Publications by authors named "Jan Hillert"

228 Publications

High antibody levels against human herpesvirus-6A interact with lifestyle factors in multiple sclerosis development.

Mult Scler 2021 Jun 14:13524585211022011. Epub 2021 Jun 14.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Background: Infection with human herpesvirus 6A (HHV-6A) has been suggested to increase multiple sclerosis (MS) risk. However, potential interactions between HHV-6A and environmental/lifestyle risk factors for MS have not previously been studied.

Methods: We used two Swedish population-based case-control studies comprising 5993 cases and 5995 controls. Using logistic regression models, subjects with different HHV-6A antibody levels, environmental exposures, and lifestyle habits were compared regarding MS risk, by calculating odds ratios (ORs) with 95% confidence intervals (CIs). Potential interactions between high HHV-6A antibody levels and common environmental exposures and lifestyle factors were evaluated on the additive scale.

Results: High HHV-6A antibody levels were associated with increased risk of developing MS (OR = 1.5, 95% CI = 1.4-1.6). Regarding MS risk, significant interactions were observed between high HHV-6A antibody levels and both smoking (attributable proportion (AP) = 0.2, 95% CI = 0.1-0.3), low ultraviolet radiation (UVR) exposure (AP = 0.3, 95% CI = 0.1-0.4), and low vitamin D levels (AP = 0.3, 95% CI = 0.0-0.6).

Conclusion: High HHV-6A antibody levels are associated with increased MS risk and act synergistically with common environmental/lifestyle risk factors for MS. Further research is needed to investigate potential mechanisms underlying the interactions presented in this study.
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http://dx.doi.org/10.1177/13524585211022011DOI Listing
June 2021

A comparative study of teriflunomide and dimethyl fumarate within the Swedish MS Registry.

Mult Scler 2021 Jun 3:13524585211019649. Epub 2021 Jun 3.

Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.

Background: Teriflunomide and dimethyl fumarate (DMF) are first-line disease-modifying treatments for multiple sclerosis with similar labels that are used in comparable populations.

Objectives: The objective of this study was to compare the effectiveness and persistence of teriflunomide and DMF in a Swedish real-world setting.

Methods: All relapsing-remitting multiple sclerosis (RRMS) patients in the Swedish MS registry initiating teriflunomide or DMF were included in the analysis. The primary endpoint was treatment persistence. Propensity score matching was used to adjust comparisons for baseline confounders.

Results: A total of 353 teriflunomide patients were successfully matched to 353 DMF. There was no difference in the rate of overall treatment discontinuation by treatment group across the entire observation period (hazard ratio (HR) = 1.12; 95% confidence interval (CI) = 0.91-1.39; = 0.277; reference = teriflunomide). Annualised relapse rate (ARR) was comparable ( = 0.237) between DMF (0.07; 95% CI = 0.05-0.10) and teriflunomide (0.09; 95% CI = 0.07-0.12). There was no difference in time to first on-treatment relapse (HR = 0.78; 95% CI = 0.50-1.21), disability progression (HR = 0.55; 95% CI = 0.27-1.12) or confirmed improvement (HR = 1.17; 95% CI = 0.57-2.36).

Conclusion: This population-based real-world study reports similarities in treatment persistence, clinical effectiveness and quality of life outcomes between teriflunomide and dimethyl fumarate.
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http://dx.doi.org/10.1177/13524585211019649DOI Listing
June 2021

Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.

Nat Genet 2021 Jun 17;53(6):817-829. Epub 2021 May 17.

Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
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http://dx.doi.org/10.1038/s41588-021-00857-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192451PMC
June 2021

Factors affecting the risk of relapsing-onset and progressive-onset multiple sclerosis.

J Neurol Neurosurg Psychiatry 2021 May 13. Epub 2021 May 13.

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Objective: It has been debated whether the different clinical disease courses in multiple sclerosis (MS) are the consequence of different pathogenic mechanisms, with distinct risk factors, or if all MS clinical phenotypes are variations of similar underlying disease mechanisms. We aimed to study environmental risk factors and their interactions with human leucocyte antigen DRB1*15:01 with regards to relapsing-onset and progressive-onset MS.

Methods: We used two Swedish population-based case-control studies, including 7520 relapsing-onset cases, 540 progressive-onset cases and 11 386 controls matched by age, sex and residential area. Logistic regression was used to estimate ORs with 95% CIs for associations between the different MS phenotypes and a number of environmental and lifestyle factors. Interaction between the DRB1*15:01 allele and environmental risk factors was evaluated on the additive scale.

Results: All environmental and lifestyle factors associated with risk of developing MS apply to both relapsing-onset and progressive-onset disease. Smoking, obesity and Epstein-Barr virus nuclear antigen-1 (EBNA-1) antibody levels were associated with increased risk of both MS phenotypes, whereas snuff use, alcohol consumption and sun exposure were associated with reduced risk. Additive interactions between DRB1*15:01 and smoking, obesity, EBNA-1 antibody levels and sun exposure, respectively, occurred to increase MS risk regardless of the clinical phenotype.

Interpretation: Our finding that the same environmental and lifestyle factors affect both relapsing-onset and progressive-onset MS supports the notion that the different clinical phenotypes share common underlying disease mechanisms.
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http://dx.doi.org/10.1136/jnnp-2020-325688DOI Listing
May 2021

Cost-of-Illness Progression Before and After Diagnosis of Multiple Sclerosis: A Nationwide Register-Based Cohort Study in Sweden of People Newly Diagnosed with Multiple Sclerosis and a Population-Based Matched Reference Group.

Pharmacoeconomics 2021 Jul 10;39(7):835-851. Epub 2021 May 10.

Division of Insurance Medicine, Department of Clinical Neuroscience, Karolinska Institutet, 171-77, Stockholm, Sweden.

Background: Multiple sclerosis (MS) is a chronic disease associated with increased healthcare utilisation and productivity losses.

Objective: The objective of this study was to explore the progression of healthcare costs and productivity losses before and after diagnosis of MS in comparison to that of a population-based matched reference group.

Methods: We conducted a nationwide, Swedish register-based cohort study of working-aged people with MS diagnosed in 2010-12 (n = 1988) and population-based matched references without MS (n = 7981). Nine years of observation spanned from 4 years prior (Y) to 4 years (Y) after the year of diagnosis (Y). Differences in annual all-cause healthcare costs (inpatient and specialised outpatient healthcare as well as pharmacy-dispensed prescribed drugs) and costs of productivity loss (days with sickness absence and disability pension) were estimated between the people with MS and references using t tests with 95% confidence intervals. The average excess costs of MS were estimated using generalised estimating equation models.

Results: People with multiple sclerosis had higher costs before the diagnosis of MS and also thereafter. The mean differences in healthcare costs and productivity losses between the people with MS and matched references in Y were 216 EUR (95% confidence interval 58-374) and 1540 EUR (95% confidence interval 848-2233), with larger cost excesses observed in later study years. Summarising the 9 study years, people with MS had fivefold higher excess healthcare costs than references, and more than twice as high productivity losses.

Conclusions: Excess healthcare costs and productivity losses occur already before the diagnosis of MS and increase with time. The excess costs findings before diagnosis could suggest that an earlier diagnosis might lead to reduced excess costs of MS over time.
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http://dx.doi.org/10.1007/s40273-021-01035-4DOI Listing
July 2021

Early treatment delays long-term disability accrual in RRMS: Results from the BMSD network.

Mult Scler 2021 Apr 26:13524585211010128. Epub 2021 Apr 26.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, Bari, Italy.

Background: The optimal timing of treatment starts for achieving the best control on the long-term disability accumulation in multiple sclerosis (MS) is still to be defined.

Objective: The aim of this study was to estimate the optimal time to start disease-modifying therapies (DMTs) to prevent the long-term disability accumulation in MS, using a pooled dataset from the Big Multiple Sclerosis Data (BMSD) network.

Methods: Multivariable Cox regression models adjusted for the time to first treatment start from disease onset (in quintiles) were used. To mitigate the impact of potential biases, a set of pairwise propensity score (PS)-matched analyses were performed. The first quintile, including patients treated within 1.2 years from onset, was used as reference.

Results: A cohort of 11,871 patients (median follow-up after treatment start: 13.2 years) was analyzed. A 3- and 12-month confirmed disability worsening event and irreversible Expanded Disability Status Scale (EDSS) 4.0 and 6.0 scores were reached by 7062 (59.5%), 4138 (34.9%), 3209 (31.1%), and 1909 (16.5%) patients, respectively. The risk of reaching all the disability outcomes was significantly lower ( < 0.0004) for the first quintile patients' group.

Conclusion: Real-world data from the BMSD demonstrate that DMTs should be commenced within 1.2 years from the disease onset to reduce the risk of disability accumulation over the long term.
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http://dx.doi.org/10.1177/13524585211010128DOI Listing
April 2021

Treatment Switching and Discontinuation Over 20 Years in the Big Multiple Sclerosis Data Network.

Front Neurol 2021 17;12:647811. Epub 2021 Mar 17.

Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.

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. 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. 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. 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.
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http://dx.doi.org/10.3389/fneur.2021.647811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010264PMC
March 2021

Bariatric and metabolic surgery in patients with morbid obesity and multiple sclerosis - a nationwide, matched cohort study.

Surg Obes Relat Dis 2021 Jun 17;17(6):1108-1114. Epub 2021 Feb 17.

Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.

Background: Despite an association between obesity and multiple sclerosis (MS), very little is known regarding the safety and efficacy outcomes for patients with MS and severe obesity undergoing metabolic surgery.

Objectives: The aim of the present study was to evaluate early complications and efficacy outcomes of metabolic surgery in patients with severe obesity and MS.

Setting: Nationwide, Sweden.

Methods: In this, matched cohort study, 196 patients with an MS diagnosis in the Swedish MS register who were undergoing metabolic surgery (gastric bypass or sleeve gastrectomy) with a registration in the Scandinavian Obesity Surgery Registry (SOReg) were matched 1:10 with a control group without MS diagnosis from the SOReg. A 2-stage matching procedure was used (exact match by surgical method, followed by propensity Score matching, including age, sex, preoperative BMI, surgical center, surgical access, year of surgery, hypertension, diabetes, sleep apnea, and dyslipidemia).

Results: Weight loss at 2 years after surgery was similar for patients with MS and controls (total weight loss 31.6 ± 9.1 versus 31.8 ± 9.2, P = .735). No significant differences were seen in either the overall postoperative complication rate (7.9% versus 7.2%, P = .778), or serious postoperative complications (3.7% versus 2.8%, P = .430). All aspects of health-related quality of life (HRQoL) improved in both groups but less so for the physical aspects of HRQoL in patients with MS.

Conclusion: Metabolic surgery is a safe and efficient treatment for severe obesity in patients with MS, and it leads to subsequent improvements in HRQoL. Further studies addressing the effects of metabolic surgery on MS-related symptoms are needed.
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http://dx.doi.org/10.1016/j.soard.2021.02.013DOI Listing
June 2021

Socioeconomic consequences of multiple sclerosis-A systematic literature review.

Acta Neurol Scand 2021 Jun 22;143(6):587-601. Epub 2021 Mar 22.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Multiple sclerosis (MS) is a challenging and disabling condition, predominantly affecting individuals in their early life, and has an impact functionally, financially, and on quality of life. However, there is a lack of systematic approach towards assessing socioeconomic consequences of MS. Our objective was to systematically review observational analytical studies investigating the socioeconomic consequences of MS. We conducted a systematic review on socioeconomic consequences of MS with a focus on employment-, income-, work ability- and relationship-related outcomes between MS and the general population. Additionally, the educational characteristics were extracted. From 4958 studies identified, 187 were assessed for eligibility and a total of 27 studies from eight countries were included in this qualitative assessment; 32 different outcomes were identified. All studies indicated pronounced differences between MS patients and the general population, for example 15%-30% lower employment, lower earnings and higher social benefits, higher absenteeism and presenteeism proportions, higher work disability (eg, sick-leave days) among MS patients. Some studies also indicated differences in the family or relationship characteristics. There were no apparent differences with regard to educational level. In conclusion, socioeconomic data can serve as robust outcome measures to study various aspects of MS reflecting the broader consequences of the disease.
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http://dx.doi.org/10.1111/ane.13411DOI Listing
June 2021

DRB1-environment interactions in multiple sclerosis etiology: results from two Swedish case-control studies.

J Neurol Neurosurg Psychiatry 2021 Jul 9;92(7):717-722. Epub 2021 Mar 9.

Karolinska Institute, Stockholm, Sweden.

Objective: We aimed to investigate the influence of environmental risk factors for multiple sclerosis (MS) in different genetic contexts, and study if interactions between environmental factors and human leucocyte antigen (HLA) genes differ in magnitude according to heterozygocity and homozygocity for .

Methods: Using population-based case-control studies (6985 cases, 6569 controls), subjects with different genotypes and smoking, EBNA-1 status and adolescent Body Mass status, were compared regarding MS risk, by calculating OR with 95% CI employing logistic regression. The interaction between different genotypes and each environmental factor was evaluated on the additive scale.

Results: The effect of each allele on MS risk was additive on the log-odds scale for each additional allele. Interaction between and each assessed environmental factor was of similar magnitude regardless of the number of alleles, although ORs were affected. When any of the environmental factors were present in carriers without the protective allele, a three-way interaction occurred and rendered high ORs, especially among homozygotes (OR 20.0, 95% CI 13.1 to 30.5 among smokers, OR 21.9, 95% CI 15.0 to 31.8 among those with elevated EBNA-1 antibody levels, and OR 44.3, 95% CI 13.5 to 145 among those who reported adolescent overweight/obesity).

Conclusions: The strikingly increased MS risk among homozygotes exposed to any of the environmental factors is a further argument in favour of these factors acting on immune-related mechanisms. The data further reinforce the importance of preventive measures, in particular for those with a genetic susceptibility to MS.
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http://dx.doi.org/10.1136/jnnp-2020-325676DOI Listing
July 2021

Long-term Socioeconomic Outcomes Associated With Pediatric-Onset Multiple Sclerosis.

JAMA Neurol 2021 Apr;78(4):478-482

Neuro Division, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Importance: Pediatric-onset multiple sclerosis (PoMS) is associated with significant cognitive and physical disability. Whether this disability translates into differences in educational achievements and earnings is unknown.

Objective: To evaluate the association between PoMS and educational level and income throughout adulthood.

Design, Setting, And Participants: A prospective register-based cohort study of individuals with PoMS and a population-based matched reference cohort was conducted using nationwide microdata from linked registers in Sweden from January 1, 1990, to December 31, 2016; analyses were completed from May 1, 2019, to September 1, 2020. Of 772 persons with PoMS identified in the Swedish MS registry, 485 had an onset during the period from 1980 to 2014 and had socioeconomic data available. The general population reference cohort without multiple sclerosis (MS) (n = 4850) was randomly selected from the full Swedish population, matched 10:1 on age, sex, and country of birth.

Exposure: Pediatric-onset MS, diagnosed by a neurologist, with onset before 18 years of age.

Main Outcomes And Measures: Highest educational level (elementary school, high school, or university) was assessed using logistic regression. Income, measured as the mean annual earnings from paid work in US dollars, was compared using Tobit models, and net annual sickness absence and disability pension days were compared using zero-inflated negative binomial regression. Earnings and days receiving disability benefits were compared within 4 age periods (19-24, 25-34, 35-44, and 45-54 years).

Results: The median age of the cohort with PoMS (n = 485) and the matched reference cohort (n = 4850) in 2016 was 32 years (interquartile range, 26-40 years), and most participants were women (348 [71.8%] in the PoMS cohort and 3480 [71.8%] in the matched reference cohort). Persons with PoMS were less likely than persons in the matched reference cohort to attend university (odds ratio, 0.80 [95% CI, 0.66-0.97]) and had significantly lower annual earnings than the reference cohort, ranging from -$1618 (95% CI, -$2558 to -$678) in the youngest age period to -$10 683 (95% CI, -$18 187 to -$3178) in the eldest. Persons with PoMS received higher rates of disability benefits, as sickness absence days in the youngest age period (rate ratio, 3.06 [95% CI, 2.08-4.52]) and disability pension days in the oldest age period (rate ratio, 1.43 [95% CI, 1.11-1.85]).

Conclusions And Relevance: This study suggests that having PoMS is associated with less educational achievement, lower earnings, and greater use of disability benefits throughout the working-age life span. As adults, persons with PoMS never earned as much as their counterparts without MS, and they exhibited a heavier reliance on disability benefits.
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http://dx.doi.org/10.1001/jamaneurol.2020.5520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900935PMC
April 2021

Depression and multiple sclerosis: A bidirectional Mendelian randomisation study.

Mult Scler 2021 Feb 19:1352458521996601. Epub 2021 Feb 19.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden/The Karolinska Neuroimmunology and Multiple Sclerosis Centre, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1177/1352458521996601DOI Listing
February 2021

A multiple sclerosis disease progression measure based on cumulative disability.

Mult Scler 2021 Jan 25:1352458520988632. Epub 2021 Jan 25.

Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden/Department of Mathematics, The Royal Institute of Technology, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1177/1352458520988632DOI Listing
January 2021

Overweight/obesity in young adulthood interacts with aspects of EBV infection in MS etiology.

Neurol Neuroimmunol Neuroinflamm 2021 01 15;8(1). Epub 2020 Dec 15.

From the Department of Clinical Neuroscience (A.K.H., J.H., T.O., L.A.), Karolinska Institutet, Stockholm, Sweden; Infections and Cancer Epidemiology (N.B., J.B., T.W.), German Cancer Research Center (DKFZ), Heidelberg; Center for Molecular Medicine (J.H., T.O.), Karolinska Institutet at Karolinska University Hospital, Solna, Sweden; and Institute of Environmental Medicine (L.A.), Karolinska Institutet, Stockholm, Sweden.

Objective: Because obesity affects the cellular immune response to infections, we aimed to investigate whether high body mass index (BMI) in young adulthood and high Epstein-Barr nuclear antigen 1 (EBNA-1) antibody levels interact with regard to MS risk. We also aimed at exploring potential 3-way interactions between BMI at age 20 years, aspects of Epstein-Barr virus (EBV) infection (high EBNA-1 antibody levels and infectious mononucleosis [IM] history, respectively) and the human leukocyte antigen allele.

Methods: Using Swedish population-based case-control studies (5,460 cases and 7,275 controls), we assessed MS risk in relation to interactions between overweight/obesity at age 20 years, IM history, EBNA-1 levels, and status by calculating ORs with 95% CIs using logistic regression. Potential interactions were evaluated on the additive scale.

Results: Overweight/obesity, compared with normal weight, interacted significantly with high (>50th percentile) EBNA-1 antibody levels (attributable proportion due to interaction 0.2, 95% CI 0.1-0.4). The strength of the interaction increased with higher category of EBNA-1 antibody levels. Furthermore, 3-way interactions were present between overweight/obesity at age 20 years, and each aspect of EBV infection.

Conclusions: With regard to MS risk, overweight/obesity in young adulthood acts synergistically with both aspects of EBV infection, predominantly among those with a genetic susceptibility to the disease. The obese state both induces a chronic immune-mediated inflammation and affects the cellular immune response to infections, which may contribute to explain our findings.
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http://dx.doi.org/10.1212/NXI.0000000000000912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803338PMC
January 2021

Prevalence of adverse pregnancy outcomes after exposure to interferon beta prior to or during pregnancy in women with MS: Stratification by maternal and newborn characteristics in a register-based cohort study in Finland and Sweden.

Mult Scler Relat Disord 2021 Feb 16;48:102694. Epub 2020 Dec 16.

StatFinn-EPID Research, Metsänneidonkuja 6, 02130 Espoo, Finland.

Background: Previous studies reported no increase in the prevalence of adverse pregnancy outcomes after exposure to interferon-beta (IFN-beta). However, no study has investigated if the prevalence of these outcomes after IFN-beta exposure is modified by maternal and newborn characteristics. Our objective was to describe the stratified prevalence of adverse pregnancy outcomes among women with multiple sclerosis (MS) exposed only to IFN-beta or unexposed to any MS disease modifying drugs (MSDMDs).

Methods: This population-based cohort study using Finnish (1996-2014) and Swedish (2005-2014) register data included pregnancies of women with MS exposed only to IFN-beta 6 months before or during pregnancy (n=718) or unexposed to MSDMDs (n=1397). The outcome prevalences were described stratified by maternal and newborn characteristics, with 95% confidence intervals (CIs). Confounder-adjusted analyses were performed if the prevalence results indicated modified effect of IFN-beta in specific strata.

Results: The stratified analysis indicated that the prevalence of serious (anomaly or stillbirth) and other adverse pregnancy outcomes was similar among the exposed and unexposed, with no statistically significant difference. Among women treated for MS >5 years, serious adverse pregnancy outcomes occurred in 4.3% (95%CI: 1.9-8.3%) of pregnancies exposed only to IFN-beta 6 months before or during pregnancy and in 2.7% (95%CI: 1.2-5.0%) of unexposed pregnancies. The confounder adjusted analyses did not support the hypothesis that MS treatment duration before pregnancy would modify the risk of adverse pregnancy outcomes after exposure to IFN-beta 6 months before or during pregnancy.

Conclusion: The prevalence of adverse pregnancy outcomes was not increased after IFN-beta exposure, when pregnancies of women with MS were stratified by maternal and newborn characteristics. The stratified results were similar to the unstratified results in the same population.
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http://dx.doi.org/10.1016/j.msard.2020.102694DOI Listing
February 2021

Types of working-life sequences among people recently diagnosed with multiple sclerosis in Sweden: a nationwide register-based cohort study.

BMJ Open 2020 12 29;10(12):e039228. Epub 2020 Dec 29.

Division of Insurance Medicine, Department of Clinical Neuroscience, Karolinska Institutet, 171-77 Stockholm, Sweden.

Objectives: To explore sequences of annual states of activity and sickness absence (SA) or disability pension (DP) (SA/DP) among working-aged people with multiple sclerosis (PwMS) as well as characteristics associated with the identified types of working-life sequences.

Design: Nationwide Swedish register-based cohort study from 1 year prior to 5 years after the year of multiple sclerosis (MS) diagnosis.

Setting: Sweden.

Participants: PwMS diagnosed in 2008-2011 when aged 20-55 (n=2652, 69.9% women).

Primary And Secondary Outcome Measures: Individual-level sequences spanning 7 years were constructed with annual states regarding activity (income from paid work, student allowances, parental leave or unemployment compensation) and/or SA/DP. Types of working-life sequences were identified among the individuals' sequences using hierarchical cluster analysis with optimal matching dissimilarity measures.

Results: Six types of working-life sequences were identified. The largest cluster, Stable High Activity, represented 48.4% of the cohort. Other types were: Stable High SA/DP (14.5%); Other (4.5%); and three types with mixed activity and varying SA/DP regarding the number of days/year and timing (32.6%). Characteristics of the different identified types of sequences were subsequently investigated. All types of sequences had lower odds for university education (OR range: 0.18-0.72) compared with Stable High Activity. Increasingly higher odds of having anxiety/depression compared with Stable High Activity were observed across the types of sequences, by increasing proportions of SA/DP. Stable High SA/DP sequences were less likely than Stable High Activity to be prescribed MS drugs in the MS diagnosis year (OR 0.61; 95% CI 0.47 to 0.78). All types of sequences had higher disposable income in the final study year than the first, except for Stable High SA/DP sequences (Swedish Krona 4669, 95% CI -1892 to 11 230).

Conclusions: Diversity in working life was influenced by sociodemographic and clinical characteristics resulting in different activity and SA/DP patterns across the six identified types of working-life sequences.
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http://dx.doi.org/10.1136/bmjopen-2020-039228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778766PMC
December 2020

Accurate classification of secondary progression in multiple sclerosis using a decision tree.

Mult Scler 2020 Dec 2:1352458520975323. Epub 2020 Dec 2.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden/The Karolinska Neuroimmunology & Multiple Sclerosis Centre, Centre for Molecular Medicine (CMM), Karolinska Institutet, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1177/1352458520975323DOI Listing
December 2020

Long-Term Consequences of High Titer Neutralizing Antibodies to Interferon-β in Multiple Sclerosis.

Front Immunol 2020 15;11:583560. Epub 2020 Oct 15.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Background: Neutralizing anti-drug antibodies (NAbs) to interferon beta (IFNβ) develop in up to 47% of multiple sclerosis (MS) treated patients inhibiting treatment effect of IFNβ. However, the long-term effect of NAbs remain unknown.

Objective: To investigate the long-term consequences of high titer NAbs to IFNβ on disease activity and progression in MS patients.

Methods: An observational study including data from all IFNβ treated relapsing remitting MS patients with sufficient NAb test results from the Swedish MS registry. Patients were classified into either confirmed 'high titer' or 'persistent negative' groups and analyzed for differences in disease activity and progression over time.

Results: A total of 197 high-titer and 2907 persistent negative patients with 19969.6 follow up years of data were included. High titer NAbs were associated with a higher degree of disease activity at baseline. However, even when accounting for this, the presence of high titer NAbs were also associated with higher disease activity during IFNβ treatment. This persisted even after the next DMT start, suggesting that earlier high titers may partially reduce the effect of later treatments. No difference was found in confirmed disability progression.

Conclusion: High titer NAbs to IFNβ are associated with higher disease activity, persisting even after IFNβ discontinuation or switch. These results support use of highly efficient treatment earlier in patients with active disease, to avoid these complications.
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http://dx.doi.org/10.3389/fimmu.2020.583560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593513PMC
June 2021

Cost-of-illness trajectories among people with multiple sclerosis by comorbidity: A register-based prospective study in Sweden.

Mult Scler J Exp Transl Clin 2020 Oct-Dec;6(4):2055217320968597. Epub 2020 Oct 23.

Division of Insurance Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Background: Comorbidities are common among people with multiple sclerosis (PwMS); yet, their impact on the cost-of-illness (COI) in MS is unknown.

Objective: Explore the heterogeneity in COI trajectories among newly diagnosed PwMS in relation to type of comorbidity.

Methods: A nationwide longitudinal cohort study, using prospectively collected Swedish register data for seven years. The COI/year of 639 PwMS diagnosed in 2006, when aged 25-60, was estimated until 2013. Using healthcare data, PwMS were categorised into six comorbidity groups: ocular; cardiovascular, genitourinary or cancer disease; musculoskeletal; mental; neurological other than MS; and injuries. One group of PwMS without comorbidity was also created. Group-based trajectory modelling was applied, examining different COI trajectories within each comorbidity group.

Results: Across the seven follow-up years, PwMS with mental comorbidities had the highest COI overall (€36,482). Four COI trajectories were identified within each comorbidity group; the largest trajectory had high healthcare costs and productivity losses (36.3%-59.6% of PwMS, across all comorbidity groups). 59.6% of PwMS with mental comorbidity had high healthcare costs and productivity losses.

Conclusion: High COI and heterogeneity in COI trajectories could be partly explained by the presence of chronic comorbidities in the year around MS diagnosis, including the presence of mental comorbidity.
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http://dx.doi.org/10.1177/2055217320968597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585903PMC
October 2020

Importance of early treatment decisions on future income of multiple sclerosis patients.

Mult Scler J Exp Transl Clin 2020 Oct-Dec;6(4):2055217320959116. Epub 2020 Oct 7.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1177/2055217320959116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564625PMC
October 2020

Pregnancy outcomes after exposure to interferon beta: a register-based cohort study among women with MS in Finland and Sweden.

Ther Adv Neurol Disord 2020 7;13:1756286420951072. Epub 2020 Oct 7.

StatFinn & EPID Research, Espoo, Finland.

Background: Our aim was to estimate and compare the prevalence of adverse pregnancy outcomes among pregnant women with multiple sclerosis (MS) exposed to interferon beta (IFNB) and among women with MS unexposed to any MS disease-modifying drug (MSDMD).

Methods: This cohort study used Finnish (1996-2014) and Swedish (2005-2014) national register data. Women with MS having IFNB dispensed 6 months before or during pregnancy as the only medication were considered as IFNB exposed (only IFNB-exposed), whereas women with MS unexposed to any MSDMD were considered unexposed (MSDMD-unexposed). Prevalence was described and compared using log-binomial or logistic regression and adjusted for potential confounders including maternal age and comorbidity.

Results: Among 2831 pregnancies, 2.2% of the only IFNB-exposed and 4.0% of the MSDMD-unexposed women had serious adverse pregnancy outcomes [elective termination of pregnancy due to foetal anomaly (TOPFA), major congenital anomaly (MCA) in live, or stillbirth]. After adjustments, the prevalence of serious adverse pregnancy outcomes was lower among the only IFNB-exposed compared with the MSDMD-unexposed [relative risk 0.55, 95% confidence interval (CI) 0.31-0.96]. The prevalence of individual outcomes, including MCA, spontaneous abortions, and stillbirths was not increased with IFNB exposure. Women with MS exposed to IFNB appeared more likely to terminate their pregnancy for reasons other than foetal anomaly, compared with MSDMD-unexposed pregnant MS patients (odds ratio 1.71, 95% CI 1.06-2.78).

Conclusion: In this large cohort study, no increase in the prevalence of adverse pregnancy outcomes was observed in women with MS exposed to IFNB compared with MS patients unexposed to any MSDMDs. This study together with other evidence led to a change in the labels of the IFNB products in September 2019 in the European Union, and IFNB use today may be considered during pregnancy, if clinically needed.
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http://dx.doi.org/10.1177/1756286420951072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549181PMC
October 2020

The DQB103:02 Genotype and Treatment for Pain in People With and Without Multiple Sclerosis.

Front Neurol 2020 4;11:993. Epub 2020 Sep 4.

Department of Medicine Solna, Centre for Pharmacoepidemiology, Karolinska Institutet, Solna, Sweden.

Murine models have demonstrated that the major histocompatibility complex (MHC) is associated with pain-like behavior in peripheral nerve injury, however, the same association has not been shown when considering injury to the central nervous system (CNS), which more closely mimics the damage to the CNS experienced by MS patients. Previous research has indicated the DQB103:02 allele of the class II HLA genes as being associated with development of neuropathic pain in persons undergoing inguinal hernia surgery or with lumbar spinal disk herniation. Whether this HLA allele plays a part in susceptibility to pain, has not, as far as we are aware, been previously investigated. This study utilizes information on DQB103:02 alleles as part of the EIMS, GEMS, and IMSE studies in Sweden. It also uses register data for 3,877 MS patients, and 4,548 matched comparators without MS, to assess whether the DQB103:02 allele is associated with prescribed pain medication use, and whether associations with this genotype differ depending on MS status. Our results showed no association between the DQB103:02 genotype and pain medication in MS patients, with an adjusted odds ratio (OR) of 1.02 (95% CI 0.85-1.24). In contrast, there was a statistically significant association of low magnitude in individuals without MS [adjusted OR 1.18 (95% CI 1.03-1.35)], which provides support for HLA influence on susceptibility to pain in the general population. Additionally, the effect of zygosity was evident for the non-MS cohort, but not among MS patients, suggesting the DQB103:02 allele effect is modified by the presence of MS.
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http://dx.doi.org/10.3389/fneur.2020.00993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500133PMC
September 2020

Cigarette smoking patterns preceding primary Sjögren's syndrome.

RMD Open 2020 Sep;6(3)

Division of Rheumatology, Department of Medicine Solna, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden

Background: Cigarette smoking is a well-established risk factor for several autoimmune diseases, but its role in primary Sjögren's syndrome (pSS) remains unclear. Here, we investigated the association between cigarette smoking and subsequent development of pSS.

Methods: Information on smoking habits was collected from lifestyle habit questionnaires of patients with pSS (n=815) and a matched control group (n=4425) for a case-control study. Differences in smoking exposure were analysed by conditional logistic regression. Potential interactions between smoking and risk-associated human leucocyte antigens (HLA) were assessed by multivariate regression.

Results: The fraction of patients with pSS having ever smoked prior to diagnosis was lower than in controls (OR 0.67, 95% CI 0.55 to 0.81). Current smoking at diagnosis was also less prevalent in cases (OR 0.37, 95% CI 0.26 to 0.53). However, period prevalence of smoking during early adulthood was not statistically different from controls (OR 0.89, 95% CI 0.66 to 1.22) but markedly decreased over time. This was partly due to patients being more prone to stop smoking, starting already 30 years prior to diagnosis (OR 2.01, 95% CI 1.22 to 3.30). Smoking patterns were also stratified by autoantibody status, yielding similar estimates. No interaction effects between HLA-DRB1 haplotypes and smoking were observed.

Conclusion: The observed smoking patterns indicate that individuals who develop pSS smoke equally much as the general population during early life but are then more prone to stop. The data can be interpreted as smoking conferring protective effects, or reflecting early symptoms of pSS that affect smoking habits, emphasising the slow, progressive development of the disease.
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http://dx.doi.org/10.1136/rmdopen-2020-001402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547543PMC
September 2020

A topological data analysis based classification method for multiple measurements.

BMC Bioinformatics 2020 Jul 29;21(1):336. Epub 2020 Jul 29.

KTH-The Royal Institute of Technology, Stockholm, Sweden.

Background: Machine learning models for repeated measurements are limited. Using topological data analysis (TDA), we present a classifier for repeated measurements which samples from the data space and builds a network graph based on the data topology. A machine learning model with cross-validation is then applied for classification. When test this on three case studies, accuracy exceeds an alternative support vector machine (SVM) voting model in most situations tested, with additional benefits such as reporting data subsets with high purity along with feature values.

Results: For 100 examples of 3 different tree species, the model reached 80% classification accuracy after 30 datapoints, which was improved to 90% after increased sampling to 400 datapoints. The alternative SVM classifier achieved a maximum accuracy of 68.7%. Using data from 100 examples from each class of 6 different random point processes, the classifier achieved 96.8% accuracy, vastly outperforming the SVM. Using two outcomes in neuron spiking data, the TDA classifier was similarly accurate to the SVM in one case (both converged to 97.8% accuracy), but was outperformed in the other (relative accuracies 79.8% and 92.2%, respectively).

Conclusions: This algorithm and software can be beneficial for repeated measurement data common in biological sciences, as both an accurate classifier and a feature selection tool.
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http://dx.doi.org/10.1186/s12859-020-03659-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392670PMC
July 2020

State of the Art and Future Challenges in Multiple Sclerosis Research and Medical Management: An Insight into the 5th International Porto Congress of Multiple Sclerosis.

Neurol Ther 2020 Dec 14;9(2):281-300. Epub 2020 Jul 14.

Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.

The 5th International Porto Congress of Multiple Sclerosis took place between the 14th and 16th of February 2019 in Porto, Portugal. Its intensive programme covered a wide-range of themes-including many of the hot topics, challenges, pitfalls and yet unmet needs in the field of multiple sclerosis (MS)-led by a number of well-acknowledged world experts. This meeting review summarizes the talks that took place during the congress, which focussed on issues in MS as diverse as the development and challenges of progressive MS, epidemiology, differential diagnosis, medical management, molecular research and imaging tools.
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http://dx.doi.org/10.1007/s40120-020-00202-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606370PMC
December 2020

COVID-19 in people with multiple sclerosis: A global data sharing initiative.

Mult Scler 2020 09 14;26(10):1157-1162. Epub 2020 Jul 14.

MSBase Registry, Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia.

Background: We need high-quality data to assess the determinants for COVID-19 severity in people with MS (PwMS). Several studies have recently emerged but there is great benefit in aligning data collection efforts at a global scale.

Objectives: Our mission is to scale-up COVID-19 data collection efforts and provide the MS community with data-driven insights as soon as possible.

Methods: Numerous stakeholders were brought together. Small dedicated interdisciplinary task forces were created to speed-up the formulation of the study design and work plan. First step was to agree upon a COVID-19 MS core data set. Second, we worked on providing a user-friendly and rapid pipeline to share COVID-19 data at a global scale.

Results: The COVID-19 MS core data set was agreed within 48 hours. To date, 23 data collection partners are involved and the first data imports have been performed successfully. Data processing and analysis is an on-going process.

Conclusions: We reached a consensus on a core data set and established data sharing processes with multiple partners to address an urgent need for information to guide clinical practice. First results show that partners are motivated to share data to attain the ultimate joint goal: better understand the effect of COVID-19 in PwMS.
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http://dx.doi.org/10.1177/1352458520941485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361123PMC
September 2020

Smoking and Epstein-Barr virus infection in multiple sclerosis development.

Sci Rep 2020 07 3;10(1):10960. Epub 2020 Jul 3.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

It is unclear whether smoking interacts with different aspects of Epstein-Barr virus (EBV) infection with regard to multiple sclerosis (MS) risk. We aimed to investigate whether smoking acts synergistically with elevated EBNA-1 antibody levels or infectious mononucleosis (IM) history regarding MS risk. Two Swedish population-based case-control studies were used (6,340 cases and 6,219 matched controls). Subjects with different smoking, EBNA-1 and IM status were compared regarding MS risk, by calculating odds ratios (OR) with 95% confidence intervals (CI) employing logistic regression. Potential interaction on the additive scale was evaluated by calculating the attributable proportion due to interaction (AP). Current and past smokers had higher EBNA-1 antibody levels than never smokers (p < 0.0001). There was an additive interaction between current smoking and high EBNA-1 antibody levels (AP 0.3, 95% CI 0.2-0.4), but not between past smoking and high EBNA-1 antibody levels (AP 0.01, 95% CI - 0.1 to 0.1), with regard to MS risk. An interaction also occurred between current smoking and IM history (AP 0.2, 95% CI 0.004-0.4), but not between past smoking and IM history (AP - 0.06, 95% CI - 0.4 to 0.3). Current smoking increases EBNA-1 antibody levels and acts synergistically with both aspects of EBV infection to increase MS risk, indicating that there is at least one pathway to disease in which both risk factors are involved.
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http://dx.doi.org/10.1038/s41598-020-67883-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335184PMC
July 2020

Multiple sclerosis lesions in motor tracts from brain to cervical cord: spatial distribution and correlation with disability.

Brain 2020 07;143(7):2089-2105

Aix-Marseille Univ, CNRS, CRMBM, Marseille, France.

Despite important efforts to solve the clinico-radiological paradox, correlation between lesion load and physical disability in patients with multiple sclerosis remains modest. One hypothesis could be that lesion location in corticospinal tracts plays a key role in explaining motor impairment. In this study, we describe the distribution of lesions along the corticospinal tracts from the cortex to the cervical spinal cord in patients with various disease phenotypes and disability status. We also assess the link between lesion load and location within corticospinal tracts, and disability at baseline and 2-year follow-up. We retrospectively included 290 patients (22 clinically isolated syndrome, 198 relapsing remitting, 39 secondary progressive, 31 primary progressive multiple sclerosis) from eight sites. Lesions were segmented on both brain (T2-FLAIR or T2-weighted) and cervical (axial T2- or T2*-weighted) MRI scans. Data were processed using an automated and publicly available pipeline. Brain, brainstem and spinal cord portions of the corticospinal tracts were identified using probabilistic atlases to measure the lesion volume fraction. Lesion frequency maps were produced for each phenotype and disability scores assessed with Expanded Disability Status Scale score and pyramidal functional system score. Results show that lesions were not homogeneously distributed along the corticospinal tracts, with the highest lesion frequency in the corona radiata and between C2 and C4 vertebral levels. The lesion volume fraction in the corticospinal tracts was higher in secondary and primary progressive patients (mean = 3.6 ± 2.7% and 2.9 ± 2.4%), compared to relapsing-remitting patients (1.6 ± 2.1%, both P < 0.0001). Voxel-wise analyses confirmed that lesion frequency was higher in progressive compared to relapsing-remitting patients, with significant bilateral clusters in the spinal cord corticospinal tracts (P < 0.01). The baseline Expanded Disability Status Scale score was associated with lesion volume fraction within the brain (r = 0.31, P < 0.0001), brainstem (r = 0.45, P < 0.0001) and spinal cord (r = 0.57, P < 0.0001) corticospinal tracts. The spinal cord corticospinal tracts lesion volume fraction remained the strongest factor in the multiple linear regression model, independently from cord atrophy. Baseline spinal cord corticospinal tracts lesion volume fraction was also associated with disability progression at 2-year follow-up (P = 0.003). Our results suggest a cumulative effect of lesions within the corticospinal tracts along the brain, brainstem and spinal cord portions to explain physical disability in multiple sclerosis patients, with a predominant impact of intramedullary lesions.
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http://dx.doi.org/10.1093/brain/awaa162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364770PMC
July 2020

Early clinical markers of aggressive multiple sclerosis.

Brain 2020 05;143(5):1400-1413

Groene Hart Ziekenhuis, Gouda, The Netherlands.

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.
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http://dx.doi.org/10.1093/brain/awaa081DOI Listing
May 2020