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Objective: Elevated healthcare use before multiple sclerosis (MS) onset suggests earlier opportunity to identify MS. Yet their timing and sociodemographic effects are unclear. We examined rates of healthcare use (and by age/sex) for >two decades pre-MS onset., Methods: We identified people with MS (PwMS) using administrative data from Canada (Ontario) and Sweden (1991-2020) ("administrative" cohort), and the Swedish MS Registry ("clinical" cohort). The first MS/demyelinating diagnostic code (administrative) or symptom onset (clinical) defined MS onset. We compared annual rates of healthcare use (hospital, physician, and emergency-room [ED]) pre-onset between PwMS and up to five matched population controls using negative binomial regression, and by age/sex., Results: The administrative cohort = 35,018/136,007 PwMS/controls (Ontario), and 10,269/51,297 (Sweden). Rates of healthcare use were higher for PwMS than controls up to 28 (of 29) years (Ontario) and up to 15 (of 19) years (Sweden) pre-onset. Annual healthcare use rose steadily as onset approached, particularly escalating 7 years pre-onset in Ontario (e.g., hospital visit rate ratios [RRs] exceeded 1.30), and 6 years in Sweden (physician visit RRs > 1.10). RRs peaked the year pre-onset (ED visits [Ontario] = 3.04; 95% CI: 2.94-3.13, physician visits [Sweden] = 2.51; 95% CI: 2.44-2.59). In the year pre-onset, RRs were disproportionately higher for males (ED RRs [Ontario] = 3.30; 95% CI: 3.13-3.48 vs. females = 2.90; 95% CI: 2.79-3.02), and dropped steadily by age (physician visit RRs [Sweden] = 2.61/2.27/1.97/1.72 for 50/40/30/20-year-olds). The smaller clinical cohort (7604/37,974 PwMS/controls) exhibited similar patterns, albeit more modest, with RRs elevated up to 5 years pre-onset (physician visit RR [year-5] = 1.08; 95% CI: 1.02-1.14; RR [year-1] = 1.39;1.33-1.46)., Interpretation: Higher healthcare use was evident decades before MS onset, escalating 6-7 years pre-onset, peaking the year before, being disproportionately higher for males and older PwMS., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Vitamin D (VitD) affects the risk of multiple sclerosis (MS), but the impact on disease activity is controversial. We assessed whether VitD is associated with the No-Evidence of Disease Activity-3 (NEDA-3) status at 2 years from disease-modifying treatment (DMT) start, and whether this association is causal or the result of confounding factors. Furthermore, we explored if a genetic predisposition to higher VitD levels affects the risk of disease activity., Methods: 230 untreated relapsing-remitting MS patients underwent serum 25-OH-vitamin-D measurement, and the association between seasonally adjusted VitD and disease activity was tested. Modelling a Polygenic Risk Score from a Genome-Wide Association Study on ~400 000 individuals, we studied the impact of genetic predisposition to higher VitD on the NEDA-3 status in 1408 independent MS patients. Two-sample Mendelian randomisation (MR) was used to assess causality., Results: Lower baseline VitD was associated with decreased probability of NEDA-3 at 2 years (p=0.019). Particularly, VitD levels <20 ng/mL conferred an over twofold risk of disease activity (OR 2.36, 95% CI 1.30 to 3.88, p=0.0037). Genetic predisposition to higher VitD levels was associated with delayed age at MS onset (p=0.018) and with a higher probability of NEDA-3 status (p=0.034). MR confirmed causality between VitD and the risk of disease activity (p=0.041)., Conclusions: VitD levels before DMT start affect the risk of disease activity in MS. Genetic predisposition to higher VitD levels confers a lower risk of disease activity and is associated with delayed MS onset. Our work prompts future prospective studies regarding VitD supplementation and lifestyle interventions to hamper disease activity in MS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Women have a higher risk of developing multiple sclerosis (MS), potentially due to hormonal factors. Elevated testosterone levels, common in polycystic ovary syndrome (PCOS), might influence MS risk., Objective: To investigate the relationship between PCOS, as a proxy for elevated testosterone levels, and MS risk through phenotypic and genomic analysis., Methods: Cox regression models analysed the association between PCOS and MS risk. The genome-wide cross-trait analysis examined the genetic architecture., Results: In a Swedish cohort of 1,374,529 women, 77 (0.3%) with PCOS and 3,654 (0.3%) without PCOS were diagnosed with MS. After adjusting for birth year and obesity, no association was found between PCOS and MS ( HR = 0.91, 95% CI = 0.72-1.15), which was confirmed by Mendelian randomization analysis, where genetically predicted PCOS propensity, sex hormone-binding globulin (SHBG), or testosterone levels did not causally affect MS risk (all p -values > 0.05). By exploring horizontal pleiotropy, we identified shared genetic regions and 19 independent pleiotropic SNPs for SHBG with MS and 11 for testosterone with MS., Conclusion: We did not find evidence for a causal role of PCOS, as a proxy of elevated testosterone, in reducing the risk of MS in women. The shared genetic loci between testosterone, SHBG, and MS provide biological insights., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Epstein-Barr virus (EBV) infection has been advocated as a prerequisite for developing multiple sclerosis (MS) and possibly the propagation of the disease. However, the precise mechanisms for such influences are still unclear. A large-scale study investigating the host genetics of EBV serology and related clinical manifestations, such as infectious mononucleosis (IM), may help us better understand the role of EBV in MS pathogenesis. This study evaluates the host genetic factors that influence serological response against EBV and history of IM and cross-evaluates them with MS risk and genetic susceptibility in the Swedish population. Plasma IgG antibody levels against EBV nuclear antigen-1 [EBNA-1, truncated = amino acids (aa) (325-641), peptide = aa(385-420)] and viral capsid antigen p18 (VCAp18) were measured using bead-based multiplex serology for 8744 MS cases and 7229 population-matched control subjects. The MS risk association for high/low EBV antibody levels and history of IM was compared to relevant clinical measures along with sex, age at sampling, and associated HLA allele variants. Genome-wide and HLA allele association analyses were also performed to identify genetic risk factors for EBV antibody response and IM history. Higher antibody levels against VCAp18 [odds ratio (OR) = 1.74, 95% confidence interval (CI) = 1.60-1.88] and EBNA-1, particularly the peptide (OR = 3.13, 95% CI = 2.93-3.35), were associated with an increased risk for MS. The risk increased with higher anti-EBNA-1 IgG levels up to 12× the reference risk. We also identified several independent HLA haplotypes associated with EBV serology overlapping with known MS risk alleles (e.g. DRB1*15:01). Although there were several candidates, no variants outside the HLA region reached genome-wide significance. Cumulative HLA risk for anti-EBNA-1 IgG levels, particularly the peptide fragment, was strongly associated with MS. In contrast, the genetic risk for high anti-VCAp18 IgG levels was not as strongly associated with MS risk. IM history was not associated with class II HLA genes but negatively associated with A*02:01, which is protective against MS. Our findings emphasize that the risk association between anti-EBNA-1 IgG levels and MS may be partly due to overlapping HLA associations. Additionally, the increasing MS risk with increasing anti-EBNA-1 levels would be consistent with a pathogenic role of the EBNA-1 immune response, perhaps through molecular mimicry. Given that high anti-EBNA-1 antibodies may reflect a poorly controlled T-cell defence against the virus, our findings would be consistent with DRB1*15:01 being a poor class II antigen in the immune defence against EBV. Last, the difference in genetic control of IM supports the independent roles of EBNA-1 and IM in MS susceptibility., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: While multiple sclerosis (MS) affects less than 1 % of the general population, immune mediated inflammatory diseases (IMIDs) collectively influence 5-10 % of the population. Understanding familial co-aggregation of MS and other IMIDs carries important clinical and public health implications that will enable early detection and personalized treatment., Objective: To estimate the familial association between MS and other IMIDs and to quantify their shared genetic basis., Design: Register-based multi-generational nested case-control familial co-aggregation study and genetic correlation study., Setting: Sweden., Participants: 24,995 individuals with MS matched with 253,870 controls and 1,283,502 first-degree relatives (mothers, fathers, full siblings, and offspring) for familial co-aggregation analysis; population of European ancestry for genetic correlation analysis., Measurements: Logistic regressions with adjustment for covariates were used to estimate the odds ratios (ORs) of developing MS in individuals with first-degree relatives diagnosed with IMIDs compared to those without such family history. Pairwise genome-wide genetic correlations were estimated with linkage-disequilibrium score regression., Results: We observed an OR for familial co-aggregation of MS of 1.09 (95 % confidence interval (95%CI) = 1.07-1.11) in families with IMIDs history compared to families without. The association remained broadly consistent after stratification by sex concordance of relative pairs and by kinships. 18 IMID subtypes showed a familial association with MS, 7 of which including other acute widespread myelin destruction, encephalitis or myelitis or encephalomyelitis, inflammatory bowel disease, autoimmune thyroid diseases, systemic lupus erythematosus, other inflammatory system diseases, and sarcoidosis withstood multiple correction. Genetic correlations further revealed a shared genetic basis between 7 IMID subtypes with MS., Conclusion: We demonstrated a modest familial co-aggregation of MS with several IMIDs, and such association is likely due to shared genetic factors., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Few studies have examined the effect of concomitant autoimmune diseases on multiple sclerosis (MS) disability worsening. We set out to examine whether concomitant Crohn's Disease (CD), Ulcerative Colitis (UC), or Type 1 Diabetes (T1D) affect MS disability worsening in a nationwide cohort of MS patients as defined by reaching expanded disability scale status (EDSS) scores 3.0, 4.0 and 6.0., Methods: Patients with MS onset between January 2004 and January 2019 were identified from the Swedish MS registry and the Swedish National Patient Register. Kaplan-Meier analysis was used to estimate the median time to reach sustained disability milestones. Adjusted Cox proportional hazard regression models were used to calculate the risk of reaching disability milestones among persons with and without CD, UC, or T1D., Results: Out of 8972 persons with MS, 88 (1.0 %) had T1D, 47 (0.8 %) had UC, and 78 (0.9 %) had CD. There was a significantly higher risk of disability progression, for persons with MS and T1D for reaching EDSS 6.0, hazard ratio (HR) = 2.21 (95 % confidence interval (CI) = 1.48 -3.31) and persons with MS and comorbid CD for reaching EDSS 3.0, HR = 2.30 (95 %CI = 1.74-3.04) and 4.0, HR = 1.59 (95 %CI = 1.09-2.32), and persons with MS and comorbid UC for reaching EDSS 3.0 HR = 1.57 (95 %CI = 1.15-2.14). As defined by Charlson's comorbidity index, the co-existence of other co-morbidities conferred a significant increase in the risk of reaching all endpoints, with HR ranging from 1.23 to 1.62., Conclusion: Comorbidity is associated with a significantly increased risk of reaching disability end-points, and T1D, CD, and UC increase the risk further. Thus, there appears to be a need for increased vigilance of comorbidites in persons with MS in order to optimise the long-term outcome of MS., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Amblyopia, the most common visual impairment of childhood, is a public health concern. An extended period of optical treatment before patching is recommended by the clinical guidelines of several countries. The aim of this study was to compare an intensive patching regimen, with and without extended optical treatment (EOT), in a randomised controlled trial., Methods: EuPatch was a randomised controlled trial conducted in 30 hospitals in the UK, Greece, Austria, Germany, and Switzerland. Children aged 3-8 years with newly detected, untreated amblyopia (defined as an interocular difference ≥0·30 logarithm of the minimum angle of resolution [logMAR] best corrected visual acuity [BCVA]) due to anisometropia, strabismus, or both were eligible. Participants were randomly assigned (1:1) via a computer-generated sequence to either the EOT group (18 weeks of glasses use before patching) or to the early patching group (3 weeks of glasses use before patching), stratified for type and severity of amblyopia. All participants were initially prescribed an intensive patching regimen (10 h/day, 6 days per week), supplemented with motivational materials. The patching period was up to 24 weeks. Participants, parents or guardians, assessors, and the trial statistician were not masked to treatment allocation. The primary outcome was successful treatment (ie, ≤0·20 logMAR interocular difference in BCVA) after 12 weeks of patching. Two primary analyses were conducted: the main analysis included all participants, including those who dropped out, but excluded those who did not provide outcome data at week 12 and remained on the study; the other analysis imputed this missing data. All eligible and randomly assigned participants were assessed for adverse events. This study is registered with the International Standard Randomised Controlled Trial Number registry (ISRCTN51712593) and is no longer recruiting., Findings: Between June 20, 2013, and March 12, 2020, after exclusion of eight participants found ineligible after detailed screening, we randomly assigned 334 participants (170 to the EOT group and 164 to the early patching group), including 188 (56%) boys, 146 (44%) girls, and two (1%) participants whose sex was not recorded. 317 participants (158 in the EOT group and 159 in the early patching group) were analysed for the primary outcome without imputation of missing data (median follow-up time 42 weeks [IQR 42] in the EOT group vs 27 weeks [27] in the early patching group). 24 (14%) of 170 participants in the EOT group and ten (6%) of 164 in the early patching group were excluded or dropped out of the study, mostly due to loss to follow-up and withdrawal of consent; ten (6%) in the EOT group and three (2%) in the early patching group missed the 12 week visit but remained on the study. A higher proportion of participants in the early patching group had successful treatment (107 [67%] of 159) than those in the EOT group (86 [54%] of 158; 13% difference; p=0·019) after 12 weeks of patching. No serious adverse events related to the interventions occurred., Interpretation: The results from this trial indicate that early patching is more effective than EOT for the treatment of most children with amblyopia. Our findings also provide data for the personalisation of amblyopia treatments., Funding: Action Medical Research, NIHR Clinical Research Network, and Ulverscroft Foundation., Competing Interests: Declaration of interests FAP, A-DN, and IG were awarded grants from Action Medical Research and the Ulverscroft Foundation for this study. FAP reports travel funding from the main grant body, Action Medical Research, to attend the 2023 Annual Research in Vision and Ophthalmology meeting 2023, New Orleans, LA, USA, to present the findings for the study; and is a consultant for Leica Microsystems. MH and GM were funded through Action Medical Research, the NIHR Clinical Research Network and the Ulverscroft Foundation. AM reports funding from Action Medical Research to provide statistical support. A-DN is the local principal investigator for commercially sponsored randomised controlled trials (through Moorfields Eye Hospital, London, UK) for MyopiaX, Nevakar/Vyluma, Ocumension/Ora Health, and the UK National Institute for Health and Care Research (NIHR); and reports honoraria for educational activities from Santen, Novartis, Zeiss, and CooperVision, and for participation on advisory boards from Santen, SightGlassVision, Thea, and CooperVision. EP, PK, JS, and CB declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: There has been interest in a possible negative association between HIV and multiple sclerosis (MS). We aimed to compare the risk of MS in a cohort of individuals living with HIV to that in the general population., Methods: Population-based health data were accessed for 2 cohorts of HIV-positive persons from Sweden and British Columbia, Canada. Incident MS was identified using MS registries or a validated algorithm applied to administrative data. Individuals with HIV were followed from 1 year after the first clinical evidence of HIV or the first date of complete administrative health data (Canada = April 1, 1992 and Sweden = January 1, 2001) until the earliest of incident MS, emigration, death, or study end (Canada = March 31, 2020 and Sweden = December 31, 2018). The observed MS incidence rate in the HIV-positive cohort was compared to the expected age-, sex-, calendar year-, income-specific, and region of birth-specific rates in a randomly selected sample of >20% of each general population. The standardized incidence ratio (SIR) for MS following the first antiretroviral therapy exposure ("ART-exposed") was also calculated., Results: The combined Sweden-Canada cohort included 29,163 (75% men) HIV-positive persons. During 242,248 person-years of follow-up, 14 incident MS cases were observed in the HIV-positive cohort, whereas 26.19 cases were expected. The SIR for MS in the HIV-positive population was 0.53 (95% confidence interval [CI] = 0.32-0.90). The SIR for MS following the first ART exposure was 0.55 (95% CI = 0.31-0.96)., Interpretation: This international population-based study demonstrated a lower risk of MS among HIV-positive individuals, and HIV-positive ART-exposed individuals. These findings provide support for further exploration into the relationship among HIV, ART, and MS. ANN NEUROL 2024;95:487-494., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Although evidence exists for a causal association between 25-hydroxyvitamin D (25(OH)D) serum levels, and multiple sclerosis (MS), the role of variation in vitamin D receptor (VDR) binding in MS is unknown. Here, we leveraged previously identified variants associated with allele imbalance in VDR binding (VDR-binding variant; VDR-BV) in ChIP-exo data from calcitriol-stimulated lymphoblastoid cell lines and 25(OH)D serum levels from genome-wide association studies to construct genetic instrumental variables (GIVs). GIVs are composed of one or more genetic variants that serve as proxies for exposures of interest. Here, GIVs for both VDR-BVs and 25(OH)D were used in a two-sample Mendelian Randomization study to investigate the relationship between VDR binding at a locus, 25(OH)D serum levels, and MS risk. Data for 13,598 MS cases and 38,887 controls of European ancestry from Kaiser Permanente Northern California, Swedish MS studies, and the UK Biobank were included. We estimated the association between each VDR-BV GIV and MS. Significant interaction between a VDR-BV GIV and a GIV for serum 25OH(D) was evidence for a causal association between VDR-BVs and MS unbiased by pleiotropy. We observed evidence for associations between two VDR-BVs (rs2881514, rs2531804) and MS after correction for multiple tests. There was evidence of interaction between rs2881514 and a 25(OH)D GIV, providing evidence of a causal association between rs2881514 and MS. This study is the first to demonstrate evidence that variation in VDR binding at a locus contributes to MS risk. Our results are relevant to other autoimmune diseases in which vitamin D plays a role., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Treatment switching is a common challenge and opportunity in real-world clinical practice. Increasing diversity in disease-modifying treatments (DMTs) has generated interest in the identification of reliable and robust predictors of treatment switching across different countries, DMTs, and time periods., Objective: The objective of this retrospective, observational study was to identify independent predictors of treatment switching in a population of relapsing-remitting MS (RRMS) patients in the Big Multiple Sclerosis Data Network of national clinical registries, including the Italian MS registry, the OFSEP of France, the Danish MS registry, the Swedish national MS registry, and the international MSBase Registry., Methods: In this cohort study, we merged information on 269,822 treatment episodes in 110,326 patients from 1997 to 2018 from five clinical registries. Patients were included in the final pooled analysis set if they had initiated at least one DMT during the relapsing-remitting MS (RRMS) stage. Patients not diagnosed with RRMS or RRMS patients not initiating DMT therapy during the RRMS phase were excluded from the analysis. The primary study outcome was treatment switching. A multilevel mixed-effects shared frailty time-to-event model was used to identify independent predictors of treatment switching. The contributing MS registry was included in the pooled analysis as a random effect., Results: Every one-point increase in the Expanded Disability Status Scale (EDSS) score at treatment start was associated with 1.08 times the rate of subsequent switching, adjusting for age, sex, and calendar year (adjusted hazard ratio [aHR] 1.08; 95% CI 1.07-1.08). Women were associated with 1.11 times the rate of switching relative to men (95% CI 1.08-1.14), whilst older age was also associated with an increased rate of treatment switching. DMTs started between 2007 and 2012 were associated with 2.48 times the rate of switching relative to DMTs that began between 1996 and 2006 (aHR 2.48; 95% CI 2.48-2.56). DMTs started from 2013 onwards were more likely to switch relative to the earlier treatment epoch (aHR 8.09; 95% CI 7.79-8.41; reference = 1996-2006)., Conclusion: Switching between DMTs is associated with female sex, age, and disability at baseline and has increased in frequency considerably in recent years as more treatment options have become available. Consideration of a patient's individual risk and tolerance profile needs to be taken into account when selecting the most appropriate switch therapy from an expanding array of treatment choices., Competing Interests: TSp received compensation for serving on scientific advisory boards, honoraria for consultancy and funding for travel from Biogen; and speaker honoraria from Novartis. MM has served on the scientific advisory board for Sanofi, Novartis, and Merck and has received honoraria for lecturing from Biogen, Merck, Novartis, Roche, Genzyme, and Bristol Myers Squibb. HB is an employee of Monash University and has accepted travel compensation from Merck; his institution receives honoraria for talks, steering committee activities, and research grants from Roche, Merck, Biogen, Novartis, UCB Pharma, Medical Research Future Fund Australia, NHMRC Australia, Trish MS Foundation, MS Australia, and the Pennycook Foundation. He receives personal compensation for steering group activities for the Brain Health Initiative from the Oxford Health Policy Forum and is funded by an NHMRC Australia Investigator Grant. SV received consulting and lecturing fees, travel grants, and research support from Biogen, Celgene, Genentech, Genzyme, Medday Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi Aventis, and Teva Pharma. MT has served on scientific advisory boards for Biogen, Novartis, Roche, and Genzyme; has received speaker honoraria and travel support from Biogen Idec, Sanofi Aventis, Merck Serono, Teva, Genzyme, and Novartis; and has received research grants for her institution from Biogen Idec, Merck Serono, and Novartis. PI has served on scientific advisory boards for Biogen Idec, Bayer, Teva, Roche, Merck Serono, Novartis, and Genzyme and has received funding for travel and/or speaker honoraria from Sanofi Aventis, Genzyme, Biogen Idec, Teva, Merck Serono, and Novartis. DH was supported by the Charles University Cooperation Program in Neuroscience, the project National Institute for Neurological Research (Programme EXCELES, ID Project No. LX22NPO5107) funded by the European Union (Next Generation EU), and by the General University Hospital in Prague project MH CZ-DRO-VFN64165. She also received compensation for travel, speaker honoraria, and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche, and Teva, as well as support for research activities from Biogen Idec. FP is an employee of Biogen. RH is an employee of Biogen and holds stock. PD served on editorial boards and has been supported to attend meetings by EMD, Biogen, Novartis, Genzyme, and TEVA Neuroscience. He holds grants from the CIHR and the MS Society of Canada and has received funding for investigator-initiated trials from Biogen, Novartis, and Genzyme. JL-S received travel compensation from Novartis, Biogen, Roche, and Merck. Her institution receives honoraria for talks and advisory board commitments, as well as research grants from Biogen, Merck, Roche, TEVA, and Novartis. SS declared no competing interests. PL received honoraria for speaking and/or travel expenses from Biogen, Merck, Novartis, Roche; consulting fees from Biogen, GeNeuro, Merck, Novartis, Roche; and research support from Biogen, Merck, Novartis. None were related to this work. SE received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche, and Teva. RAI received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche, and Sanofi-Genzyme. MT received travel grants from Novartis, Bayer-Schering, Merck, and Teva; and has participated in clinical trials by Sanofi Aventis, Roche, and Novartis. MG received consulting fees from Teva Canada Innovation, Biogen, Novartis, and Genzyme Sanofi; and lecture payments from Teva Canada Innovation, Novartis, and EMD. He has also received a research grant from the Canadian Institutes of Health Research. TK served on scientific advisory boards for MS International Federation and World Health Organization, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck, and Biogen; on the steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi-Genzyme, Teva, BioCSL, and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene, and Merck. FG received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, and ATARA Pharmaceuticals. OS received honoraria and consulting fees from Bayer-Schering, Novartis, Merck, Biogen, and Genzyme. SK received compensation for scientific advisory board activity from Merck and Roche. BY received honoraria as a speaker and member of scientific advisory boards from Sanofi, Bayer, Biogen, Merck, Janssen, Novartis, Roche, and Aspen. MJ received consulting fees, speaker honoraria, and/or travel expenses for scientific meetings from Alexion, Bayer Healthcare, Biogen, Bristol Myers Squibb, Celgene, Janssen, Merck Serono, Novartis, Roche, Sanofi, and Teva. YB received speaker honoraria/consulting fees from Merck, Biogen, Roche, Bristol Myers Squibb, Novartis, Sanofi, and Sandoz. CO-G received honoraria as a consultant on scientific advisory boards from Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme, and TEVA. AA received speaker honoraria from Novartis and Alexion. SH has received unrestricted educational grants or speaking honoraria from Biogen, Merck Serono, Novartis, Roche, and Sanofi Genzyme. PM received speaker fees and travel grants from Novartis, Biogen, T'évalua, and Sanofi. RAm received conference travel support from Novartis, Teva, Biogen, Bayer, and Merck and has participated in clinical trials by Biogen, Novartis, Teva, and Actelion. KdG served on scientific advisory boards for Roche, Janssen, Sanofi-Genzyme, Novartis, and Merck, received conference fees and travel support from Novartis, Biogen, Sanofi-Genzyme, Teva, AbbVie, and Merck, and received educational event support from Novartis. CM received honoraria as a consultant on scientific advisory boards for Genzyme, BMS, Janssen, Biogen, Merck, Roche, and Novartis; has received travel grants from Roche and Novartis. JP accepted travel compensation from Novartis, Biogen, Genzyme, Teva, and speaking honoraria from Biogen, Novartis, Genzyme, and Teva. NJ is a local principal investigator on commercial studies funded by Novartis, Biogen, Amicus, and Sanofi. JI declared no competing interests. FS has served on scientific advisory boards for, served as a consultant for, received support for congress participation, or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, and Sanofi Genzyme. His laboratory has received research support from Biogen, Merck, Novartis, Roche, and Sanofi Genzyme. HJ declared no competing interests. PR has served on scientific advisory boards for, served as consultant for, received support for congress participation, or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, and Sanofi Genzyme. TSe received and has served on scientific advisory boards for, served as a consultant for, received support for congress participation, or received speaker honoraria from Biogen, Merck, Novartis, Roche, and Sanofi. T. Sejbaeks received unrestricted research grants to his research institution from Biogen, Merck, and Roche and is currently engaged in sponsor-initiated research projects by Eisai, Lundbeck, Roche, and Sanofi. MP declared no competing interests. JC has received speaker honoraria from Biogen. MS has served on scientific advisory boards for, served as a consultant for, received support for congress participation, participated in industrial trials with, or received speaker honoraria from Bayer, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme. JH has received honoraria for serving on advisory boards for Biogen, Sanofi-Genzyme, and Novartis and speaker's fees from Biogen, Novartis, Merck Serono, Bayer-Schering, Teva, and Sanofi-Genzyme. He has served as P.I. for projects or received unrestricted research support from BiogenIdec, Merck Serono, TEVA, Sanofi-Genzyme, and Bayer-Schering. His MS research is funded by the Swedish Research Council and the Swedish Brain Foundation. The authors declare that this study received funding from Biogen. The funder had the following involvement with the study: study design and manuscript review. The funder was not involved in the collection of data, analysis, writing of the article, or the decision to submit it for publication. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Spelman, Magyari, Butzkueven, Van Der Walt, Vukusic, Trojano, Iaffaldano, Horáková, Drahota, Pellegrini, Hyde, Duquette, Lechner-Scott, Sajedi, Lalive, Shaygannejad, Ozakbas, Eichau, Alroughani, Terzi, Girard, Kalincik, Grand'Maison, Skibina, Khoury, Yamout, Sa, Gerlach, Blanco, Karabudak, Oreja-Guevara, Altintas, Hughes, McCombe, Ampapa, de Gans, McGuigan, Soysal, Prevost, John, Inshasi, Stawiarz, Manouchehrinia, Forsberg, Sellebjerg, Glaser, Pontieri, Joensen, Rasmussen, Sejbaek, Poulsen, Christensen, Kant, Stilund, Mathiesen, Hillert and the Big MS Data Network: a collaboration of the Czech MS Registry, the Danish MS Registry, Italian MS Registry, Swedish MS Registry, MSBase Study Group, and OFSEP.)

Introduction: Prescribing guidance for disease-modifying treatment (DMT) in multiple sclerosis (MS) is centred on a clinical diagnosis of relapsing-remitting MS (RRMS). DMT prescription guidelines and monitoring vary across countries. Standardising the approach to diagnosis of disease course, for example, assigning RRMS or secondary progressive MS (SPMS) diagnoses, allows examination of the impact of health system characteristics on the stated clinical diagnosis and treatment access., Methods: We analysed registry data from six cohorts in five countries (Czech Republic, Denmark, Germany, Sweden and United Kingdom) on patients with an initial diagnosis of RRMS. We standardised our approach utilising a pre-existing algorithm (DecisionTree, DT) to determine patient diagnoses of RRMS or secondary progressive MS (SPMS). We identified five global drivers of DMT prescribing: Provision, Availability, Funding, Monitoring and Audit, data were analysed against these concepts using meta-analysis and univariate meta-regression., Results: In 64,235 patients, we found variations in DMT use between countries, with higher usage in RRMS and lower usage in SPMS, with correspondingly lower usage in the UK compared to other registers. Factors such as female gender ( p  = 0.041), increasing disability via Expanded Disability Status Scale (EDSS) score ( p  = 0.004), and the presence of monitoring ( p  = 0.029) in SPMS influenced the likelihood of receiving DMTs. Standardising the diagnosis revealed differences in reclassification rates from clinical RRMS to DT-SPMS, with Sweden having the lowest rate Sweden (Sweden 0.009, range: Denmark 0.103 - UK portal 0.311). Those with higher EDSS at index ( p  < 0.03) and female gender ( p  < 0.049) were more likely to be reclassified from RRMS to DT-SPMS. The study also explored the impact of diagnosis on DMT usage in clinical SPMS, finding that the prescribing environment and auditing practices affected access to treatment., Discussion: This highlights the importance of a healthcare system's approach to verifying the clinical label of MS course in facilitating appropriate prescribing, with some flexibility allowed in uncertain cases to ensure continued access to treatment., (© The Author(s), 2023.)

Importance: Multiple sclerosis (MS) severity may be informed by premorbid sociodemographic factors., Objective: To determine whether premorbid education, income, and marital status are associated with future MS disability and symptom severity, independent of treatment, in a universal health care context., Design, Setting, and Participants: This nationwide observational cohort study examined data from the Swedish MS Registry linked to national population registries from 2000 to 2020. Participants included people with MS onset from 2005 to 2015 and of working age (aged 23 to 59 years) 1 year and 5 years preceding disease onset., Exposures: Income quartile, educational attainment, and marital status measured at 1 and 5 years preceding disease onset., Main Outcome and Measures: Repeated measures of Expanded Disability Status Scale (EDSS) scores and patient-reported Multiple Sclerosis Impact Scale (MSIS-29) scores. Models were adjusted for age, sex, relapses, disease duration, and treatment exposure. Secondary analyses further adjusted for comorbidity. All analyses were stratified by disease course (relapse onset and progressive onset)., Results: There were 4557 patients (mean [SD] age, 37.5 [9.3] years; 3136 [68.8%] female, 4195 [92.1%] relapse-onset MS) with sociodemographic data from 1-year preonset of MS. In relapse-onset MS, higher premorbid income and education correlated with lower disability (EDSS, -0.16 [95% CI, -0.12 to -0.20] points) per income quartile; EDSS, -0.47 [95% CI, -0.59 to -0.35] points if tertiary educated), physical symptoms (MSIS-29 physical subscore, -14% [95% CI, -11% to -18%] per income quartile; MSIS-29 physical subscore, -43% [95% CI, -35% to -50%] if tertiary educated), and psychological symptoms (MSIS-29 psychological subscore, -12% [95% CI, -9% to -16%] per income quartile; MSIS-29 psychological subscore, -25% [95% CI, -17% to -33%] if tertiary educated). Marital separation was associated with adverse outcomes (EDSS, 0.34 [95% CI, 0.18 to 0.51]; MSIS-29 physical subscore, 35% [95% CI, 12% to 62%]; MSIS-29 psychological subscore, 25% [95% CI, 8% to 46%]). In progressive-onset MS, higher income correlated with lower EDSS (-0.30 [95% CI, -0.48 to -0.11] points per income quartile) whereas education correlated with lower physical (-34% [95% CI, -53% to -7%]) and psychological symptoms (-33% [95% CI, -54% to -1%]). Estimates for 5-years preonset were comparable with 1-year preonset, as were the comorbidity-adjusted findings., Conclusions and Relevance: In this cohort study of working-age adults with MS, premorbid income, education, and marital status correlated with disability and symptom severity in relapse-onset and progressive-onset MS, independent of treatment. These findings suggest that socioeconomic status may reflect both structural and individual determinants of health in MS.

Background: The two main phenotypes of multiple sclerosis (MS), primary progressive (PPMS) and relapsing Onset (ROMS), show clinical and demographic differences suggesting possible differential risk mechanisms. Understanding the heritable features of these phenotypes could provide aetiological insight., Objectives: To evaluate the magnitude of familial components in PPMS and ROMS and to estimate the heritability of disease phenotypes., Methods: We used data from 25,186 MS patients of Nordic ancestry from the Swedish MS Registry between 1987 and 2019 with known disease phenotype (1593 PPMS and 16,718 ROMS) and 251,881 matched population-based controls and 3,364,646 relatives of cases and controls. Heritability was calculated using threshold-liability models. For familial odds ratios (ORs), logistic regression with robust sandwich estimator was utilized., Results: The OR of MS diagnosis in those with a first-degree family member with ROMS was 7.00 and 8.06 in those with PPMS. The corresponding ORs for having a second-degree family member with ROMS was 2.16 and 2.18 in PPMS. The additive genetic effect in ROMS was 0.54 and 0.22 in PPMS., Conclusion: Risk of MS increases by several folds in those with a relative with MS. The likelihood of developing either disease phenotype appears independent of genetic predisposition.

Background: Multiple sclerosis (MS) quality of care guidelines are consensus-based. The effectiveness of the recommendations is unknown., Objective: To determine whether clinic-level quality of care affects clinical and patient-reported outcomes., Methods: This nationwide observational cohort study included patients with adult-onset MS in the Swedish MS registry with disease onset 2005-2015. Clinic-level quality of care was measured by four indicators: visit density, magnetic resonance imaging (MRI) density, mean time to commencement of disease-modifying therapy, and data completeness. Outcomes were Expanded Disability Status Scale (EDSS) and patient-reported symptoms measured by the Multiple Sclerosis Impact Scale (MSIS-29). Analyses were adjusted for individual patient characteristics and disease-modifying therapy exposure., Results: In relapsing MS, all quality indicators benefitted EDSS and physical symptoms. Faster treatment, frequent visits, and higher data completeness benefitted psychological symptoms. After controlling for all indicators and individual treatment exposures, faster treatment remained independently associated with lower EDSS (-0.06, 95% confidence interval (CI): -0.01, -0.10) and more frequent visits were associated with milder physical symptoms (MSIS-29 physical score: -16.2%, 95% CI: -1.8%, -29.5%). Clinic-level quality of care did not affect any outcomes in progressive-onset disease., Conclusion: Certain quality of care indicators correlated to disability and patient-reported outcomes in relapse-onset but not progressive-onset disease. Future guidelines should consider recommendations specific to disease course.

Objectives: High rates of anti-drug antibodies (ADA) to rituximab have been demonstrated in patients undergoing treatment for SLE. However, little is known with regard to their long-term dynamics, impact on drug kinetics and subsequent implications for treatment response. In this study, we aimed to evaluate ADA persistence over time, impact on circulating drug levels, assess clinical outcomes and whether they are capable of neutralizing rituximab., Methods: Patients with SLE undergoing treatment with rituximab were recruited to this study (n = 35). Serum samples were collected across a follow-up period of 36 months following treatment (n = 114). Clinical and laboratory data were collected pre-treatment and throughout follow-up. ADA were detected via electrochemiluminescent immunoassays. A complement dependent cytotoxicity assay was used to determine neutralizing capacity of ADA in a sub-cohort of positive samples (n = 38)., Results: ADA persisted over the 36-month study period in 64.3% of patients undergoing treatment and titres peaked earlier and remained higher in those who had previously been treated with rituximab when compared with than those who were previously treatment naive. ADA-positive samples had a significantly lower median drug level until six months post rituximab infusion (P = 0.0018). Patients with persistent ADA positivity showed a significant early improvement in disease activity followed by increased rates of relapse. In vitro analysis confirmed the neutralizing capacity of ADA to rituximab., Conclusions: ADA to rituximab were common and persisted over the 36-month period of this study. They associated with earlier drug elimination, an increased rate of relapse and demonstrated neutralizing capacity in vitro., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: The present study is aimed at determining the effect of cigarette smoking (CS) on serum uric acid (UA) levels quantitatively before and after smoking cessation among people with MS (pwMS). Additionally, a possible correlation between UA levels and both disability progression and disease severity was also investigated. A retrospective cross-sectional study was conducted using the Nottingham University Hospitals MS Clinics database. It involves 127 people with definite MS recorded when reporting the latest smoking status and the clinical diagnosis. All necessary demographics and clinical characteristics were collected. We found that smoker pwMS had significantly lower serum UA levels than non-smoker pwMS ( p -value = 0.0475), and this reduction was recovered after smoking cessation ( p -value = 0.0216). However, the levels of disability or disease severity were not correlated with the levels of serum UA in current smoker pwMS, measured by the expanded disability status scale (EDSS; r = -0.24; p -value = 0.38), multiple sclerosis impact scale 29 (MSIS-29; r = 0.01; p -value = 0.97) and MS severity score (MSSS; r = -0.16; p -value = 0.58), respectively. Our result suggests that the reduction in UA levels is more likely a consequence of oxidative stress triggered by many risk factors, including CS, and could be considered a potential indicator of smoking cessation. In addition, the absence of a correlation between UA levels and disease severity and disability suggests that UA is not an optimal biomarker for disease severity and disability prediction among current smoker, ex-smoker or non-smoker pwMS.

Background: Timing of disease-modifying therapy affects clinical disability in multiple sclerosis, but it is not known whether patient reported outcomes are also affected. This study investigates the relationship between treatment timing and patient-reported symptoms and health-related quality of life., Methods: This was a nationwide observational cohort study of adults with relapsing multiple sclerosis, with disease onset between 2001 and 2016, and commenced on disease-modifying treatment within 4 years from disease onset. Patients commencing treatment within 0-2 years were compared with patients commencing treatment at 2-4 years. Indication bias was mitigated by propensity matching. Outcomes were patient-reported symptoms and health-related quality of life as measured by the Multiple Sclerosis Impact Scale (MSIS-29) and EuroQol-5 Dimensions-3 Level (EQ-5D). The follow-up period was 4-10 years from disease onset., Results: There were 2648 patients (69% female, median age 32.8) eligible for matching. Mean follow-up time was 3.7 years. Based on 780 matched patients, each year of treatment delay was associated with a worse MSIS physical score by 2.75 points (95% CI 1.29 to 4.20), and worse MSIS psychological score by 2.02 points (95% CI 0.03 to 3.78), in the adjusted models.Among 690 matched patients, earlier treatment start was not associated with EQ-5D score during the follow-up., Conclusions: Earlier commencement of disease-modifying treatment was associated with better patient-reported physical symptoms when measured using a disease-specific metric; however, general quality of life was not affected. This indicates that other factors may inform patients' overall quality of life., Competing Interests: Competing interests: TS received compensation for serving on scientific advisory boards, honoraria for consultancy and funding for travel from Biogen. JH has received honoraria for serving on advisory boards for Biogen, Celgene, Sanofi-Genzyme, Merck KGaA, Novartis and Sandoz and speaker’s fees from Biogen, Novartis, Merck KGaA, Teva and Sanofi-Genzyme; he has served as P.I. for projects, or received unrestricted research support from, Biogen, Celgene, Merck KGaA, Novartis, Roche and Sanofi-Genzyme., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cognitive impairment occurs in 40%-70% of persons with multiple sclerosis (MS)., Objective: To examine the effectiveness of natalizumab compared with other disease-modifying treatments (DMTs) on improving cognition as measured by the Symbol Digit Modalities Test (SDMT)., Methods: Data were collected as part of Swedish nationwide phase IV surveillance studies (2007-2020). An increase in SDMT score by ⩾10% of the difference between maximum score possible (110) and the baseline value was defined as cognitive improvement. The likelihood of improvement was compared between natalizumab-treated individuals and individuals treated with other DMTs using mixed effect logistic regression. Trend in odds of improvement was investigated using slope analyses., Results: We included 2100 persons with relapsing-remitting MS treated with natalizumab and 2622 persons treated with other DMTs. At 6 months, 45% reached improvement. The natalizumab group showed largest odds of improvement during follow-up (odds ratio: 2.3, 95% confidence interval (CI): 1.5-3.5). The odds of improvement increased by 7% (95% CI: 6-7) per month of natalizumab treatment. The equivalent estimate was 4% (95% CI: 2-5) for other monoclonal antibodies and nonsignificant for oral or platform therapies., Conclusion: Treatment with natalizumab or other monoclonal antibodies is associated with a significantly faster likelihood of cognitive improvement than platform or oral DMTs.

Background: To assign a course of secondary progressive multiple sclerosis (MS) (SPMS) may be difficult and the proportion of persons with SPMS varies between reports. An objective method for disease course classification may give a better estimation of the relative proportions of relapsing-remitting MS (RRMS) and SPMS and may identify situations where SPMS is under reported., Materials and Methods: Data were obtained for 61,900 MS patients from MS registries in the Czech Republic, Denmark, Germany, Sweden, and the United Kingdom (UK), including date of birth, sex, SP conversion year, visits with an Expanded Disability Status Scale (EDSS) score, MS onset and diagnosis date, relapses, and disease-modifying treatment (DMT) use. We included RRMS or SPMS patients with at least one visit between January 2017 and December 2019 if ≥ 18 years of age. We applied three objective methods: A set of SPMS clinical trial inclusion criteria ("EXPAND criteria") modified for a real-world evidence setting, a modified version of the MSBase algorithm, and a decision tree-based algorithm recently published., Results: The clinically assigned proportion of SPMS varied from 8.7% (Czechia) to 34.3% (UK). Objective classifiers estimated the proportion of SPMS from 15.1% (Germany by the EXPAND criteria) to 58.0% (UK by the decision tree method). Due to different requirements of number of EDSS scores, classifiers varied in the proportion they were able to classify; from 18% (UK by the MSBase algorithm) to 100% (the decision tree algorithm for all registries). Objectively classified SPMS patients were older, converted to SPMS later, had higher EDSS at index date and higher EDSS at conversion. More objectively classified SPMS were on DMTs compared to the clinically assigned., Conclusion: SPMS appears to be systematically underdiagnosed in MS registries. Reclassified patients were more commonly on DMTs., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Lars Forsberg has nothing to disclose. Tim Spelman has received compensation for serving on the scientific advisory board for Biogen and speaker honoraria from Novartis. Pernilla Klyve has nothing to disclose. Ali Manouchehrinia is supported by the Margaretha af Ugglas Foundation. Ryan Ramanujam has nothing to disclose. Elena Mouresan has nothing to disclose. Jiri Drahota has nothing to disclose. Dana Horakova was supported by the Czech Ministry of Education (project Cooperatio LF1, research area Neuroscience). She also received compensation for travel, speaker honoraria, and consultant fees from Biogen Idec, Novartis, Merck, Sanofi, Roche, and Teva, as well as support for research activities from Biogen Idec. Hanna Joensen has received honoraria for an advisory board from Biogen. Luigi Pontieri has nothing to disclose. Melinda Magyari has served on the scientific advisory board, served as a consultant for, received support for congress participation, and received speaker honoraria from Biogen, Sanofi, Roche, Novartis, Merck, Abbvie, and Alexion. The Danish MR Registry received research support from Biogen, Genzyme, Roche, Merck, and Novartis. David Ellenberger has nothing to disclose. Alexander Stahmann has no personal pecuniary interests to disclose, other than being the lead of the German MS Registry, which receives funding from a range of public and corporate sponsors, recently including The German Innovation Fund (G-BA), The German MS Trust, German MS Society, Biogen, Celgene (Bristol-Myers Squibb), Merck, Novartis, Roche, and Sanofi. None resulted in a conflict of interest. Jeff Rodgers has nothing to disclose. The UK MS Register is funded by the MS Society. James Witts has nothing to disclose. The UK MS Register is funded by the MS Society. Rod Middleton has nothing to disclose. The UK MS Register is funded by the MS Society. Richard Nicholas has received support from advisory boards from Roche and Biogen. He has grant support from the UK MS Society and Berkeley Foundation and is a vice chair of a NICE HTA committee. Vladimir Bezlyak is an employee of Novartis Pharma AG. Nicholas Adlard is an employee of Novartis Pharma AG. Thomas Hach is an employee of Novartis Pharma AG. Carol Lines is an employee of Novartis Pharma AG. Sandra Vukusic has received grants, personal fees, unrestricted research grants, and nonfinancial support from Biogen, BMS-Celgene, Genzyme, Janssen, Merck Serono, Novartis, Roche, Sanofi, and Teva. Merja Soilu-Hanninen has received congress fee covering and lecture and consultation fees by Biogen, Celgene, Merck, Novartis, Roche, Sanofi, and Teva. Anneke van der Walt served on advisory boards and receives unrestricted research grants from Novartis, Biogen, Merck, Alexion, NervGen, and Roche. She has received speaker's honoraria and travel support from Novartis, Roche, Biogen, and Merck. She receives grant support from the National Health and Medical Research Council of Australia and MS Research Australia. Helmut Butzkueven's institution (Monash University) has received compensation for his services on scientific advisory boards and as a speaker from Biogen, Novartis, Roche, Merck, and UCB. He serves on steering committees for trials conducted by Biogen, Merck, and Novartis, and his institution has received research support from Roche, Merck, Novartis, and Biogen. Pietro Iaffaldano has received advisory board membership, speaker honoraria, and travel support from Almirall, Bayer Shering, Biogen, Genzyme, Merck, Novartis, Sanofi, Roche, Teva, and their local affiliates. Maria Trojano received advisory board membership, speaker honoraria, travel support and research grant from Almirall, Bayer Shering, Biogen, Genzyme, Merck, Novartis, Sanofi, Roche, Teva, and their local affiliates. Anna Glaser has received research support from Novartis. Jan Hillert has received honoraria for serving on advisory boards for Biogen, Celgene, Sanofi-Genzyme, Merck KGaA, Novartis, and Sandoz and speaker's fees from Biogen, Novartis, Merck KGaA, Teva, and Sanofi-Genzyme. He has served as PI for projects or received unrestricted research support from Biogen, Celgene, Merck KGaA, Novartis, Roche, and Sanofi-Genzyme. His MS research was funded by the Swedish Research Council and the Swedish Brain foundation., (© The Author(s), 2023.)

Background: Neurofilament light (NfL) levels reflect inflammatory disease activity in multiple sclerosis (MS), but it is less clear if NfL also can serve as a biomarker for MS progression in treated patients without relapses and focal lesion accrual. In addition, it has not been well established if clinically effective treatment re-establishes an age and sex pattern for cerebrospinal fluid NfL (cNfL) as seen in controls, and to what degree levels are affected by disability level and magnetic resonance imaging (MRI) atrophy metrics., Methods: We included subjects for whom cNfL levels had been determined as per clinical routine or in clinical research, classified as healthy controls (HCs, n = 89), MS-free disease controls (DCs, n = 251), untreated MS patients (uMS; n = 296), relapse-free treated MS patients (tMS; n = 78), and ProTEct-MS clinical trial participants (pMS; n = 41)., Results: Using linear regression, we found a positive association between cNfL and age, as well as lower concentrations among women, in all groups, except for uMS patients. In contrast, disability level in the entire MS cohort, or T1 and T2 lesion volumes, brain parenchymal fraction, thalamic fraction, and cortical thickness in the pMS trial cohort, did not correlate with cNfL concentrations. Furthermore, the cNfL levels in tMS and pMS groups did not differ., Conclusions: In participants with MS lacking signs of inflammatory disease activity, disease modulatory therapy reinstates an age and sex cNfL pattern similar to that of control subjects. No significant association was found between cNfL levels and clinical worsening, disability level, or MRI metrics., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Most previous multiple sclerosis (MS) brain atrophy studies using MS impact scale 29 (MSIS-29) or symbol digit modalities test (SDMT) have been cross-sectional with limited sets of clinical outcomes., Objectives: To investigate which brain and lesion volume metrics show the strongest long-term associations with the expanded disability status scale (EDSS), SDMT, and MSIS-29, and whether MRI-clinical associations vary with age., Methods: We acquired MRI and clinical data from a real-world Swedish MS cohort. FreeSurfer and SPM Lesion Segmentation Tool were used to obtain brain parenchymal, cortical and subcortical grey matter, thalamic and white matter fractions as well as T 1 - and T 2 -lesion volumes. Mixed-effects and rolling regression models were used in the statistical analyses., Results: We included 989 persons with MS followed for a median of 9.3 (EDSS), 10.1 (SDMT), and 9.3 (MSIS-29) years, respectively. In a cross-sectional analysis, the strength of the associations of the MRI metrics with the EDSS and MSIS-29 was found to drastically increase after 40-50 years of age. Low baseline regional grey matter fractions were associated with longitudinal increase of EDSS and physical MSIS-29 scores and decrease in SDMT scores and these atrophy measures were stronger predictors than the lesion volumes., Conclusions: The strength of MRI-clinical associations increase with age. Grey matter volume fractions are stronger predictors of long-term disability measures than lesion volumes., Competing Interests: T. Moridi has received funding from ALF Medicine Region Stockholm and EU Horizon 2020. L. Stawiarz reports no disclosures relevant to the manuscript. K. A. McKay reports no disclosures relevant to the manuscript. B. V. Ineichen reports no disclosures relevant to the manuscript. R. Ouellette reports no disclosures relevant to the manuscript D. Ferreira reports no disclosures relevant to the manuscript. J-S. Muehlboeck reports no disclosures relevant to the manuscript. E. Westman reports no disclosures relevant to the manuscript. I. Kockum has received funding from ALF Medicine Region Stockholm, EU Horizon2020, and the Swedish Brain foundation; and received payment for a lecture held in November 2020 for Northern Connections, Scotland. T. Olsson has received funding from the Swedish Research council and the Swedish Brain Foundation; and received honoraria from Biogen, Merck, Novartis, Roche and Sanofi for lectures. F. Piehl has received funding from the Swedish Research council, Merck KGaA and UCB; served as DMC chairman for phase III trials in NMO (Chugai/Parexel); and served as unpaid chairman in the research committee for the Swedish national patient organization for persons with neurological diseases. J. Hillert has received funding from Merck, Biogen, Novartis and Roche; served on the advisory boards of Merck KGaA, Biogen, Novartis, Sandoz, Celgene and Sanofi-Genzyme; and received speaker's fee from Merck KGaA, Biogen, Novartis, Sanofi-Genzyme and Teva. A. Manouchehrinia has received funding from the Margaretha af Ugglas Foundation. T. Granberg is a recipient of the Grant for MS Innovation Award funded by Merck., (© The Author(s), 2022.)

Background: Early treatment with disease modifying therapies (DMTs) for multiple sclerosis (MS) has been associated with lower disability progression; the aim was to explore its association with cost of illness (COI) in MS., Methods: All people with relapsing-remitting MS in the Swedish MS register, aged 20-57 years and receiving their first MS DMT in 2006-2009, were followed in nationwide registers for 8 years. Healthcare costs (in- and outpatient healthcare, DMTs and other prescribed drugs), and productivity losses (sickness absence and disability pension) of individuals receiving therapy in ≤6 months after diagnosis (early treatment group) were compared to those receiving therapy >6 months (late treatment group). Using Poisson regressions, the mean COI per patient per year, and per group, was estimated, adjusted for disability progression., Results: The early treatment group comprised 74% of the 1562 individuals included in the study. The early treatment group had lower productivity losses over time. Both groups had similar healthcare costs, which first increased and then decreased over time., Conclusions: Early DMT in MS could result in lower productivity losses possibly through maintained work capacity. COI serves as an objective measure showing the advantage of early vs. late treatment initiation in MS., Competing Interests: Declaration of conflicting interests: All authors (KK, HG, CM, KA, JH, AK, TO, AM, EF) are employed or affiliated at the Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. KK is currently employed by Celgene/Bristol Myers Squibb; she initiated this study while being employed at Karolinska Institutet (employment ended in October 2019); since then, she has not received any salary from Karolinska Institutet or other type of funding for this research. HG is currently employed part-time by Statfinn/EPID Research (which is part of IQVIA); both companies are contract research organizations that perform commissioned pharmaco-epidemiological studies, and therefore are collaborating with several pharmaceutical companies. CM's employment at Karolinska Institutet is partly funded by research grant from Biogen. AM is supported by Margaretha af Ugglas foundation. KA has received unrestricted MS research grants from Biogen. JH has received honoraria for serving on advisory boards for Biogen, Celgene, Sanofi-Genzyme, Merck KGaA, Novartis and Sandoz and speaker's fees from Biogen, Novartis, Merck KGaA, Teva and Sanofi-Genzyme. He has served as P.I. for projects, or received unrestricted research support from, Biogen, Bristol-Myers-Squibb, Merck KGaA, Novartis, Roche and Sanofi-Genzyme. His MS research is funded by the Swedish Research Council and the Swedish Brain foundation. TO has received advisory board and/or lecture honoraria, and unrestricted MS research grants from Biogen, Novartis, Sanofi, Merck and Roche. EF is partly funded by research grants from Biogen, and has received an unrestricted MS research grant from Celgene/Bristol Myers Squibb., (© The Author(s), 2022.)

Background: The β-D-Mannuronic acid (M2000) as a novel immunosuppressive drug, patented (PCT/EP2017/067920), has shown positive effects in experimental model of multiple sclerosis (MS). In this study, our aim was to assess efficacy and safety outcomes in MS treated patients with mannuronic acid compared to the conventional drug., Methods: In a 6-month, randomized controlled, phase II trial, we enrolled patients who had secondary progressive multiple sclerosis (SPMS), were 21-54 years of age, with a score of 1-7 on the Expanded Disability Status Scale (EDSS), and who had at least one relapse in the previous 6 months. Patients were administered orally 1000 mg/day (two 500 mg/capsule daily) of M2000. Endpoints included changes in brain magnetic resonance imaging (MRI) measures and the EDSS score, as compared to the conventional drug (interferon beta-1a, interferon beta-1b)., Results: A total of 25 (92.5%) of the M2000 treated patients and 25 conventionally treated patients completed the study. M2000 had better performance compared to the conventional drug regarding to MRI-related measurements, however, the differences between groups were not statistically significant. M2000 decreased the disability progression over the 6-month period. The EDSS score was decreased in the M2000 treated group in the sixth month versus the conventional drug ( p  < 0.009). Furthermore, we did not observe any short-term side effects., Conclusions: As compared with the conventional drug, mannuronic acid (M2000) improved the rate of disability progression. This clinical trial demonstrated the efficacy and safety of mannuronic acid in patients with SPMS. (Registered Clinical Trials number, IRCT2016111313739N6).

Tobacco smoke is an important modifiable environmental risk factor for multiple sclerosis (MS) risk. The population attributable fraction (AF) of MS due to smoking can be used to assess the contribution of smoking to the risk of MS development. We conducted a matched case-control study, including individuals with MS and population-based controls. Overall, sex- and genetic risk score-stratified AF due to smoking were calculated by fitting logistic regression models. We included 9,419 individuals with MS and 9,419 population-based matched controls. At the time of MS onset 44.1% of persons with MS and 35.9% of controls ever regularly smoked of which 38.1% and 29.2% were still smoking. The overall AF was 13.1% (95%CI: 10.7 to 15.4). The AF was 10.6% (95%CI: 7.4 to 13.7) in females and 19.1% (95%CI: 13.1 to 25.1) in males. The AF was 0.6% (95%CI: 0.0 to 2) in ex-smokers. In those having human leucocyte antigen (HLA) and non-HLA risk scores above the median levels of controls, the AF was 11.4% (95%CI: 6.8 to 15.9) and 12% (95%CI: 7.7 to 16.3), respectively. The AF was 17.6% (95%CI: 10.2 to 24.9) and 18.6% (95%CI: 5.5 to 31.6) in those with HLA and non-HLA risk scores below the median levels in controls, respectively. We noticed a decline in AF in recent birth cohorts. This study indicates that at least 13% of cases of MS could be prevented through the avoidance of tobacco smoking. Considering the prevalence of MS, this represents a very large group of people in absolute number., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Manouchehrinia, Huang, Hillert, Alfredsson, Olsson, Kockum and Constantinescu.)

Objective: The purpose of this study was to explore the longitudinal relationship between multiple sclerosis (MS) relapses and information processing efficiency among persons with relapsing-remitting MS., Methods: We conducted a Swedish nationwide cohort study of persons with incident relapsing-remitting MS (2001-2019). Relapse information and symbol digit modalities test (SDMT) scores were obtained from the Swedish MS Registry. Follow-up was categorized into 2 periods based on relapse status: "relapse" (90 days pre-relapse to 730 days post-relapse, subdivided into 10 periods) and "remission." Linear mixed models compared SDMT scores during the relapse periods to SDMT scores recorded during remission (reference) with results reported as β-coefficients and 95% confidence intervals (CIs), adjusted for age, sex, SDMT type (written vs oral), time-varying, disease-modifying therapy exposure and sequence of SDMT., Results: Over a mean (SD) follow-up of 10.7 (4.3) years, 31,529 distinct SDMTs were recorded among 3,877 persons with MS. There was a significant decline in information processing efficiency that lasted from 30 days pre-relapse up to 550 days post-relapse, with the largest decline occurring 0 to 30 days post-relapse (β-coefficient: -4.00 (95% CI = -4.61 to -3.39), relative to the period of remission., Interpretation: We found evidence of cognitive change up to 1 month prior to relapse onset. The reduction in SDMT lasted 1.5 years and was clinically significant up to 3 months post-relapse. These results suggest that the effects of a relapse on cognition are longer than previously thought and highlight the importance of reducing relapse rates as a potential means of preserving cognitive function. ANN NEUROL 2022;91:417-423., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: The latitude gradient in multiple sclerosis incidence indicates that low sun exposure and therefore vitamin D deficiency is associated with multiple sclerosis risk., Objective: Investigation of the effect of month of birth, which influences postnatal vitamin D levels, on multiple sclerosis risk and severity in Sweden., Methods: Patients and population-based controls were included from three nationwide cohorts. Differences in month of birth between cases and controls were analyzed using logistic regression and examined for effect modification by calendar year and geographic region at birth., Results: Males had a reduced risk of multiple sclerosis if born in the winter and increased risk if born in the early fall. Individuals born before 1960 had an increased risk if born in summer or fall. Being born in late summer and early fall was associated with more severe disease., Conclusions: We identified a birth cohort effect on the association between the month of birth and multiple sclerosis, with a more significant effects for births before 1960. This coincides with a period of lower breastfeeding rates, recommended intake of vitamin D, and sun exposure, resulting in a lower vitamin D exposure during the fall/winter season for infants born in the summer., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: PS, JHu, AKH, LA, JHi, AM, and IK declare(s) that there is no conflict of interest. Outside of this work, TO has received unrestricted MS research grants from Biogen, Novartis and Merck, including personal honoraria for advisory boards, (© The Author(s), 2021.)

Objectives: Multiple sclerosis (MS) is a chronic neurodegenerative disease of the central nervous system. Identifying MS at the population level is important for disease surveillance and allocation of resources. The Swedish National Patient Registry (NPR) has been used to study the epidemiology of MS, but the accuracy of this resource is not known. We aimed to validate a definition of MS using the Swedish NPR in Värmland County using a longitudinal cohort design., Materials and Methods: Data were extracted from the NPR, the Total Population Register, the Swedish MS Register, and medical records for the years 2001-2013. Fifteen algorithms of hospitalizations and clinic visits for MS were developed and compared with findings in medical records, which acted as the "gold standard" definition. Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were estimated., Results: Of 805 eligible persons identified in the NPR, 763 had MS (94.8%) according to medical records. Of these, 544 (71.3%) were also registered in the SMSreg. The case definition that had a well-balanced sensitivity and specificity required three or more clinic or hospital visits for MS (sensitivity of 85.3% (95% CI: 82.6-87.8) and specificity of 81.0% (95%CI: 65.9-91.4)., Conclusions: Multiple case definitions with high sensitivity and moderate specificity were found, suggesting that the NPR can be used to accurately identify persons with MS., (© 2021 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

Depression is common in multiple sclerosis (MS); however, the underlying mechanism for the relationship remains unknown. In this study, we examined a putative causal relationship between depression and MS using a bidirectional Mendelian randomisation (MR) framework. Using the latest genome-wide association study data available, 168 non-major histocompatibility complex (MHC) independent variants associated with MS and 96 independent genetic variants associated with depression susceptibility were used. Maximum likelihood, weighted median, inverse variance weighted method and MR-Egger regression analyses were performed. There was no significant risk for the development of MS in persons carrying variants associated with depression or for risk of depression in individuals who are genetically susceptible to MS.

Background: Existing severity measurements in multiple sclerosis (MS) are often cross-sectional, making longitudinal comparisons of disease course between individuals difficult., Objective: The objective of this study is to create a severity metric that can reliably summarize a patient's disease course., Methods: We developed the nARMSS - normalized ARMSS (age-related MS severity score) over follow-up, using the deviation of individual ARMSS scores from the expected value and integrated over the corresponding time period. The nARMSS scales from -5 to +5; a positive value indicates a more severe disease course for a patient when compared to other patients with similar disease timings., Results: Using Swedish MS registry data, the nARMSS was tested using data at 2 and 4 years of follow-up to predict the most severe quartile during the subsequent period up to 10 years total follow-up. The metric used was area under the curve of the receiver operating characteristic (AUC-ROC). This resulted in measurements of 0.929 and 0.941. In an external Canadian validation cohort, the equivalent AUC-ROCs were 0.901 and 0.908., Conclusion: The nARMSS provides a reliable, generalizable and easily measurable metric which makes longitudinal comparison of disease course between individuals feasible.

Multiple sclerosis (MS) patients with immunoglobulin gamma (IgG) oligoclonal bands (OCB) in the cerebrospinal fluid (CSF) have different genetic backgrounds and brain MRI features compared to those without. In this study, we aimed to determine whether CSF-OCB status is associated with long-term disability outcomes. We used Swedish MS register data on clinically definite MS patients with known OCB status. Date of birth, age at MS onset, and time to sustained Expanded Disability Status Scale (EDSS) milestones 3, 4, and 6; time to conversion to secondary progressive (SP) MS, sex, and immunomodulatory treatment (IMTs) duration were collected. Multivariate Cox regression models were used to investigate the association between OCB status and risk of reaching each milestone. The OCB-positive group reached disability milestones at an earlier time and younger age. OCB-positivity significantly increased the risk of reaching EDSS 3.0 (HR = 1.29, 95% CI 1.12 to 1.48, P < 0.001) and 4.0 (HR = 1.38, 95% CI 1.17 to 1.63, P < 0.001). The OCB-positive group had a 20% higher risk of conversion to SPMS. CSF-OCB presence is associated with higher risk of reaching EDSS milestones and conversion to SPMS. Our findings suggest higher disease modifying effect of OCB presence in the early inflammatory stages of MS., (© 2021. The Author(s).)

Background: The absence of reliable imaging or biological markers of phenotype transition in multiple sclerosis (MS) makes assignment of current phenotype status difficult., Objective: The authors sought to determine whether clinical information can be used to accurately assign current disease phenotypes., Methods: Data from the clinical visits of 14,387 MS patients in Sweden were collected. Classifying algorithms based on several demographic and clinical factors were examined. Results obtained from the best classifier when predicting neurologist recorded disease classification were replicated in an independent cohort from British Columbia and were compared to a previously published algorithm and clinical judgment of three neurologists., Results: A decision tree (the classifier) containing only most recently available expanded disability scale status score and age obtained 89.3% (95% confidence intervals (CIs): 88.8-89.8) classification accuracy, defined as concordance with the latest reported status. Validation in the independent cohort resulted in 82.0% (95% CI: 81.0-83.1) accuracy. A previously published classification algorithm with slight modifications achieved 77.8% (95% CI: 77.1-78.4) accuracy. With complete patient history of 100 patients, three neurologists obtained 84.3% accuracy compared with 85% for the classifier using the same data., Conclusion: The classifier can be used to standardize definitions of disease phenotype across different cohorts. Clinically, this model could assist neurologists by providing additional information.

Purpose: Observational studies have suggested a protective effect of alcohol intake with autoimmune disorders, which was not supported by Mendelian randomization (MR) analyses that used only a few (<20) instrumental variables. Methods: We systemically interrogated a putative causal relationship between alcohol consumption and four common autoimmune disorders, using summary-level data from the largest genome-wide association study (GWAS) conducted on inflammatory bowel disease (IBD), rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE). We quantified the genetic correlation to examine a shared genetic similarity. We constructed a strong instrument using 99 genetic variants associated with drinks per week and applied several two-sample MR methods. We additionally incorporated excessive drinking as reflected by alcohol use disorder identification test score. Results: We observed a negatively shared genetic basis between alcohol intake and autoimmune disorders, although none was significant ( r = -0.07 to -0.02). For most disorders, genetically predicted alcohol consumption was associated with a slightly (10-25%) decreased risk of onset, yet these associations were not significant. Meta-analyzing across RA, MS, and IBD, the three Th1-related disorders yielded to a marginally significantly reduced effect [OR = 0.70 (0.51-0.95), g = -0.07 to -0.02). For most disorders, genetically predicted alcohol consumption was associated with a slightly (10-25%) decreased risk of onset, yet these associations were not significant. Meta-analyzing across RA, MS, and IBD, the three Th1-related disorders yielded to a marginally significantly reduced effect [OR = 0.70 (0.51-0.95), P With its greatly augmented sample size and substantially improved statistical power, our MR study does not convincingly support a beneficial role of alcohol consumption in each individual autoimmune disorder. Future studies may be designed to replicate our findings and to understand a causal effect on disease prognosis.Conclusions: With its greatly augmented sample size and substantially improved statistical power, our MR study does not convincingly support a beneficial role of alcohol consumption in each individual autoimmune disorder. Future studies may be designed to replicate our findings and to understand a causal effect on disease prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jiang, Zhu, Manouchehrinia, Olsson, Alfredsson and Kockum.)

Background: Although over a dozen disease modifying treatments (DMTs) are available for relapsing forms of multiple sclerosis (MS), treatment interruption, switching and discontinuation are common challenges. The objective of this study was to describe treatment interruption and discontinuation in the Big MS data network. Methods: We merged information on 269,822 treatment episodes in 110,326 patients from 1997 to 2016 from five clinical registries in this cohort study. Treatment stop was defined as a clinician recorded DMT end for any reason and included treatment interruptions, switching to alternate DMTs and long-term or permanent discontinuations. Results: The incidence of DMT stopping cross the full observation period was lowest in FTY (19.7 per 100 person-years (PY) of treatment; 95% CI 19.2-20.1), followed by NAT (22.6/100 PY; 95% CI 22.2-23.0), IFNβ (23.3/100 PY; 95% CI 23.2-23.5). Of the 184,013 observed DMT stops, 159,309 (86.6%) switched to an alternate DMT within 6 months. Reasons for stopping a drug were stable during the observation period with lack of efficacy being the most common reason followed by lack of tolerance and side effects. The proportion of patients continuing on most DMTs were similarly stable until 2014 and 2015 when drop from 83 to 75% was noted. Conclusions: DMT stopping reasons and rates were mostly stable over time with a slight increase in recent years, with the availability of more DMTs. The overall results suggest that discontinuation of MS DMTs is mostly due to DMT properties and to a lesser extent to risk management and a competitive market., Competing Interests: TS received compensation for serving on scientific advisory boards, honoraria for consultancy and funding for travel from Biogen; speaker honoraria from Novartis. MM has served on scientific advisory board for Biogen Idec and Teva and has received honoraria for lecturing from Biogen Idec, Merck Serono, Sanofi-Aventis and Teva. MM has received support for congress participation from Biogen Idec, Merck Serono, Novartis and Genzyme. PS has served on scientific advisory boards for Merck Serono, Teva, Novartis, Sanofi-Aventis and Biogen Idec and has received research support from Biogen Idec, Novartis and Sanofi-Aventis and received speaker honoraria from Merck Serono, Novartis, Teva, Sanofi-Aventis, Biogen Idec and Genzyme. HB received compensation for serving on scientific advisory boards and as a consultant for Biogen, Novartis; speaker honoraria from Biogen Australia, Merck Serono Australia, Novartis Australia; travel support from Biogen Australia, Merck Serono Australia; research support from the CASS Foundation (Australia), Merck Serono Australia, the Royal Melbourne Hospital. SV received consulting and lecturing fees, travel grants and research support from Biogen, Celgene, Genentech, Genzyme, Medday pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi Aventis, and Teva Pharma. MT has served on scientific Advisory Boards for Biogen, Novartis, Roche, and Genzyme; has received speaker honoraria and travel support from Biogen Idec, Sanofi-Aventis, Merck Serono, Teva, Genzyme and Novartis; and has received research grants for her Institution from Biogen Idec, Merck Serono, and Novartis. PI has served on scientific advisory boards for Biogen Idec, Bayer, Teva, Roche, Merck Serono, Novartis, and Genzyme and has received funding for travel and/or Speaker honoraria from Sanofi Aventis, Genzyme, Biogen Idec, Teva, Merck Serono, and Novartis. FP is an employee of Biogen. RH is an employee of Biogen and holds stock. JH has received honoraria for serving on advisory boards for Biogen, Sanofi-Genzyme, and Novartis and speaker's fees from Biogen, Novartis, Merck-Serono, Bayer-Schering, Teva, and Sanofi-Genzyme. JH has served as PI for projects, or received unrestricted research support from BiogenIdec, Merck-Serono, TEVA, Sanofi-Genzyme, and Bayer-Schering. JH MS research is funded by the Swedish Research Council and the Swedish Brain Foundation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hillert, Magyari, Soelberg Sørensen, Butzkueven, Van Der Welt, Vukusic, Trojano, Iaffaldano, Pellegrini, Hyde, Stawiarz, Manouchehrinia and Spelman.)

Background: Early initiation of disease-modifying treatment (DMT) is associated with better disability outcomes in multiple sclerosis (MS). However, little is known of how treatment decisions affect socio-economic outcomes., Objective: To estimate the long-term impact of early initiation of DMT on the income of MS patients., Methods: In total, 3610 MS patients were included in this register-based cohort study. We measured the association between the time to treatment and the outcome, defined as time from treatment initiation to a 95% decrease in annual earnings compared to each patient´s baseline level. Additionally, the association between time to treatment and increase of social benefits (sickness absence, disability pension) was investigated. A Cox model was adjusted for sex, onset age, education, family situation, country of birth, living area, and disability., Results: MS patients initiating treatment later had a higher risk of reaching the outcome- those who started treatment after 2 years from MS onset lost 95% of their earnings sooner (HR, 1.19; 95% CI, 1.04-1.37). Furthermore, risk to receive an annual compensation of SEK 100,000 (≈EUR 10,500) was higher for the delayed treatment group., Conclusion: Early treatment initiation in MS is associated with better socioeconomic outcome, adding to previous studies showing benefits regarding disability., (© The Author(s) 2020.)

Objective: To investigate the association between plasma neurofilament light chain (pNfL) levels and the risk of developing sustained disability worsening., Methods: Concentrations of pNfL were determined in 4,385 persons with multiple sclerosis (MS) and 1,026 randomly selected population-based sex- and age-matched controls using the highly sensitive Single Molecule Array (SimoaTM) NF-Light Advantage Kit. We assessed the impact of age-stratified pNfL levels above the 80th, 95th, and 99th percentiles among controls on the risk of Expanded Disability Status Scale (EDSS) worsening within the following year and reaching sustained EDSS scores of 3.0, 4.0, and 6.0 and conversion to secondary progressive multiple sclerosis (SPMS)., Results: The median (interquartile range [IQR]) pNfL was 7.5 (4.1) pg/mL in controls and 11.4 (9.6) pg/mL in MS ( p < 0.001). The median (IQR) duration of follow-up was 5 (5.1) years. High pNfL was associated with increased adjusted rates of EDSS worsening ranging between 1.4 (95% confidence intervals [CIs]: 1.1-1.8) and 1.7 (95% CI: 1.4-2.3). High pNfL was also associated with the risk of reaching a sustained EDSS score of 3.0, with adjusted rates ranging between 1.5 (95% CI: 1.2-1.8) and 1.55 (95% CI: 1.3-1.8) over all percentile cutoffs (all p < 0.001). Similar increases were observed for the risk of sustained EDSS score 4.0. In contrast, the risk of reaching sustained EDSS score 6.0 and conversion to SPMS was not consistently significant., Conclusions: Elevated pNfL levels at early stages of MS are associated with an increased risk of reaching sustained disability worsening. Hence, pNfL may serve as a prognostic tool to assess the risk of developing permanent disability in MS., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Patients with the 'aggressive' form of multiple sclerosis accrue disability at an accelerated rate, typically reaching Expanded Disability Status Score (EDSS) ≥ 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive multiple sclerosis, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive multiple sclerosis is essential to optimize treatment in this multiple sclerosis subtype. We evaluated whether patients who will develop aggressive multiple sclerosis can be identified based on early clinical markers. We then replicated this analysis in an independent cohort. Patient data were obtained from the MSBase observational study. Inclusion criteria were (i) first recorded disability score (EDSS) within 12 months of symptom onset; (ii) at least two recorded EDSS scores; and (iii) at least 10 years of observation time, based on time of last recorded EDSS score. Patients were classified as having 'aggressive multiple sclerosis' if all of the following criteria were met: (i) EDSS ≥ 6 reached within 10 years of symptom onset; (ii) EDSS ≥ 6 confirmed and sustained over ≥6 months; and (iii) EDSS ≥ 6 sustained until the end of follow-up. Clinical predictors included patient variables (sex, age at onset, baseline EDSS, disease duration at first visit) and recorded relapses in the first 12 months since disease onset (count, pyramidal signs, bowel-bladder symptoms, cerebellar signs, incomplete relapse recovery, steroid administration, hospitalization). Predictors were evaluated using Bayesian model averaging. Independent validation was performed using data from the Swedish Multiple Sclerosis Registry. Of the 2403 patients identified, 145 were classified as having aggressive multiple sclerosis (6%). Bayesian model averaging identified three statistical predictors: age > 35 at symptom onset, EDSS ≥ 3 in the first year, and the presence of pyramidal signs in the first year. This model significantly predicted aggressive multiple sclerosis [area under the curve (AUC) = 0.80, 95% confidence intervals (CIs): 0.75, 0.84, positive predictive value = 0.15, negative predictive value = 0.98]. The presence of all three signs was strongly predictive, with 32% of such patients meeting aggressive disease criteria. The absence of all three signs was associated with a 1.4% risk. Of the 556 eligible patients in the Swedish Multiple Sclerosis Registry cohort, 34 (6%) met criteria for aggressive multiple sclerosis. The combination of all three signs was also predictive in this cohort (AUC = 0.75, 95% CIs: 0.66, 0.84, positive predictive value = 0.15, negative predictive value = 0.97). Taken together, these findings suggest that older age at symptom onset, greater disability during the first year, and pyramidal signs in the first year are early indicators of aggressive multiple sclerosis., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To determine factors (including the role of specific disease modulatory treatments [DMTs]) associated with (1) baseline, (2) on-treatment, and (3) change (from treatment start to on-treatment assessment) in plasma neurofilament light chain (pNfL) concentrations in relapsing-remitting multiple sclerosis (RRMS)., Methods: Data including blood samples analyses and long-term clinical follow-up information for 1,261 Swedish patients with RRMS starting novel DMTs were analyzed using linear regressions to model pNfL and changes in pNfL concentrations as a function of clinical variables and DMTs (alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, rituximab, and teriflunomide)., Results: The baseline pNfL concentration was positively associated with relapse rate, Expanded Disability Status Scale score, Age-Related MS Severity Score, and MS Impact Score (MSIS-29), and negatively associated with Symbol Digit Modalities Test performance and the number of previously used DMTs. All analyses, which used inverse propensity score weighting to correct for differences in baseline factors at DMT start, highlighted that both the reduction in pNfL concentration from baseline to on-treatment measurement and the on-treatment pNfL level differed across DMTs. Patients starting alemtuzumab displayed the highest reduction in pNfL concentration and lowest on-treatment pNfL concentrations, while those starting teriflunomide had the smallest decrease and highest on-treatment levels, but also starting from lower values. Both on-treatment pNfL and decrease in pNfL concentrations were highly dependent on baseline concentrations., Conclusion: Choice of DMT in RRMS is significantly associated with degree of reduction in pNfL, which supports a role for pNfL as a drug response marker., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To evaluate quality of life (QoL), measured by the EQ-5D, in adults with pediatric-onset multiple sclerosis (POMS) or adult-onset multiple sclerosis (AOMS) and explore determinants of QoL in both groups., Methods: Data were collected from the nationwide Swedish multiple sclerosis (MS) registry. Demographic characteristics, EQ-5D-3 level, Multiple Sclerosis Impact Scale (MSIS-29) score, Expanded Disability Status Scale (EDSS) score, Symbol Digit Modalities Test score, relapses, and disease-modifying therapy (DMT) exposure were collected on an approximately annual basis (2011-2019). Patients with definite MS with ≥2 EQ-5D measurements collected between ages 18 and 50 were included. The principal outcome was the EQ-5D visual analogue scale (EQ-VAS) score. Linear mixed models compared all available EQ-VAS scores between patients with POMS and patients with AOMS and determinants of EQ-VAS among patients with POMS and patients with AOMS (assessed separately)., Results: A total of 5,094 persons met inclusion criteria: 354 (6.9%) had POMS. A total of 21,357 unique EQ-5D scores were recorded. Most participants were female (70.0%) with a relapsing-onset disease course (98.1%). There was no difference in EQ-VAS scores between patients with POMS and patients with AOMS following adjustment for confounders (β-coefficient for patients with POMS vs patients with AOMS [reference]: 0.99; 95% confidence interval -0.89 to 2.87). Experiencing a relapse, severe neurologic disability (EDSS ≥6.0 vs <3.0), and higher MSIS-29 psychological score were consistently associated with lower QoL, while higher information processing efficiency and exposure to first-line DMTs were associated with higher QoL scores in both groups., Conclusions: There were no differences in QoL between patients with POMS and patients with AOMS in adulthood. Findings provide support for a focus on reducing neurologic disability and improving psychological status as approaches to potentially improve the QoL of persons with MS., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Blood Neurofilament light chain (NfL) has been suggested as a promising biomarker in several neurological conditions. Since blood NfL is the consequence of leaked NfL from the cerebrospinal fluid, differences in individuals' Body Mass Index (BMI) or blood volume (BV) might affect its correlation to other biomarkers and disease outcomes. Here, we investigated the correlation between plasma NfL, BMI, and BV in 662 controls and 2,586 multiple sclerosis cases. We found a significant negative correlation between plasma NfL, BMI/BV in both groups. Our results highlight the potential confounding effect of BMI/BV on associations between blood NfL and disease outcomes., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Objective: Depression is common in multiple sclerosis (MS), but its impact on disability worsening has not yet been determined. We explored the risk of disability worsening associated with depression in a nationwide longitudinal cohort., Methods: This retrospective cohort study used linked data from 3 Swedish nationwide registries: the MS Register, National Patient Register, and Prescribed Drug Register. Two incident cohorts were developed: cohort 1 included all registered cases of MS in the MS Registry (2001-2014) with depression defined as ≥1 ICD-10 code for depression; and cohort 2 comprised all cases of MS in the MS Registry (2005-2014) with depression defined as ≥1 prescription filled for an antidepressant. Cox regression models were used to compare the risk of reaching sustained disability milestone scores of 3.0, 4.0, and 6.0 on the Expanded Disability Status Scale (EDSS) between persons with MS with and without depression., Results: Cohort 1 included 5,875 cases; 502 (8.5%) had depression. Cohort 2 had 3,817 cases; 1,289 (33.8%) were prescribed an antidepressant. Persons with depression were at a significantly higher risk of reaching sustained EDSS scores of 3.0, 4.0, and 6.0, with hazard ratios of 1.50 (95% confidence interval [CI] 1.20-1.87), 1.79 (95% CI 1.40-2.29), and 1.89 (95% CI 1.38-2.57), respectively. A similar increased risk among persons exposed to antidepressants was observed, with hazard ratios of 1.37 (95% CI 1.18-1.60), 1.93 (95% CI 1.61-2.31), and 1.86 (95% CI 1.45-2.40) for sustained EDSS scores of 3.0, 4.0, and 6.0, respectively., Conclusion: Persons with MS and comorbid depression had a significantly increased risk of disability worsening. This finding highlights the need for early recognition and appropriate treatment of depression in persons with MS., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Reductions of the peripapillary retinal nerve fiber layer (pRNFL) thickness has been indicated even in early-stages of multiple sclerosis (MS). The aim was to investigate the association between pRNFL thickness, measured with optical coherence tomography (OCT), and physical disability and cognitive impairment in MS., Methods: 465 MS patients and 168 healthy controls (HCs) were included. MS subjects were divided into subgroups according to disease subtype. All subjects underwent OCT examination of all pRNFL quadrants using Canon OCT-HS100. Associations were tested using linear mixed effect models. Physical disability was assessed with the Expanded Disability Status Scale (EDSS) and cognitive function with the Symbol Digit Modalities Test (SDMT)., Results: The average pRNFL, inferior pRNFL and temporal pRNFL thicknesses were significantly correlated to both EDSS (-1.0 µm, p < 0.01; -1.2 µm, p < 0.05; -1.2 µm, p < 0.01) and SDMT (0.1 µm, p < 0.05; 0.2 µm, p < 0.05; 0.2 µm, p < 0.01). A significant thickness loss compared with HCs was seen in the average pRNFL and in all quadrants except for the superior quadrant of primary progressive MS. The largest reduction compared with HCs was seen in the temporal pRNFL of PPMS eyes (-15.8 µm; p < 0.001)., Conclusion: The reduction of average pRNFL, inferior pRNFL and temporal pRNFL thickness is associated with physical and cognitive disability in MS. We suggest the use of temporal pRNFL as a more sensitive outcome as it showed the strongest association to both EDSS and SDMT., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Importance: Cognitive impairment in multiple sclerosis (MS) can lead to reduced quality of life, social functioning, and employment. Few studies have investigated cognitive outcomes among patients with pediatric-onset MS (POMS) over the long term., Objective: To compare long-term information-processing efficiency between patients with POMS and adult-onset MS (AOMS)., Design, Setting, and Participants: This population-based longitudinal cohort study accessed the Swedish MS Registry (SMSreg), which collates information from all 64 neurology clinics in Sweden. Registered cases with definite MS in the SMSreg with an onset before April 15, 2018, and at least 2 Symbol Digit Modalities Test (SDMT) scores recorded were included. Only persons aged 18 to 55 years and with duration of disease of less than 30 years at the time of SDMT administration were included, to ensure comparable ranges between patients with POMS and AOMS. Of 8247 persons with an SDMT recorded in the SMSreg, 5704 met inclusion criteria, 300 (5.3%) of whom had POMS. Data were collected from April 1, 2006, through April 15, 2018 and analyzed from April through August 2018., Exposures: Pediatric-onset MS (onset <18 years of age) vs AOMS (onset ≥18 years of age)., Main Outcomes and Measures: Information-processing efficiency measured every 6 or 12 months by the SDMT. Linear mixed-effects models were used to compare all available SDMT scores between patients with POMS and those with AOMS. Persons with cognitive impairment (ever vs never) were identified using regression-based norms and compared between POMS and AOMS groups using logistic regression., Results: Of the 5704 participants, 4015 were female (70.4%), and 5569 had a relapsing-onset disease course (97.6%). Most participants were exposed to a disease-modifying therapy (DMT) during follow-up (98.8%). Median age at baseline for the POMS group was 25.6 years (interquartile range, 21.0-31.7 years) and for the AOMS group, 38.3 years (interquartile range, 31.4-45.2 years). A total of 46 429 unique SDMT scores were analyzed. After adjustment for sex, age, disease duration, disease course, total number of SDMTs completed, oral or visual SDMT form, and DMT exposure, the SDMT score for patients with POMS was significantly lower than that of patients with AOMS (β coefficient, -3.59 [95% CI, -5.56 to -1.54]). The SDMT score for patients with POMS declined faster than that of patients with AOMS (β coefficient, -0.30 [95% CI, -0.42 tp -0.17]). The odds of cognitive impairment were also significantly elevated in the POMS group (odds ratio, 1.44; 95% CI, 1.06-1.98)., Conclusions and Relevance: In adulthood, patients with POMS demonstrated a more rapid reduction in information-processing efficiency over time and were more likely to experience cognitive impairment than patients with AOMS, independent of age or disease duration. Further investigation is required to understand the mechanisms by which early MS onset influences cognitive outcomes.

Background: As the prevalence and incidence of Multiple Sclerosis (MS) are increasing remarkably in Iran, gathering standardized information regarding the individual's diagnosis, care, and outcomes through a uniform registry system would enable policy-makers to systematically plan for care quality improvements., Objective: To design a valid and reliable Persian version of a minimum data set to be utilized and integrated into the national MS registry system of Iran., Method: The minimum data set consisted of six domains including patient identification, family history of MS, diagnosis, disease course, disability status, and medications. The content validity was assessed based on 27 experts' opinions. Item-Content Validity Index (I-CVI) and Scale-Content Validity Index (S-CVI) were used to assess the questions and their validities. Reliability was evaluated using the intra-class correlation coefficient (ICC) of the test-retest results., Results: For validity appraisal, 27 experts reviewed the developed minimum data set. All the items had I-CVI values higher than the critical value of 0.78 in terms of relevance, clarity, and simplicity, except for "medication start date" and "medication end date" in relevance (I-CVI = 0.75 and 0.73, respectively) and "MS type" in simplicity (I-CVI = 0.76). The total S-CVI scores for relevance, clarity, and simplicity were higher than 0.9. In reliability assessment, 27 patients (out of 74 interviewed patients) were re-interviewed to assess the test-retest reliability. All ICCs were higher than the critical value of 0.7 (in 14 items out of 16), except for "progression to secondary-progressive MS" with the ICC = 0.68 and "the reason for medication discontinuance" with the ICC = 0.64., Conclusion: The use of standardized validated minimum data set has the potential to enable the researchers and policy-makers to systematically compare and analyze patient information. The Persian version of the minimum data set found to be valid and reliable in Iran., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: We aimed at designing a nomogram, a prediction tool, to predict the individual's risk of conversion to secondary progressive multiple sclerosis (SPMS) at the time of multiple sclerosis (MS) onset., Methods: One derivation and three validation cohorts were established. The derivation cohort included 8825 relapsing-onset MS patients in Sweden. A nomogram was built based on a survival model with the best statistical fit and prediction accuracy. The nomogram was validated using data from 3967 patients in the British Columbia cohort, 176 patients in the ACROSS and 2355 patients in FREEDOMS/FREEDOMS II extension studies., Results: Sex, calendar year of birth, first-recorded Expanded Disability Status Scale (EDSS) score, age at the first EDSS and age at disease onset showed significant predictive ability to estimate the risk of SPMS conversion at 10, 15 and 20 years. The nomogram reached 84% (95% confidence intervals (CIs): 83-85) internal and 77% (95% CI: 76-78), 77% (95% CI: 70-85) and 87% (95% CI: 84-89) external accuracy., Conclusions: The SPMS nomogram represents a much-needed complementary tool designed to assist in decision-making and patient counselling in the early phase of MS. The SPMS nomogram may improve outcomes by prompting timely and more efficacious treatment for those with a worse prognosis.

Objective: Benign multiple sclerosis (BMS) is often defined by the Expanded Disability Status Scale (EDSS) score of ≤3.0 after ≥15 years of disease duration. This classification's clinical relevance remains unclear as benign patients may suffer other impairments and advance towards a progressive course, prompting our objective to holistically investigate factors associated with BMS and its long-term prognosis., Methods: Benign cases were identified in the Swedish Multiple Sclerosis registry. Baseline clinical data, demographic features and influence of multiple sclerosis (MS) major risk alleles on likelihood of benign course were investigated. Physical disability (EDSS), cognitive function (Symbol Digit Modalities Test; SDMT) and self-reported and socioeconomic differences between benign and non-benign patients were evaluated using generalised estimation equations models., Results: 11222 patients (2420 benign/8802 non-benign) were included. Benign patients were more likely to be female and younger at MS onset, have fewer relapses within the first two and 5 years from onset and fully recover from the first relapse (p<0.001). No association between human leucocyte antigen ( HLA ) DRB1*15:01 carriership (OR: 0.97, 95% CI: 0.86 to 1.09) or HLA-A*02:01 lacking (OR: 0.99, 95% CI: 0.87 to 1.11) and benign/non-benign was found. Non-benign patients accumulated an extra 0.04 (95% CI 0.03 to 0.04, p<0.001) EDSS score/year, lost an extra 0.3 (95% CI - 0.39 to - 0.18, p<0.001) SDMT score/year and deteriorated faster in self-reported impact and socioeconomic measures (p<0.001)., Conclusion: Patients with BMS have a better disease course as they progress more slowly at the group level in all respects. Lack of an association with major genetic risk factors indicates that MS course is most likely influenced by either environmental factor(s) or genetic factors outside the HLA region., Competing Interests: Competing interests: LC, RM, AK, AM declare no conflict of interests. TO has received honoraria for lectures and advisory boards from Biogen, Novartis, Genzyme, Merck and TEVA. Unrestricted research grants from Biogen, Novartis and Genzyme. JH received honoraria for serving on advisory boards for Biogen, Sanofi-Genzyme and Novartis and speaker’s fees from Biogen, Merck-Serono, Bayer-Schering, Teva and Sanofi-Genzyme. He has served as P.I. for projects sponsored by, or received unrestricted research support from, Biogen, Merck-Serono, TEVA, Novartis, Sanofi-Genzyme and Bayer-Schering., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)