Publications by authors named "Ali Manouchehrinia"

46 Publications

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

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

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

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

A controlled, randomized phase II clinical trial for efficacy and safety evaluation of mannuronic acid in secondary progressive form of multiple sclerosis.

Int J Neurosci 2020 Sep 7:1-10. Epub 2020 Sep 7.

Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.

Background: The β-D-Mannuronic acid (M2000) as a novel immunosuppressive drug, patented (PCT/EP2017/067920), has shown positive effects in experimental model of multiple sclerosis (MS). In this study, our aim was to assess efficacy and safety outcomes in MS treated patients with mannuronic acid compared to the conventional drug.

Methods: In a 6-month, randomized controlled, phase II trial, we enrolled patients who had secondary progressive multiple sclerosis (SPMS), were 21-54 years of age, with a score of 1-7 on the Expanded Disability Status Scale (EDSS), and who had at least one relapse in the previous 6 months. Patients were administered orally 1000 mg/day (two 500 mg/capsule daily) of M2000. Endpoints included changes in brain magnetic resonance imaging (MRI) measures and the EDSS score, as compared to the conventional drug (interferon beta-1a, interferon beta-1b).

Results: A total of 25 (92.5%) of the M2000 treated patients and 25 conventionally treated patients completed the study. M2000 had better performance compared to the conventional drug regarding to MRI-related measurements, however, the differences between groups were not statistically significant. M2000 decreased the disability progression over the 6-month period. The EDSS score was decreased in the M2000 treated group in the sixth month versus the conventional drug ( < 0.009). Furthermore, we did not observe any short-term side effects.

Conclusions: As compared with the conventional drug, mannuronic acid (M2000) improved the rate of disability progression. This clinical trial demonstrated the efficacy and safety of mannuronic acid in patients with SPMS. (Registered Clinical Trials number, IRCT2016111313739N6).
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http://dx.doi.org/10.1080/00207454.2020.1818741DOI Listing
September 2020

Plasma neurofilament light levels are associated with risk of disability in multiple sclerosis.

Neurology 2020 06 20;94(23):e2457-e2467. Epub 2020 May 20.

From the Department of Clinical Neuroscience (A.M., P.S., M.K., F.P., T.O., I.K.), The Karolinska Neuroimmunology & Multiple Sclerosis Centre, Karolinska Institutet; Centre for Molecular Medicine (A.M., P.S., M.K., F.P., T.O., I.K.), Karolinska University Hospital, Stockholm, Sweden; Departments of Medicine, Biomedicine, and Clinical Research (D.L., C.B., Z.M., L.K., J.K.), Neurologic Clinic and Policlinic, University Hospital Basel, University of Basel; Clinical Trial Unit (P.B.), Department of Clinical Research, University Hospital Basel, University of Switzerland; Institution of Neuroscience and Physiology (J.L.), Sahlgrenska Academy, University of Gothenburg, Gothenburg; Institute of Environmental Medicine (L.A.), Karolinska Institutet, Stockholm; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.

Objective: To investigate the association between plasma neurofilament light chain (pNfL) levels and the risk of developing sustained disability worsening.

Methods: Concentrations of pNfL were determined in 4,385 persons with multiple sclerosis (MS) and 1,026 randomly selected population-based sex- and age-matched controls using the highly sensitive Single Molecule Array (SimoaTM) NF-Light Advantage Kit. We assessed the impact of age-stratified pNfL levels above the 80th, 95th, and 99th percentiles among controls on the risk of Expanded Disability Status Scale (EDSS) worsening within the following year and reaching sustained EDSS scores of 3.0, 4.0, and 6.0 and conversion to secondary progressive multiple sclerosis (SPMS).

Results: The median (interquartile range [IQR]) pNfL was 7.5 (4.1) pg/mL in controls and 11.4 (9.6) pg/mL in MS ( < 0.001). The median (IQR) duration of follow-up was 5 (5.1) years. High pNfL was associated with increased adjusted rates of EDSS worsening ranging between 1.4 (95% confidence intervals [CIs]: 1.1-1.8) and 1.7 (95% CI: 1.4-2.3). High pNfL was also associated with the risk of reaching a sustained EDSS score of 3.0, with adjusted rates ranging between 1.5 (95% CI: 1.2-1.8) and 1.55 (95% CI: 1.3-1.8) over all percentile cutoffs (all < 0.001). Similar increases were observed for the risk of sustained EDSS score 4.0. In contrast, the risk of reaching sustained EDSS score 6.0 and conversion to SPMS was not consistently significant.

Conclusions: Elevated pNfL levels at early stages of MS are associated with an increased risk of reaching sustained disability worsening. Hence, pNfL may serve as a prognostic tool to assess the risk of developing permanent disability in MS.
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http://dx.doi.org/10.1212/WNL.0000000000009571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455371PMC
June 2020

Early clinical markers of aggressive multiple sclerosis.

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

CORe Unit, Department of Medicine, University of Melbourne, Melbourne, Australia.

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

Blood neurofilament light levels segregate treatment effects in multiple sclerosis.

Neurology 2020 03 11;94(11):e1201-e1212. Epub 2020 Feb 11.

From the Department of Medicine Solna, Clinical Epidemiology Division (B.D.), The Karolinska Neuroimmunology & Multiple Sclerosis Centre, Department of Clinical Neuroscience (A.M., I.K., T.O., F.P.), and Institute of Environmental Medicine (L.A.), Karolinska Institutet; Centre for Molecular Medicine (A.M., I.K., T.O., F.P.), Karolinska University Hospital, Stockholm, Sweden; Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine, and Clinical Research (C.B., Z.M., L.K., D.L., J.K.), and Clinical Trial Unit, Department of Clinical Research (P.B.), University Hospital Basel, University of Basel, Switzerland; Sanofi Genzyme (J.A.T.), Stockholm, Sweden; Biogen (T.P., B.C.K.), Cambridge, MA; Department of Neurology, Medical Faculty (B.C.K.), Heinrich-Heine University, Duesseldorf, Germany; and Institution of Neuroscience and Physiology (J.L.), Sahlgrenska Academy, University of Gothenburg, Sweden.

Objective: To determine factors (including the role of specific disease modulatory treatments [DMTs]) associated with (1) baseline, (2) on-treatment, and (3) change (from treatment start to on-treatment assessment) in plasma neurofilament light chain (pNfL) concentrations in relapsing-remitting multiple sclerosis (RRMS).

Methods: Data including blood samples analyses and long-term clinical follow-up information for 1,261 Swedish patients with RRMS starting novel DMTs were analyzed using linear regressions to model pNfL and changes in pNfL concentrations as a function of clinical variables and DMTs (alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, rituximab, and teriflunomide).

Results: The baseline pNfL concentration was positively associated with relapse rate, Expanded Disability Status Scale score, Age-Related MS Severity Score, and MS Impact Score (MSIS-29), and negatively associated with Symbol Digit Modalities Test performance and the number of previously used DMTs. All analyses, which used inverse propensity score weighting to correct for differences in baseline factors at DMT start, highlighted that both the reduction in pNfL concentration from baseline to on-treatment measurement and the on-treatment pNfL level differed across DMTs. Patients starting alemtuzumab displayed the highest reduction in pNfL concentration and lowest on-treatment pNfL concentrations, while those starting teriflunomide had the smallest decrease and highest on-treatment levels, but also starting from lower values. Both on-treatment pNfL and decrease in pNfL concentrations were highly dependent on baseline concentrations.

Conclusion: Choice of DMT in RRMS is significantly associated with degree of reduction in pNfL, which supports a role for pNfL as a drug response marker.
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http://dx.doi.org/10.1212/WNL.0000000000009097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387108PMC
March 2020

Confounding effect of blood volume and body mass index on blood neurofilament light chain levels.

Ann Clin Transl Neurol 2020 01 1;7(1):139-143. Epub 2020 Jan 1.

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

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.
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http://dx.doi.org/10.1002/acn3.50972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952306PMC
January 2020

Determinants of quality of life in pediatric- and adult-onset multiple sclerosis.

Neurology 2020 03 15;94(9):e932-e941. Epub 2019 Nov 15.

From the Departments of Clinical Neuroscience (K.A.M., A.M., T.O., J.H.) and Learning, Informatics, Management and Ethics (O.E.), Karolinska Institutet; and Centre for Molecular Medicine (K.A.M., A.M., T.O.), Karolinska University Hospital, Stockholm, Sweden.

Objective: To evaluate quality of life (QoL), measured by the EQ-5D, in adults with pediatric-onset multiple sclerosis (POMS) or adult-onset multiple sclerosis (AOMS) and explore determinants of QoL in both groups.

Methods: Data were collected from the nationwide Swedish multiple sclerosis (MS) registry. Demographic characteristics, EQ-5D-3 level, Multiple Sclerosis Impact Scale (MSIS-29) score, Expanded Disability Status Scale (EDSS) score, Symbol Digit Modalities Test score, relapses, and disease-modifying therapy (DMT) exposure were collected on an approximately annual basis (2011-2019). Patients with definite MS with ≥2 EQ-5D measurements collected between ages 18 and 50 were included. The principal outcome was the EQ-5D visual analogue scale (EQ-VAS) score. Linear mixed models compared all available EQ-VAS scores between patients with POMS and patients with AOMS and determinants of EQ-VAS among patients with POMS and patients with AOMS (assessed separately).

Results: A total of 5,094 persons met inclusion criteria: 354 (6.9%) had POMS. A total of 21,357 unique EQ-5D scores were recorded. Most participants were female (70.0%) with a relapsing-onset disease course (98.1%). There was no difference in EQ-VAS scores between patients with POMS and patients with AOMS following adjustment for confounders (β-coefficient for patients with POMS vs patients with AOMS [reference]: 0.99; 95% confidence interval -0.89 to 2.87). Experiencing a relapse, severe neurologic disability (EDSS ≥6.0 vs <3.0), and higher MSIS-29 psychological score were consistently associated with lower QoL, while higher information processing efficiency and exposure to first-line DMTs were associated with higher QoL scores in both groups.

Conclusions: There were no differences in QoL between patients with POMS and patients with AOMS in adulthood. Findings provide support for a focus on reducing neurologic disability and improving psychological status as approaches to potentially improve the QoL of persons with MS.
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http://dx.doi.org/10.1212/WNL.0000000000008667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238943PMC
March 2020

Disability worsening among persons with multiple sclerosis and depression: A Swedish cohort study.

Neurology 2019 12 8;93(24):e2216-e2223. Epub 2019 Nov 8.

From the Department of Clinical Neuroscience (S.B., K.A.M., J.H., A.M.), Department of Medicine Solna (P.B.), and Karolinska Neuroimmunology & Multiple Sclerosis Centre and Centre for Molecular Medicine (A.M.) Karolinska Institutet, Stockholm, Sweden, Odense University Hospital (S.B.), Department of Neurology, Denmark; and Karolinska University Hospital (J.H.), Stockholm, Sweden.

Objective: Depression is common in multiple sclerosis (MS), but its impact on disability worsening has not yet been determined. We explored the risk of disability worsening associated with depression in a nationwide longitudinal cohort.

Methods: This retrospective cohort study used linked data from 3 Swedish nationwide registries: the MS Register, National Patient Register, and Prescribed Drug Register. Two incident cohorts were developed: cohort 1 included all registered cases of MS in the MS Registry (2001-2014) with depression defined as ≥1 ICD-10 code for depression; and cohort 2 comprised all cases of MS in the MS Registry (2005-2014) with depression defined as ≥1 prescription filled for an antidepressant. Cox regression models were used to compare the risk of reaching sustained disability milestone scores of 3.0, 4.0, and 6.0 on the Expanded Disability Status Scale (EDSS) between persons with MS with and without depression.

Results: Cohort 1 included 5,875 cases; 502 (8.5%) had depression. Cohort 2 had 3,817 cases; 1,289 (33.8%) were prescribed an antidepressant. Persons with depression were at a significantly higher risk of reaching sustained EDSS scores of 3.0, 4.0, and 6.0, with hazard ratios of 1.50 (95% confidence interval [CI] 1.20-1.87), 1.79 (95% CI 1.40-2.29), and 1.89 (95% CI 1.38-2.57), respectively. A similar increased risk among persons exposed to antidepressants was observed, with hazard ratios of 1.37 (95% CI 1.18-1.60), 1.93 (95% CI 1.61-2.31), and 1.86 (95% CI 1.45-2.40) for sustained EDSS scores of 3.0, 4.0, and 6.0, respectively.

Conclusion: Persons with MS and comorbid depression had a significantly increased risk of disability worsening. This finding highlights the need for early recognition and appropriate treatment of depression in persons with MS.
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http://dx.doi.org/10.1212/WNL.0000000000008617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937491PMC
December 2019

Retinal nerve fiber layer thickness associates with cognitive impairment and physical disability in multiple sclerosis.

Mult Scler Relat Disord 2019 Nov 26;36:101414. Epub 2019 Sep 26.

Unit of Optometry, Department of Clinical Neuroscience, Karolinska Institutet, Box 8056, S-104 20 Stockholm, Sweden.

Background: Reductions of the peripapillary retinal nerve fiber layer (pRNFL) thickness has been indicated even in early-stages of multiple sclerosis (MS). The aim was to investigate the association between pRNFL thickness, measured with optical coherence tomography (OCT), and physical disability and cognitive impairment in MS.

Methods: 465 MS patients and 168 healthy controls (HCs) were included. MS subjects were divided into subgroups according to disease subtype. All subjects underwent OCT examination of all pRNFL quadrants using Canon OCT-HS100. Associations were tested using linear mixed effect models. Physical disability was assessed with the Expanded Disability Status Scale (EDSS) and cognitive function with the Symbol Digit Modalities Test (SDMT).

Results: The average pRNFL, inferior pRNFL and temporal pRNFL thicknesses were significantly correlated to both EDSS (-1.0 µm, p < 0.01; -1.2 µm, p < 0.05; -1.2 µm, p < 0.01) and SDMT (0.1 µm, p < 0.05; 0.2 µm, p < 0.05; 0.2 µm, p < 0.01). A significant thickness loss compared with HCs was seen in the average pRNFL and in all quadrants except for the superior quadrant of primary progressive MS. The largest reduction compared with HCs was seen in the temporal pRNFL of PPMS eyes (-15.8 µm; p < 0.001).

Conclusion: The reduction of average pRNFL, inferior pRNFL and temporal pRNFL thickness is associated with physical and cognitive disability in MS. We suggest the use of temporal pRNFL as a more sensitive outcome as it showed the strongest association to both EDSS and SDMT.
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http://dx.doi.org/10.1016/j.msard.2019.101414DOI Listing
November 2019

Long-term Cognitive Outcomes in Patients With Pediatric-Onset vs Adult-Onset Multiple Sclerosis.

JAMA Neurol 2019 Jun 17. Epub 2019 Jun 17.

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

Importance: Cognitive impairment in multiple sclerosis (MS) can lead to reduced quality of life, social functioning, and employment. Few studies have investigated cognitive outcomes among patients with pediatric-onset MS (POMS) over the long term.

Objective: To compare long-term information-processing efficiency between patients with POMS and adult-onset MS (AOMS).

Design, Setting, And Participants: This population-based longitudinal cohort study accessed the Swedish MS Registry (SMSreg), which collates information from all 64 neurology clinics in Sweden. Registered cases with definite MS in the SMSreg with an onset before April 15, 2018, and at least 2 Symbol Digit Modalities Test (SDMT) scores recorded were included. Only persons aged 18 to 55 years and with duration of disease of less than 30 years at the time of SDMT administration were included, to ensure comparable ranges between patients with POMS and AOMS. Of 8247 persons with an SDMT recorded in the SMSreg, 5704 met inclusion criteria, 300 (5.3%) of whom had POMS. Data were collected from April 1, 2006, through April 15, 2018 and analyzed from April through August 2018.

Exposures: Pediatric-onset MS (onset <18 years of age) vs AOMS (onset ≥18 years of age).

Main Outcomes And Measures: Information-processing efficiency measured every 6 or 12 months by the SDMT. Linear mixed-effects models were used to compare all available SDMT scores between patients with POMS and those with AOMS. Persons with cognitive impairment (ever vs never) were identified using regression-based norms and compared between POMS and AOMS groups using logistic regression.

Results: Of the 5704 participants, 4015 were female (70.4%), and 5569 had a relapsing-onset disease course (97.6%). Most participants were exposed to a disease-modifying therapy (DMT) during follow-up (98.8%). Median age at baseline for the POMS group was 25.6 years (interquartile range, 21.0-31.7 years) and for the AOMS group, 38.3 years (interquartile range, 31.4-45.2 years). A total of 46 429 unique SDMT scores were analyzed. After adjustment for sex, age, disease duration, disease course, total number of SDMTs completed, oral or visual SDMT form, and DMT exposure, the SDMT score for patients with POMS was significantly lower than that of patients with AOMS (β coefficient, -3.59 [95% CI, -5.56 to -1.54]). The SDMT score for patients with POMS declined faster than that of patients with AOMS (β coefficient, -0.30 [95% CI, -0.42 tp -0.17]). The odds of cognitive impairment were also significantly elevated in the POMS group (odds ratio, 1.44; 95% CI, 1.06-1.98).

Conclusions And Relevance: In adulthood, patients with POMS demonstrated a more rapid reduction in information-processing efficiency over time and were more likely to experience cognitive impairment than patients with AOMS, independent of age or disease duration. Further investigation is required to understand the mechanisms by which early MS onset influences cognitive outcomes.
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http://dx.doi.org/10.1001/jamaneurol.2019.1546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580443PMC
June 2019

Multiple sclerosis national registry system in Iran: Validity and reliability of a minimum data set.

Mult Scler Relat Disord 2019 Aug 9;33:158-161. Epub 2019 Jun 9.

Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.

Background: As the prevalence and incidence of Multiple Sclerosis (MS) are increasing remarkably in Iran, gathering standardized information regarding the individual's diagnosis, care, and outcomes through a uniform registry system would enable policy-makers to systematically plan for care quality improvements.

Objective: To design a valid and reliable Persian version of a minimum data set to be utilized and integrated into the national MS registry system of Iran.

Method: The minimum data set consisted of six domains including patient identification, family history of MS, diagnosis, disease course, disability status, and medications. The content validity was assessed based on 27 experts' opinions. Item-Content Validity Index (I-CVI) and Scale-Content Validity Index (S-CVI) were used to assess the questions and their validities. Reliability was evaluated using the intra-class correlation coefficient (ICC) of the test-retest results.

Results: For validity appraisal, 27 experts reviewed the developed minimum data set. All the items had I-CVI values higher than the critical value of 0.78 in terms of relevance, clarity, and simplicity, except for "medication start date" and "medication end date" in relevance (I-CVI = 0.75 and 0.73, respectively) and "MS type" in simplicity (I-CVI = 0.76). The total S-CVI scores for relevance, clarity, and simplicity were higher than 0.9. In reliability assessment, 27 patients (out of 74 interviewed patients) were re-interviewed to assess the test-retest reliability. All ICCs were higher than the critical value of 0.7 (in 14 items out of 16), except for "progression to secondary-progressive MS" with the ICC = 0.68 and "the reason for medication discontinuance" with the ICC = 0.64.

Conclusion: The use of standardized validated minimum data set has the potential to enable the researchers and policy-makers to systematically compare and analyze patient information. The Persian version of the minimum data set found to be valid and reliable in Iran.
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http://dx.doi.org/10.1016/j.msard.2019.06.009DOI Listing
August 2019

Plasma protein profiling reveals candidate biomarkers for multiple sclerosis treatment.

PLoS One 2019 29;14(5):e0217208. Epub 2019 May 29.

Department of Clinical Neuroscience and Centrum for Molecular Medicine at Karolinska, Institutet, Stockholm, Sweden.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217208PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541274PMC
January 2020

Long-term disability progression of pediatric-onset multiple sclerosis.

Neurology 2019 06 15;92(24):e2764-e2773. Epub 2019 May 15.

From the Department of Clinical Neuroscience (K.A.M., J.H., A.M.), Karolinska Institutet; and Centre for Molecular Medicine (A.M.), Karolinska Hospital, Stockholm, Sweden.

Objective: To evaluate long-term disability progression in pediatric-onset multiple sclerosis (POMS) and compare to adult-onset multiple sclerosis (AOMS).

Methods: This 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 <18 years) and AOMS (MS onset ≥18 years).

Results: A 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.

Conclusions: Patients with pediatric-onset MS follow a distinctive clinical course, which should be considered in the treatment and management of the disease.
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http://dx.doi.org/10.1212/WNL.0000000000007647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598792PMC
June 2019

Changes in the Risk of Reaching Multiple Sclerosis Disability Milestones In Recent Decades: A Nationwide Population-Based Cohort Study in Sweden.

JAMA Neurol 2019 06;76(6):665-671

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, 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, 12 512 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.
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http://dx.doi.org/10.1001/jamaneurol.2019.0330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563565PMC
June 2019

Factors associated with and long-term outcome of benign multiple sclerosis: a nationwide cohort study.

J Neurol Neurosurg Psychiatry 2019 07 1;90(7):761-767. Epub 2019 Mar 1.

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

Objective: Benign multiple sclerosis (BMS) is often defined by the Expanded Disability Status Scale (EDSS) score of ≤3.0 after ≥15 years of disease duration. This classification's clinical relevance remains unclear as benign patients may suffer other impairments and advance towards a progressive course, prompting our objective to holistically investigate factors associated with BMS and its long-term prognosis.

Methods: Benign cases were identified in the Swedish Multiple Sclerosis registry. Baseline clinical data, demographic features and influence of multiple sclerosis (MS) major risk alleles on likelihood of benign course were investigated. Physical disability (EDSS), cognitive function (Symbol Digit Modalities Test; SDMT) and self-reported and socioeconomic differences between benign and non-benign patients were evaluated using generalised estimation equations models.

Results: 11222 patients (2420 benign/8802 non-benign) were included. Benign patients were more likely to be female and younger at MS onset, have fewer relapses within the first two and 5 years from onset and fully recover from the first relapse (p<0.001). No association between human leucocyte antigen () carriership (OR: 0.97, 95% CI: 0.86 to 1.09) or lacking (OR: 0.99, 95% CI: 0.87 to 1.11) and benign/non-benign was found. Non-benign patients accumulated an extra 0.04 (95% CI 0.03 to 0.04, p<0.001) EDSS score/year, lost an extra 0.3 (95% CI - 0.39 to - 0.18, p<0.001) SDMT score/year and deteriorated faster in self-reported impact and socioeconomic measures (p<0.001).

Conclusion: Patients with BMS have a better disease course as they progress more slowly at the group level in all respects. Lack of an association with major genetic risk factors indicates that MS course is most likely influenced by either environmental factor(s) or genetic factors outside the region.
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http://dx.doi.org/10.1136/jnnp-2018-319913DOI Listing
July 2019

Familial risk of early- and late-onset multiple sclerosis: a Swedish nationwide study.

J Neurol 2019 Feb 21;266(2):481-486. Epub 2018 Dec 21.

Centre for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

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 < 18 years of age) and late onset (first MS symptom ≥ 50 years).

Methods: Nationwide registries in Sweden were used to identify cases of MS and controls, and their familial relations. We estimated the odds ratio (OR) of an MS diagnosis for individuals with a relative diagnosed with early-onset or late-onset MS compared with those whose relatives did not have MS, using a nested case-control design.

Results: 629 early-onset and 1148 late-onset MS patients were identified and matched to 10 controls from the general population by age and sex. The OR of MS for individuals with a first-degree relative diagnosed with early-onset MS was 10.86 (95% CI 6.87-17.17); and for late-onset MS was 8.08 (95% CI 6.12-10.67).

Conclusions: Our findings demonstrate no substantial differences in familial risk in persons with early- and late-onset MS.
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http://dx.doi.org/10.1007/s00415-018-9163-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373346PMC
February 2019

Effects of cigarette smoke on immunity, neuroinflammation and multiple sclerosis.

J Neuroimmunol 2019 04 9;329:24-34. Epub 2018 Oct 9.

Division of Clinical Neuroscience, Section of Clinical Neurology, University of Nottingham, Nottingham, United Kingdom. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jneuroim.2018.10.004DOI Listing
April 2019

Predicting risk of secondary progression in multiple sclerosis: A nomogram.

Mult Scler 2019 07 18;25(8):1102-1112. Epub 2018 Jun 18.

Department of Clinical Neuroscience (CNS), Karolinska Institutet, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1177/1352458518783667DOI Listing
July 2019

Association of Pre-Disease Body Mass Index With Multiple Sclerosis Prognosis.

Front Neurol 2018 11;9:232. Epub 2018 May 11.

Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.

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,  = 0.036). This association of obesity at age 20 with increased risk of SP was not observed in non-smokers (hazard rate 0.97,  = 0.900). Since the risk is confined to smokers, the interaction observed may give insight to disease driving mechanisms.
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http://dx.doi.org/10.3389/fneur.2018.00232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958198PMC
May 2018

The Temporal Retinal Nerve Fiber Layer Thickness Is the Most Important Optical Coherence Tomography Estimate in Multiple Sclerosis.

Front Neurol 2017 13;8:675. Epub 2017 Dec 13.

Unit of Optometry, Department of Clinical Neuroscience, St. Erik Eye Hospital, Karolinska Institute, Stockholm, Sweden.

Background: Reduced peripapillary retinal nerve fiber layer (pRNFL) and combined ganglion cell and inner plexiform layer (GCIP) thicknesses as measured by optical coherence tomography (OCT) have been observed in multiple sclerosis (MS) patients. The purpose was to determine the most associative OCT measure to level of cognitive and physical disability in MS.

Methods: Data were collected from 546 MS patients and 175 healthy controls (HCs). We compared the average pRNFL, temporal pRNFL (T-pRNFL), overall inner ganglion cell/inner plexiform layer (GCIP), and the overall ganglion cell complex (GCC) including macular RNFL and GCIP thicknesses measurements in differentiating MS subtypes from HCs. The association between OCT measures, Expanded Disability Status Scale (EDSS), and Symbol Digit Modalities Test (SDMT) were assessed using generalized estimating equations models.

Results: Both peripapillary and macular OCT measurements could differentiate all MS subtypes from HCs. The SDMT score was significantly associated with reduced thickness of all OCT measures, mostly in average pRNFL (0.14 µm,  = 0.001) and T-pRNFL (0.17 µm,  < 0.001). The EDSS score was significantly associated with reduced inner retinal layer thickness. The largest reduction was seen in T-pRNFL (-1.52 μm,  < 0.001) and inner GCC (-1.78 μm,  < 0.001).

Conclusion: The T-pRNFL is highly sensitive and associated with level of both cognitive and physical disability.
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http://dx.doi.org/10.3389/fneur.2017.00675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733353PMC
December 2017

Cognitive function is a major determinant of income among multiple sclerosis patients in Sweden acting independently from physical disability.

Mult Scler 2019 01 16;25(1):104-112. Epub 2017 Nov 16.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden/Department of Neurology, Karolinska University Hospital, Stockholm, Sweden/Centre for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1177/1352458517740212DOI Listing
January 2019

Towards personalized therapy for multiple sclerosis: prediction of individual treatment response.

Brain 2017 Sep;140(9):2426-2443

Department of Neurology, Royal Melbourne Hospital, 300 Grattan St, Melbourne, 3050, Australia.

Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (>80%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2-4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to secondary progressive disease and treatment discontinuation. We conclude that demographic, clinical and paraclinical information helps predict individual response to disease-modifying therapies at the time of their commencement.
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http://dx.doi.org/10.1093/brain/awx185DOI Listing
September 2017

Multiple sclerosis treatment effects on plasma cytokine receptor levels.

Clin Immunol 2018 02 21;187:15-25. Epub 2017 Sep 21.

Department of Clinical Neuroscience and Centrum for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address:

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.
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http://dx.doi.org/10.1016/j.clim.2017.08.023DOI Listing
February 2018

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

J Neurovirol 2017 12 11;23(6):839-844. Epub 2017 Sep 11.

Division of Clinical Neuroscience, Section of Clinical Neurology, University of Nottingham, Nottingham University Hospital NHS Trust, Queen's Medical Centre, C Floor S Block, Nottingham, NG7 2UH, UK.

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.
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http://dx.doi.org/10.1007/s13365-017-0569-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725504PMC
December 2017

Rituximab in multiple sclerosis: Frequency and clinical relevance of anti-drug antibodies.

Mult Scler 2018 08 1;24(9):1224-1233. Epub 2017 Aug 1.

Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden / Center for Molecular Medicine, Karolinska University Hospital Solna, Stockholm, Sweden.

Background: Rituximab is a chimeric monoclonal anti-CD20 B-cell-depleting antibody increasingly used off-label in multiple sclerosis (MS). The clinical relevance of anti-drug antibodies (ADAs) against rituximab in MS is unknown.

Objective: To determine frequency of ADA in relation to B-cell counts, allergic reactions and clinical efficacy in a large cohort of MS-treated patients.

Methods: Cross-sectional study with collection of serum samples from 339 MS patients immediately before a scheduled rituximab infusion. ADAs were detected using an in-house-validated electrochemiluminescent immunoassay and a commercial enzyme-linked immunosorbent assay (ELISA) to compare methods. Data on patient demographics and clinical outcomes were retrieved from the Swedish MS Registry and patient records.

Results: ADAs were detected in 37% of relapsing-remitting MS and 26% in progressive forms of MS. Presence of ADAs decreased with increasing number of rituximab infusions. There was a significant association between both presence and titres of ADAs and incomplete B-cell depletion, but not with infusion/adverse reactions or clinical outcomes at the group level. Only five patients terminated rituximab during follow-up, four of which were ADA positive.

Conclusion: Rituximab treatment is associated with a high degree of ADAs, which correlates with efficacy of B-cell depletion; however, the clinical relevance of ADAs remains uncertain.
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http://dx.doi.org/10.1177/1352458517720044DOI Listing
August 2018