or EDSS (p>0.05). In this highly treated MS cohort with low disability accrual, only cross-sectional BV showed an association with future EDSS scores, while no MRI metric predicted 6-month CDP. These findings highlight the limitations of current clinical MRI measures in predicting disability worsening in real-world settings.

One of the promising areas in the pathogenetic treatment of multiple sclerosis (MS) is anti-B-cell therapy using ocrelizumab, an anti-CD20 monoclonal antibody. The drug is indicated for primary progressive MS (PPMS), secondary progressive MS (SPMS) and exacerbations, and highly active MS. Objective : to analyze the use of the drug in 32 patients with different types of MS in everyday neurological practice. Patients and methods . The investigation included 32 patients diagnosed with MS using the 2017 McDonald criteria: 12 patients with PPMS, 12 with highly active MS and 8 with SPMS and exacerbations. The median Expanded Disability Status Scale (EDSS) score was 4.0; the most severe course of the disease was observed in patients with SPMS. All the patients received a treatment cycle of 600-mg intravenous ocrelizumab injections (with an infusion pump) every 6 months; the initial dose was by 300 mg every 2 weeks. The follow-up period was 6 to 18 months. Results and discussion. During ocrelizumab therapy, the patients with PPMS showed stabilization of EDSS score; and 6 (50%) had even its slight decrease by 0.5–1.0 scores, which may be caused by compensation for the existing symptoms due to pathogenetic treatment. In highly active MS, only 1 of the 12 ocrelizumab-treated patients had an ongoing exacerbation of the disease. During a subsequent 6–18-month follow-up, magnetic resonance imaging revealed that none of the patients had manifestations of MS activity; the EDSS score decreased in all the patients, indicating their achievement of stable remission. Six (75%) of the 8 patients with SPMS and exacerbations also displayed a decrease in EDSS score in the absence of exacerbations. No adverse events, including infusion reactions, were recorded during drug administration. The drug has a good tolerance and safety profile and ease-to-use. Conclusion . Ocrelizumab therapy with will be able to improve the quality of treatment in patients with different types of MS, which is of great medical and social importance

Aim This study aims to investigate the intricate interplay between lesion localization and kappa light chain (KLC) levels in patients diagnosed with Secondary Progressive Multiple Sclerosis (SPMS), unraveling the underlying mechanisms contributing to lesion distribution and potential drivers of the observed relentless progression of neurological disability in SPMS. Material and Methods An observational study was conducted with a cohort of 23 SPMS patients meeting diagnostic criteria. Clinical, demographic data, and MRI scans were collected of 14 patients who had received any treatment in the past year. Serum KLC levels were measured, and statistical analyses were performed to identify correlations between age, KLC levels, and lesion distribution. Results The study revealed a significant positive correlation between age and the number of periventricular lesions, indicating a potential influence of aging processes on lesion distribution dynamics. Serum KLC levels showed a noteworthy positive correlation with the number of infratentorial lesions. However, no significant correlations were observed between Expanded Disability Status Scale (EDSS) scores and lesion counts. Conclusion The findings underscore the complex and multifaceted nature of SPMS pathogenesis. While age and serum KLC levels demonstrated associations with periventricular and infratentorial lesions, the lack of correlation between EDSS scores and lesion counts emphasizes the heterogeneous aspects of SPMS progression. These insights highlight the importance of a comprehensive understanding beyond lesion quantification to unravel the intricate mechanisms driving disability progression in SPMS.

Approaches and challenges in the diagnosis and management of secondary progressive multiple sclerosis: A Central Eastern European perspective from healthcare professionals

Utilization of the multiple sclerosis functional composite in follow-up: relationship to disease phenotype, disability and treatment strategies

Objective To investigate the efficacy, safety and compliance of interferon β-1b(IFNβ-1b) in Chinese patients with multiple sclerosis(MS). Methods This multicenter, non-interventional, retrospective study was conducted in 22 hospitals in northern China to analyze data from 385 Chinese patients with MS treated with IFNβ-1b enrolled from January 2011 to February 2014. Annualized relapse rate(ARR), MRI activity, Expanded Disability Status Scale(EDSS) scores, side effects and discontinuation rates were assessed. Results (1) Among 27 patients with clinically isolated syndrome(CIS), 92.6% patients had no clinical relapse; 96.3% patients had no new T2 lesion and 100.0% patients had no enhanced lesion on MRI; no statistically significant difference was found in EDSS scores in 14 patients before and after treatment(t= 1.344, P= 0.202). (2) Among 346 patients with relapsing remitting MS(RRMS), 164 patients received treatment more than 1 year, and their median ARR reduced from 1.0 before treatment to 0 after treatment (Z=-9.667, P= 0.000); 309(89.3%) patients had no new T2 lesion and 321(92.8%) patients had no enhanced lesion on MRI; 178 patients' EDSS scores reduced from 3.3±1.8 before treatment to 2.9±1.9 after treatment(t= 4.603, P= 0.000). (3) Among 12 patients with secondary progressive MS, 7 patients received treatment more than 1 year, and their median ARR reduced from 0.3 before treatment to 0 after treatment, though the difference was not statistically significant (Z=-1.690, P= 0.091); 11(91.7%) patients had no new T2 lesion and 12(100.0%) patients had no enhanced lesion on MRI; no statistically significant difference was found in EDSS scores in 7 patients before and after treatment (t=-0.795, P= 0.457). (4)Totally 25.4% patients stopped using drug, mainly due to economical reason(25.5%), side effects(19.4%) and perception of lack of efficacy(15.3%). The common side effects included flu-like symptoms, injection site reactions, increased liver transaminases and abnormal count of blood cells. Conclusions IFNβ-1b reduces clinical relapse and MRI lesion activity of Chinese patients with CIS and RRMS, improves EDSS score of patients with RRMS, and has good safety. The economical reason is the most important one for Chinese patients to stop using the drug. Key words: Multiple sclerosis; Interferon-beta; Medication adherence; Retrospective studies

The ability to better predict disease progression represents a major unmet need in multiple sclerosis (MS), and would help to inform therapeutic and management choices. To develop multilevel models using longitudinal data on disease progression in patients with relapsing-remitting MS (RRMS) or secondary-progressive MS (SPMS); and to use these models to estimate the association of disease-modifying therapy (DMT) with progression. Secondary analysis of three MS cohorts. Two natural history cohorts: University of Wales Multiple Sclerosis (UoWMS) cohort, UK, and British Columbia Multiple Sclerosis (BCMS) cohort, Canada. One observational DMT-treated cohort: UK MS risk-sharing scheme (RSS). The UoWMS database has > 2000 MS patients and the BCMS database (as of 2009) has > 5900 MS patients. All participants who had definite MS (RRMS/SPMS), who reached the criteria set out by the Association of British Neurologists (ABN) for eligibility for DMT [i.e. age ≥ 18 years, Expanded Disability Status Scale (EDSS) score of ≤ 6.5, occurrence of two or more relapses in the previous 2 years] and who had at least two repeated outcome measures were included: 404 patients for the UoWMS cohort and 978 patients for the BCMS cohort. Through the UK MS RSS scheme, 5583 DMT-treated patients were recruited, with the analysis sample being the 4137 who had RRMS and were eligible and treated at baseline, with at least one valid EDSS score post baseline. EDSS score observations post ABN eligibility. We used multilevel models in the development cohort (UoWMS) to develop a model for EDSS score with time since ABN eligibility, allowing for covariates and appropriate transformation of outcome and/or time. These methods were then applied to the BCMS cohort to obtain a 'natural history' model for changes in the EDSS score with time. We then used this natural history model to predict the trajectories of EDSS score in treated patients in the UK MS RSS database. Differences between the progression predicted by the natural history model and the progression observed at 6 years' follow-up for the UK MS RSS cohort were used as indicators of the effectiveness of the DMTs. Previously developed utility scores were assigned to each EDSS score, and differences in utility also examined. The model best fitting the UoWMS data showed a non-linear increase in EDSS score over time since ABN eligibility. This model fitted the BCMS cohort data well, with similar coefficients, and the BCMS model predicted EDSS score in UoWMS data with little evidence of bias. Using the natural history model predicts EDSS score in a treated cohort (UK MS RSS) higher than that observed [by 0.59 points (95% confidence interval 0.54 to 0.64 points)] at 6 years post treatment. Only two natural history cohorts were compared, limiting generalisability. The comparison of a treated cohort with untreated cohorts is observational, thus limiting conclusions about causality. EDSS score progression in two natural history cohorts of MS patients showed a similar pattern. Progression in the natural history cohorts was slightly faster than EDSS score progression in the DMT-treated cohort, up to 6 years post treatment. Long-term follow-up of randomised controlled trials is needed to replicate these findings and examine duration of any treatment effect. The National Institute for Health Research Health Technology Assessment programme.

To assess whether the level of multiple sclerosis (MS) -related disability in the Olmsted County population has changed over a decade, and to evaluate how the rate of initial progression to moderate disability impacts further disability. The Minimal Record of Disability (MRD) measured impairment, disability, and handicap for the 2000 (n = 201) prevalence cohort. The authors compared these results with the 1991 (n = 162) cohort; 115 patients were in both cohorts. The authors assessed retrospectively intervals at which Expanded Disability Status Scale (EDSS) scores of 3 (moderate disability), 6 (cane), and 8 (wheelchair) were reached. The distribution of the 2000 EDSS and MRD scores were not significantly different from the 1991 distribution. The median time from MS diagnosis, for the entire cohort, to EDSS scores of 3 and 6 was 17 and 24 years, respectively. At 20 years after onset, only 25% of those with relapsing-remitting MS had EDSS scores > or =3. The median time from diagnosis to EDSS score of 6 for the secondary and primary progressive groups was 10 and 3 years, respectively. Rate of progression from onset or diagnosis to EDSS score of 3 did not affect the rate of further disease progression. However, once an EDSS score of 3 was reached, progression of disability was more likely, and rate of progression increased. The distribution of multiple sclerosis disability in the Olmsted community has remained stable for 10 years. Progression of disability for patients with relapsing-remitting multiple sclerosis or secondary progressive multiple sclerosis may be more favorable than reported previously. Once a clinical threshold of disability is reached, rate of progression increased.