Premorbid Sociodemographic Status and Multiple Sclerosis Outcomes in a Universal Health Care Context

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

Similar familial risk in multiple sclerosis subgroups Introduction

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Prevalence of a history of prior varicella/herpes zoster infection in multiple sclerosis

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

Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study

Background: Serum neurofilament light chain (sNfL) is a biomarker of neuronal damage that is used not only to monitor disease activity and response to drugs and to prognosticate disease course in people with multiple sclerosis on the group level. The absence of representative reference values to correct for physiological age-dependent increases in sNfL has limited the diagnostic use of this biomarker at an individual level. We aimed to assess the applicability of sNfL for identification of people at risk for future disease activity by establishing a reference database to derive reference values corrected for age and body-mass index (BMI). Furthermore, we used the reference database to test the suitability of sNfL as an endpoint for group-level comparison of effectiveness across disease-modifying therapies. Methods: For derivation of a reference database of sNfL values, a control group was created, comprising participants with no evidence of CNS disease taking part in four cohort studies in Europe and North America. We modelled the distribution of sNfL concentrations in function of physiological age-related increase and BMI-dependent modulation, to derive percentile and Z score values from this reference database, via a generalised additive model for location, scale, and shape. We tested the reference database in participants with multiple sclerosis in the Swiss Multiple Sclerosis Cohort (SMSC). We compared the association of sNfL Z scores with clinical and MRI characteristics recorded longitudinally to ascertain their respective disease prognostic capacity. We validated these findings in an independent sample of individuals with multiple sclerosis who were followed up in the Swedish Multiple Sclerosis registry. Findings: We obtained 10 133 blood samples from 5390 people (median samples per patient 1 [IQR 1–2] in the control group). In the control group, sNfL concentrations rose exponentially with age and at a steeper increased rate after approximately 50 years of age. We obtained 7769 samples from 1313 people (median samples per person 6·0 [IQR 3·0–8·0]). In people with multiple sclerosis from the SMSC, sNfL percentiles and Z scores indicated a gradually increased risk for future acute (eg, relapse and lesion formation) and chronic (disability worsening) disease activity. A sNfL Z score above 1·5 was associated with an increased risk of future clinical or MRI disease activity in all people with multiple sclerosis (odds ratio 3·15, 95% CI 2·35–4·23; p<0·0001) and in people considered stable with no evidence of disease activity (2·66, 1·08–6·55; p=0·034). Increased Z scores outperformed absolute raw sNfL cutoff values for diagnostic accuracy. At the group level, the longitudinal course of sNfL Z score values in people with multiple sclerosis from the SMSC decreased to those seen in the control group with use of monoclonal antibodies (ie, alemtuzumab, natalizumab, ocrelizumab, and rituximab) and, to a lesser extent, oral therapies (ie, dimethyl fumarate, fingolimod, siponimod, and teriflunomide). However, longitudinal sNfL Z scores remained elevated with platform compounds (interferons and glatiramer acetate; p<0·0001 for the interaction term between treatment category and treatment duration). Results were fully supported in the validation cohort (n=4341) from the Swedish Multiple Sclerosis registry. Interpretation: The use of sNfL percentiles and Z scores allows for identification of individual people with multiple sclerosis at risk for a detrimental disease course and suboptimal therapy response beyond clinical and MRI measures, specifically in people with disease activity-free status. Additionally, sNfL might be used as an endpoint for comparing effectiveness across drug classes in pragmatic trials. Funding: Swiss National Science Foundation, Progressive Multiple Sclerosis Alliance, Biogen, Celgene, Novartis, Roche

Proportion and characteristics of secondary progressive multiple sclerosis in five European registries using objective classifiers

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.</p

Changes in the risk of reaching multiple sclerosis disability milestones in recent decades: A nationwide population-based cohort study in sweden

Importance: Clinicians' experience and findings from recent natural history studies suggest that multiple sclerosis (MS) may now be running a more slowly progressing course than before. Objective: To investigate whether the risk of reaching MS disability milestones has changed over the last decade in Sweden. Design, Setting, and Participants: A nationwide population-based retrospective cohort study. By April 2017, 12512 patients with available information on demographics, MS phenotype, and date of MS onset and diagnosis were registered in the Swedish MS Registry of which 7331 patients with at least 2 recorded Expanded Disability Status Scale scores (EDSS) and diagnosed between January 1995 and December 2010 were included. No further exclusion criteria were applied. Patients were followed up until December 2016 with a median duration follow-up of 8.5 (interquartile range, 4.7-13.8) years. Statistical analysis began in April 2017. Main Outcomes and Measures: Patients were followed up from MS onset date to the date of sustained EDSS 3.0, 4.0, and 6.0. To handle interval-censored observations, a Weibull model was fit, and the change in the risk of EDSS 3.0, 4.0, and 6.0 over calendar years was estimated and hazard ratios (HRs) with corresponding CIs were calculated. Results: Of 7331 patients, 5196 (70.9%) were women, and the mean (SD) age at diagnosis was 38.3 (11.7) years. Adjusting for sex, number of clinic visits, diagnostic delay, and onset age, a 3% decrease per calendar year of diagnosis for the risk of sustained EDSS 3.0 (HR, 0.97; 95% CI, 0.96-0.97), a 6% decrease for the risk of EDSS 4.0 (HR, 0.94; 95% CI, 0.93-0.95), and a 7% decrease for the risk of EDSS 6.0 (HR, 0.93; 95% CI, 0.91-0.94) among patients with relapsing-onset MS was found. The trends were not significant for patients with progressive-onset MS (EDSS 3.0: HR, 1.01; 95% CI, 0.98-1.03; EDSS 4.0: HR, 1.00; 95% CI, 0.98-1.02; EDSS 6.0: HR, 1.00; 95% CI, 0.98-1.02). Conclusions and Relevance: Risk of reaching major disability milestones has significantly decreased over the last decade in patients with relapsing-onset MS in Sweden. Several factors could potentially be responsible for this observation. However, given that no change was seen in disability accrual of patients with progressive-onset MS and the absence of efficacious treatment option in this group, increased use of more efficacious disease-modifying treatments could be a possible driver of this change

Reduced EDSS progression in multiple sclerosis patients treated with modafinil for three years or more compared to matched untreated subjects

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

Smoking and worsening disability in multiple sclerosis: A meta-analysis

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. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Lt

Smoking and worsening disability in multiple sclerosis: A meta-analysis

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. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Lt