Identification of the genetic mechanism that associates L3MBTL3 to multiple sclerosis.

Multiple sclerosis (MS) is a complex and demyelinating disease of the central nervous system. One of the challenges of the post-genome-wide association studies (GWAS) era is to understand the molecular basis of statistical associations to reveal gene networks and potential therapeutic targets. The L3MBTL3 locus has been associated with MS risk by GWAS. To identify the causal variant of the locus, we performed fine mapping in a cohort of 3440 MS patients and 1688 healthy controls. The variant that best explained the association was rs6569648 (P = 4.13E-10, odds ratio = 0.71, 95% confidence interval (CI) = 0.64-0.79), which tagged rs7740107, located in intron 7 of L3MBTL3. The rs7740107 (A/T) variant has been reported to be the best expression and splice quantitative trait locus (eQTL and sQTL) of the region in up to 35 human genotype-tissue expression (GTEx) tissues. By sequencing RNA from blood of 17 MS patients and quantification by digital qPCR, we determined that this eQTL/sQTL originated from the expression of a novel short transcript starting in intron 7 near rs7740107. The short transcript was translated into three proteins starting at different translation initiation codons. These N-terminal truncated proteins lacked the region where L3MBTL3 interacts with the transcriptional regulator Recombination Signal Binding Protein for Immunoglobulin Kappa J Region which, in turn, regulates the Notch signalling pathway. Our data and other functional studies suggest that the genetic mechanism underlying the MS association of rs7740107 affects not only the expression of L3MBTL3 isoforms, but might also involve the Notch signalling pathway.

Emulating randomised clinical trials in relapsing-remitting multiple sclerosis with non-randomised real-world evidence: an application using data from the MSBase Registry.

BACKGROUND: To mimic as closely as possible a randomised controlled trial (RCT) and calibrate the real-world evidence (RWE) studies against a known treatment effect would be helpful to understand if RWE can support causal conclusions in selected circumstances. The aim was to emulate the TRANSFORMS trial comparing Fingolimod (FTY) versus intramuscular interferon ß-1a (IFN) using observational data. METHODS: We extracted from the MSBase registry all the patients with relapsing-remitting multiple sclerosis (RRMS) collected in the period 2011-2021 who received IFN or FTY (0.5 mg) and with the same inclusion and exclusion criteria of the TRANSFORMS RCT. The primary endpoint was the annualised relapse rate (ARR) over 12 months. Patients were 1:1 propensity-score (PS) matched. Relapse-rate ratio (RR) was calculated by mean of a negative binomial regression. RESULTS: A total of 4376 patients with RRMS (1140 in IFN and 3236 in FTY) were selected. After PS, 856 patients in each group were matched. The ARR was 0.45 in IFN and 0.25 in FTY with a significant difference between the two groups (RR: 0.55, 95% CI: 0.45 to 0.68; p<0.001). The result of the emulation was very similar and fell within the 95% CI of that observed in the RCT (RR: 0.49, 95% CI: 0.37 to 0.64; p<0.001) with a standardised difference of 0.66 (p=0.51). CONCLUSIONS: By applying the same inclusion and exclusion criteria used in the RCT and employing appropriate methodology, we successfully replicated the RCT results with only minor discrepancies. Also, even if the confounding bias cannot be fully eliminated, conducting a rigorous target trial emulation could still yield valuable insights for comparative effectiveness research.

Serum biomarker levels predict disability progression in patients with primary progressive multiple sclerosis.

BACKGROUND: We aimed to investigate the potential of serum biomarker levels to predict disability progression in a multicentric real-world cohort of patients with primary progressive multiple sclerosis (PPMS). METHODS: A total of 141 patients with PPMS from 18 European MS centres were included. Disability progression was investigated using change in Expanded Disability Status Scale (EDSS) score over three time intervals: baseline to 2 years, 6 years and to the last follow-up. Serum levels of neurofilament light chain (sNfL), glial fibrillar acidic protein (sGFAP) and chitinase 3-like 1 (sCHI3L1) were measured using single-molecule array assays at baseline. Correlations between biomarker levels, and between biomarkers and age were quantified using Spearman's r. Univariable and multivariable linear models were performed to assess associations between biomarker levels and EDSS change over the different time periods. RESULTS: Median (IQR) age of patients was 52.9 (46.4-58.5) years, and 58 (41.1%) were men. Median follow-up time was 9.1 (7.0-12.6) years. Only 8 (5.7%) patients received treatment during follow-up. sNfL and sGFAP levels were moderately correlated (r=0.43) and both weakly correlated with sCHI3L1 levels (r=0.19 and r=0.17, respectively). In multivariable analyses, levels of the three biomarkers were associated with EDSS changes across all time periods. However, when analysis was restricted to non-inflammatory patients according to clinical and radiological parameters (n=64), only sCHI3L1 levels remained associated with future EDSS change. CONCLUSIONS: Levels of sNfL, sGFAP and sCHI3L1 are prognostic biomarkers associated with disability progression in patients with PPMS, being CHI3L1 findings less dependent on the inflammatory component associated with disease progression.

No evidence for association between rs10191329 severity locus and longitudinal disease severity in 1813 relapse-onset multiple sclerosis patients from the MSBase registry.

BACKGROUND: The International Multiple Sclerosis Genetics Consortium and MultipleMS Consortium recently reported a genetic variant associated with multiple sclerosis (MS) severity. However, it remains unclear if these variants remain associated with more robust, longitudinal measures of disease severity. METHODS: We examined the top variant, rs10191329, from Harroud et al.'s study in 1813 relapse-onset MS patients from the MSBase Registry to assess association with longitudinal disease severity. RESULTS: Our analysis revealed no significant association between rs10191329 genotype and longitudinal binary disease severity (p > 0.05). CONCLUSION: These findings highlight the complexity of genetic factors mediating long-term MS outcomes and the need for further research.

Not all roads lead to the immune system: the genetic basis of multiple sclerosis severity.

Multiple sclerosis is a leading cause of neurological disability in adults. Heterogeneity in multiple sclerosis clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international multiple sclerosis registry, MSBase. We assembled a cohort of deeply phenotyped individuals of European ancestry with relapse-onset multiple sclerosis. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined multiple sclerosis severity phenotypes in 1813 individuals. Our primary analyses did not identify any genetic variants of moderate to large effect sizes that met genome-wide significance thresholds. The strongest signal was associated with rs7289446 (ß = -0.4882, P = 2.73 × 10-7), intronic to SEZ6L on chromosome 22. However, we demonstrate that clinical outcomes in relapse-onset multiple sclerosis are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62 000 variants together with clinical and demographic variables available at multiple sclerosis disease onset, we could predict severity with an area under the receiver operator curve of 0.84 (95% CI 0.79-0.88). Our machine learning algorithm achieved positive predictive value for outcome assignation of 80% and negative predictive value of 88%. This outperformed our machine learning algorithm that contained clinical and demographic variables alone (area under the receiver operator curve 0.54, 95% CI 0.48-0.60). Secondary, sex-stratified analyses identified two genetic loci that met genome-wide significance thresholds. One in females (rs10967273; ßfemale = 0.8289, P = 3.52 × 10-8), the other in males (rs698805; ßmale = -1.5395, P = 4.35 × 10-8), providing some evidence for sex dimorphism in multiple sclerosis severity. Tissue enrichment and pathway analyses identified an overrepresentation of genes expressed in CNS compartments generally, and specifically in the cerebellum (P = 0.023). These involved mitochondrial function, synaptic plasticity, oligodendroglial biology, cellular senescence, calcium and G-protein receptor signalling pathways. We further identified six variants with strong evidence for regulating clinical outcomes, the strongest signal again intronic to SEZ6L (adjusted hazard ratio 0.72, P = 4.85 × 10-4). Here we report a milestone in our progress towards understanding the clinical heterogeneity of multiple sclerosis outcomes, implicating functionally distinct mechanisms to multiple sclerosis risk. Importantly, we demonstrate that machine learning using common single nucleotide variant clusters, together with clinical variables readily available at diagnosis can improve prognostic capabilities at diagnosis, and with further validation has the potential to translate to meaningful clinical practice change.

The risk of secondary progressive multiple sclerosis is geographically determined but modifiable.

Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients was 39 (95% confidence interval: 37 to 43) years. Higher latitude [median hazard ratio = 1.21, 95% credible interval (1.16, 1.26)], higher national multiple sclerosis prevalence [1.07 (1.03, 1.11)], male sex [1.30 (1.22, 1.39)], older age at onset [1.35 (1.30, 1.39)], higher disability [2.40 (2.34, 2.47)] and frequent relapses [1.18 (1.15, 1.21)] at inclusion were associated with increased hazard of secondary progressive multiple sclerosis. Higher proportion of time on high-to-moderate efficacy therapy substantially reduced the hazard of secondary progressive multiple sclerosis [0.76 (0.73, 0.79)] and reduced the effect of latitude [interaction: 0.95 (0.92, 0.99)]. At the country-level, patients in Oman, Tunisia, Iran and Canada had higher risks of secondary progressive multiple sclerosis relative to the other studied regions. Higher latitude of residence is associated with a higher probability of developing secondary progressive multiple sclerosis. High-to-moderate efficacy immunotherapy can mitigate some of this geographically co-determined risk.

Multifaceted Analysis of Cerebrospinal Fluid and Serum from Progressive Multiple Sclerosis Patients: Potential Role of Vitamin C and Metal Ion Imbalance in the Divergence of Primary Progressive Multiple Sclerosis and Secondary Progressive Multiple Sclerosis.

The progressive forms of multiple sclerosis (MS) primary progressive MS (PPMS) and secondary progressive MS (SPMS) are clinically distinguished by the rate at which symptoms worsen. Little is however known about the pathological mechanisms underlying the differential rate of accumulation of pathological changes. In this study, 1H NMR spectroscopy was used to measure low-molecular-weight metabolites in paired cerebrospinal fluid (CSF) and serum of PPMS, SPMS, and control patients, as well as to determine lipoproteins and glycoproteins in serum samples. Additionally, neurodegenerative and inflammatory markers, neurofilament light (NFL) and chitinase-3-like protein 1 (CHI3L1), and the concentration of seven metal elements, Mg, Mn, Cu, Fe, Pb, Zn, and Ca, were also determined in both CSF and serum. The results indicate that the pathological changes associated with progressive MS are mainly localized in the central nervous system (CNS). More so, PPMS and SPMS patients with comparable disability status are pathologically similar in relation to neurodegeneration, neuroinflammation, and some metabolites that distinguish them from controls. However, the rapid progression of PPMS from the onset may be driven by a combination of neurotoxicity induced by heavy metals coupled with diminished CNS antioxidative capacity associated with differential intrathecal ascorbate retention and imbalance of Mg and Cu.

Risk of secondary progressive multiple sclerosis after early worsening of disability.

BACKGROUND: Whether progression independent of relapse activity (PIRA) heralds earlier onset of secondary progressive multiple sclerosis (SPMS) and more rapid accumulation of disability during SPMS remains to be determined. We investigated the association between early PIRA, relapse-associated worsening (RAW) of disability and time to SPMS, subsequent disability progression and their response to therapy. METHODS: This observational cohort study included patients with relapsing-remitting multiple sclerosis (RRMS) from the MSBase international registry across 146 centres and 39 countries. Associations between the number of PIRA and RAW during early multiple sclerosis (MS) (the initial 5 years of MS onset) were analysed with respect to: time to SPMS using Cox proportional hazards models adjusted for disease characteristics; and disability progression during SPMS, calculated as the change of Multiple Sclerosis Severity Scores over time, using multivariable linear regression. RESULTS: 10 692 patients met the inclusion criteria: 3125 (29%) were men and the mean MS onset age was 32.2 years. A higher number of early PIRA (HR=1.50, 95% CI 1.28 to 1.76, p<0.001) and RAW (HR=2.53, 95% CI 2.25 to 2.85, p<0.001) signalled a higher risk of SPMS. A higher proportion of early disease-modifying therapy exposure (per 10%) reduced the effect of early RAW (HR=0.94, 95% CI 0.89 to 1.00, p=0.041) but not PIRA (HR=0.97, 95% CI 0.91 to 1.05, p=0.49) on SPMS risk. No association between early PIRA/RAW and disability progression during SPMS was found. CONCLUSIONS: Early disability increase during RRMS is associated with a greater risk of SPMS but not the rate of disability progression during SPMS. The deterioration associated with early relapses represents a potentially treatable risk factor of SPMS. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12605000455662).

Heterogeneity on long-term disability trajectories in patients with secondary progressive MS: a latent class analysis from Big MS Data network.

BACKGROUND: Over the decades, several natural history studies on patients with primary (PPMS) or secondary progressive multiple sclerosis (SPMS) were reported from international registries. In PPMS, a consistent heterogeneity on long-term disability trajectories was demonstrated. The aim of this study was to identify subgroups of patients with SPMS with similar longitudinal trajectories of disability over time. METHODS: All patients with MS collected within Big MS registries who received an SPMS diagnosis from physicians (cohort 1) or satisfied the Lorscheider criteria (cohort 2) were considered. Longitudinal Expanded Disability Status Scale (EDSS) scores were modelled by a latent class growth analysis (LCGA), using a non-linear function of time from the first EDSS visit in the range 3-4. RESULTS: A total of 3613 patients with SPMS were included in the cohort 1. LCGA detected three different subgroups of patients with a mild (n=1297; 35.9%), a moderate (n=1936; 53.6%) and a severe (n=380; 10.5%) disability trajectory. Median time to EDSS 6 was 12.1, 5.0 and 1.7 years, for the three groups, respectively; the probability to reach EDSS 6 at 8 years was 14.4%, 78.4% and 98.3%, respectively. Similar results were found among 7613 patients satisfying the Lorscheider criteria. CONCLUSIONS: Contrary to previous interpretations, patients with SPMS progress at greatly different rates. Our identification of distinct trajectories can guide better patient selection in future phase 3 SPMS clinical trials. Additionally, distinct trajectories could reflect heterogeneous pathological mechanisms of progression.

Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial.

BACKGROUND: Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years. METHODS: Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement. RESULTS: 23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability. CONCLUSIONS: The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously.

Disability accrual in primary and secondary progressive multiple sclerosis.

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.

Prediction of relapse activity when switching to cladribine for multiple sclerosis.

BACKGROUND: Patients with relapsing-remitting multiple sclerosis commonly switch between disease-modifying therapies (DMTs). Identifying predictors of relapse when switching could improve outcomes. OBJECTIVE: To determine predictors of relapse hazard when switching to cladribine. METHODS: Data of patients who switched to cladribine, grouped by prior disease-modifying therapy (pDMT; interferon-ß/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab (NTZ)), were extracted from the MSBase Registry. Predictors of relapse hazard during the treatment gap and the first year of cladribine therapy were determined. RESULTS: Of 513 patients, 22 relapsed during the treatment gap, and 38 within 1 year of starting cladribine. Relapse in the year before pDMT cessation predicted treatment gap relapse hazard (hazard ratio (HR) = 2.43, 95% confidence interval (CI) = 1.03-5.71). After multivariable adjustment, relapse hazard on cladribine was predicted by relapse before pDMT cessation (HR = 2.00, 95% CI = 1.01-4.02), treatment gap relapse (HR = 6.18, 95% confidence interval (CI) = 2.65-14.41), switch from NTZ (HR compared to injectable therapies 4.08, 95% CI = 1.35-12.33) and age at cladribine start (HR = 0.96, 95% CI = 0.91-0.99). CONCLUSION: Relapse during or prior to the treatment gap, and younger age, are of prognostic relevance in the year after switching to cladribine. Switching from NTZ is also independently associated with greater relapse hazard.

Early non-disabling relapses are important predictors of disability accumulation in people with relapsing-remitting multiple sclerosis.

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.

Comparative effectiveness in multiple sclerosis: A methodological comparison.

BACKGROUND: In the absence of evidence from randomised controlled trials, observational data can be used to emulate clinical trials and guide clinical decisions. Observational studies are, however, susceptible to confounding and bias. Among the used techniques to reduce indication bias are propensity score matching and marginal structural models. OBJECTIVE: To use the comparative effectiveness of fingolimod vs natalizumab to compare the results obtained with propensity score matching and marginal structural models. METHODS: Patients with clinically isolated syndrome or relapsing remitting MS who were treated with either fingolimod or natalizumab were identified in the MSBase registry. Patients were propensity score matched, and inverse probability of treatment weighted at six monthly intervals, using the following variables: age, sex, disability, MS duration, MS course, prior relapses, and prior therapies. Studied outcomes were cumulative hazard of relapse, disability accumulation, and disability improvement. RESULTS: 4608 patients (1659 natalizumab, 2949 fingolimod) fulfilled inclusion criteria, and were propensity score matched or repeatedly reweighed with marginal structural models. Natalizumab treatment was associated with a lower probability of relapse (PS matching: HR 0.67 [95% CI 0.62-0.80]; marginal structural model: 0.71 [0.62-0.80]), and higher probability of disability improvement (PS matching: 1.21 [1.02 -1.43]; marginal structural model 1.43 1.19 -1.72]). There was no evidence of a difference in the magnitude of effect between the two methods. CONCLUSIONS: The relative effectiveness of two therapies can be efficiently compared by either marginal structural models or propensity score matching when applied in clearly defined clinical contexts and in sufficiently powered cohorts.

Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis.

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.

Assessment of the treating physicians' first-hand experience with handling and satisfaction of ofatumumab therapy: findings from the PERITIA survey conducted in Europe.

BACKGROUND: Real-world evidence on experience and satisfaction of ofatumumab as a treatment option for relapsing multiple sclerosis (RMS) is limited. OBJECTIVE: To present cumulative responses from a questionnaire related to first-hand experience of treating physicians on handling and convenience of ofatumumab therapy along with concerns related to COVID-19. METHODS: PERITIA was a multicentre survey conducted to collect responses from the ASCLEPIOS I/II trial investigators from Europe via an online questionnaire. RESULTS: Forty-six physicians (Germany, n = 14; Spain, n = 12; Portugal, n = 10; Italy, n = 10) completed the survey. Overall, 43% of the physicians considered the benefit-risk ratio of ofatumumab as very good. Over 93% were in favour of ofatumumab self-administration at home and the majority (83%) believed it to be completely true that self-administration of ofatumumab eases the burden for patients in terms of time. All investigators would like to potentially use anti-CD20 therapy as a long-term strategy. Even during the COVID-19 pandemic, physicians were in favour of a self-administration of MS therapy at home over other anti-CD20 therapy infusions. CONCLUSION: European neurologists who were part of this survey considered the benefit-risk-ratio of ofatumumab as favourable and the monthly self-administered subcutaneous injections offering convenience for patients in the clinical practice.

Early predictors of disability in paediatric multiple sclerosis: evidence from a multi-national registry.

BACKGROUND: Early recognition of markers of faster disability worsening in paediatric-onset multiple sclerosis (MS) is a key requisite of personalised therapy for children with MS at the earliest possible time. OBJECTIVE: To identify early predictors of rapid disability accrual in patients with paediatric-onset MS. METHODS: Using the global MSBase registry, we identified patients who were <18 years old at the onset of MS symptoms. The clinico-demographic characteristics examined as predictors of future MS Severity Score (MSSS) included sex, age at symptom onset, absence of disability at the initial assessment, maximum Expanded Disability Status Scale (EDSS) score, relapse frequency and presence of brainstem, pyramidal, visual or cerebellar symptoms in the first year. A Bayesian log-normal generalised linear mixed model adjusted for cumulative proportion of time on higher-efficacy disease-modifying therapies (DMTs) was used to analyse the data. RESULTS: 672 patients (70% female) contributing 9357 visits were included. The median age at symptom onset was 16 (quartiles 15-17) years. Older age at symptom onset (exp(ß)=1.10 (95% CI 1.04 to 1.17)), higher EDSS score (1.22 (1.12 to 1.34)) and pyramidal (1.31 (1.11 to 1.55)), visual (1.25 (1.10 to 1.44)) or cerebellar (1.18 (1.01 to 1.38)) symptoms in the first year were associated with higher MSSS. MSSS was reduced by 4% for every 24% increase in the proportion of time on higher-efficacy DMTs (0.96 (0.93 to 0.99)). CONCLUSIONS: A relatively later onset of MS in childhood, higher disability and pyramidal, visual or cerebellar symptoms during the first year predicted significant worsening in disability in patients with paediatric-onset MS. Persistent treatment with higher-efficacy DMTs was associated with a reduced rate of disability worsening.

Multiple Sclerosis Severity Score (MSSS) improves the accuracy of individualized prediction in MS.

BACKGROUND: The MSBase prediction model of treatment response leverages multiple demographic and clinical characteristics to estimate hazards of relapses, confirmed disability accumulation (CDA), and confirmed disability improvement (CDI). The model did not include Multiple Sclerosis Severity Score (MSSS), a disease duration-adjusted ranked score of disability. OBJECTIVE: To incorporate MSSS into the MSBase prediction model and compare model accuracy with and without MSSS. METHODS: The associations between MSSS and relapse, CDA, and CDI were evaluated with marginal proportional hazards models adjusted for three principal components representative of patients' demographic and clinical characteristics. The model fit with and without MSSS was assessed with penalized r2 and Harrell C. RESULTS: A total of 5866 MS patients were started on disease-modifying therapy during prospective follow-up (age 38.4 ± 10.6 years; 72% female; disease duration 8.5 ± 7.7 years). Including MSSS into the model improved the accuracy of individual prediction of relapses by 31%, of CDA by 23%, and of CDI by 24% (Harrell C) and increased the amount of variance explained for relapses by 49%, for CDI by 11%, and for CDA by 10% as compared with the original model. CONCLUSION: Addition of a single, readily available metric, MSSS, to the comprehensive MSBase prediction model considerably improved the individual accuracy of prognostics in MS.

Prediction of multiple sclerosis outcomes when switching to ocrelizumab.

BACKGROUND: Increasingly, people with relapsing-remitting multiple sclerosis (RRMS) are switched to highly effective disease-modifying therapies (DMTs) such as ocrelizumab. OBJECTIVE: To determine predictors of relapse and disability progression when switching from another DMT to ocrelizumab. METHODS: Patients with RRMS who switched to ocrelizumab were identified from the MSBase Registry and grouped by prior disease-modifying therapy (pDMT; interferon-ß/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). RESULTS: 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: 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.

Confirmed disability progression as a marker of permanent disability in multiple sclerosis.

BACKGROUND AND PURPOSE: The prevention of disability over the long term is the main treatment goal in multiple sclerosis (MS); however, randomized clinical trials evaluate only short-term treatment effects on disability. This study aimed to define criteria for 6-month confirmed disability progression events of MS with a high probability of resulting in sustained long-term disability worsening. METHODS: In total, 14,802 6-month confirmed disability progression events were identified in 8741 patients from the global MSBase registry. For each 6-month confirmed progression event (13,321 in the development and 1481 in the validation cohort), a sustained progression score was calculated based on the demographic and clinical characteristics at the time of progression that were predictive of long-term disability worsening. The score was externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial. RESULTS: The score was based on age, sex, MS phenotype, relapse activity, disability score and its change from baseline, number of affected functional system domains and worsening in six of the domains. In the internal validation cohort, a 61% lower chance of improvement was estimated with each unit increase in the score (hazard ratio 0.39, 95% confidence interval 0.29-0.52; discriminatory index 0.89). The proportions of progression events sustained at 5 years stratified by the score were 1: 72%; 2: 88%; 3: 94%; 4: 100%. The results of the CLARITY trial were confirmed for reduction of disability progression that was >88% likely to be sustained (events with score ˃1.5). CONCLUSIONS: Clinicodemographic characteristics of 6-month confirmed disability progression events identify those at high risk of sustained long-term disability. This knowledge will allow future trials to better assess the effect of therapy on long-term disability accrual.