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IMPORTANCE: Natalizumab cessation is associated with a risk of rebound disease activity. It is important to identify the optimal switch disease-modifying therapy strategy after natalizumab to limit the risk of severe relapses. OBJECTIVES: To compare the effectiveness and persistence of dimethyl fumarate, fingolimod, and ocrelizumab among patients with relapsing-remitting multiple sclerosis (RRMS) who discontinued natalizumab. DESIGN, SETTING, AND PARTICIPANTS: In this observational cohort study, patient data were collected from the MSBase registry between June 15, 2010, and July 6, 2021. The median follow-up was 2.7 years. This was a multicenter study that included patients with RRMS who had used natalizumab for 6 months or longer and then were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months after natalizumab discontinuation. Patients without baseline data were excluded from the analysis. Data were analyzed from May 24, 2022, to January 9, 2023. EXPOSURES: Dimethyl fumarate, fingolimod, and ocrelizumab. MAIN OUTCOMES AND MEASURES: Primary outcomes were annualized relapse rate (ARR) and time to first relapse. Secondary outcomes were confirmed disability accumulation, disability improvement, and subsequent treatment discontinuation, with the comparisons for the first 2 limited to fingolimod and ocrelizumab due to the small number of patients taking dimethyl fumarate. The associations were analyzed after balancing covariates using an inverse probability of treatment weighting method. RESULTS: Among 66 840 patients with RRMS, 1744 had used natalizumab for 6 months or longer and were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months of natalizumab discontinuation. After excluding 358 patients without baseline data, a total of 1386 patients (mean [SD] age, 41.3 [10.6] years; 990 female [71%]) switched to dimethyl fumarate (138 [9.9%]), fingolimod (823 [59.4%]), or ocrelizumab (425 [30.7%]) after natalizumab. The ARR for ea

BACKGROUND AND PURPOSE: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS). METHODS: We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow-up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12-month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics. RESULTS: Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45-0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41-0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09-1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity. CONCLUSIONS: DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.

IMPORTANCE: Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS). OBJECTIVE: To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials. DESIGN, SETTING, AND PARTICIPANTS: This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics. EXPOSURE: AHSCT vs fingolimod, natalizumab, or ocrelizumab. MAIN OUTCOMES: Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. RESULTS: Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730

IMPORTANCE: Ocrelizumab, a humanized monoclonal antibody targeted against CD20+ B cells, reduces the frequency of relapses by 46% and disability worsening by 40% compared with interferon beta 1a in relapsing-remitting multiple sclerosis (MS). Rituximab, a chimeric monoclonal anti-CD20 agent, is often prescribed as an off-label alternative to ocrelizumab. OBJECTIVE: To evaluate whether the effectiveness of rituximab is noninferior to ocrelizumab in relapsing-remitting MS. DESIGN, SETTING, AND PARTICIPANTS: This was an observational cohort study conducted between January 2015 and March 2021. Patients were included in the treatment group for the duration of study therapy and were recruited from the MSBase registry and Danish MS Registry (DMSR). Included patients had a history of relapsing-remitting MS treated with ocrelizumab or rituximab, a minimum 6 months of follow-up, and sufficient data to calculate the propensity score. Patients with comparable baseline characteristics were 1:6 matched with propensity score on age, sex, MS duration, disability (Expanded Disability Status Scale), prior relapse rate, prior therapy, disease activity (relapses, disability accumulation, or both), magnetic resonance imaging lesion burden (missing values imputed), and country. EXPOSURE: Treatment with ocrelizumab or rituximab after 2015. MAIN OUTCOMES AND MEASURES: Noninferiority comparison of annualized rate of relapses (ARRs), with a prespecified noninferiority margin of 1.63 rate ratio. Secondary end points were relapse and 6-month confirmed disability accumulation in pairwise-censored groups. RESULTS: Of the 6027 patients with MS who were treated with ocrelizumab or rituximab, a total of 1613 (mean [SD] age; 42.0 [10.8] years; 1089 female [68%]) fulfilled the inclusion criteria and were included in the analysis (898 MSBase, 715 DMSR). A total of 710 patients treated with ocrelizumab (414 MSBase, 296 DMSR) were matched with 186 patients treated with rituximab (110 MSBase, 76 DMSR). O

Background: Some studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS. Methods: We compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age ≥18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS. Results: Included patients comprised 1872 with PPMS (47% men; 50% with activity) and 2575 with SPMS (32% men; 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2-47.3) vs 43.9 (43.3-44.4); p<0.001), greater baseline disability, slower disability accrual (HR 0.86 (0.78-0.94); p<0.001) and similar age at wheelchair dependence. Conclusions: We demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials.

BACKGROUND: The prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear. OBJECTIVE: To determine whether early non-disabling relapses predict disability accumulation in RRMS. METHODS: We redefined mild relapses in MSBase as 'non-disabling', and moderate or severe relapses as 'disabling'. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up. RESULTS: People who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated (n = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00-1.68) or given platform DMTs (n = 1074 vs 7262; HR = 1.33, 95% CI = 1.15-1.54), but not if given high-efficacy DMTs (n = 572 vs 3534; HR = 0.90, 95% CI = 0.71-1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically. CONCLUSION: This study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions.

Background: the prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear. Objective: to determine whether early non-disabling relapses predict disability accumulation in RRMS. Methods: we redefined mild relapses in MSBase as 'non-disabling', and moderate or severe relapses as 'disabling'. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up. Results: people who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated (n = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00-1.68) or given platform DMTs (n = 1074 vs 7262; HR = 1.33, 95% CI = 1.15-1.54), but not if given high-efficacy DMTs (n = 572 vs 3534; HR = 0.90, 95% CI = 0.71-1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically. Conclusion: this study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions., The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was financially supported by National Health and Medical Research Council of Australia (fellowship nos.1140766 and 1080518, project grant nos. 1129189 and 1083539), the University of Melbourne (Faculty of Medicine, Dentistry and Health Sciences research fellowship), National Institute for Health and Care Research (UK) Advanced Fellowship (grant no. 301728; recipient JWLB) and Academic Clinical Fellowship (grant no. EAN/ACA-006/7488627/C; recipient CD). The MSBase Foundation is a not-for-profit organization that receives support from Roche, Merck, Biogen, Novartis, Bayer Schering, Sanofi Genzyme, and Teva. Role of the Funder/Sponsor: The National Health and Medical Research Council of Australia, the University of Melbourne and the National Institute for Health and Care Research (UK) had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

BACKGROUND AND OBJECTIVES: The severity of multiple sclerosis (MS) varies widely among individuals. Understanding the determinants of this heterogeneity will help clinicians optimize the management of MS. The aim of this study was to investigate the association between latitude of residence, ultraviolet B radiation exposure (UVB) and the severity of MS. METHOD(S): This observational study used the MSBase registry data. The included patients met the 2005 or 2010 McDonald diagnostic criteria for MS and had a minimum dataset recorded in the registry (date of birth, sex, clinic location, date of MS symptom onset, disease phenotype at baseline and censoring, and >=1 EDSS [Expanded Disability Status Scale] score recorded). The latitude of each study center and cumulative annualized UVB dose at study center (calculated from NASA's Total Ozone Mapping Spectrometer) at ages 6 and 18 and the year of disability assessment were calculated. Disease severity was quantified with MS Severity Score (MSSS). Quadratic regression was used to model the associations between latitude, UVB and MSSS. RESULT(S): 46,128 patients contributing 453,208 visits and a cumulative follow-up of 351,196 patient-years (70% women, mean age 39.2+/-12, resident between latitudes 19degree35' and 56degree16') were included in this study. Latitude showed a non-linear association with MS severity. In latitudes greater than 40degree, more severe disease was associated with higher latitudes (beta=0.08, 95%CI: 0.04 to 0.12). For example, this translates into a mean difference of 1.3 points of MSSS between patients living in Madrid and Copenhagen. No such association was observed in latitudes <40degree (beta=-0.02, 95% CI:-0.06 to 0.03). The overall disability accrual was faster in those with a lower level of estimated UVB exposure before the age of 6 (beta=- 0.5, 95% CI: -0.6 to 0.4) and 18 years (beta=- 0.6, 95%CI:-0.7 to 0.4), as well as with lower life-time UVB exposure at the time of disability assessment (be

OBJECTIVES: To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy. METHOD(S): This was a retrospective cohort study from two large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12-months were included in the analysis. The primary study outcome was annualised relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation. RESULT(S): 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for seven therapies. Annualised rates of relapse (ARR) started to increase 2-months after natalizumab cessation (month 2-4 ARR, 95% confidence interval): 0.47, 0.43-0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08-0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1-2 ARR: 0.80, 0.70-0.89), and stabilised faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, -0.01-0.29). Magnitude of disease reactivation for other therapies was low, but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were higher relapse rate in the year before cessation, female sex, younger age and higher EDSS. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95%CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80). CONCLUSION(S): The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued different t

BACKGROUND AND OBJECTIVES: To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy. METHODS: This was a retrospective cohort study from 2 large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12 months were included in the analysis. The primary study outcome was annualized relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation. RESULTS: A total of 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for 7 therapies. Annualized rates of relapse (ARRs) started to increase 2 months after natalizumab cessation (month 2-4 ARR 0.47, 95% CI 0.43-0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08-0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1-2 ARR: 0.80, 0.70-0.89) and stabilized faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, -0.01 to 0.29). The magnitude of disease reactivation for other therapies was low but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were a higher relapse rate in the year before cessation, female sex, younger age, and higher EDSS score. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95% CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80). DISCUSSION: The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued di

Background: Ocrelizumab (OCR) is a humanised anti-CD20+ monoclonal antibody approved for the treatment of primary progressive multiple sclerosis (PPMS), and relapsing forms of MS, including both relapsing-remitting (RRMS) and secondary progressive MS (SPMS) with relapses. Objective(s): In a real-world setting, to describe 1) baseline characteristics of patients with MS treated with OCR, 2) treatment pathway across lines of therapy up to initiation of OCR, and 3) initial clinical experience in patients with >=6 months follow-up data from OCR initiation. Method(s): Secondary data analysis using MSBase Registry data including patients with a confirmed diagnosis of MS and started OCR therapy within 3 months prior to or at time of MSBase eligible/ initial visit. Descriptive statistics were used to analyze baseline patient characteristics' recorded within 3 months of OCR initiation, including demographics, disease course and duration, prior disease modifying therapies (DMT), and EDSS. Occurrence of relapse was analyzed in patients with >=6 months follow-up data from OCR initiation. Result(s): As of 4th June 2020, MSBase included 2531 patients newly treated with OCR, of whom 1679 had an EDSS evaluation within 3 months of OCR start. There were 1185 patients with RRMS, 236 with SPMS, and 183 with PPMS. Median age at OCR initiation was 41.9 years, 49.5 years, to 50.1 years in RRMS, SPMS, and PPMS, respectively. Mean disease duration from symptom onset up to OCR initiation was longer in SPMS (19.7 years) than in RRMS (10.6 years) and PPMS (9.7 years). OCR was initiated as first line therapy in 17.5%, 5.5%, and 54.2% of RRMS, SPMS, and PPMS patients respectively. Most frequent previous DMT's in RRMS were fingolimod (25.7%) and natalizumab (23.5%). 693 patients with RRMS had >=6 months followup during OCR exposure. Of these, 643 remained relapse free (93%; 95% CI 86.0, 100.0) over a mean OCR exposure of 1.23 years. The annualized relapse rate (ARR) was 0.08 (95% CI 0.06- 0.10)

Background: Increasingly, people with relapsing-remitting multiple sclerosis (RRMS) are switched to highly effective disease-modifying therapies (DMTs) such as ocrelizumab. Objective(s): To determine predictors of relapse and disability progression when switching from another DMT to ocrelizumab. Method(s): Patients with RRMS who switched to ocrelizumab were identified from the MSBase Registry and grouped by prior disease-modifying therapy (pDMT; interferon-beta/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab) and washout duration (<1 month, 1-2 months or 2-6 months). Survival analyses including multivariable Cox proportional hazard regression models were used to identify predictors of on-ocrelizumab relapse within 1 year, and 6-month confirmed disability progression (CDP). Result(s): After adjustment, relapse hazard when switching from fingolimod was greater than other pDMTs, but only in the first 3 months of ocrelizumab therapy (hazard ratio (HR) = 3.98, 95% confidence interval (CI) = 1.57-11.11, p = 0.004). The adjusted hazard for CDP was significantly higher with longer washout (2-6 m compared to <1 m: HR = 9.57, 95% CI = 1.92-47.64, p = 0.006). Conclusion(s): The risk of disability worsening during switch to ocrelizumab is reduced by short treatment gaps. Patients who cease fingolimod are at heightened relapse risk in the first 3 months on ocrelizumab. Prospective evaluation of strategies such as washout reduction may help optimise this switch.Copyright © The Author(s), 2021.

Background: Our current understanding of demographic and clinical modifiers of the effectiveness of multiple sclerosis (MS) therapies is limited. Objective(s): To assess whether patients' response to disease modifying therapies (DMT) in MS varies by disease activity (annualised relapse rate, presence of new MRI lesions), disability, age, MS duration or disease phenotype. Method(s): Using the international MSBase registry, we selected patients with MS followed for >=1 year, with >=3 visits, >=1 visit per year. Marginal structural models (MSMs) were used to compare the hazard ratios (HR) of 6-month confirmed worsening and improvement of disability (EDSS), and the incidence of relapses between treated and untreated periods. MSMs were continuously re-adjusted for patient age, sex, pregnancy, date, time from first symptom, prior relapse history, disability and MRI activity. Result(s): Among 23 687 patients with relapsing MS, those on DMT experienced 20% greater chance of disability improvement [HR 1.20 (95% CI 1.0-1.5)], 47% lower risk of disability worsening [HR 0.53 (0.39-0.71)] and 51% reduction in relapses [HR 0.49 (0.43-0.55)]. The effect of DMT on relapses and EDSS worsening was attenuated with longer MS duration and higher prior relapse rate. The effect of DMT on EDSS improvement and relapses was more evident in low EDSS categories. DMT was associated with 51% EDSS improvement in patients without new MRI lesions [HR 1.51 (1.00-2.28)] compared to 4% in those with MRI activity [HR 1.04 (0.88-1.24)]. Among 26329 participants with relapsing or progressive MS, DMT was associated with 25% reduction in EDSS worsening and 42% reduction in relapses in patients with relapsing MS [HR 0.75 (0.65-0.86) and HR 0.58 (CI 0.54-62), respectively], while evidence for such beneficial effects of treatment in patients with progressive MS was not found [HR 1.11 (0.91-1.46) and HR 1.16 (0.91-1.46), respectively]. Conclusion(s): DMTs are associated with reduction in relapse frequency, pro

Introduction: Ocrelizumab, a monoclonal antibody targeted against CD20+ B cells, has become a popular treatment for relapsing-remitting multiple sclerosis (MS). The effectiveness of ocrelizumab compared to other treatments is however unknown. Aim(s): To compare the effectiveness of ocrelizumab with interferon-beta, fingolimod and natalizumab in relapsing-remitting MS. Method(s): Using the MSBase registry, we identified patients with relapsing-remitting MS treated for >=6 months with ocrelizumab, interferon- beta (interferon beta-1a, interferon beta-1b subcutaneous or interferon beta-1b intramuscular), fingolimod or natalizumab. All patients required >12-month pre-treatment follow up and the minimum dataset. Patients with comparable baseline characteristics were matched with propensity score on age, sex, MS duration, EDSS, prior relapse rate, prior therapy, disease activity, MRI lesion burden (missing values imputed), reason for discontinuation of preceding therapy (imputed) and country. Annualised rate of relapses (ARR) and cumulative hazard of relapses were compared in pairwise-censored groups. Result(s): 106 patients treated with ocrelizumab were matched with 209 patients on interferon therapies with a mean age of 39 years, 0.8 relapses per year and mean EDSS of 2.4-2.5. Over a pairwise-censored mean follow up of 1.3 years, ocrelizumab was associated with lower relapse rates (ARR 0.08 vs 0.27, p<0.001) and lower risk of relapse (HR 0.30, 95%CI 0.15-0.57) than interferon-beta. 297 patients treated with ocrelizumab were matched with 811 fingolimod-treated patients with a mean age of 41 years, 0.6 relapses per year and mean EDSS of 2.7-2.8. Over a pairwisecensored mean follow up of 1.5 years, ocrelizumab was associated with lower relapse rates (ARR 0.03 vs 0.14, p<0.001) and lower risk of relapse than fingolimod (HR 0.21, 0.13-0.32). 262 ocrelizumab- treated patients were matched with 343 natalizumab treated patients with a mean age of 39 years, 0.8 relapses per year

Background: Some cohort studies have reported similar onset age and disability accrual in primary and secondary progressive MS (PPMS, SPMS); others have reported later onset and faster disability accrual in SPMS. Comparisons are complicated by differences in baseline disability and exposure to disease-modifying therapies (DMT), and by lack of a standardized definition of SPMS. Objective(s): We compared hazards of disability accrual in PPMS and SPMS patients from the MSBase cohort using multivariable Cox models, applying validated diagnostic criteria for SPMS (Lorscheider et al., Brain 2016). Method(s): Inclusion required adult-onset progressive MS; >= 3 recorded Expanded Disability Status Scale (EDSS) scores; and, for SPMS, initial records with EDSS <= 3 to allow objective identification of SPMS conversion. Phenotypes were subgrouped as active (PPMS-A, SPMS-A) if >= 1 progressive-phase relapse was recorded, and inactive (PPMS-N, SPMS-N) otherwise. Disability accrual was defined by sustained EDSS increases confirmed over >= 6 months. Hazard ratios (HR) for disability accrual were obtained using Andersen-Gill Cox models, adjusted for sex and time-varying age, disability, visit frequency, and proportion of time on DMT or immunosuppressive therapy. Sensitivity analyses were performed using (1) PPMS and SPMS diagnosed since 1995, and (2) physician-diagnosed SPMS. Cumulative probability of reaching EDSS >= 7 (wheelchair required) was assessed (Kaplan-Meier). Result(s): 5461 patients were included (1257 PPMS-N; 1308 PPMS-A; 1731 SPMS-N; 1165 SPMS-A). Age at progression onset was older in SPMS than PPMS (47.2 +/- 10.2, vs. 41.5 +/- 10.7 [mean +/- SD]), and in the inactive subgroups of each phenotype. Hazard of disability accrual was decreased in SPMS relative to PPMS (HR 0.85; 95% CI 0.78-0.92); decreased by proportion of time on DMT (HR 0.99 per 10% increment; 0.98-0.99); and higher in males (1.18; 1.12-1.25). Relative to PPMS-N, hazard was decreased in SPMS-A (0.79; 0.71

Introduction: Cladribine tablets are approved for relapsing multiple sclerosis (RMS) treatment in many jurisdictions. MSBase investigators are committed to characterising real-world longitudinal treatment outcomes using this registry data. Objective(s): To describe cladribine treatment outcomes in the MSBase cohort. These include baseline characteristics, treatment pathways, discontinuation rate, and relapse outcomes. Method(s): We extracted from the MSBase registry data for all patients with a confirmed diagnosis of MS who were newly treated with cladribine tablets. Descriptive statistics were used to analyse baseline patient characteristics recorded within 3 months prior to cladribine tablets initiation, including demographics, disease course and duration, prior disease modifying drugs (DMD), and EDSS. Relapse and discontinuation outcomes were described in patients with a minimum 6 month observation period. Result(s): As of 3rd March 2021, a total of 782 patients, predominantly from Australia, Canada and Spain, were included. 696 were relapsing-remitting MS (RRMS) patients. The median age of cladribine tablet start was 43.8 years and median disease duration was 11.8 years. Median EDSS at cladribine initiation was 2 (IQR 1.5,4). 13.3% of all RRMS patients initiated cladribine as first line therapy. Of all RRMS patients switching to cladribine tablets with a treatment gap of <6 months, the most common immediate prior DMD was Fingolimod (15%), followed by Natalizumab (10%) and Teriflunomide (9.5%). Total follow-up time was 629 patientyears. Annualised relapse rate (ARR) on cladribine tablets was 0.11 (95% CI 0.09-0.14) compared to a 12-month pre-cladribine ARR of 0.41. Treatment persistence was 96% at 12 months (95% CI 0.94-0.98) and 90% after 24months (95% CI 0.85-0.94). Conclusion(s): The growing MSBase real-world cladribine cohort shows excellent outcomes to date. The most common switches to cladribine are from other high-efficacy DMTs such as Natalizumab or Fingo

First described in 1991, Yin Yang 1 (YY1) is a transcription factor that is ubiquitously expressed throughout mammalian cells. It regulates both transcriptional activation and repression, in a seemingly context-dependent manner. YY1 has a well-established role in the development of the central nervous system, where it is involved in neurogenesis and maintenance of homeostasis in the developing brain. In neurodevelopmental and neurodegenerative disease, the crucial role of YY1 in cellular processes in the central nervous system is further underscored. In this mini-review, we discuss the various mechanisms leading to the transcriptional activating and repressing roles of YY1, including its role as a traditional transcription factor, its interactions with cofactors and chromatin modifiers, the role of YY1 in the non-coding genome and 3D chromatin organization and the possible implications of the phase-separation mechanism on YY1 function. We provide examples on how these processes can be involved in normal development and how alterations can lead to various diseases.

Noranda's drilling and blasting programme provides technical support to their mines and has also included activities such as the development of blast design software, instrumentation for blast monitoring and blasthole deviation survey instruments, blast damage studies and drilling optimisation. Achievements of the programme include the development of the Noranda accelorometer, a blast monitor, a borehole survey system, the BLASTCAD design software and plasma blasting technology. Current research includes work on drilling accuracy, real-time drill-bit location, real-time drill set-up instrumentation, a total drill alignment system, drill angle sensors, fragmentation measurement, pastefill blast damage and inverse drop raise blasting., Noranda's drilling and blasting programme provides technical support to their mines and has also included activities such as the development of blast design software, instrumentation for blast monitoring and blasthole deviation survey instruments, blast damage studies and drilling optimisation. Achievements of the programme include the development of the Noranda accelorometer, a blast monitor, a borehole survey system, the BLASTCAD design software and plasma blasting technology. Current research includes work on drilling accuracy, real-time drill-bit location, real-time drill set-up instrumentation, a total drill alignment system, drill angle sensors, fragmentation measurement, pastefill blast damage and inverse drop raise blasting.

A paste fill blast damage study was carried out at Louvicourt, Quebec, in June 1997 on the 860 m level. Instrumentation included vibration monitors (using 6 sets of triaxial geophones grouted in the pastefill), a borehole camera to observe the damage and a cavity monitoring system for three-dimensional surveys of the blasted stope. The test stope was mined out by four slot blasts and three mass blasts. Most of the damage was created by the mass blasts. It was discovered that the accumulation of ground vibration was mainly due to the low seismic velocities in the pastefill and the relatively tight delay between blastholes. In addition, there was a substantial difference between the critical peak particle velocities in the confined and unconfined pastefill. Modifications to the mining sequence of secondary stopes and blast design are currently being investigated for the near future with the objective of reducing pastefill sloughage., A paste fill blast damage study was carried out at Louvicourt, Quebec, in June 1997 on the 860 m level. Instrumentation included vibration monitors (using 6 sets of triaxial geophones grouted in the pastefill), a borehole camera to observe the damage and a cavity monitoring system for three-dimensional surveys of the blasted stope. The test stope was mined out by four slot blasts and three mass blasts. Most of the damage was created by the mass blasts. It was discovered that the accumulation of ground vibration was mainly due to the low seismic velocities in the pastefill and the relatively tight delay between blastholes. In addition, there was a substantial difference between the critical peak particle velocities in the confined and unconfined pastefill. Modifications to the mining sequence of secondary stopes and blast design are currently being investigated for the near future with the objective of reducing pastefill sloughage.