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Multiple sclerosis (MS) patients with and without the oligoclonal band (OCB) distribution of immunoglobulin gamma (IgG) in the cerebrospinal fluid (CSF) has a different genetic background and brain MRI features. In this study we have 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, MS onset and date at sustained Expanded Disability Status Scale (EDSS) score milestones 3, 4, 6, date at 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 earlier time and at younger age. OCB-positivity significantly increased the risk of reaching EDSS score 3.0 (HR=1.29, 95%CI: 1.12 to 1.48, P.

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.

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.

ObjectiveTo evaluate long-term disability progression in pediatric-onset multiple sclerosis (POMS) and compare to adult-onset multiple sclerosis (AOMS).MethodsThis was a retrospective cohort study using prospectively collected clinical information from the Swedish MS Registry. Clinical features were compared and Kaplan-Meier and Cox proportional hazards regression were used to assess the risk of reaching sustained Expanded Disability Status Scale (EDSS) 3, 4, and 6 in POMS (multiple sclerosis [MS] onset ResultsA total of 12,482 persons were included; 549 (4.4%) were classified as POMS. The POMS cohort took longer to reach all 3 disability milestones from their MS onset, but did so at a younger age than the AOMS cohort. Primary progressive course (hazard ratio [HR] 4.63; 95% confidence interval [CI] 1.46–14.7), higher relapse rate in the first 5 years of disease (HR 5.35; 95% CI 3.37–8.49), and complete remission from the initial relapse (HR 0.41; 95% CI 0.18–0.94) were associated with an altered risk of progression to EDSS 4 among POMS cases. The same pattern emerged for the risk of reaching EDSS 3 and 6.ConclusionsPatients with pediatric-onset MS follow a distinctive clinical course, which should be considered in the treatment and management of the disease.

Cigarette smoking is the most prominent significant cause of death and morbidity. It is recognised as a risk factor for a number of immune mediated, inflammatory diseases including multiple sclerosis (MS). Here, we review the complex immunological effects of smoking on the immune system, which include enhancement of inflammatory responses with a parallel reduction of some immune defences, resulting in an increased susceptibility to infection and a persistent proinflammatory environment. We discuss the effect of smoking on the susceptibility, clinical course, disability, and mortality in MS, the likely benefits of smoking cessation, and the specific immunological effects of smoking in MS. In conclusion, smoking is an important environmental risk factor for MS occurrence and outcome, and it acts in significant part through immunological mechanisms.

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 Varmland 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. Funding Agencies|Swedish Research Council for Health, Working Life and WelfareSwedish Research CouncilSwedish Research Council for Health Working Life & Welfare (Forte) [2019-00190]

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., National Health and Medical Research Council of Australia; Roche; Merck; Biogen; Novartis; Bayer Schering; Sanofi Genzyme; Teva

We thank Gabriel Bsteh and Thomas Berger for their comment on our study.1 While acknowledging the interesting results of the study by Besteh et al.2 that we ought to have included in our discussion, we disagree that the studies are noteworthily different with regards to capture rate.

Transition from a relapsing-remitting to the secondary progressive phenotype is an important milestone in the clinical evolution of multiple sclerosis. In the absence of reliable imaging or biological markers of phenotype transition, assignment of current phenotype status relies on retrospective evaluation of the medical history of an individual. Here, we sought to determine if demographic and clinical information from multiple sclerosis patients can be used to accurately assign current disease phenotypes: either relapsing-remitting or secondary progressive status. Data from the most recent clinical visit of 14,387 multiple sclerosis patients were extracted from the Swedish Multiple Sclerosis Registry. Decision trees based on sex, symptom onset age, Expanded Disability Scale Status score, and age & disease duration at the most recent clinic visit, were examined to build a classifier to determine disease phenotype. Validation was conducted using an independent cohort of multiple sclerosis patients from British Columbia, Canada, and a previously published classifier to assign phenotype was also tested. Clinical records of 100 randomly selected patients were used to manually categorize phenotype by three independent neurologists. A decision tree (the classifier) containing only most recently available disability score and age obtained 89.3% (95% confidence intervals (CI): 88.8% to 89.8%) classification accuracy, defined as concordance with the latest reported status in the registry. Replication in an independent cohort from British Columbia resulted in 82.0% (95%CI: 81.0% to 83.1%) accuracy. A previously published classification algorithm with slight modifications achieved 77.8% (95%CI: 77.1% to 78.4%) accuracy when assigning disease phenotype. With complete patient history data, three neurologists obtained 84.7% accuracy on average compared with 85 for the classifier using the same data. The model is easily interpretable and could allow research studies and randomized clinical trials to estimate the probability of patients having already reached the secondary progressive stage when they have not yet been retrospectively assigned this status, and to standardize definitions of disease phenotype across different cohorts. Clinically, this model could assist neurologists by providing additional information about the probability of having secondary progressive disease. This could also benefit patients who may be introduced to new therapies targeting progressive multiple sclerosis.

Objectives Multiple sclerosis (MS) is a chronic demyelinating disorder affecting young adults. Environmental factors and lifestyle behaviors are pivotal in MS pathophysiology. Smoking has been considered as an important risk factor in MS. Various recent studies have been conducted to measure the role of smoking on worsening disability in patients with MS, thus we intended to systematically assess effect of smoking on evolution of disability in this study. Materials & methods We queried MEDLINE, EMBASE and Cochrane Library with following keywords “Multiple Sclerosis, Smoking, Tobacco Use, Disability” on December 1st 2016. Original articles were included when smoking history was mentioned, disability was measured via expanded disability status scale (EDSS) or multiple sclerosis severity score (MSSS). Studies with insufficient outcome data, non‐human, or in other languages than English were excluded. Results Through literature review after duplicate removals, 268 articles were retrieved. A total of 56 articles were screened and 15 articles were assessed for eligibility, finally, eleven articles were included in this systematic review and meta‐analysis. Ever smoking was significantly associated with increased EDSS (standardized mean difference (SMD) = 0.15, 95% CI = 0.01‐0.28), but had no significant association with risk of reaching EDSS 4 (HR = 1.24, 95% CI = 0.89‐1.72) or EDSS 6 (HR = 1.17, 95% CI = 0.88‐1.57). Smoking had no effect on MSSS (SMD = 0.14, 95% CI = −0.04‐0.32) or T2 lesion volume (SMD = 0.07, 95% CI = −0.08‐0.22). Conclusions This meta‐analysis showed smoking increased EDSS, insignificant findings were possibly due to the small number of studies, significant differences in methodologies, and variations in reporting of disability outcomes.

Genetic variants within some cytokine receptor genes have been associated with MS susceptibility, including IL7RA and IL2RA. As these genes are expressed by cells targeted by immune-modulatory drugs, we explored the potential role of their gene products as biomarkers in monitoring MS treatment. We assessed the impact of natalizumab followed by fingolimod on the intra-individual changes of plasma protein levels of sIL-7Rα, sIL-2Rα and also sIL-6R and sgp130 in MS patients. During natalizumab treatment we observed a decline in sgp130 and sIL-7Rα levels, while subsequent fingolimod treatment lead to increased sgp130 and sIL-7Rα and decreased sIL-2Rα levels. In addition, during fingolimod treatment sIL-7Rα levels were increasing significantly more in patients homozygous for the MS risk genotype of rs6897932. We also observed an effect of the MS associated rs71624119 on sgp130 levels. These results may elucidate the pharmacodynamics of treatments and help identify biomarkers for MS outcomes.

Background: In multiple sclerosis (MS), various aspects of cognitive function can be detrimentally affected, thus patients’ employment and social functioning is commonly impacted. Objective: To analyse income among MS patients in relation to cognitive function, assessed with the Symbol Digit Modalities Test (SDMT). Methods: A cross-sectional study including 2080 MS patients was conducted linking national register-based data. Descriptive statistics and a two-part model were used to estimate differences in earnings and social benefits. Results: MS patients in the highest SDMT score quartile earned more than twice annually compared to patients in the lowest quartile, whereas patients in the lowest quartile received three times more income through social benefits. The difference in earnings and benefits across the SDMT performance quartiles remained statistically significant after adjusting for various clinical and socio-demographic variables, including physical disability. The corrected prevalence ratios for MS patients in the highest quartile for having income from earnings and benefits were 1.40 (95% confidence interval (CI): 1.29–1.49) and 0.81 (95% CI: 0.71–0.90), respectively, when compared to the patients in the lowest quartile. Conclusion: Cognitive function affects the financial situation of MS patients negatively and independently of physical disability. This warrants cognitive testing as a routine measure in health care services for MS patients.

Varicella zoster virus (VZV) infection has been implicated in multiple sclerosis (MS), but direct causal involvement has been disputed. Nevertheless, knowledge of VZV exposure is important, given the risk of serious complications of first exposure while undergoing immunosuppressive treatment, in particular with fingolimod. We distributed questionnaires to MS clinic patients, requesting information about history of chickenpox, sibling/household/occupational exposure, history of zoster (shingles), and disease-modifying treatment. A random, proportionally representative sample of 51 patients that included patients with positive, negative, and unknown chickenpox history were selected for determination of VZV IgG by ELISA. Of 1206 distributed questionnaires, 605 were returned (50% response rate). Of these, 86% reported history of chickenpox, 5.6% gave negative history, and 8.5% did not know. Of 594 who answered the zoster question, 78% gave a negative response, 4% did not know, and 104 (17%) answered yes. Of these, 83 reported 1 episode; 12 had 2; 5 had 3; and 1 each reported 5, 6, and 15 episodes. Of 51 patients tested for VZV IgG (44 "yes," 4 "no," and 3 "I don't know" answers to the question of whether they had chickenpox), 48 were seropositive; the 3 seronegative all had reported having had chickenpox. The high rate of MS patients reporting prior chickenpox infection is comparable with previous reports. A substantial proportion of MS patients, estimated to be higher than an age-matched general population, report single or multiple episodes of zoster. These data are useful for consideration of immunosuppressive treatments and/or VZV and zoster vaccination.

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. 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). 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 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).

Patients with the ‘aggressive’ form of MS accrue disability at an accelerated rate, typically reaching EDSS >= 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive MS, 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 MS is essential to optimise treatment in this MS subtype. We evaluated whether patients who will develop aggressive MS can be identified based on early clinical markers, and to replicate this analysis in an independent cohort. Patient data were obtained from MSBase. Inclusion criteria were (a) first recorded disability score (EDSS) within 12 months of symptom onset, (b) at least 2 recorded EDSS scores, and (c) at least 10 years of observation time. Patients were classified as having ‘aggressive MS’ if they: (a) reached EDSS >= 6 within 10 years of symptom onset, (b) EDSS >=6 was confirmed and sustained over >=6 months, and (c) EDSS >=6 was 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, hospitalisation). Predictors were evaluated using Bayesian Model Averaging (BMA). Independent validation was performed using data from the Swedish MS Registry. Of the 2,403 patients identified, 145 were classified as having aggressive MS (6%). BMA 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 MS (AUC = .80, 95% CIs = .75, .84). 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 MS Registry cohort, 34 (6%) met criteria for aggressive MS. The combination of all three signs was also predictive in this cohort (AUC = .75, 95% CIs = .66, .84). 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 MS.

Background: A subgroup of patients diagnosed with multiple sclerosis (MS) present with no oligoclonal bands (OCB) in the cerebrospinal fluid (CSF). Several studies report different clinical characteristics and genetic associations between the two groups. Objective: To investigate whether the OCB negative subgroup has a distinct etiology from band positive MS. Methods: Using nationwide registers to estimate familial risks, which reflect the genetic contribution of a disease. Results: Odds ratios of MS were similar for relatives to band positive and negative patients. Conclusion: From the perspective of familial liability, MS without OCB is etiologically closely related to the dominant subgroup of OCB positive MS.

Objectives: The aim of this study was to identify factors influencing the long-term clinical progression of multiple sclerosis (MS). A special objective was to investigate whether early treatment decisions influence outcome. Methods: We included 639 patients diagnosed with MS from 2001 to 2007. The median follow-up time was 99 months (8.25 years). Cox regression models were applied to identify factors correlating with the outcome variable defined as time from treatment start to irreversible score 4 of the Expanded Disability Status Scale (EDSS). Results: Patients initiated on treatment later had a greater risk of reaching EDSS 4 (hazard ratio of 1.074 (95% confidence interval (CI), 1.048−1.101)), increased by 7.4% for every year of delay in treatment start after MS onset. Patients who started treatment after 3 years from MS onset reached the outcome sooner with hazard ratio of 2.64 (95% CI, 1.71−4.08) compared with the patients who started treatment within 1 year from MS onset. Baseline EDSS and age at onset were found to be predictive factors of disability progression. Conclusion: Early treatment initiation was associated with a better clinical outcome. In addition, we confirmed the well-established prognostic factors of late age at onset and early disability.

Background: Several reports indicate changes to prevalence, incidence, female-to-male ratio in multiple sclerosis. Diagnostic criteria, course definitions and clinical management of the disease have also undergone change during the recent decades. Objective: To investigate temporal trends in the diagnosis of primary progressive multiple sclerosis (PPMS) in Sweden. Methods: Through the Swedish MS registry we investigated the proportion of PPMS diagnosis in birth, diagnosis and age period cohorts using Poisson regression. Results: A total of 16,915 patients were categorised into six birth-cohorts from 1946 to 1975 and seven date-of-diagnosis-cohorts from 1980 to 2014. We observed a decrease in the uncorrected analysis of diagnosis of PPMS from 19.2% to 2.2% and an average decrease of 23% ( p Conclusion: The diagnosis of PPMS has significantly decreased in Sweden specifically after introduction of disease-modifying treatments. Such decrease can have severe impacts on the future research on PPMS. Our data also suggest that the current trend to emphasise presence or absence of inflammatory activity is already reflected in clinical practice.

Multiple sclerosis (MS) treatment options have improved significantly over the past decades, but the consequences of MS can still be devastating and the needs for monitoring treatment surveillance are considerable. In the current study we used affinity proteomics technology to identify potential biomarkers which could ultimately be used to as facilitate treatment decisions. We profiled the intra-individual changes in the levels of 59 target proteins using an antibody suspension bead array in serial plasma samples from 44 MS patients during treatment with natalizumab followed by fingolimod. Nine proteins showed decreasing plasma levels during natalizumab treatment, with PEBP1 and RTN3 displaying the most significant changes. Protein levels remained stable during fingolimod treatment for both proteins. The decreasing PEBP1 levels during natalizumab treatment could be validated using ELISA and replicated in an independent cohort. These results support the use of this technology as a high throughput method of identifying potentially useful biomarkers of MS treatment.

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.

ObjectiveBenign 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.MethodsBenign 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.Results11222 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 (pHLA) 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, pConclusionPatients 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.

Background Persons who develop multiple sclerosis (MS) at a young age may bear a higher genetic risk load than persons who develop MS later in life; however, the contribution of familial influence to the risk of MS, in relation to onset age, has not been established. Objective To investigate the familial risk of MS at two extremes of the spectrum of MS onset age: early onset (first MS symptom

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.

Both high body mass index (BMI) and smoking tobacco are known risk factors for developing multiple sclerosis (MS). However, it is unclear whether BMI, like smoking, is a risk factor for the secondary progressive (SP) course. We, therefore, sought to determine if high/low BMI at age 20 is associated to risk of SP development, in the context of smoking status. Using data from MS patients with BMI and smoking information available, we examined relapsing onset patients with MS onset after 20 years of age. Cox regressions were conducted on smokers and non-smokers, with BMI as the main exposure. In total, 5,598 relapsing onset MS patients were included. The models demonstrated that BMI > 30 was associated to increased risk of SPMS in smokers (hazard ratio 1.50, p = 0.036). This association of obesity at age 20 with increased risk of SP was not observed in non-smokers (hazard rate 0.97, p = 0.900). Since the risk is confined to smokers, the interaction observed may give insight to disease driving mechanisms.

Background Smoking is associated with a more severe disease course in people with multiple sclerosis (MS). The magnitude of effect of smoking cessation on MS progression is unknown. The aim of this study was to quantify the impact of smoking cessation on reaching MS disability milestones. Aims and methods This is a cross-sectional study with retrospective reports. A comprehensive smoking questionnaire was sent to 1270 patients with MS registered between 1994 and 2013 in the Nottingham University Hospital MS Clinics database. Demographic and clinical data were extracted from the clinical database. Cox proportional hazard regression was used to estimate effects of smoke-free years on the time to Expanded Disability Status Scale (EDSS) scores 4.0 and 6.0. MS Impact Scale 29 and Patient Determined Disease Steps were used to assess the physical and psychological impact of smoking. Results Each "smoke-free year" was associated with 0.96 (95% confidence interval: 0.95 to 0.97) times decreased risk of reaching EDSS 4.0 and 0.97 (95% confidence interval: 0.95 to 0.98) times decreased risk of reaching EDSS 6.0. Nonsmokers showed a significantly lower level of disability in all the self-reported outcomes compared with current smokers. Conclusions The reduction in the risk of disability progression after smoking cessation is significant and time dependent. The earlier the patients quit, the stronger the reduction in the risk of reaching disability milestones. The quantitative estimates of the impact of smoking cessation on reaching disability milestones in MS can be used in interventional trials. Implications This study provides for the first time quantitative estimates of the effects of smoking cessation in MS, essential for informing smoking cessation trials. The clear effect of smoking cessation on MS progression suggests the need to consider adjusting for smoking cessation when assessing for treatment effects in clinical trials of treatments for MS. Smoking cessation should be an early intervention in people with MS.

Objective There are inconsistent data on mortality in people with multiple sclerosis (MS). We performed a meta-analysis of all-cause, cause-specific and gender-specific crude mortality rates (CMRs), and standardised mortality ratios (SMRs) in MS, and estimated the rate of change of CMR and SMR over the past 50 years. Methods Medline, Embase and the Cochrane Library were searched. Keywords: ‘Multiple Sclerosis’ and (‘standardised mortality’ or ‘standardized mortality’). Inclusion criteria: availability of data on the number of deaths; mean or median patient follow-up or reports of SMRs; being a longitudinal study. 12 studies were included covering the period 1949–2012 (27 423 patients; 6628 deaths; 437 832 person-years follow-up). CMR was calculated. SMRs were extracted. CMRs and natural logarithm of SMRs were pooled by the method of the inverse of the variance. Meta-regression models were used to investigate the secular trends. Results Pooled CMR was 9.78/1000 person-years (95% CI 6.81 to 14.02). Pooled all-cause SMR was 2.80 (95% CI 2.74 to 2.87). All-cause SMR was 2.56 (95% CI 2.47 to 2.66) in males and 3.06 (95% CI 2.97 to 3.17) in females. SMR due to cancer was 0.89 (95% CI 0.83 to 0.97). SMRs due to cardiovascular diseases, suicide, infection and respiratory diseases were 1.29 (95% CI 1.20 to 1.38), 2.13 (95% CI 1.80 to 2.51) and 2.91 (95% CI 2.60 to 3.26). There was no trend in CMRs, all-cause, and gender-specific SMRs. Conclusions The excess mortality in MS relative to the general population has not changed over the past 50 years. Female patients with MS have higher survival disadvantage compared to that of males. Death due to cardiovascular diseases, suicide and infection is higher in patients with MS compared to the general population.

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.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).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).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.

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

Background: The course of multiple sclerosis (MS) has been studied in several cohorts; however, results have varied significantly. Objective: To describe the clinical course of MS in a nationwide cohort of patients. Method: Data from the Swedish MS register (SMSreg) were used to estimate the median time to the sustained Expanded Disability Status Scale (EDSS) scores 3.0, 4.0 and 6.0, onset of secondary progressive multiple sclerosis (SPMS) and death using Kaplan–Meier method. A possible effect of first-line treatments on age at EDSS 6.0 and SPMS was estimated. Results: In all, 12,703 patients were included. Median ages at EDSS scores 3.0, 4.0 and 6.0 were 55.4 (95% confidence interval (CI): 54.8−55.8), 60.7 (95% CI: 60.1−61.2) and 64.3 (95% CI: 63.6−64.7), respectively. Median age at SPMS was 57.4 (95% CI: 56.9−57.9). The median age at the time of death was 80.5 (95% CI: 79.9−81.1). Males and progressive-onset patients showed higher risks of disability worsening. On average, treated patients gained 1.6 years (95% CI: 0.2−3) to EDSS 6.0 as a result of treatment. Conclusion: Ages at disability milestones in this population-based cohort were higher than previously described in clinic- and regional-based samples. Nevertheless, MS patients die at younger age and live at an average almost 20 years with moderate and 30 years with severe disability.

Background: Modafinil is a wakefulness-promoting drug used to treat narcolepsy, obstructive sleep apnoea, and shift-work sleep disorder. Modafinil has also been used for the treatment of fatigue and excessive sleepiness in other neurological disorders including multiple sclerosis, psychiatric disorders, and for cognitive enhancement. Recent preclinical studies suggest a potential neuroprotective effect of modafinil in neurodegenerative diseases. Therefore, we investigated its neuroprotective potential in multiple sclerosis. Objective: To retrospectively assess disease progression in a group of MS patients that had received treatment with modafinil, and a matched group that received no treatment with modafinil. Methods: We assessed the expanded disability status scale (EDSS) score change, over at least three years, in 30 patients with MS treated with modafinil, and in 90 patients who did not receive modafinil. The two groups were matched for initial EDSS, age, sex, type of disease, disease duration, duration of follow-up, and concomitant disease modifying therapies. Statistical analysis was performed using a general linear regression model. Results: In relapsing-remitting (RR) patients treated with modafinil there was no significant EDSS change over the follow-up period. In RR patients not treated with modafinil, the mean EDSS increased significantly (0.94; p=0.0001) over the follow-up period. Independent of modafinil treatment status, our model indicated an additional mean EDSS increase of 1.1 point (p=0.0002) for progressive patients i.e. mean EDSS change was 1.1 point for modafinil treated, and 1.10.94=2.04 points for modafinil-untreated patients. Conclusion: Our results support the hypothesis that modafinil has neuroprotective potential, and may play a role in the treatment of multiple sclerosis. A prospective study will need to confirm this finding. © 2012 Elsevier B.V.

Background Multiple sclerosis (MS) is a disease with profound heterogeneity in clinical course. Objective To analyze sources and levels of income among MS patients in relation to disease phenotype with a special focus on identifying differences/similarities between primary progressive MS (PPMS) and secondary progressive MS (SPMS). Methods A total of 6890 MS patients aged 21−64 years and living in Sweden in 2010 were identified for this cross-sectional study. Descriptive statistics, logistic, truncated linear, and zero-inflated negative binomial regression models were used to estimate differences in income between SPMS, PPMS and relapsing-remitting MS (RRMS) patients. Results RRMS patients earned almost twice as much as PPMS and SPMS patients (on average SEK 204,500, SEK 114,500, and SEK 79,800 in 2010, respectively). The difference in earnings between PPMS and SPMS was not statistically significant when analyzed with multivariable regression. The estimated odds ratio for PPMS patients to have income from earnings was not significantly different from SPMS patients (95% CI 0.98 to 1.59). PPMS and RRMS patients were less likely to receive benefits when compared to SPMS patients (by 6% and 27% lower, respectively). Conclusion Our findings argue for similarities between PPMS and SPMS and highlight the socioeconomic importance of preventing RRMS patients convert to SPMS.

Multiple sclerosis (MS) is a leading cause of disability among young adults and has a significant economic impact on society. Although MS is not currently a curable disease, costly treatments known as disease-modifying therapies (DMTs) are available to reduce the disease impact in certain types of MS. In the current economic downturn, cost-effectiveness analysis (CEA) of therapies in MS has become an important part of the decision-making process in order to use resources efficiently in the face of the rapidly escalating costs of MS. While some studies have reported costs of DMTs at the level of cost-effectiveness thresholds, some have estimated their costs beyond the tolerance level of health care systems. On the basis of the current literature and given the difficulties in accurately assessing cost-effectiveness in diseases like MS, it is challenging to determine whether DMTs are cost-effective. Further population-based studies are required regarding the cost-effectiveness of therapies in MS.

Objective To determine if comorbid asthma is associated with accumulation of multiple sclerosis (MS)-related impairment and disability. Method We sent a comprehensive questionnaire to a cohort of patients with MS and examined the association between comorbid asthma and reaching Expanded Disability Status Scale (EDSS) scores 4.0 and 6.0. Multiple Sclerosis Impact Scale (MSIS-29) scores were compared between patients with MS with and without comorbid asthma. Results 680 patients participated in our study of whom 88 (12.9%) had comorbid asthma. There was no difference in the prevalence of asthma between our MS cohort and the England general population (OR: 0.89, 95% CI 0.68 to 1.17). We did not observe a significant association between having asthma and the risk of reaching EDSS scores 4.0 and 6.0 (HR: 1.29, 95% CI 0.93 to 1.77, and HR: 1.33, 95% CI 0.93 to 1.89, respectively) after controlling for confounders. Patients with MS with asthma reported higher level of psychological impairments (coefficient: 2.29, 95% CI 0.1 to 4.49). Conclusions Asthma is a prevalent condition among patients with MS and it may contribute to the psychological impairment in MS. Although we did not observe significant association between comorbid asthma and physical disability in MS, it seems that the two conditions influence one another.

Since its first comprehensive clinico-pathological description by Charcot, Multiple sclerosis (MS) has remained a mysterious clinical entity and has represented a fascination to scientists and clinicians of the most diverse disciplines. With an incompletely known pathogenesis and aetiology, it has given rise to numerous theories including the more plausible ones of infection, autoimmunity and primary neurodegenerative disease to the more daring ones of vascular disease, psychological abnormality or even neurocristopathy.

Smoking tobacco is a well-established risk factor for multiple sclerosis (MS), a chronic inflammatory disorder of the central nervous system usually characterized by bouts and remissions and typically followed by a secondary progressive (SP) course. However, it is not clear whether smoking after diagnosis is detrimental.To determine whether smoking after MS diagnosis is associated with a change in time to SP disease.Cross-sectional study of patients with prevalent MS who smoked at diagnosis (n = 728) taken from the Genes and Environment in Multiple Sclerosis Study, which consists of patients from the Swedish National MS Registry. The study entrance date was at time of first-year smoking. The study was conducted between November 2008 and December 2011, with patient environmental data collected from November 2009 to March 2011 via questionnaire. Study participants were from all counties in Sweden diagnosed as having MS at the time of the Genes and Environment in Multiple Sclerosis Study and registered in the Swedish National MS Registry. Patients with MS with relapsing-remitting disease course or SP were included. These patients' conditions were diagnosed according to the McDonald criteria and the patients responded to recruitment letters with detailed questionnaires.Smoking, considered yearly after diagnosis and combined into a time-invariant covariate before diagnosis.Time to SPMS, measured using an accelerated failure time model, with smoking as a time-varying covariate. Other covariates included sex, age at diagnosis, snuff use, and smoking before diagnosis.The optimized model illustrated that each additional year of smoking after diagnosis accelerated the time to conversion to SPMS by 4.7% (acceleration factor, 1.047; 95% CI, 1.023-1.072; P .001). Kaplan-Meier plots demonstrated that those who continued to smoke continuously each year after diagnosis converted to SPMS faster than those who quit smoking, reaching SP disease at 48 and 56 years of age, respectively.This study provides evidence that continued smoking is associated with an acceleration in time to SPMS and that those who quit fare better. Therefore, we propose that patients with MS should be advised to stop smoking once a diagnosis has been made, not only to lessen risks for comorbidities, but also to avoid aggravating MS-related disability.