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Abstract Background Natalizumab and fingolimod are used as high-efficacy treatments in relapsing–remitting multiple sclerosis. Several observational studies comparing these two drugs have shown variable results, using different methods to control treatment indication bias and manage censoring. The objective of this empirical study was to elucidate the impact of methods of causal inference on the results of comparative effectiveness studies. Methods Data from three observational multiple sclerosis registries (MSBase, the Danish MS Registry and French OFSEP registry) were combined. Four clinical outcomes were studied. Propensity scores were used to match or weigh the compared groups, allowing for estimating average treatment effect for treated or average treatment effect for the entire population. Analyses were conducted both in intention-to-treat and per-protocol frameworks. The impact of the positivity assumption was also assessed. Results Overall, 5,148 relapsing–remitting multiple sclerosis patients were included. In this well-powered sample, the 95% confidence intervals of the estimates overlapped widely. Propensity scores weighting and propensity scores matching procedures led to consistent results. Some differences were observed between average treatment effect for the entire population and average treatment effect for treated estimates. Intention-to-treat analyses were more conservative than per-protocol analyses. The most pronounced irregularities in outcomes and propensity scores were introduced by violation of the positivity assumption. Conclusions This applied study elucidates the influence of methodological decisions on the results of comparative effectiveness studies of treatments for multiple sclerosis. According to our results, there are no material differences between conclusions obtained with propensity scores matching or propensity scores weighting given that a study is sufficiently powered, models are correctly specified and positivity assumption is fulfilled.

Genome-wide association studies identified over 200 risk loci for multiple sclerosis (MS) focusing on common variants, which account for about 50% of disease heritability. The goal of this study was to investigate whether low-frequency and rare functional variants, located in MS-established associated loci, may contribute to disease risk in a relatively homogeneous population, testing their cumulative effect (burden) with gene-wise tests. We sequenced 98 genes in 588 Italian patients with MS and 408 matched healthy controls (HCs). Variants were selected using different filtering criteria based on allelic frequency and in silico functional impacts. Genes showing a significant burden (n = 17) were sequenced in an independent cohort of 504 MS and 504 HC. The highest signal in both cohorts was observed for the disruptive variants (stop-gain, stop-loss, or splicing variants) located in EFCAB13, a gene coding for a protein of an unknown function (p < 10–4). Among these variants, the minor allele of a stop-gain variant showed a significantly higher frequency in MS versus HC in both sequenced cohorts (p = 0.0093 and p = 0.025), confirmed by a meta-analysis on a third independent cohort of 1298 MS and 1430 HC (p = 0.001) assayed with an SNP array. Real-time PCR on 14 heterozygous individuals for this variant did not evidence the presence of the stop-gain allele, suggesting a transcript degradation by non-sense mediated decay, supported by the evidence that the carriers of the stop-gain variant had a lower expression of this gene (p = 0.0184). In conclusion, we identified a novel low-frequency functional variant associated with MS susceptibility, suggesting the possible role of rare/low-frequency variants in MS as reported for other complex diseases.

It is well established that temperature variability affects a range of outcomes relevant to human welfare, including health, emotion and mood, and productivity across a number of economic sectors. However, a critical and still unresolved empirical question is whether temperature variation has a long-lasting effect on economic productivity and, therefore, whether damages compound over time in response to long-lived changes in temperature expected with climate change. Several studies have identified a relationship between temperature and gross domestic product (GDP), but empirical evidence as to the persistence of these effects is still weak. This paper presents a novel approach to isolate the persistent component of temperature effects on output using lower frequency temperature variation. The effects are heterogeneous across countries but collectively, using three different GDP datasets, we find evidence of persistent effects, implying temperature affects the determinants of economic growth, not just economic productivity. This, in turn, means that the aggregate effects of climate change on GDP may be far larger and far more uncertain than currently represented in integrated assessment models used to calculate the social cost of carbon.

Background: Hypogammaglobulinemia (HG) is a known side effect of treatment with anti-CD20 monoclonal antibodies, and it is associated with the risk of infections., Objectives: Aim of this retrospective multicentre study was to assess the frequency of HG in Multiple Sclerosis (MS) and Neuromyelitis Optica Spectrum Disorder patients treated with Ocrelizumab or Rituximab and its association with the occurrence of severe infections (SI). Furthermore, predictors of HG and SI were sought., Methods: We included 556 patients (190M, 366F, mean age: 47 years) with a mean follow-up of 28 months (range 12-90 months)., Results: IgG HG occurred in 20% and IgM HG in 34% of patients. At multivariable analysis, the risk of IgG HG was influenced by an older age (≥50 years) (OR 1.64, 95%CI: 1.06-2.54, p=0.027), and by the number of treatment cycles (OR: 1.20, 95%CI: 1.09-1.33, p<0.001). A total of 25 SI occurred (100 person-years rate: 1.8), with a disease phenotype other than relapsing-remitting (OR 1.50, 95%CI: 1.02-2.20; p=0.039) and IgG HG (OR 2.65, 95%CI: 1.15-6.12; p=0.022) increasing its risk., Conclusions: IgG and IgM HG occurred in a considerable proportion of patients. IgG HG increased the risk of SI, which were, nevertheless, relatively infrequent. Our results highlight the importance of monitoring immunoglobulin levels during treatment with anti-CD20 agents, to personalize treatment strategies., Competing Interests: Declaration of competing interest K. Smolik: nothing to disclose, F. Camilli: nothing to disclose, I. Panzera: nothing to disclose, A. Fiore: nothing to disclose, A. Franceschini: nothing to disclose, M. Foschi has received travel and meeting support from Novartis, Roche, Biogen, Sanofi-Genzyme and Merck., A. Surcinelli nothing to disclose, I. Pesci nothing to disclose, C. Ferri: has received travel or speaker honoraria from Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, Roche, and Bristol Meyer Squibb, V. Bazzurri nothing to disclose, L. Mancinelli nothing to disclose, C. Zini nothing to disclose, A.M. Simone nothing to disclose, A. Lugaresi has served as a Biogen, Bristol Myers Squibb, Horizon, Janssen, Merck Serono, Novartis, Roche, Sanofi/Genzyme Advisory Board Member. She received congress and travel/accommodation expense compensations or speaker honoraria from Alexion, Biogen, Merck Serono, Novartis, Roche, Sanofi/Genzyme, and Fondazione Italiana Sclerosi Multipla (FISM). Her institutions received research grants from Novartis and Sanofi/Genzyme., F. Falzone nothing to disclose, F. Granella has received research funding from Roche; fees for advisory boards and speaker honoraria from Biogen, Merck Serono, Novartis, Roche, and Sanofi Genzyme; travel funding from Biogen, Sanofi Genzyme, and BMS., M.G. Piscaglia nothing to disclose, A. Guareschi nothing to disclose, E. Baldi has received a grant for the organization of a scientific congress from Biogen Idec and has received travel or speaker honoraria from Biogen Idec, Sanofi Genzyme, Merck Serono, and Teva Neurosciences., P. Immovilli, S. Montepietra, M. Santangelo: nothing to disclose, N. Poma: nothing to disclose, M. Cardi: nothing to disclose, G. De Napoli: nothing to disclose, F. Vitetta has received travel grants and/or speaker/advisory board honoraria from Merck, Novartis, Sanofi, Biogen and Roche. D. Ferraro has received travel grants and/or speaker/advisory board honoraria from Biogen, Merck, Sanofi, Novartis and Roche., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: To compare Expanded Disability Status Scale (EDSS) trajectories over time between Multiple Sclerosis (MS) groups with pediatric (POMS), adult (AOMS) and late (LOMS) onset, and between patients with and without progression independent of relapse activity (PIRA)., Methods: Patients with a first visit within 1 year from onset, ≥ 5-year follow-up and ≥ 1 visit every 6 months were selected from the Italian MS Register. Adjusted disability trajectories were assessed by longitudinal models for repeated measures. Comparisons between groups and between patients with and without PIRA in subgroups were performed by evaluating the yearly differences of mean EDSS score changes versus baseline (delta-EDSS). A first CDA event was defined as a 6-months confirmed disability increase from study baseline, measured by EDSS (increase ≥ 1.5 points with baseline EDSS = 0; ≥ 1.0 with baseline EDSS score ≤ 5.0 and ≥ 0.5 point with baseline EDSS > 5.5). PIRA was defined as a CDA event occurring more than 90 days after and more than 30 days before the onset of a relapse., Results: 3777 MS patients (268 POMS, 3282 AOMS, 227 LOMS) were included. The slope of disability trajectories significantly diverged in AOMS vs POMS starting from the second year of follow-up (Year 2: delta2-EDSS 0.18 (0.05; 0.31), p = 0.0054) and then mean delta2-EDSS gradually increased up to 0.23 (0.07; 0.39, p = 0.004) at year 5. Patients with PIRA had significant (p < 0.0001) steeper increase in EDSS scores than those without PIRA in all groups, although in POMS, the disability trajectories began to diverge later and at a lesser extent with delta-EDSS score of 0.48 vs 0.83 in AOMS and 1.57 in LOMS, at 3 years after the first PIRA., Conclusions: Age is relevant in determining disability progression in MS. POMS shows a less steep increase in EDSS scores over time than older patients. The effect of PIRA in accelerating EDSS progression is less pronounced in POMS than in AOMS and LOMS., (© 2024. The Author(s).)

Background: Evidence on the impact of dimethyl fumarate (DMF) during pregnancy in women with multiple sclerosis (MS) is limited., Objectives: To investigate disease activity and pregnancy outcomes in a retrospective cohort of women exposed to DMF in early pregnancy., Methods: Women discontinuing DMF after pregnancy confirmation were identified from 29 Italian MS Centers. Disease activity 12 months before conception, during pregnancy, and 12 months postpartum were recorded, exploring reactivation predictors. Pregnancy and fetal outcomes were assessed., Results: The study analyzed 137 pregnancies (12 pregnancy losses, 125 live births) from 137 women (mean age 32.9 ± 4.7 years), discontinuing DMF within a median (interquartile range (IQR)) interval of 4.9 (3.7-5.7) weeks from conception. In live birth pregnancies, annualized relapse rate (ARR) significantly decreased during pregnancy (ARR = 0.07, 95% confidence interval (CI): 0.03-0.14, p = 0.021) compared to pre-conception (ARR = 0.21 (95% CI: 0.14-0.30)) and increased postpartum ((ARR = 0.22 (95% CI: 0.15-0.32), p = 0.006). Median time to first relapse (TTFR) was 3.16 (IQR: 1:87-5.42) months. Higher pre-conception relapse number (hazard ratio (HR) = 2.33, 95% CI: 1.08-5.02) and Expanded Disability Status Scale (EDSS; HR = 1.81, 95% CI: 1.17-2.74) were associated with shorter TTFR, while treatment resumption with longer TTFR (HR = 0.29, 95% CI: 0.11-0.74). Fetal outcomes were unaffected by DMF exposure., Conclusion: DMF discontinuation does not increase relapse risk during pregnancy. Early therapy restart prevents postpartum relapses. Early DMF exposure shows no adverse fetal outcomes., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: D.L. received travel funding from Biogen, Merck-Serono, Sanofi-Genzyme, Teva, Bristol-Myers Squibb, Mylan, Novartis, Roche, Horizon, Alexion speaking or consultation fees from Sanofi-Genzyme, Merck-Serono, Teva, Biogen, Roche, Novartis, Bristol-Myers Squibb, Bayer-Schering. S.B. received travel funding from Biogen and Bristol-Myers Squibb. F.B. reported receiving teaching honoraria from Novartis and personal fees from Eisai, Biogen, and Chiesi outside the submitted work. M.P.A. has received research grants honoraria as a speaker and member of Advisory Boards from Biogen, Bayer, Novartis, Roche, Teva, Sanofi-Genzyme, Merck, Roche Celgene BMS, Janssen, Horizon. S.B. speaker honoraria and/or travel/congress grant from: Novartis, Merck-Serono, Alexion, BMS, Biogen, Roche, Janssen-Cilag. Research grant from Roche. G.B. received honoraria for speaking or consultation fee from Almirall, Biogen, Merck, Novartis, Sanofi, Teva, Roche. M.B. declares fees from Biogen, Sanofi-Genzyme, Roche, and Novartis. S.B. has been founded for advisory board, academic purposes and speech honoraria by Genzyme, Roche, Biogen, Merck-Serono, Novartis and Almirall. P.C. received honoraria for speaking and/or for consultancy and support for participation to scientific congresses from Almirall, Biogen, Merck-Serono, Novartis, Sanofi-Genzyme, Roche, Teva, Alexion, Celgene BMS, Janssen, Horizon. M.C. received personal compensations for public speaking from Novartis, Sanofi-Genzyme, Teva and consulting fees from Roche and Zambon. D.C. is an Advisory Board member of Almirall, Bayer-Schering, Biogen, GW Pharmaceutical, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva and received honoraria for speaking or consultation fee from Almirall, Bayer-Schering, Biogen, GW Pharmaceuticals, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva. He is also the principal investigator in clinical trials for Bayer-Schering, Biogen, Merck-Serono, Novartis, Roche, Sanofi-Genzyme. E.C. received travel grant, speaker fee and consultancy from Biogen Idec, Teva, Genzyme, Merck-Serono, Novartis, Roche and Admirall. A.C. has served on scientific advisory boards for Merck-Serono, Sanofi-Genzyme, Biogen, Novartis, Almirall. She has received institutional research support from Roche and Biogen. A.C. received speaker honoraria from Biogen, Sanofi-Genzyme, Teva and travel grants from Biogen, Merck, Sanofi-Genzyme, Teva; advisory boards member honoraria from Biogen, Merck, Novartis, Teva. E.D.A. received speaking honoraria from Biogen, Merck-Serono, Novartis, Sanofi-Genzyme, Bayer-Schering. M.D.F. participated on advisory boards and steering committees for and received speaker or writing honoraria, research support and funding for traveling from Alexion, BMS, Bayer, Biogen Idec, Genzyme, Horizon, Merck, Mylan, Novartis, Roche, Siemens Healthineers, Teva and Viatris. R.D. received honoraria as a speaker and member of advisory boards by: Merck-Serono, Roche, Novartis and travel funding from Almirall, Biogen, Novartis and Sanofi-Genzyme, Roche, Merck-Serono. R.F. has received consulting fees and honoraria for advisory boards from Biogen Idec, Merck-Serono, Novartis, Roche, and TEVA. E.F. has received travel grants from Biogen, Merck, Sanofi-Genzyme, Novartis, and Roche. M.F. is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Associate Editor of Radiology, and Associate Editor of Neurological Sciences; received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and Teva; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme; he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and Fondazione Italiana di Ricerca per la SLA. M.F. published opinions in a medical journal on other pharmaceuticals and received financial support for travel and meeting attendance from Biogen, Merck, Roche, Sanofi-Genzyme and Novartis. A.G. received honoraria for speaking and travel grants from Merck, Genzyme, Teva, Mylan, Roche and Novartis. F.G. received research funding from Sanofi-Genzyme and Biogen, fees for advisory boards and speaking honoraria from Biogen, Novartis, Sanofi-Genzyme, Merck-Serono and Roche, travel funding from Biogen, Sanofi-Genzyme, Merck-Serono, and Roche. A.I. received consulting fees from Janssen. R.L. received personal compensations for speaking or consultancy from Biogen, BMS, Sanofi, Merck, Novartis, Roche and Alexion. L.L. received travel grant, speaker fee and consultancy from Biogen Idec, Teva, Sanofi-Genzyme, Merck-Serono, Novartis, Roche and Almirall. M.L. has served on advisory boards and/or has received travel grants and/or speaker honoraria from Merck, Biogen, Almirall, Novartis, and Sanofi-Genzyme. G.L. received speaker honoraria and/or consultancy from Biogen, Teva, Genzyme, Merck, Novartis, Almirall, Roche. G.M. received travel funding from Almirall, Biogen, Novartis and Sanofi-Genzyme, Bristol-Myers Squibb, Horizon, Roche, Merck-Serono. M.M. received compensation for consulting services, speaking activities, and participation in advisory board from Alexion, Almirall, Bayer, Biogen, Bristol-Myers Squibb, Celgene, CSL Behring, Novartis, Roche, Sanofi-Genzyme, Janssen, Merck-Serono, and Viatris; he received research support from Biogen, Merck-Serono, Novartis, and Roche. L.M. received honoraria for speaking activity at scientific meetings and/or advisory boards from Biogen, Merck-Serono, Sanofi-Genzyme, Novartis, Roche, Alexion, Celgene, Almirall. G.N. received travel funding from Almirall, Biogen, Novartis and Sanofi-Genzyme, Horizon, Roche, Merck-Serono. F.P. reports grants from Biogen, grants from Merck, grants from FISM, grants from Onlus association, grants from University of Catania, personal fees from Almirall, personal fees from Bayer, personal fees from Biogen, personal fees from Merck, personal fees from Roche, personal fees from Sanofi, personal fees from TEVA, outside the submitted work. P.R. received travel expenses or honoraria for speaking or participating to advisory board by: Biogen idec, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi. S.R. has received travel expenses or honoraria for speaking or participating to advisory boardby: Biogen idec, Merck, Sanofi-Genzyme, Novartis, Teva, Roche, Bristol-Myers squibb. G.S. received travel expenses by Roche and Novartis. E.S. received speaker honoraria and/or consultancy from Biogen, Teva, Genzyme, Merck, Novartis, Almirall, and Roche. L.S. received congress grants from Merck-Serono, Biogen and board grants from Norvartis, Merck-Serono. M.P.S. has received consulting fees from Biogen, GeNeuro, MedDay, Merck, Novartis, Roche, Sanofi and Teva. V.T. has received honoraria, travel grants and research grant support from FISM, Italian Ministry of Health, Alexion, Roche, Merck, Biogen, Novartis, Viatris, Bristol-Myers Squibb, Almirall, Horizon, Lundbeck, Sanofi, Janssen. D.V. has received travel grants and honoraria for Advisory Boards from Novartis, Roche, Teva, Sanofi-Genzyme, Merck-Serono, and Almirall. G.A.M. received ravel funding, speaking or consultation fees from Almirall, Bayer-Schering, Biogen, Sanofi-Genzyme, Merck-Serono, Novartis, Teva, Mylan, Bristol Mayers Squibb and research grants from Roche and Biogen. The remaining authors have nothing to disclose.

Objectives: We investigated the occurrence and relative contribution of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) to confirmed disability accrual (CDA) and transition to secondary progression (SP) in relapsing multiple sclerosis (MS)., Methods: Relapsing-onset MS patients with follow-up > / = 5 years (16,130) were extracted from the Italian MS Registry. CDA was a 6-month confirmed increase in Expanded Disability Status Scale (EDSS) score. Sustained disability accumulation (SDA) was a CDA with no EDSS improvement in all subsequent visits. Predictors of PIRA and RAW and the association between final EDSS score and type of CDA were assessed using logistic multivariable regression and multivariable ordinal regression models, respectively., Results: Over 11.8 ± 5.4 years, 16,731 CDA events occurred in 8998 (55.8%) patients. PIRA (12,175) accounted for 72.3% of CDA. SDA occurred in 8912 (73.2%) PIRA and 2583 (56.7%) RAW (p < 0.001). 4453 (27.6%) patients transitioned to SPMS, 4010 (73.2%) out of 5476 patients with sustained PIRA and 443 (24.8%) out of 1790 patients with non-sustained PIRA. In the multivariable ordinal regression analysis, higher final EDSS score was associated with PIRA (estimated coefficient 0.349, 95% CI 0.120-0.577, p = 0.003)., Discussion: In this real-world relapsing-onset MS cohort, PIRA was the main driver of disability accumulation and was associated with higher disability in the long term. Sustained PIRA was linked to transition to SP and could represent a more accurate PIRA definition and a criterion to mark the putative onset of the progressive phase., (© 2024. The Author(s).)

Objective: No direct comparisons of the effect of natalizumab and ocrelizumab on progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) events are currently available. We aimed to compare the risk of achieving first 6 months confirmed PIRA and RAW events and irreversible Expanded Disability Status Scale (EDSS) 4.0 and 6.0 in a cohort of naïve patients treated with natalizumab or ocrelizumab from the Italian Multiple Sclerosis Register., Methods: Patients with a first visit within 1 year from onset, treated with natalizumab or ocrelizumab, and ≥3 visits were extracted. Pairwise propensity score-matched analyses were performed. Risk of reaching the first PIRA, RAW, and EDSS 4.0 and 6.0 events were estimated using multivariable Cox proportional hazards models. Kaplan-Meier curves were used to show cumulative probabilities of reaching outcomes., Results: In total, 770 subjects were included (natalizumab = 568; ocrelizumab = 212) and the propensity score-matching retrieved 195 pairs. No RAW events were found in natalizumab group and only 1 was reported in ocrelizumab group. A first PIRA event was reached by 23 natalizumab and 25 ocrelizumab exposed patients; 7 natalizumab- and 10 ocrelizumab-treated patients obtained an irreversible EDSS 4.0, while 13 natalizumab- and 15 ocrelizumab-treated patients reached an irreversible EDSS 6.0. No differences between the two groups were found in the risk (HR, 95%CI) of reaching a first PIRA (1.04, 0.59-1.84; p = 0.88) event, an irreversible EDSS 4.0 (1.23, 0.57-2.66; p = 0.60) and 6.0 (0.93, 0.32-2.68; p = 0.89)., Interpretation: Both medications strongly suppress RAW events and, in the short term, the risk of achieving PIRA events, EDSS 4.0 and 6.0 milestones is not significantly different., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Treatment options for secondary progressive MS (SPMS) are limited, especially considering that the new drugs recently approved are licensed for actively relapsing patients. We aimed to compare the disability progression in a real-world cohort of SPMS patients treated with natalizumab (NTZ) or interferon beta-1b (IFNb-1b). This multicenter retrospective enrolled patients with a diagnosis of SPMS according to 2014 Lublin criteria, who received NTZ or IFNb-1b for at least 48 months between the 1st June 2012 and the 15th May 2018 ​at 33 Italian MS centers contributing to the Italian MS Registry NTZ or IFNb-1b. Confirmed Expanded Disability Status Scale worsening (CEW) and progression independent of relapse (PIRA) were evaluated. In order to correct for non-randomization, a propensity score matching of the groups was performed. Out of 5206 MS patients identified at the time of data extraction, 421 SPMS patients treated with NTZ (224 [53.2%] females, mean age 45.3 ​± ​25.4 years) and 353 with IFNb-1b (133 [37.8%] females, mean age 48.5 ​± ​19.8 years) were enrolled. After applying the matching procedure, 102 patients were retained in the NTZ group and 98 in the IFNb-2b group. The proportion of patients who reached the 48-month 1-point CEW was significantly higher in IFNb-1b compared to NTZ group (58.2% versus 30.4%, p ​= ​0.01). The proportion of patients who developed PIRA at 48 months were significantly higher in IFNb-1b compared to NTZ (72.4% versus 40.2%, p ​= ​0.01). EDSS before treatment initiation and SPMS duration were risk factors for disability progression in terms of PIRA (HR 2.54, 25%CI 1.67-5.7; p ​= ​0.006 and HR 2.04, 25%CI 1.22-3.35; p ​= ​0.01, respectively). Patients treated with IFNb-1b were 1.64 times more to likely to develop PIRA (HR 1.64, 25%CI 1.04-4.87; p ​= ​0.001). Treatment with NTZ in SPMS patients showed more favorable disability outcomes compared to IFNb-1b with beneficial effects over 48 months., Competing Interests: Declaration of competing interest CGC has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. UA reports no disclosures relevant to the manuscript. MPA has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. RB reports no disclosures relevant to the manuscript. AB has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. SB served as speaker and/or advisory board fee, and/or travel grant from Novartis, Teva, Sanofi-Genzyme, Roche, Biogen-Idec, Merck-Serono. VBM received fees for consultancies or public speaking from Merck, Novartis, Biogen, Roche, Genzyme and Biogen. PC has served as an advisory board member for Almirall, Biogen, Merck-Serono, Sanofi-Genzyme, Roche, Teva; she has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. EC reports no disclosures relevant to the manuscript. AC reports no disclosures relevant to the manuscript. SC has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. GDL reports no disclosures relevant to the manuscript. ADS reports no disclosures relevant to the manuscript. MF is Editor-in-Chief of the Journal of Neurology; received compensation for consulting services and/or speaking activities from Biogen Idec, Merck-Serono, Novartis, Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Teva Pharmaceutical Industries, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA(Fondazione Italiana di Ricerca per la SLA). AG reports no disclosures relevant to the manuscript. CG reports no disclosures relevant to the manuscript. FG received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. GL reports no disclosures relevant to the manuscript. DM reports no disclosures relevant to the manuscript. GTM has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. GAM has served as an advisory board member and received speaker honoraria, congress, travel and accommodation expense compensations from Merck, Teva, Mylan, Bayer, Novartis, Roche, Almirall, Biogen and Sanofi Genzyme. LM reports no disclosures relevant to the manuscript. DP has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. IP reports no disclosures relevant to the manuscript. PR reports no disclosures relevant to the manuscript. MR received travel grants and fees for consulting and public speaking from Almirall, Biogen, Genzyme-Sanofi, Merck Serono, Mylan and Novartis. GS has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. CS has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. RT reports no disclosures relevant to the manuscript. ST reports no disclosures relevant to the manuscript. MT has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. MV reports no disclosures relevant to the manuscript. VL reports no disclosures relevant to the manuscript. MZ has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. FP has received honoraria for speaking activities by Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA; he also served as advisory board member the following companies: Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA; he was also funded by Pfizer and FISM for epidemiological studies; he received grants for congress participation from Almirall, Bayer Shering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA., (Copyright © 2024. Published by Elsevier Inc.)

Objective: Multiple sclerosis (MS) is a complex disorder in which environmental and genetic factors interact modifying disease risk and course. This multicentre, case-control study involving 18 Italian MS Centres investigated MS course by ethnicity and native-country economic status in foreign-born patients living in Italy., Methods: We identified 457 MS patients who migrated to Italy and 893 age- and sex-matched native-born Italian patients. In our population, 1225 (93.2%) subjects were White Europeans and White Northern Americans (WENA) and 89 (6.8%) patients were from other ethnical groups (OEG); 1109 (82.1%) patients were born in a high-income (HI) Country and 241 (17.9%) in a low-middle-income (LMI) Country. Medical records and patients interviews were used to collect demographic and disease data., Results: We included 1350 individuals (973 women and 377 men); mean (SD) age was 45.0 (11.7) years. At onset, 25.45% OEG patients vs 12.47% WENA (p = 0.039) had > 3 STIR spine lesions. At recruitment, the same group featured mean (SD) EDSS score of 2.85 (2.23) vs 2.64 (2.28) (p = 0.044) reached in 8.9 (9.0) vs 12.0 (9.0) years (p = 0.018) and underwent 1.10 (4.44) vs. 0.99 (0.40) annual MRI examinations (p = 0.035). At disease onset, patients from LMI countries had higher EDSS score than HI patients (2.40 (1.43) vs 1.99 (1.17); p = 0.032)., Discussion: Our results suggested that both ethnicity and socio-economic status of native country shape MS presentation and course and should be considered for an appropriate management of patients. To the best of our knowledge, this is the first study reporting on the impact of ethnicity in MS at an individual level and beyond an ecological population-perspective., (© 2024. The Author(s).)

Background: Active relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS) are currently defined as "relapsing MS" (RMS). The aim of this cross-sectional study was to assess drivers of treatment switches due to clinical relapses in a population of RMS patients collected in the Italian MS and Related Disorders Register (I-MS&RD)., Methods: RRMS and SPMS patients with at least one relapse in a time window of 2 years before of data extraction were defined as RMS. Factors associated with disease-modifying therapy (DMT) switching due to clinical activity were assessed through multivariable logistic regression models in which treatment exposure was included as the last recorded DMT and the last DMT's class [moderate-efficacy (ME), high-efficacy (HE) DMTs and anti-CD20 drugs]., Results: A cohort of 4739 RMS patients (4161 RRMS, 578 SPMS) was extracted from the I-MS&RD. A total of 2694 patients switching DMTs due to relapses were identified. Switchers were significantly (p < 0.0001) younger, less disabled, more frequently affected by an RR disease course in comparison to non-switcher patients. The multivariable logistic regression models showed that Alemtuzumab (OR 0.08, 95% CI 0.02-0.37), Natalizumab (0.48, 0.30-0.76), Ocrelizumab (0.1, 0.02-0.45) and Rituximab (0.23, 0.06-0.82) exposure was a protective factor against treatment switch due to relapses. Moreover, the use of HE DMTs (0.43, 0.31-0.59), especially anti-CD20 drugs (0.14, 0.05-0.37), resulted to be a protective factor against treatment switch due to relapses in comparison with ME DMTs., Conclusions: More than 50% of RMS switched therapy due to disease activity. HE DMTs, especially anti-CD20 drugs, significantly reduce the risk of treatment switch., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: During the COVID-19 pandemic, ocrelizumab (OCR) infusions for MS patients were often re-scheduled because of MS center's disruption and concerns regarding immunosuppression. The aim of the present study was to assess changes in OCR schedule during the first wave of pandemic in Italy and to evaluate the effect of delayed infusion on clinical/radiological endpoints., Methods: Data were extracted from the Italian MS Register database. Standard interval dosing was defined as an infusion interval ≤ 30 weeks, while extended interval dosing was defined as an infusion interval > 30 weeks at the time of the observation period. Clinico-demographics variables were tested as potential predictors for treatment delay. Time to first relapse and time to first MRI event were evaluated. Cumulative hazard curves were reported along their 95% confidence intervals. A final sample of one-thousand two patients with MS from 65 centers was included in the analysis: 599 pwMS were selected to evaluate the modification of OCR infusion intervals, while 717 pwRMS were selected to analyze the effect of infusion delay on clinical/MRI activity., Results: Mean interval between two OCR infusions was 28.1 weeks before pandemic compared to 30.8 weeks during the observation period, with a mean delay of 2.74 weeks (p < 0.001). No clinico-demographic factors emerged as predictors of infusion postponement, except for location of MS centers in the North of Italy. Clinical relapses (4 in SID, 0 in EID) and 17 MRI activity reports (4 in SID, 13 in EID) were recorded during follow-up period., Discussion: Despite the significant extension of OCR infusion interval during the first wave of pandemic in Italy, a very small incidence of clinical/radiological events was observed, thus suggesting durable efficacy of OCR, as well as the absence of rebound after its short-term suspension., (© 2023. The Author(s).)

Aim: To evaluate the real-world comparative effectiveness and the cost-effectiveness, from a UK National Health Service perspective, of natalizumab versus fingolimod in patients with rapidly evolving severe relapsing-remitting multiple sclerosis (RES-RRMS)., Methods: Real-world data from the MSBase Registry were obtained for patients with RES-RRMS who were previously either naive to disease-modifying therapies or had been treated with interferon-based therapies, glatiramer acetate, dimethyl fumarate, or teriflunomide (collectively known as BRACETD). Matched cohorts were selected by 3-way multinomial propensity score matching, and the annualized relapse rate (ARR) and 6-month-confirmed disability worsening (CDW6M) and improvement (CDI6M) were compared between treatment groups. Comparative effectiveness results were used in a cost-effectiveness model comparing natalizumab and fingolimod, using an established Markov structure over a lifetime horizon with health states based on the Expanded Disability Status Scale. Additional model data sources included the UK MS Survey 2015, published literature, and publicly available sources., Results: In the comparative effectiveness analysis, we found a significantly lower ARR for patients starting natalizumab compared with fingolimod (rate ratio [RR] = 0.65; 95% confidence interval [CI], 0.57-0.73) or BRACETD (RR = 0.46; 95% CI, 0.42-0.53). Similarly, CDI6M was higher for patients starting natalizumab compared with fingolimod (hazard ratio [HR] = 1.25; 95% CI, 1.01-1.55) and BRACETD (HR = 1.46; 95% CI, 1.16-1.85). In patients starting fingolimod, we found a lower ARR (RR = 0.72; 95% CI, 0.65-0.80) compared with starting BRACETD, but no difference in CDI6M (HR = 1.17; 95% CI, 0.91-1.50). Differences in CDW6M were not found between the treatment groups. In the base-case cost-effectiveness analysis, natalizumab dominated fingolimod (0.302 higher quality-adjusted life-years [QALYs] and £17,141 lower predicted lifetime costs). Similar cost-effectiveness results were observed across sensitivity analyses., Conclusions: This MSBase Registry analysis suggests that natalizumab improves clinical outcomes when compared with fingolimod, which translates to higher QALYs and lower costs in UK patients with RES-RRMS.

Importance: Although up to 20% of patients with multiple sclerosis (MS) experience onset before 18 years of age, it has been suggested that people with pediatric-onset MS (POMS) are protected against disability because of greater capacity for repair., Objective: To assess the incidence of and factors associated with progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) in POMS compared with typical adult-onset MS (AOMS) and late-onset MS (LOMS)., Design, Setting, and Participants: This cohort study on prospectively acquired data from the Italian MS Register was performed from June 1, 2000, to September 30, 2021. At the time of data extraction, longitudinal data from 73 564 patients from 120 MS centers were available in the register., Main Outcomes and Measures: The main outcomes included age-related cumulative incidence and adjusted hazard ratios (HRs) for PIRA and RAW and associated factors., Exposures: Clinical and magnetic resonance imaging features, time receiving disease-modifying therapy (DMT), and time to first DMT., Results: After applying the inclusion and exclusion criteria, the study assessed 16 130 patients with MS (median [IQR] age at onset, 28.7 [22.8-36.2 years]; 68.3% female). Compared with AOMS and LOMS, patients with POMS had less disability, exhibited more active disease, and were exposed to DMT for a longer period. A first 48-week-confirmed PIRA occurred in 7176 patients (44.5%): 558 patients with POMS (40.4%), 6258 patients with AOMS (44.3%), and 360 patients with LOMS (56.8%) (P < .001). Factors associated with PIRA were older age at onset (AOMS vs POMS HR, 1.42; 95% CI, 1.30-1.55; LOMS vs POMS HR, 2.98; 95% CI, 2.60-3.41; P < .001), longer disease duration (HR, 1.04; 95% CI, 1.04-1.05; P < .001), and shorter DMT exposure (HR, 0.69; 95% CI, 0.64-0.74; P < .001). The incidence of PIRA was 1.3% at 20 years of age, but it rapidly increased approximately 7 times between 21 and 30 years of age (9.0%) and nearly doubled for each age decade from 40 to 70 years (21.6% at 40 years, 39.0% at 50 years, 61.0% at 60 years, and 78.7% at 70 years). The cumulative incidence of RAW events followed a similar trend from 20 to 60 years (0.5% at 20 years, 3.5% at 30 years, 7.8% at 40 years, 14.4% at 50 years, and 24.1% at 60 years); no further increase was found at 70 years (27.7%). Delayed DMT initiation was associated with higher risk of PIRA (HR, 1.16; 95% CI, 1.00-1.34; P = .04) and RAW (HR, 1.75; 95% CI, 1.28-2.39; P = .001)., Conclusions and Relevance: PIRA can occur at any age, and although pediatric onset is not fully protective against progression, this study's findings suggest that patients with pediatric onset are less likely to exhibit PIRA over a decade of follow-up. However, these data also reinforce the benefit for DMT initiation in patients with POMS, as treatment was associated with reduced occurrence of both PIRA and RAW regardless of age at onset.

Ecosystems generate a wide range of benefits for humans, including some market goods as well as other benefits that are not directly reflected in market activity 1 . Climate change will alter the distribution of ecosystems around the world and change the flow of these benefits 2,3 . However, the specific implications of ecosystem changes for human welfare remain unclear, as they depend on the nature of these changes, the value of the affected benefits and the extent to which communities rely on natural systems for their well-being 4 . Here we estimate country-level changes in economic production and the value of non-market ecosystem benefits resulting from climate-change-induced shifts in terrestrial vegetation cover, as projected by dynamic global vegetation models (DGVMs) driven by general circulation climate models. Our results show that the annual population-weighted mean global flow of non-market ecosystem benefits valued in the wealth accounts of the World Bank will be reduced by 9.2% in 2100 under the Shared Socioeconomic Pathway SSP2-6.0 with respect to the baseline no climate change scenario and that the global population-weighted average change in gross domestic product (GDP) by 2100 is -1.3% of the baseline GDP. Because lower-income countries are more reliant on natural capital, these GDP effects are regressive. Approximately 90% of these damages are borne by the poorest 50% of countries and regions, whereas the wealthiest 10% experience only 2% of these losses., (© 2023. The Author(s).)

Introduction: EASIER is a multicenter, observational, cross-sectional study investigating the consumption of healthcare resources, including healthcare professional (HCP) active working time, the costs associated with the current natalizumab intravenous (IV) administration, and the potential impact of the adoption of subcutaneous (SC) route., Methods: The EASIER study has three parts: (1) time and motion study to measure healthcare resources and working time needed for natalizumab IV administration using a digital data collection tool operated directly by HCPs; (2) HCP structured questionnaire-based estimation of the potential impact of natalizumab SC vs. IV administration; and (3) patient survey on the burden of natalizumab administration., Results: Nine Italian multiple sclerosis (MS) centers measured 404 IV natalizumab administration procedures and administered 26 HCP questionnaires and 297 patient questionnaires. Patients had a mean of 52 (range 1-176) previous IV administrations and spent a mean (median, IQR) of 152 (130, 94-184) minutes in the center per each IV procedure, with IV infusion covering 50% of the total. Including patient travel time, an average of 5 h was dedicated to each IV administration. Active working time by HCP amounted to 29 min per IV administration procedure, 70% of which by nursing staff. With adoption of the SC route, HCPs estimated a 50% reduction in patient procedure time and 55% lower HCP active working time. This translated into a 63% cost reduction for the MS center per natalizumab administration procedure., Conclusions: SC natalizumab administration will consistently reduce consumption of patient and HCP times per procedure and associated costs., (© 2023. The Author(s).)

Background: The intervals between two courses of anti CD20 therapies in the COVID19 pandemic era provided the opportunity to individually delay therapy, known as extended interval dosing (EID)., Methods: We collect real-world data on patients with primary progressive MS (PPMS) treated with Ocrelizumab (OCR) during the COVID'19 pandemic. The observation period in which the standard interval dosing (SID) or EID occurred (always a maintenance cycle, 600 mg) was from January 2020 to June 2021. All patients had two infusions during the observation period. Our first aim was to compare confirmed disability progression (CDP) between SID and EID patients., Results: From a total cohort of 410 patients treated with OCR, 96 patients fulfilled the inclusion criteria. All patients received two infusions during the index window, 71 received only SID infusions whilst 25 received at least one EID infusion throughout the entire follow-up. During the entire available follow-up (median 10 months, IQR 7-11), CDP was recorded in 5 patients (3/71, 4.2% SID and 2/25, 8% EID, V-Cramer = 0.141, p-value = 0.167). EID regimen did not influence the risk of CDP during the investigated follow up., Conclusion: In our multicentre real-world cohort, the EID regimen in PPMS patients did not result in increased CDP during the available follow-up., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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., Competing Interests: Competing interests: The authors report the following relationships: speaker honoraria, advisory board or steering committee fees, research support and/or conference travel support from Acthelion (EKH, RA), Almirall (MT, FG, RB, CRT, JLS-M), Bayer (MT, AL, PS, RA, MT, CB, JL-S, EP, VVP, RB, DS, RA, JO, JLSM, SH, CR, AGK, TC, NS, BT, MS, CAS), BioCSL (TK, AGK, BT), Biogen (TK, TS, DH, EKH, MT, GI, AL, MG, PD, PG, VJ, AVW, FG, PS, DF, RA, RH, CB, JLS, EP, VVP, FG, RB, RA, CRT, JP, JO, MB, JLSM, SH, CR, CSh, OGerlach, AGK, TC, BS, NS, BT, MS, HB), Biologix (RA), BMS/Celgene (EKH, AL), Genpharm (RA), Genzyme-Sanofi (TK, EKH, MT, GI, AL, MG, PD, PG, AVW, FG, PS, DF, RA, RH, MT, CB, JLS, EP, EP, VVP, FG, RB, RB, DS, CRT, JP, JO, MB, JLSM, SH, O Gerlach, AGK, HB), GSK (RA), Innate Immunotherapeutics (AGK), Lundbeck (EP), Merck / EMD (TK, DH, EKH, MT, GI, AL(Merck Serono), MG, PD, PG, VJ, AVW, PS, DF, RA, RH, MT, CB, JLS, EP, VVP, FG, RB, DS, RA, JO, MB, JLSM, CR, FM, O Gerlach, AGK, TC, BS, MS, HB), Mitsubishi (FG),Novartis (TK, TS, DH, EKH, MT, GI, AL, MG, PD, PG, VJ, AVW, FG, PS, DF, RA, RH, MT, CB, JLS, EP, VVP, FG, RB, DS, RA, CRT, JP, JO, MB, JLSM, SH, CR, FM, CSh, OG, AGK, TC, NS, BT, MS, HB), ONO Pharmaceuticals (FG), Roche (TK, EKH, AL, MT, CB, VVP, BT), Teva (TK, DH, EKH, MT, GI, AL, MG, PD, PG, VJ, FG, PS, DF, RH, MT, CB, JLS, VVP, RB, DS, RA, JP, JO, JLSM, CR, AGK, TC, MS, CAS), WebMD (TK), UCB (EP)., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: No evidence of disease activity (NEDA) is becoming a gold standard in the evaluation of disease modifying therapies (DMT) in relapsing-remitting multiple sclerosis (RRMS). NEDA-3 status is the absence of relapses, new activity on brain MRI, and disability progression. NEDA-4 meets all NEDA-3 criteria plus lack of brain atrophy., Objective: Aim of this study was to investigate the prevalence of two-year NEDA-3, NEDA-4, six-month delayed NEDA-3 (6mdNEDA-3), and six-month delayed NEDA-4 (6mdNEDA-4) in a cohort of patients with RRMS. Six-month delayed measures were introduced to consider latency of action of drugs., Methods: Observational retrospective monocentric study. All the patients with RRMS starting DMT between 2015 and 2018, and with 2-year of follow-up, were included. Annualized brain volume loss (a-BVL) was calculated by SIENA software., Results: We included 108 patients, the majority treated with first line DMT. At 2-year follow-up, 35 % of patients were NEDA-3 (50 % 6mdNEDA-3), and 17 % NEDA-4 (28 % 6mdNEDA-4). Loss of NEDA-3 status was mainly driven by MRI activity (70 %), followed by relapses (56 %), and only minimally by disability progression (7 %)., Conclusion: In our cohort 2-year NEDA status, especially including lack of brain atrophy, was hard to achieve. Further studies are needed to establish the prognostic value of NEDA-3 and NEDA4 in the long-term follow-up., Competing Interests: Declaration of Competing Interest F. Granella received research grants from Biogen and Roche and fees for consultation from Biogen, Sanofi, Merck Serono, Novartis, and Roche. The other authors report no conflict of interest relevant to the manuscript., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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., Competing Interests: Competing interests: IR served on scientific advisory boards for Novartis and Merck, and received conference travel support and/or speaker honoraria from Roche, Novartis, Biogen, Teva, Sanofi Genzyme, and Merck. A-LN received grants from MS Research Australia; grants, personal fees, and nonfinancial support from Biogen; grants and personal fees from Merck Serono; personal fees from Teva and Novartis; and nonfinancial support from Roche and Sanofi Genzyme. GI received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall, and Teva. SE received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche, and Teva. FP received speaker honoraria and advisory board fees from Almirall, Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi Genzyme, and Teva, and research funding from Biogen, Merck, FISM (Fondazione Italiana Sclerosi Multipla), Reload Onlus Association, and the University of Catania. DH received speaker honoraria and consulting fees from Biogen, Merck, Teva, Roche, Sanofi Genzyme, and Novartis, and support for research activities from Biogen and the Czech Ministry of Education (project PROGRES Q27/LF1). EVH received honoraria or research support from Biogen, Merck Serono, Novartis, Roche, and Teva; has been a member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novartis, and Sanofi Genzyme; and received research support from the Czech Ministry of Education (project PROGRES Q27/LF1). MG received consulting fees from Teva Canada Innovation, Biogen, Novartis, and Sanofi Genzyme; lecture payments from Teva Canada Innovation, Novartis, and EMD; and research support from the Canadian Institutes of Health Research. PD served on editorial boards for, and has been supported to attend meetings by, EMD, Biogen, Novartis, Genzyme, and Teva Neuroscience; he holds grants from the Canadian Institutes of Health Research and the MS Society of Canada, and received funding for investigator-initiated trials from Biogen, Novartis, and Genzyme. FG’M received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, Mitsubishi, and ONO Pharmaceuticals. AL received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Biogen, Merck Serono, Mylan, Novartis, Roche, Sanofi Genzyme, and Teva; her institutions have received research grants from Novartis (in the past 4 years). PG served on advisory boards for Novartis, EMD Serono, Roche, Biogen Idec, Sanofi Genzyme, and Pendopharm; received grant support from Genzyme and Roche; and received research grants for his institution from Biogen Idec, Sanofi Genzyme, and EMD Serono. MPA received honoraria as a consultant on scientific advisory boards for Biogen, Bayer Schering, Merck, Teva, and Sanofi-Aventis, and received research grants by Biogen, Bayer Schering, Merck, Teva, and Novartis. PS served on scientific advisory boards for Biogen Idec and Teva; received funding for travel and speaker honoraria from Biogen Idec, Merck, Teva, Sanofi Genzyme, Novartis, and Bayer; and received research grants for her institution from Bayer, Biogen, Merck, Novartis, Sanofi, and Teva. DF received travel grants and/or speaker honoraria from Merck, Teva, Novartis, Biogen, and Sanofi Genzyme. KB received honoraria and consulting fees from Biogen, Teva, Novartis, Sanofi Genzyme, Roche, Merck, CSL, and Grifols. JL-S received travel compensation from Novartis, Biogen, Roche, and Merck; her institution received honoraria for talks and advisory board commitments, as well as research grants from Biogen, Merck, Roche, Teva, and Novartis. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche, and Sanofi Genzyme. CB received conference travel support from Biogen, Novartis, Bayer Schering, Merck, and Teva, and participated in clinical trials by Sanofi-Aventis, Roche, and Novartis. VVP received travel grants from Merck, Biogen, Sanofi, Celgene, Almirall, and Roche; his institution received research grants and consultancy fees from Roche, Biogen, Sanofi, Celgene, Merck, and Novartis Pharma. MT received travel grants from Novartis, Bayer Schering, Merck, and Teva, and participated in clinical trials by Sanofi-Aventis, Roche, and Novartis. DM received speaker honoraria for advisory board service and travel grants from Almirall, Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva. CR-T received research funding, compensation for travel, or speaker honoraria from Biogen, Novartis, Genzyme, and Almirall. DLS received honoraria as a consultant on scientific advisory boards from Bayer Schering, Novartis, and Sanofi-Aventis, and compensation for travel from Novartis, Biogen, Sanofi-Aventis, Teva, and Merck. FG received an institutional research grant from Biogen and Sanofi Genzyme; served on scientific advisory boards for Biogen, Novartis, Merck, Sanofi Genzyme, and Roche; and received funding for travel and speaker honoraria from Biogen, Merck, and Sanofi-Aventis. MS participated in, but did not receive honoraria for, advisory board activity for Biogen, Merck, Bayer Schering, Sanofi-Aventis, and Novartis. RB received speaker honoraria from Bayer Schering, Biogen, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva; research grants from Bayer Schering, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva; and congress, travel, and accommodation expense compensations from Almirall, Bayer Schering, Biogen, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva. RA received conference travel support from Novartis, Teva, Biogen, Bayer, and Merck, and participated in clinical trials by Biogen, Novartis, Teva, and Actelion. JLS-M received travel compensation from Novartis and Biogen; received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer, and Teva; and participated in a clinical trial by Biogen. JP received travel compensation from Novartis, Biogen, Genzyme, and Teva, and speaking honoraria from Biogen, Novartis, Genzyme and Teva. TC-T received speaking or consulting fees and/or travel funding from Bayer, Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva. GL received travel and/or consultancy compensation from Sanofi Genzyme, Roche, Teva, Merck, Novartis, Celgene, and Biogen. JO received research funding from the MS Society of Canada, the National MS Society, Brain Canada, Biogen Idec, Roche, and EMD Serono, and personal compensation for consulting or speaking from EMD Serono, Sanofi Genzyme, Biogen Idec, Roche, Celgene, and Novartis. AA received personal fees and speaker honoraria from Teva, Merck, Biogen Gen Pharma, Roche, Novartis, Bayer, and Sanofi Genzyme, and received travel and registration grants from Merck, Biogen Gen Pharma, Roche, Sanofi Genzyme, and Bayer. HB received compensation for consulting, talks, and advisory or steering board activities from Biogen, Merck, Novartis, Genzyme, Alfred Health, and Oxford Health Policy Forum, and research support from Novartis, Biogen, Roche, Merck, the National Health and Medical Research Council of Australia, Pennycook Foundation, and MS Research Australia MB served on scientific advisory boards for Biogen, Novartis, and Genzyme, received conference travel support from Biogen and Novartis, and serves on steering committees for trials conducted by Novartis; his institution received research support from Biogen, Merck, and Novartis. EC Cristiano received honoraria as a consultant on scientific advisory boards for Biogen, Bayer Schering, Merck, Genzyme, and Novartis, and participated in clinical trials or other research projects by Merck, Roche, and Novartis. SH received honoraria and consulting fees from Novartis, Bayer Schering, and Sanofi, and travel grants from Novartis, Biogen Idec, and Bayer Schering. GI received compensation for travel, accommodations, and meeting expenses from Bayer Schering, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva. LK received research support from Acorda, Actelion, Allozyne, BaroFold, Bayer HealthCare, Bayer Schering, Bayhill Therapeutics, Biogen, Elan, European Union, Genmab, Gianni Rubatto Foundation, GlaxoSmithKline, Glenmark, MediciNova, Merck, Novartis, Novartis Research Foundation, Roche, Roche Research Foundation, Sanofi-Aventis, Santhera, the Swiss MS Society, the Swiss National Research Foundation, Teva Neuroscience, UCB, and Wyeth. BW-G participated in speakers' bureaus and/or served as a consultant for Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, Bayer, Janssen, and Horizon; received grant/research support from these same agencies; and serves on editorial boards for BMJ Neurology, Children, CNS Drugs, MS International, and Frontiers Epidemiology. BVW received research and travel grants and honoraria for advisory and speaking fees from Bayer Schering, Biogen, Sanofi Genzyme, Merck, Novartis, Roche, and Teva. TK served on scientific advisory boards for BMS, Roche, Sanofi Genzyme, Novartis, Merck, and Biogen, and the steering committee for the Brain Atrophy Initiative by Sanofi Genzyme; received conference travel support and/or speaker honoraria from WebMD Global, Novartis, Biogen, Sanofi Genzyme, Teva, BioCSL, and Merck; and received support for research or educational events from Biogen, Novartis, Genzyme, Roche, Celgene, and Merck., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Objectives: 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., Methods: 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., Results: 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)., Discussion: 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., Classification of Evidence: This study provides Class III evidence that autologous hematopoietic stem cell transplants prolonged the time to CDP compared with other DMTs., (© 2022 American Academy of Neurology.)

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.

Background: Patients with relapsing-remitting multiple sclerosis (RRMS) who experience relapses on a first-line therapy (interferon, glatiramer acetate, dimethyl fumarate, or teriflunomide; collectively, "BRACETD") often switch to another therapy, including natalizumab or fingolimod. Here we compare the effectiveness of switching from a first-line therapy to natalizumab or fingolimod after ≥1 relapse., Methods: Data collected prospectively in the MSBase Registry, a global, longitudinal, observational registry, were extracted on February 6, 2018. Included patients were adults with RRMS with ≥1 relapse on BRACETD therapy in the year before switching to natalizumab or fingolimod. Included patients received natalizumab or fingolimod for ≥3 months after the switch., Results: Following 1:1 propensity score matching, 1000 natalizumab patients were matched to 1000 fingolimod patients. Mean (standard deviation) follow-up time was 3.02 (2.06) years after switching to natalizumab and 2.58 (1.64) years after switching to fingolimod. Natalizumab recipients had significantly lower annualized relapse rate (relative risk=0.66; 95% confidence interval [CI], 0.59-0.74), lower risk of first relapse (hazard ratio [HR]=0.69; 95% CI, 0.60-0.80), and higher confirmed disability improvement (HR=1.27; 95% CI, 1.03-1.57) than fingolimod recipients. No difference in confirmed disability worsening was observed., Conclusions: Patients with RRMS switching from BRACETD demonstrated better outcomes with natalizumab than with fingolimod., Competing Interests: Declaration of Competing Interest Dr Spelman has received honoraria for consultancy and funding for travel from Biogen and Novartis. Dr Horakova has received speaker honoraria and consulting fees from Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva, as well as support for research activities from Biogen and the Czech Ministry of Education (project Progres Q27/LF1). Dr Alroughani has received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche, and Sanofi Genzyme. Dr Kalincik has served on scientific advisory boards for Biogen, Merck, Novartis, Roche, and Sanofi Genzyme and a steering committee for Genzyme's Brain Atrophy Initiative; has received conference travel support and/or speaker honoraria from BioCSL, Biogen, Merck, Novartis, Sanofi Genzyme, Teva, and WebMD Global; and has received research support from Biogen. Dr Terzi has received travel grants from Bayer Schering, Merck, Novartis, and Teva and has participated in clinical trials by Novartis, Roche, and Sanofi. Dr Grammond has served on advisory boards for Biogen, Genzyme, Merck, Novartis, and Teva Neuroscience and as a consultant for Merck; has received payments for lectures from Merck, Teva Neuroscience, and the Canadian Multiple Sclerosis Society; and has received grants for travel from Novartis and Teva Neuroscience. Dr Patti has received speaker honoraria or advisory board fees from Almirall, Bayer, Biogen, Celgene, Merck, Mylan, Novartis, Roche, Sanofi Genzyme, and Teva and research funding from Biogen, Merck, the Italian Ministry of Education, University and Research, and the Italian Multiple Sclerosis Society Foundation. Dr Csepany has received speaker honoraria and/or conference travel support from Bayer Schering, Biogen, Merck, Novartis, Roche, Sanofi, and Teva. Dr Boz has received conference travel support from Bayer Schering, Biogen, Merck, Novartis, and Teva and has participated in clinical trials by Novartis, Roche, and Sanofi. Dr Lechner-Scott has received travel compensation from Biogen, Merck, and Novartis and has been involved in clinical trials with Biogen, Novartis, and Teva. Her institution has received honoraria for talks and advisory board service from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi Genzyme, and Teva. Dr Granella has received research funding from Biogen and Sanofi Genzyme; fees for advisory boards and speaker honoraria from Biogen, Merck Serono, Novartis, Roche, and Sanofi Genzyme; and travel funding from Biogen, Merck Serono, Roche, and Sanofi Genzyme. Dr Grand'Maison has received honoraria or research funding from Biogen, Genzyme, Mitsubishi, Novartis, Ono Pharmaceuticals, and Teva Neuroscience. Dr. van der Walt reports grants from Roche and Novartis; and has served on advisory boards for and received travel support from Merck, Roche, Biogen, Novartis, Alexion, and BMS. Dr Butzkueven has served on scientific advisory boards for Biogen, Novartis, and Sanofi and steering committees for trials conducted by Biogen and Novartis; has received conference travel support from Biogen, Novartis, and Sanofi; and has received research support from Biogen, Merck, and Novartis. Drs Ozakbas, Onofrj, Prat, and Zhu have nothing to disclose., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Definitions for reliable identification of transition from relapsing-remitting multiple sclerosis (MS) to secondary progressive (SP)MS in clinical cohorts are not available., Objectives: To compare diagnostic performances of two different data-driven SPMS definitions., Methods: Data-driven SPMS definitions based on a version of Lorscheider's algorithm (DDA) and on the EXPAND trial inclusion criteria were compared, using the neurologist's definition (ND) as gold standard, in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), Akaike information criterion (AIC) and area under the curve (AUC)., Results: A cohort of 10,240 MS patients with ⩾5 years of follow-up was extracted from the Italian MS Registry; 880 (8.5%) patients were classified as SPMS according to the neurologist definition, 1806 (17.6%) applying the DDA and 1134 (11.0%) with the EXPAND definition. The DDA showed greater discrimination power (AUC: 0.8 vs 0.6) and a higher sensitivity (77.1% vs 38.0%) than the EXPAND definition, with similar specificity (88.0% vs 91.5%). PPV and NPV were higher using the DDA than considering EXPAND definition (37.5% vs 29.5%; 97.6% vs 94.0%)., Conclusion: Data-driven definitions demonstrated greater ability to capture SP transition than neurologist's definition and the global accuracy of DDA seems to be higher than the EXPAND definition.

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.

Objective: Assessing the risk of clinical and radiological reactivation during pregnancy and post partum in women with multiple sclerosis (MS) treated with natalizumab (NTZ) throughout pregnancy (LONG&#95;EXP) compared with women interrupting treatment before (NO&#95;EXP) and within >-30 days and ≤90 days from conception (SHORT&#95;EXP), and describing newborns' outcomes., Methods: Maternal clinical and radiological outcomes and obstetric and fetal outcomes were retrospectively collected and compared among groups (NO&#95;EXP, SHORT&#95;EXP, LONG&#95;EXP). Predictors of clinical and radiological reactivation were investigated through univariable and multivariable analysis., Results: 170 eligible pregnancies from 163 women referring to 29 Italian MS centres were included. Annualised relapse rate (ARR) was significantly lower in LONG&#95;EXP (n=66, 0.02 (0.001-0.09)) compared with NO&#95;EXP (n=31, 0.43 (0.21-0.75), p=0.002) and SHORT&#95;EXP (n=73, 0.46 (0.30-0.66), p=0.0004) during pregnancy, and in LONG&#95;EXP (0.12 (0.05-0.24)) compared with SHORT&#95;EXP (0.30 (0.17-0.50), p=0.008) during post partum. Gadolinium-enhancing (Gd+) lesions were less frequent in LONG&#95;EXP (n=6/50, 2.00%) compared with NO&#95;EXP (n=9/21, 42.86%) and SHORT&#95;EXP after delivery (n=17/49, 34.69%, p=0.010).Delaying NTZ resumption after delivery significantly increased the risk of relapses (OR=1.29 (95% CI 1.07 to 1.57), p=0.009) and Gd+ lesions (OR=1.49 (95% CI 1.17 to 1.89, p=0.001). Newborns' weight, length, head circumference and gestational age did not differ among groups after adjusting for confounders. Anaemia was tracked in 4/69 LONG&#95;EXP newborns. Congenital anomaly rate was within the expected range for the untreated MS population., Conclusions: Our findings indicate that in women with MS treated with NTZ before conception, continuation of NTZ throughout pregnancy and its early resumption after delivery mitigate the risk of clinical and radiological reactivation. This approach has no major impact on newborns' outcomes., Competing Interests: Competing interests: DL received travel funding from Biogen, Merck-Serono, Sanofi-Genzyme, Teva, speaking or consultations fees from Sanofi-Genzyme, Merck-Serono, Teva, Biogen, Roche; FB received teaching honoraria from Novartis; AGr reports no disclosures relevant to the manuscript; PA received travel support, compensation for serving on scientific advisory boards and speaker's fees from Almirall, Biogen, Celgene, Merck-Serono, Mylan, Novartis, Sanofi-Genzyme and Teva; ABe reports no disclosures relevant to the manuscript; ABi reports no disclosures relevant to the manuscript; GB received honoraria for speaking or consultation fee from Almirall, Biogen, Merck, Novartis, Sanofi, Teva, Roche; VB received fees for consultancies or public speaking from Merck, Novartis, Biogen, Roche, Genzyme and Biogen; SB has been founded for advisory board, academic purposes and speech honoraria by Genzyme, Roche, Biogen, Merck-Serono, Novartis and Almirall; MCB has advisory board membership and honoraria for speaking from Teva, Novartis, Sanofi, Merck-Serono and Biogen; FC received honoraria for advisory board and/or for public speaking, and/or travel grant, from Biogen, Merck, Teva, Sanofi-Genzyme, Roche; RCa received lecture fees and/or travel grants from Novartis, Biogen, Roche, Celgene and Merck; DC is an Advisory Board member of Almirall, Bayer-Schering, Biogen, GW Pharmaceutical, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva and received honoraria for speaking or consultation fee from Almirall, Bayer-Schering, Biogen, GW Pharmaceuticals, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva. He is also the principal investigator in clinical trials for Bayer-Schering, Biogen, Merck-Serono, Novartis, Roche, Sanofi-Genzyme; RCe has received funding for travel and/or speaker honoraria from Sanofy, Biogen Idec, Merck-Serono and Roche; CGC received grants for congress participation from Almirall, Biogen, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva; MCa received personal compensation for speaking/advising/consulting from Merck, Sanofi-Genzyme, Biogen, Novartis, Roche, Teva, EMF Serono; was supported in travelling expenses for congresses from Merck, Sanofi-Genzyme, Biogen, Novartis, Roche, Teva, Almirall; received research grants from Italian MS Foundation (FISM), Italian Ministry of Research, Merck, Sanofi-Genzyme, Biogen, Novartis; ECo received travel grant, speaker fee and consultancy from Biogen Idec, Teva, Genzyme, Merck-Serono, Novartis, Roche and Admirall; CC received personal compensation for advisory board and speaking from: Biogen, Roche, Novartis, Almirall, Merck-Serono; ECu received fees for advisory boards and speaking honoraria from Merck-Serono, Novartis and Biogen, travel funding from Biogen, Sanofi-Genzyme, Merck-Serono, Roche, Novartis and Teva; AD reports no disclosures relevant to the manuscript; EDA received speaking honoraria from Biogen, Merck-Serono, Novartis, Sanofi-Genzyme, Bayer-Schering; GDL served on scientific advisory boards for Merck, Sanofi-Genzyme and Roche, and has received travel and/or speaker honoraria from Merck, Roche, Teva, Biogen, Novartis and Sanofi-Genzyme; MDF participated on advisory boards for and received speaker or writing honoraria and funding for travelling from Bayer, Biogen Idec, Genzyme, Merck, Mylan, Novartis, Roche and Teva; DF has received travel grants, speaker honoraria and/or research support to her institution by Merck-Serono, Biogen, Roche, Genzyme, Novartis, Teva and Binding Site; AGa received speaker and consulting fees from Actelion, Biogen, Coloplast, Merck-Serono, Mylan, Roche, Sanofi-Genzyme, Teva; CG received fee as speaker or advisory board from Merck, Biogen, Teva, Bayer, Roche, Sanofi, Almirall; FG received research funding from Sanofi-Genzyme and Biogen, fees for advisory boards and speaking honoraria from Biogen, Novartis, Sanofi-Genzyme, Merck-Serono and Roche, travel funding from Biogen, Sanofi-Genzyme, Merck-Serono and Roche; MI received grants from NIH, NMSS, FISM; received fees for consultation from Roche, Genzyme, Merck, Biogen and Novartis; RL received fees for consultancies or public speaking from Merck, Novartis, Biogen, Roche, Genzyme and Biogen; LL received travel grant, speaker fee and consultancy from Biogen Idec, Teva, Genzyme, Merck-Serono, Novartis, Roche and Admirall; GL received speaker honoraria and/or consultancy from Biogen, Teva, Genzyme, Merck, Novartis, Almirall, Roche; MM received personal fees from Sanofi-Genzyme, Merck-Serono, Novartis and Almirall; MM has scientific advisory board membership of Bayer-Schering, Biogen, Sanofi-Genzyme, Merck, Novartis, Teva; consulting and/or speaking fees, research support or travel grants from Almirall, Bayer-Schering, Biogen, CSL, Sanofi-Genzyme, Merck, Novartis, Teva, Roche, Ultragenix; principal investigator in clinical trials for Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, Teva, Ultragenix, CSL Behring; LM received honoraria for speaking activity at scientific meetings and/or advisory boards from Biogen Idec, Merck-Serono, Sanofi-Genzyme, Novartis, Roche; CGN received travel funding from Almirall, Biogen, Novartis and Sanofi-Genzyme, Merck-Serono; VN has received consulting fees from Novartis, Roche, Mylan, Biogen Idec, Merk and Bayer; speaker and writing honoraria from Mylan, Teva, Biogen Idec, Bayer, Sanofi-Genzyme and Merk; travel grants from Teva, Biogen Idec, Sanofi-Genzyme, Roche and Novartis; FPa received honoraria for speaking activities by Almirall, Bayer-Schering, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva; he also served as advisory board member the following companies: Bayer-Schering, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva; he was also funded by Pfizer and FISM for epidemiological studies; he received grants for congress participation from Almirall, Bayer Shering, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva; EP received compensation for travel grants, participation in advisory board and/or speaking activities from Biogen, Merck-Serono, Sanofi, Teva and Novartis; serves on the editorial board of Frontiers in Neurology and Brain Sciences; CP received honoraria for speaking or consultation fee from Almirall, Biogen, Merck, Novartis, Sanofi, Teva, Roche; PR received travel expenses or honoraria for speaking or participating to advisory board by: Biogen, Merck, Sanofi-Genzyme, Novartis, Teva, Roche; GS received travel expenses or honoraria for speaking or participating to advisory board by: Biogen idec, Sanofi-Genzyme, Novartis, Roche; ESi received speaker honoraria and/or consultancy from Biogen, Teva, Genzyme, Merck, Novartis, Almirall, Roche; FV has received travel grants and/or speaker honoraria by Merck-Serono, Biogen, Roche, Genzyme, Novartis and Teva; RT has served on advisory boards and/or received honoraria for speaking or consultation fees from Almirall, Biogen, Laborest, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva; MPS received personal fees from Biogen, Merck, Teva, Novartis, Sanofi-Genzyme, Roche, GeNeuro and Medday, outside the submitted work; MPA received research grants and honoraria as a speaker and member of advisory boards by: Bayer, Biogen, Merck, Novartis, Sanofi-Genzyme, Teva, Almirall, Celgene and Roche; GAM received speaking or consultation fees from Almirall, Bayer-Schering, Biogen, Genzyme, Merck-Serono, Novartis, Teva, Sanofi-Genzyme., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Multiple sclerosis (MS) is characterized by phenotypical heterogeneity, partly resulting from demographic and environmental risk factors. Socio-economic factors and the characteristics of local MS facilities might also play a part., Methods: This study included patients with a confirmed MS diagnosis enrolled in the Italian MS and Related Disorders Register in 2000-2021. Patients at first visit were classified as having a clinically isolated syndrome (CIS), relapsing-remitting (RR), primary progressive (PP), progressive-relapsing (PR), or secondary progressive MS (SP). Demographic and clinical characteristics were analyzed, with centers' characteristics, geographic macro-areas, and Deprivation Index. We computed the odds ratios (OR) for CIS, PP/PR, and SP phenotypes, compared to the RR, using multivariate, multinomial, mixed effects logistic regression models., Results: In all 35,243 patients from 106 centers were included. The OR of presenting more advanced MS phenotypes than the RR phenotype at first visit significantly diminished in relation to calendar period. Females were at a significantly lower risk of a PP/PR or SP phenotype. Older age was associated with CIS, PP/PR, and SP. The risk of a longer interval between disease onset and first visit was lower for the CIS phenotype, but higher for PP/PR and SP. The probability of SP at first visit was greater in the South of Italy., Discussion: Differences in the phenotype of MS patients first seen in Italian centers can be only partly explained by differences in the centers' characteristics. The demographic and socio-economic characteristics of MS patients seem to be the main determinants of the phenotypes at first referral., (© 2022. The Author(s).)

Importance: Except for ocrelizumab, treatment options in primary progressive multiple sclerosis (PPMS) are lacking., Objective: To investigate the effectiveness of DMTs on the risk of becoming wheelchair dependent in a real-world population of patients with PPMS., Design, Setting, and Participants: This was a multicenter, observational, retrospective, comparative effectiveness research study. Data were extracted on November 28, 2018, from the Italian multiple sclerosis register and analyzed from June to December 2021. Mean study follow-up was 11 years. Included in the study cohort were patients with a diagnosis of PPMS and at least 3 years of Expanded Disability Status Scale (EDSS) evaluations and 3 years of follow-up., Main Outcomes and Measures: The risk of reaching an EDSS score of 7.0 was assessed through multivariable Cox regression models., Exposures: Patients who received DMT before the outcome were considered treated. DMT was assessed as a time-dependent variable and by class of DMT (moderately and highly effective)., Results: From a total of 3298 patients with PPMS, 2633 were excluded because they did not meet the entry criteria for the phase 3, multicenter, randomized, parallel-group, double-blind, placebo-controlled study to evaluate the efficacy and safety of ocrelizumab in adults with PPMS (ORATORIO) trial. Among the remaining 665 patients (mean [SD] age, 43.0 [10.7] years; 366 female patients [55.0%]), 409 were further selected for propensity score matching (288 treated and 121 untreated patients). In the matched cohort, during the study follow-up, 37% of patients (152 of 409) reached an EDSS score of 7.0 after a mean (SD) follow-up of 10.6 (5.6) years. A higher EDSS score at baseline (adjusted hazard ratio [aHR], 1.32; 95% CI, 1.13-1.55; P < .001), superimposed relapses (aHR, 2.37; 95% CI, 1.24-4.54; P = .009), and DMT exposure (aHR, 1.75; 95% CI, 1.04-2.94; P = .03) were associated with a higher risk of an EDSS score of 7.0, whereas the interaction term between DMT and superimposed relapses was associated with a reduced risk of EDSS score of 7.0 (aHR, 0.33; 95% CI, 0.16-0.71; P = .004). Similar findings were obtained when treatment according to DMT class was considered and when DMT was included as a time-dependent covariate. These results were confirmed in the subgroup of patients with available magnetic resonance imaging data., Conclusions and Relevance: Results of this comparative effectiveness research study suggest that inflammation also occurs in patients with PPMS, may contribute to long-term disability, and may be associated with a reduced risk of becoming wheelchair dependent by current licensed DMTs.

In the COVID-19 pandemic era, safety concerns have been raised regarding the risk of severe infection following administration of ocrelizumab (OCR), a B-cell-depleting therapy. We enrolled all relapsing remitting multiple sclerosis (RRMS) patients who received maintenance doses of OCR from January 2020 to June 2021. Data were extracted in December 2021. Standard interval dosing (SID) was defined as a regular maintenance interval of OCR infusion every 6 months, whereas extended interval dosing (EID) was defined as an OCR infusion delay of at least 4 weeks. Three infusions were considered in defining SID vs. EID (infusions A, B, and C). Infusion A was the last infusion before January 2020. The primary study outcome was a comparison of disease activity during the A-C interval, which was defined as either clinical (new relapses) or radiological (new lesions on T1-gadolinium or T2-weighted magnetic resonance imaging (MRI) sequences). Second, we aimed to assess confirmed disability progression (CDP). A total cohort of 278 patients (174 on SID and 104 on EID) was enrolled. Patients who received OCR on EID had a longer disease duration and a higher rate of vaccination against severe acute respiratory syndrome-coronavirus 2 (p &lt; 0.05). EID was associated with an increased risk of MRI activity during the A-C interval (OR 5.373, 95% CI 1.203-24.001, p = 0.028). Being on SID or EID did not influence CDP (V-Cramer 0.47, p = 0.342). EID seemed to be associated with a higher risk of MRI activity in our cohort. EID needs to be carefully considered for OCR-treated patients., (© 2022. The Author(s).)

Disability accrual in multiple sclerosis may occur as relapse-associated worsening or progression independent of relapse activity. The role of progression independent of relapse activity in early multiple sclerosis is yet to be established. The objective of this multicentre, observational, retrospective cohort study was to investigate the contribution of relapse-associated worsening and progression independent of relapse activity to confirmed disability accumulation in patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis, assessed within one year from onset and with follow-up ≥5 years (n = 5169). Data were extracted from the Italian Multiple Sclerosis Register. Confirmed disability accumulation was defined by an increase in Expanded Disability Status Scale score confirmed at 6 months, and classified per temporal association with relapses. Factors associated with progression independent of relapse activity and relapse-associated worsening were assessed using multivariable Cox regression models. Over a follow-up period of 11.5 ± 5.5 years, progression independent of relapse activity occurred in 1427 (27.6%) and relapse-associated worsening in 922 (17.8%) patients. Progression independent of relapse activity was associated with older age at baseline [hazard ratio (HR) = 1.19; 95% confidence interval (CI) 1.13-1.25, P < 0.001], having a relapsing-remitting course at baseline (HR = 1.44; 95% CI 1.28-1.61, P < 0.001), longer disease duration at baseline (HR = 1.56; 95% CI 1.28-1.90, P < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.92; 95% CI 0.88-0.96, P < 0.001) and lower number of relapses before the event (HR = 0.76; 95% CI 0.73-0.80, P < 0.001). Relapse-associated worsening was associated with younger age at baseline (HR = 0.87; 95% CI 0.81-0.93, P < 0.001), having a relapsing-remitting course at baseline (HR = 1.55; 95% CI 1.35-1.79, P < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.94; 95% CI 0.89-0.99, P = 0.017) and a higher number of relapses before the event (HR = 1.04; 95% CI 1.01-1.07, P < 0.001). Longer exposure to disease-modifying drugs was associated with a lower risk of both progression independent of relapse activity and relapse-associated worsening (P < 0.001). This study provides evidence that in an early relapsing-onset multiple sclerosis cohort, progression independent of relapse activity was an important contributor to confirmed disability accumulation. Our findings indicate that insidious progression appears even in the earliest phases of the disease, suggesting that inflammation and neurodegeneration can represent a single disease continuum, in which age is one of the main determinants of disease phenomenology., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)