Publications by authors named "Ludwig Kappos"

434 Publications

No evidence for loss of natalizumab effectiveness with every-6-week dosing: a propensity score-matched comparison with every-4-week dosing in patients enrolled in the Tysabri Observational Program (TOP).

Ther Adv Neurol Disord 2021 27;14:17562864211042458. Epub 2021 Sep 27.

Biogen, Cambridge, MA, USA.

Background: Extended interval dosing of natalizumab is associated with significantly lower progressive multifocal leukoencephalopathy risk compared with every-4-week (Q4W) dosing in patients with relapsing-remitting multiple sclerosis. Previous studies have suggested that natalizumab effectiveness is maintained in patients who switch from Q4W to extended interval dosing but have been limited by a lack of well-matched patient cohorts.

Methods: Tysabri Observational Program (TOP) data as of November 2019 were used to identify patients with relapsing-remitting multiple sclerosis treated with natalizumab Q4W and those with a single physician-indicated dosing change from Q4W to every-6-week (Q6W) dosing after ⩾1 year of Q4W treatment. Patients were propensity score matched at the time of the switch from Q4W to Q6W dosing. Clinical outcomes (annualized relapse rate and probability of remaining relapse free or free of 24-week confirmed disability worsening) and safety outcomes were assessed for the two cohorts.

Results: This study included 219 pairs of propensity score-matched Q6W and Q4W patients. Annualized relapse rates were similar for Q6W (0.150) and Q4W (0.157) patients. The probability of remaining relapse free [hazard ratio = 1.243 (95% confidence interval = 0.819-1.888);  = 0.307] and of remaining free of 24-week confirmed disability worsening [hazard ratio = 0.786 (95% confidence interval = 0.284-2.176);  = 0.644] did not differ significantly between Q6W and Q4W patients. Summarized safety results for the matched Q6W and Q4W patients are also presented.

Conclusion: These real-world findings in well-matched patient cohorts from TOP demonstrate that natalizumab effectiveness is maintained in patients who switch to Q6W dosing after ⩾1 year of Q4W dosing.

Clinicaltrialsgov Identifier: NCT00493298.
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http://dx.doi.org/10.1177/17562864211042458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8481711PMC
September 2021

Central nervous system atrophy predicts future dynamics of disability progression in a real-world multiple sclerosis cohort.

Eur J Neurol 2021 Sep 6. Epub 2021 Sep 6.

Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research and Biomedical Engineering, University Hospital Basel and University of Basel, Basel, Switzerland.

Background And Purpose: In an era of individualized multiple sclerosis (MS) patient management, biomarkers for accurate prediction of future clinical outcomes are needed. We aimed to evaluate the potential of short-term magnetic resonance imaging (MRI) atrophy measures and serum neurofilament light chain (sNfL) as predictors of the dynamics of disability accumulation in relapse-onset MS.

Methods: Brain gray and white matter, thalamic, striatal, pallidal and cervical spinal cord volumes, and lesion load were measured over three available time points (mean time span 2.24 ± 0.70 years) for 183 patients (140 relapsing-remitting [RRMS] and 43 secondary-progressive MS (SPMS); 123 female, age 46.4 ± 11.0 years; disease duration 15.7 ± 9.3 years), and their respective annual changes were calculated. Baseline sNfL was also measured at the third available time point for each patient. Subsequently, patients underwent annual clinical examinations over 5.4 ± 3.7 years including Expanded Disability Status Scale (EDSS) scoring, the nine-hole peg test and the timed 25-foot walk test.

Results: Higher annual spinal cord atrophy rates and lesion load increase predicted higher future EDSS score worsening over time in SPMS. Lower baseline thalamic volumes predicted higher walking speed worsening over time in RRMS. Lower baseline gray matter, as well as higher white matter and spinal cord atrophy rates, lesion load increase, baseline striatal volumes and baseline sNfL, predicted higher future hand dexterity worsening over time. All models showed reasonable to high prediction accuracy.

Conclusion: This study demonstrates the capability of short-term MRI metrics to accurately predict future dynamics of disability progression in a real-world relapse-onset MS cohort. The present study represents a step towards the utilization of structural MRI measurements in patient care.
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http://dx.doi.org/10.1111/ene.15098DOI Listing
September 2021

Safety of Ocrelizumab in Patients With Relapsing and Primary Progressive Multiple Sclerosis.

Neurology 2021 Sep 2. Epub 2021 Sep 2.

Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), TX; *R. Hughes was an employee of F. Hoffmann-La Roche Ltd during completion of the work related to this manuscript.** H. Koendgen was an employee of F. Hoffmann-La Roche Ltd during completion of the work related to this manuscript.

ObjectiveTo report safety of ocrelizumab (OCR) up to 7 years in patients with relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) enrolled in clinical trials or treated in real-world postmarketing settings.MethodsSafety analyses are based on integrated clinical and laboratory data for all patients who received OCR in 11 clinical trials, including the controlled treatment and open-label extension (OLE) periods of the phase 2 and 3 trials, plus the phase 3b trials VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, CONSONANCE, and LIBERTO. For selected adverse events (AEs), additional postmarketing data were used. Incidence rates of serious infections (SIs) and malignancies were contextualized using multiple epidemiologic sources.ResultsAt data cut-off (January 2020), 5,680 patients with multiple sclerosis (MS) received OCR (18,218 patient years [PY] of exposure) in clinical trials. Rates per 100 PY (95% CI) of AEs (248; 246-251), serious AEs (7.3; 7.0-7.7), infusion-related reactions (25.9; 25.1-26.6), and infections (76.2; 74.9-77.4) were similar to those within the controlled treatment period of the phase 3 trials. Rates of the most common serious AEs, including SIs (2.01; 1.81-2.23) and malignancies (0.46; 0.37-0.57), were consistent with the ranges reported in epidemiologic data.ConclusionContinuous administration of OCR for up to 7 years in clinical trials, as well as its broader use for more than 3 years in the real-world setting, are associated with a favorable and manageable safety profile, without emerging safety concerns in a heterogeneous MS population.Classification of evidenceThis analysis provides Class III evidence that long-term, continuous treatment with OCR has a consistent and favorable safety profile in patients with RMS and PPMS. This study is rated Class III because of the use of OLE data and historical controls.
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http://dx.doi.org/10.1212/WNL.0000000000012700DOI Listing
September 2021

Long-term safety and efficacy of dimethyl fumarate for up to 13 years in patients with relapsing-remitting multiple sclerosis: Final ENDORSE study results.

Mult Scler 2021 Sep 1:13524585211037909. Epub 2021 Sep 1.

Biogen, Cambridge, MA, USA.

Background: Dimethyl fumarate (DMF) demonstrated favorable benefit-risk in relapsing-remitting multiple sclerosis (RRMS) patients in phase-III DEFINE and CONFIRM trials, and ENDORSE extension.

Objective: The main aim of this study is assessing DMF safety/efficacy up to 13 years in ENDORSE.

Methods: Randomized patients received DMF 240 mg twice daily or placebo (PBO; Years 0-2), then DMF (Years 3-10; continuous DMF/DMF or PBO/DMF); maximum follow-up (combined studies), 13 years.

Results: By January 2020, 1736 patients enrolled/dosed in ENDORSE (median follow-up 8.76 years (ENDORSE range: 0.04-10.98) in DEFINE/CONFIRM and ENDORSE); 52% treated in ENDORSE for ⩾6 years. Overall, 551 (32%) patients experienced serious adverse events (mostly multiple sclerosis (MS) relapse or fall; one progressive multifocal leukoencephalopathy); 243 (14%) discontinued treatment due to adverse events (4% gastrointestinal (GI) disorders). Rare opportunistic infections, malignancies, and serious herpes zoster occurred, irrespective of lymphocyte count. For DMF/DMF ( = 501), overall annualized relapse rate (ARR) remained low (0.143 (95% confidence interval (CI), 0.120-0.169)), while for PBO/DMF ( = 249), ARR decreased after initiating DMF and remained low throughout (ARR 0-2 years, 0.330 (95% CI, 0.266-0.408); overall ARR (ENDORSE, 0.151 (95% CI, 0.118-0.194)). Over 10 years, 72% DMF/DMF and 73% PBO/DMF had no 24-week confirmed disability worsening.

Conclusion: Sustained DMF safety/efficacy was observed in patients followed up to 13 years, supporting DMF's positive benefit/risk profile for long-term RRMS treatment.
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http://dx.doi.org/10.1177/13524585211037909DOI Listing
September 2021

Death Anxiety and Attitudes towards Death in Patients with Multiple Sclerosis: An Exploratory Study.

Brain Sci 2021 Jul 22;11(8). Epub 2021 Jul 22.

Neuropsychology and Behavioral Neurology Unit, Division of Molecular and Cognitive Neuroscience, Department of Psychology, University of Basel, Birmannsgasse 8, 4055 Basel, Switzerland.

Background: Death and the anxiety of it becomes more apparent when confronted with a chronic disease. Even though multiple sclerosis (MS) is a treatable condition today, it is still accompanied by a multitude of impairments, which in turn may intensify of death anxiety.

Objective: The aim of this study is to explore the relationship between depression, anxiety and death anxiety in individuals with MS.

Methods: Fifty-six MS patients were recruited at the Department of Neurology of the University Clinic in Basel. Death anxiety was assessed using the Bochumer Questionnaire on attitude to death and death anxiety 2.0 (BOFRETTA 2.0).

Results: Scores of death anxiety towards it in MS patients were low. Only disability (EDSS) was moderately correlated with death anxiety. Depression in MS was significantly correlated with fatigue and disability, but not with the BOFRETTA 2.0.

Conclusion: Scores of death anxiety and the attitude towards death are low in this MS cohort. It was shown that both psychopathological and neurological deficits impact the subject of death with respect to multiple sclerosis.
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http://dx.doi.org/10.3390/brainsci11080964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391402PMC
July 2021

Baseline characteristics and effects of fingolimod on cognitive performance in patients with relapsing-remitting multiple sclerosis.

Eur J Neurol 2021 Aug 24. Epub 2021 Aug 24.

Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB) and MS Center, Neurology, Departments of Head, Spine and Neuromedicine and Clinical Research, University Hospital and University of Basel, Spitalstrasse 2, Basel, Schweiz, 4031, Switzerland.

Background And Purpose: Studies reporting the baseline determinants of cognitive performance and treatment effect on cognition in patients with multiple sclerosis (MS) are limited. We investigated the baseline correlates of cognition and the long-term treatment effects of fingolimod 0.5 mg once daily on cognitive processing speed and attention in patients with relapsing-remitting MS.

Methods: This post hoc analysis pooled data from the phase 3 FREEDOMS and FREEDOMS II trials (N = 1556). We assessed the correlation between baseline patient demographic and disease characteristics and baseline 3-second Paced Auditory Serial Addition Test (PASAT-3) scores (Spearman's rank test) and the changes from baseline in PASAT-3 (mixed model repeated measures model) in the fingolimod and placebo (up to 24 months) or placebo-fingolimod switched (from Month 24 up to 120 months) groups. Additionally, the predictive value of PASAT-3 score for future disease outcomes was assessed (Cox or logistic regression models).

Results: Among the variables assessed, lower PASAT-3 score at baseline correlated with higher disease burden (total brain volume, T2 lesion volume, and Expanded Disability Status Scale score), longer disease duration and older age (p < 0.0001 for all). Fingolimod significantly improved PASAT-3 scores from baseline versus placebo at 6 (1.3; p = 0.0007), 12 (1.1; p = 0.0044) and 24 months (1.1; p = 0.0028), with a sustained effect (overall treatment effect p = 0.0012) up to 120 months. Improvements were seen regardless of baseline cognitive status (PASAT quartile). Baseline PASAT-3 score was predictive of both clinical and magnetic resonance imaging measures of disease activity at Month 24 (p < 0.001 for all).

Conclusion: Early fingolimod treatment may offer long-term cognitive benefit in patients with relapsing-remitting MS.
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http://dx.doi.org/10.1111/ene.15081DOI Listing
August 2021

Quantification of Cervical Cord Cross-Sectional Area: Which Acquisition, Vertebra Level, and Analysis Software? A Multicenter Repeatability Study on a Traveling Healthy Volunteer.

Front Neurol 2021 4;12:693333. Epub 2021 Aug 4.

Department of Radiology and Nuclear Medicine, Multiple Sclerosis Center Amsterdam, Amsterdam Neuroscience Amsterdam University Medical Centers (UMC), Vrije Universiteit Medical Center (VUmc), Amsterdam, Netherlands.

Considerable spinal cord (SC) atrophy occurs in multiple sclerosis (MS). While MRI-based techniques for SC cross-sectional area (CSA) quantification have improved over time, there is no common agreement on whether to measure at single vertebral levels or across larger regions and whether upper SC CSA can be reliably measured from brain images. To compare in a multicenter setting three CSA measurement methods in terms of repeatability at different anatomical levels. To analyze the agreement between measurements performed on the cervical cord and on brain MRI. One healthy volunteer was scanned three times on the same day in six sites (three scanner vendors) using a 3T MRI protocol including sagittal 3D T1-weighted imaging of the brain (covering the upper cervical cord) and of the SC. Images were analyzed using two semiautomated methods [NeuroQLab (NQL) and the Active Surface Model (ASM)] and the fully automated Spinal Cord Toolbox (SCT) on different vertebral levels (C1-C2; C2/3) on SC and brain images and the entire cervical cord (C1-C7) on SC images only. CSA estimates were significantly smaller using SCT compared to NQL and ASM ( < 0.001), regardless of the cord level. Inter-scanner repeatability was best in C1-C7: coefficients of variation for NQL, ASM, and SCT: 0.4, 0.6, and 1.0%, respectively. CSAs estimated in brain MRI were slightly lower than in SC MRI (all ≤ 0.006 at the C1-C2 level). Despite protocol harmonization between the centers with regard to image resolution and use of high-contrast 3D T1-weighted sequences, the variability of CSA was partly scanner dependent probably due to differences in scanner geometry, coil design, and details of the MRI parameter settings. For CSA quantification, dedicated isotropic SC MRI should be acquired, which yielded best repeatability in the entire cervical cord. In the upper part of the cervical cord, use of brain MRI scans entailed only a minor loss of CSA repeatability compared to SC MRI. Due to systematic differences between scanners and the CSA quantification software, both should be kept constant within a study. The MRI dataset of this study is available publicly to test new analysis approaches.
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http://dx.doi.org/10.3389/fneur.2021.693333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371197PMC
August 2021

Regional Cerebellar Volume Loss Predicts Future Disability in Multiple Sclerosis Patients.

Cerebellum 2021 Aug 21. Epub 2021 Aug 21.

Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research and Biomedical Engineering, University Hospital Basel and University of Basel, Basel, Switzerland.

Cerebellar symptoms in multiple sclerosis (MS) are well described; however, the exact contribution of cerebellar damage to MS disability has not been fully explored. Longer-term observational periods are necessary to better understand the dynamics of pathological changes within the cerebellum and their clinical consequences. Cerebellar lobe and single lobule volumes were automatically segmented on 664 3D-T1-weighted MPRAGE scans (acquired at a single 1.5 T scanner) of 163 MS patients (111 women; mean age: 47.1 years; 125 relapsing-remitting (RR) and 38 secondary progressive (SP) MS, median EDSS: 3.0) imaged annually over 4 years. Clinical scores (EDSS, 9HPT, 25FWT, PASAT, SDMT) were determined per patient per year with a maximum clinical follow-up of 11 years. Linear mixed-effect models were applied to assess the association between cerebellar volumes and clinical scores and whether cerebellar atrophy measures may predict future disability progression. SPMS patients exhibited faster posterior superior lobe volume loss over time compared to RRMS, which was related to increase of EDSS over time. In RRMS, cerebellar volumes were significant predictors of motor scores (e.g. average EDSS, T25FWT and 9HPT) and SDMT. Atrophy of motor-associated lobules (IV-VI + VIII) was a significant predictor of future deterioration of the 9HPT of the non-dominant hand. In SPMS, the atrophy rate of the posterior superior lobe (VI + Crus I) was a significant predictor of future PASAT performance deterioration. Regional cerebellar volume reduction is associated with motor and cognitive disability in MS and may serve as a predictor for future disease progression, especially of dexterity and impaired processing speed.
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http://dx.doi.org/10.1007/s12311-021-01312-0DOI Listing
August 2021

Sustained reduction of serum neurofilament light chain over 7 years by alemtuzumab in early relapsing-remitting MS.

Mult Scler 2021 Aug 11:13524585211032348. Epub 2021 Aug 11.

Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Departments of Medicine, Biomedicine, and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.

Background: Alemtuzumab efficacy and safety was demonstrated in CARE-MS I and extension studies (CAMMS03409; TOPAZ).

Objective: Evaluate serum neurofilament light chain (sNfL) in CARE-MS I patients and highly active disease (HAD) subgroup, over 7 and 2 years for alemtuzumab and subcutaneous interferon beta-1a (SC IFNB-1a), respectively.

Methods: Patients received SC IFNB-1a 44 µg 3×/week or alemtuzumab 12 mg/day at baseline and month 12, with further as-needed 3-day courses. sNfL was measured using single-molecule array (Simoa™). HAD definition was ⩾2 relapses in year before randomization and ⩾1 baseline gadolinium-enhancing lesion.

Results: Baseline median sNfL levels were similar in alemtuzumab ( = 354) and SC IFNB-1a-treated ( = 159) patients (31.7 vs 31.4 pg/mL), but decreased with alemtuzumab versus SC IFNB-1a until year 2 (Y2; 13.2 vs 18.7 pg/mL; < 0.0001); 12.7 pg/mL for alemtuzumab at Y7. Alemtuzumab-treated patients had sNfL at/below healthy control median at Y2 (72% vs 47%; < 0.0001); 73% for alemtuzumab at Y7. HAD patients ( = 102) had higher baseline sNfL (49.4 pg/mL) versus overall population; alemtuzumab HAD patients attained similar levels (Y2, 12.8 pg/mL; Y7, 12.7 pg/mL; 75% were at/below control median at Y7).

Conclusion: Alemtuzumab was superior to SC IFNB-1a in reducing sNfL, with levels in alemtuzumab patients remaining stable through Y7.

Clinicaltrials.gov Identifier: NCT00530348, NCT00930553, NCT02255656.
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http://dx.doi.org/10.1177/13524585211032348DOI Listing
August 2021

No consensus about consensus?

Authors:
Ludwig Kappos

Neurol Res Pract 2021 Aug 6;3(1):46. Epub 2021 Aug 6.

Research Center Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital and University of Basel, Spitalstrasse 2, CH-4031, Basel, Switzerland.

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http://dx.doi.org/10.1186/s42466-021-00144-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344178PMC
August 2021

Imaging multiple sclerosis pathology at 160 μm isotropic resolution by human whole-brain ex vivo magnetic resonance imaging at 3 T.

Sci Rep 2021 07 29;11(1):15491. Epub 2021 Jul 29.

Translational Imaging in Neurology (ThINk) Basel, Department of Biomedical Engineering, University Hospital Basel and University of Basel, Gewerbestrasse 14, 4123, Allschwil, Switzerland.

Postmortem magnetic resonance imaging (MRI) of the fixed healthy and diseased human brain facilitates spatial resolutions and image quality that is not achievable with in vivo MRI scans. Though challenging-and almost exclusively performed at 7 T field strength-depicting the tissue architecture of the entire brain in fine detail is invaluable since it enables the study of neuroanatomy and uncovers important pathological features in neurological disorders. The objectives of the present work were (1) to develop a 3D isotropic ultra-high-resolution imaging approach for human whole-brain ex vivo acquisitions working on a standard clinical 3 T MRI system; and (2) to explore the sensitivity and specificity of this concept for specific pathoanatomical features of multiple sclerosis. The reconstructed images demonstrate unprecedented resolution and soft tissue contrast of the diseased human brain at 3 T, thus allowing visualization of sub-millimetric lesions in the different cortical layers and in the cerebellar cortex, as well as unique cortical lesion characteristics such as the presence of incomplete/complete iron rims, and patterns of iron accumulation. Further details such as the subpial molecular layer, the line of Gennari, and some intrathalamic nuclei are also well distinguishable.
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http://dx.doi.org/10.1038/s41598-021-94891-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322069PMC
July 2021

Plasma neurofilament light chain concentrations as a biomarker of clinical and radiologic outcomes in relapsing multiple sclerosis: Post hoc analysis of Phase 3 ozanimod trials.

Eur J Neurol 2021 Jul 22. Epub 2021 Jul 22.

Mellen Center for MS Treatment and Research, Department of Neurology, Cleveland Clinic, Cleveland, Ohio, USA.

Background And Purpose: We investigated plasma neurofilament light chain concentration (pNfL) as a biomarker for neuroaxonal damage and disease activity using data from Phase 3 trials of ozanimod in relapsing multiple sclerosis (RMS).

Methods: pNfL was measured before and after ozanimod 0.46 mg or 0.92 mg daily or interferon β-1a 30 µg weekly in the randomized, double-blind SUNBEAM and RADIANCE trials. In these post hoc analyses, we investigated relationships between pNfL (at baseline and median percentage change from baseline to Month 12 [SUNBEAM] or 24 [RADIANCE]) and clinical and magnetic resonance imaging outcomes.

Results: Median (Q1, Q3) baseline pNfL, available in 1244 of 1346 SUNBEAM participants, was 14.70 (10.16, 23.26) pg/ml and in 1109 of 1313 RADIANCE participants was 13.35 (9.42, 20.41) pg/ml. Baseline gadolinium-enhancing (GdE) and T2 lesion counts increased and brain volume decreased with increasing baseline pNfL. Baseline pNfL was higher in those with versus without on-treatment relapse. Median percentage reduction in pNfL at 12 months in SUNBEAM (n = 1238) and 24 months in RADIANCE (n = 1088) was greater for ozanimod (20%-27%) than interferon β-1a (13%-16%; p < 0.01). Greater pNfL reduction was associated with fewer GdE lesions, fewer new/enlarging T2 lesions per scan, less loss of brain volume, lower annualized relapse rate (ARR), and no evidence of disease activity. The following models predicted ARR: 0.5111 + 0.0116 × ΔNfL at 12 months (SUNBEAM) and 0.4079 + 0.0088 × ΔNfL at 24 months (RADIANCE).

Conclusions: pNfL was associated with clinical and radiologic measures of disease and treatment effects in RMS, supporting its use as a biomarker.
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http://dx.doi.org/10.1111/ene.15009DOI Listing
July 2021

Microstructure-Weighted Connectomics in Multiple Sclerosis.

Brain Connect 2021 Sep 8. Epub 2021 Sep 8.

Neurology Clinic and Policlinic, Departments of Medicine, Clinical Research and Biomedical Engineering, University Hospital Basel and University of Basel, Basel, Switzerland.

Graph theory has been applied to study the pathophysiology of multiple sclerosis (MS) since it provides global and focal measures of brain network properties that are affected by MS. Typically, the connection strength and, consequently, the network properties are computed by counting the number of streamlines (NOS) connecting couples of gray matter regions. However, recent studies have shown that this method is not quantitative. We evaluated diffusion-based microstructural measures extracted from three different models to assess the network properties in a group of 66 MS patients and 64 healthy subjects. Besides, we assessed their correlation with patients' disability and with a biological measure of neuroaxonal damage. Graph metrics extracted from connectomes weighted by intra-axonal microstructural components were the most sensitive to MS pathology and the most related to clinical disability. In contrast, measures of network segregation extracted from the connectomes weighted by maps describing extracellular diffusivity were the most related to serum concentration of neurofilament light chain. Network properties assessed with NOS were neither sensitive to MS pathology nor correlated with clinical and pathological measures of disease impact in MS patients. Using tractometry-derived graph measures in MS patients, we identified a set of metrics based on microstructural components that are highly sensitive to the disease and that provide sensitive correlates of clinical and biological deterioration in MS patients. Impact statement Graph theory has been widely used to study the alterations in the structural connectivity of multiple sclerosis (MS) patients. Usually, brain graphs used for the extraction of network metrics are created by counting the number of streamlines connecting gray matter regions, however, this method is not quantitative. In this study, we used tractometry to average the values of diffusion-based microstructural maps along the reconstructed streamlines. Our results show that network metrics extracted from the connectomes weighted on microstructural maps provide sensitive information to MS pathology, which correlate with clinical and biological measures of disease impact.
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http://dx.doi.org/10.1089/brain.2021.0047DOI Listing
September 2021

Longitudinal machine learning modeling of MS patient trajectories improves predictions of disability progression.

Comput Methods Programs Biomed 2021 Sep 18;208:106180. Epub 2021 May 18.

19 Mayis University, Samsun, Turkey.

Background And Objectives: Research in Multiple Sclerosis (MS) has recently focused on extracting knowledge from real-world clinical data sources. This type of data is more abundant than data produced during clinical trials and potentially more informative about real-world clinical practice. However, this comes at the cost of less curated and controlled data sets. In this work we aim to predict disability progression by optimally extracting information from longitudinal patient data in the real-world setting, with a special focus on the sporadic sampling problem.

Methods: We use machine learning methods suited for patient trajectories modeling, such as recurrent neural networks and tensor factorization. A subset of 6682 patients from the MSBase registry is used.

Results: We can predict disability progression of patients in a two-year horizon with an ROC-AUC of 0.85, which represents a 32% decrease in the ranking pair error (1-AUC) compared to reference methods using static clinical features.

Conclusions: Compared to the models available in the literature, this work uses the most complete patient history for MS disease progression prediction and represents a step forward towards AI-assisted precision medicine in MS.
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http://dx.doi.org/10.1016/j.cmpb.2021.106180DOI Listing
September 2021

2021 MAGNIMS-CMSC-NAIMS consensus recommendations on the use of MRI in patients with multiple sclerosis.

Lancet Neurol 2021 08 14;20(8):653-670. Epub 2021 Jun 14.

Section of Neuroradiology, Department of Radiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address:

The 2015 Magnetic Resonance Imaging in Multiple Sclerosis and 2016 Consortium of Multiple Sclerosis Centres guidelines on the use of MRI in diagnosis and monitoring of multiple sclerosis made an important step towards appropriate use of MRI in routine clinical practice. Since their promulgation, there have been substantial relevant advances in knowledge, including the 2017 revisions of the McDonald diagnostic criteria, renewed safety concerns regarding intravenous gadolinium-based contrast agents, and the value of spinal cord MRI for diagnostic, prognostic, and monitoring purposes. These developments suggest a changing role of MRI for the management of patients with multiple sclerosis. This 2021 revision of the previous guidelines on MRI use for patients with multiple sclerosis merges recommendations from the Magnetic Resonance Imaging in Multiple Sclerosis study group, Consortium of Multiple Sclerosis Centres, and North American Imaging in Multiple Sclerosis Cooperative, and translates research findings into clinical practice to improve the use of MRI for diagnosis, prognosis, and monitoring of individuals with multiple sclerosis. We recommend changes in MRI acquisition protocols, such as emphasising the value of three dimensional-fluid-attenuated inversion recovery as the core brain pulse sequence to improve diagnostic accuracy and ability to identify new lesions to monitor treatment effectiveness, and we provide recommendations for the judicious use of gadolinium-based contrast agents for specific clinical purposes. Additionally, we extend the recommendations to the use of MRI in patients with multiple sclerosis in childhood, during pregnancy, and in the post-partum period. Finally, we discuss promising MRI approaches that might deserve introduction into clinical practice in the near future.
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http://dx.doi.org/10.1016/S1474-4422(21)00095-8DOI Listing
August 2021

Chronic White Matter Inflammation and Serum Neurofilament Levels in Multiple Sclerosis.

Neurology 2021 08 4;97(6):e543-e553. Epub 2021 Jun 4.

From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.

Objective: To assess whether chronic white matter inflammation in patients with multiple sclerosis (MS) as detected in vivo by paramagnetic rim MRI lesions (PRLs) is associated with higher serum neurofilament light chain (sNfL) levels, a marker of neuroaxonal damage.

Methods: In 118 patients with MS with no gadolinium-enhancing lesions or recent relapses, we analyzed 3D-submillimeter phase MRI and sNfL levels. Histopathologic evaluation was performed in 25 MS lesions from 20 additional autopsy MS cases.

Results: In univariable analyses, participants with ≥2 PRLs (n = 43) compared to those with ≤1 PRL (n = 75) had higher age-adjusted sNfL percentiles (median, 91 and 68; < 0.001) and higher Multiple Sclerosis Severity Scale scores (MSSS median, 4.3 and 2.4; = 0.003). In multivariable analyses, sNfL percentile levels were higher in PRLs ≥2 cases (β, 16.3; 95% confidence interval [CI], 4.6-28.0; < 0.01), whereas disease-modifying treatment (DMT), Expanded Disability Status Scale (EDSS) score, and T2 lesion load did not affect sNfL. In a similar model, sNfL percentile levels were highest in cases with ≥4 PRLs (n = 30; β, 30.4; 95% CI, 15.6-45.2; < 0.01). Subsequent multivariable analysis revealed that PRLs ≥2 cases also had higher MSSS (β, 1.1; 95% CI, 0.3-1.9; < 0.01), whereas MSSS was not affected by DMT or T2 lesion load. On histopathology, both chronic active and smoldering lesions exhibited more severe acute axonal damage at the lesion edge than in the lesion center (edge vs center: = 0.004 and = 0.0002, respectively).

Conclusion: Chronic white matter inflammation was associated with increased levels of sNfL and disease severity in nonacute MS, suggesting that PRL contribute to clinically relevant, inflammation-driven neurodegeneration.
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http://dx.doi.org/10.1212/WNL.0000000000012326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424501PMC
August 2021

Intrathecal Immunoglobulin M Synthesis is an Independent Biomarker for Higher Disease Activity and Severity in Multiple Sclerosis.

Ann Neurol 2021 Sep 22;90(3):477-489. Epub 2021 Jun 22.

Neurology Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, University of Basel, Basel, Switzerland.

Objective: We aimed to determine in relapsing multiple sclerosis (MS) whether intrathecal synthesis of immunoglobulin (Ig) M and IgG is associated with outcomes reflecting inflammatory activity and chronic worsening.

Methods: We compared cerebrospinal fluid analysis, clinical and magnetic resonance imaging data, and serum neurofilament light chain (sNfL) levels at baseline and follow-up in 530 patients with relapsing MS. Patients were categorized by the presence of oligoclonal IgG bands (OCGB) and intrathecal synthesis of IgG and IgM (intrathecal fraction [IF]: IgG and IgM ). Relationships with the time to first relapse, sNfL concentrations, T2-weighted (T2w) lesions, MS Severity Score (MSSS), and time to initiation of high-efficacy therapy were analyzed in covariate-adjusted statistical models.

Results: By categorical analysis, in patients with IgM the median time to first relapse was 28 months shorter and MSSS on average higher by 1.11 steps compared with patients without intrathecal immunoglobulin synthesis. Moreover, patients with IgM had higher sNfL concentrations, more new/enlarging T2w lesions, and higher total T2w lesion counts (all p ≤ 0.01). These associations were absent or equally smaller in patients who were positive for only OCGB or OCGB/IgG . Furthermore, quantitative analyses revealed that in patients with IgM  ≥ median, the time to first relapse and to initiation of high-efficacy therapy was shorter by 32 and by 203 months, respectively (both p < 0.01), in comparison to patients with IgM  < median. Dose-dependent associations were also found for IgM but not for IgG with magnetic resonance imaging-defined disease activity and sNfL.

Interpretation: This large study supports the value of intrathecal IgM synthesis as an independent biomarker of disease activity and severity in relapsing MS. ANN NEUROL 2021;90:477-489.
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http://dx.doi.org/10.1002/ana.26137DOI Listing
September 2021

Quantitative magnetic resonance imaging towards clinical application in multiple sclerosis.

Brain 2021 06;144(5):1296-1311

Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research and Biomedical Engineering, University Hospital Basel and University of Basel, Basel, Switzerland.

Quantitative MRI provides biophysical measures of the microstructural integrity of the CNS, which can be compared across CNS regions, patients, and centres. In patients with multiple sclerosis, quantitative MRI techniques such as relaxometry, myelin imaging, magnetization transfer, diffusion MRI, quantitative susceptibility mapping, and perfusion MRI, complement conventional MRI techniques by providing insight into disease mechanisms. These include: (i) presence and extent of diffuse damage in CNS tissue outside lesions (normal-appearing tissue); (ii) heterogeneity of damage and repair in focal lesions; and (iii) specific damage to CNS tissue components. This review summarizes recent technical advances in quantitative MRI, existing pathological validation of quantitative MRI techniques, and emerging applications of quantitative MRI to patients with multiple sclerosis in both research and clinical settings. The current level of clinical maturity of each quantitative MRI technique, especially regarding its integration into clinical routine, is discussed. We aim to provide a better understanding of how quantitative MRI may help clinical practice by improving stratification of patients with multiple sclerosis, and assessment of disease progression, and evaluation of treatment response.
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http://dx.doi.org/10.1093/brain/awab029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219362PMC
June 2021

Ozanimod in relapsing multiple sclerosis: Pooled safety results from the clinical development program.

Mult Scler Relat Disord 2021 Jun 15;51:102844. Epub 2021 Feb 15.

Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital and University of Basel, Petersgraben 4, CH-4031 Basel, Switzerland. Electronic address:

Background: Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for the treatment of relapsing multiple sclerosis (RMS). In phase 3 trials, ozanimod was well tolerated and superior to interferon beta-1a 30 µg once-weekly in reducing clinical and radiologic disease activity. The objective of this integrated safety analysis was to evaluate the safety of extended ozanimod exposure in participants with RMS from all clinical trials and compare it with phase 3 trial data.

Methods: We report pooled incidence and study duration‒adjusted incidence rates (IR) of treatment-emergent adverse events (TEAEs) from an interim data cut (January 31, 2019) of RMS participants treated with ozanimod. Data were pooled from a phase 1 pharmacokinetic/pharmacodynamic trial, a placebo-controlled phase 2 trial with dose-blinded extension, 2 large active-controlled phase 3 trials, and an open-label extension (OLE). Results were compared with pooled phase 3 trial data.

Results: At the data cutoff, 2631 RMS participants had exposure to ozanimod 0.92 mg (mean 32.0 months) and 2787 had exposure to either ozanimod 0.46 or 0.92 mg (mean 37.1 months). The IRs per 1000 person-years (PY) for any TEAE (772.2) and serious TEAEs (33.2) in the overall population were similar to those in the phase 3 population (896.1 and 31.2, respectively). There were no serious opportunistic infections. There were no second-degree or higher atrioventricular blocks on electrocardiogram. Hepatic enzyme elevations declined over time. Malignancy rates remained low with longer exposure. Pulmonary function tests showed minimal reductions in lung function. Seven ozanimod-treated participants with comorbid risk factors had confirmed macular edema, including 3 in the ongoing OLE.

Conclusions: Safety results in this larger RMS population with greater ozanimod exposure demonstrated no new safety concerns and were consistent with phase 3 trial results.
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http://dx.doi.org/10.1016/j.msard.2021.102844DOI Listing
June 2021

GAMER-MRI in Multiple Sclerosis Identifies the Diffusion-Based Microstructural Measures That Are Most Sensitive to Focal Damage: A Deep-Learning-Based Analysis and Clinico-Biological Validation.

Front Neurosci 2021 6;15:647535. Epub 2021 Apr 6.

Translational Imaging in Neurology (ThINk) Basel, Department of Biomedical Engineering, University Hospital Basel and University of Basel, Basel, Switzerland.

Conventional magnetic resonance imaging (cMRI) in multiple sclerosis (MS) patients provides measures of focal brain damage and activity, which are fundamental for disease diagnosis, prognosis, and the evaluation of response to therapy. However, cMRI is insensitive to the damage to the microenvironment of the brain tissue and the heterogeneity of MS lesions. In contrast, the damaged tissue can be characterized by mathematical models on multishell diffusion imaging data, which measure different compartmental water diffusion. In this work, we obtained 12 diffusion measures from eight diffusion models, and we applied a deep-learning attention-based convolutional neural network (CNN) (GAMER-MRI) to select the most discriminating measures in the classification of MS lesions and the perilesional tissue by attention weights. Furthermore, we provided clinical and biological validation of the chosen metrics-and of their most discriminative combinations-by correlating their respective mean values in MS patients with the corresponding Expanded Disability Status Scale (EDSS) and the serum level of neurofilament light chain (sNfL), which are measures of disability and neuroaxonal damage. Our results show that the neurite density index from neurite orientation and dispersion density imaging (NODDI), the measures of the intra-axonal and isotropic compartments from microstructural Bayesian approach, and the measure of the intra-axonal compartment from the spherical mean technique NODDI were the most discriminating (respective attention weights were 0.12, 0.12, 0.15, and 0.13). In addition, the combination of the neurite density index from NODDI and the measures for the intra-axonal and isotropic compartments from the microstructural Bayesian approach exhibited a stronger correlation with EDSS and sNfL than the individual measures. This work demonstrates that the proposed method might be useful to select the microstructural measures that are most discriminative of focal tissue damage and that may also be combined to a unique contrast to achieve stronger correlations to clinical disability and neuroaxonal damage.
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http://dx.doi.org/10.3389/fnins.2021.647535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055933PMC
April 2021

Development and evaluation of a manual segmentation protocol for deep grey matter in multiple sclerosis: Towards accelerated semi-automated references.

Neuroimage Clin 2021 6;30:102659. Epub 2021 Apr 6.

Radiology and Nuclear Medicine, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Location VUmc, Amsterdam, NL, Netherlands.

Background: Deep grey matter (dGM) structures, particularly the thalamus, are clinically relevant in multiple sclerosis (MS). However, segmentation of dGM in MS is challenging; labeled MS-specific reference sets are needed for objective evaluation and training of new methods.

Objectives: This study aimed to (i) create a standardized protocol for manual delineations of dGM; (ii) evaluate the reliability of the protocol with multiple raters; and (iii) evaluate the accuracy of a fast-semi-automated segmentation approach (FASTSURF).

Methods: A standardized manual segmentation protocol for caudate nucleus, putamen, and thalamus was created, and applied by three raters on multi-center 3D T1-weighted MRI scans of 23 MS patients and 12 controls. Intra- and inter-rater agreement was assessed through intra-class correlation coefficient (ICC); spatial overlap through Jaccard Index (JI) and generalized conformity index (CIgen). From sparse delineations, FASTSURF reconstructed full segmentations; accuracy was assessed both volumetrically and spatially.

Results: All structures showed excellent agreement on expert manual outlines: intra-rater JI > 0.83; inter-rater ICC ≥ 0.76 and CIgen ≥ 0.74. FASTSURF reproduced manual references excellently, with ICC ≥ 0.97 and JI ≥ 0.92.

Conclusions: The manual dGM segmentation protocol showed excellent reproducibility within and between raters. Moreover, combined with FASTSURF a reliable reference set of dGM segmentations can be produced with lower workload.
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http://dx.doi.org/10.1016/j.nicl.2021.102659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082260PMC
July 2021

Disease-modifying therapies and SARS-CoV-2 vaccination in multiple sclerosis: an expert consensus.

J Neurol 2021 Nov 12;268(11):3961-3968. Epub 2021 Apr 12.

MS Center and Neurology Unit, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132, Milan, Italy.

Coronavirus disease (COVID-19) appeared in December 2019 in the Chinese city of Wuhan and has quickly become a global pandemic. The disease is caused by the severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2), an RNA beta coronavirus phylogenetically similar to SARS coronavirus. To date, more than 132 million cases of COVID19 have been recorded in the world, of which over 2.8 million were fatal ( https://coronavirus.jhu.edu/map.html ). A huge vaccination campaign has started around the world since the end of 2020. The availability of vaccines has raised some concerns among neurologists regarding the safety and efficacy of vaccination in patients with multiple sclerosis (MS) taking immunomodulatory or immunosuppressive therapies.
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http://dx.doi.org/10.1007/s00415-021-10545-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038920PMC
November 2021

Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study: A Randomized Clinical Trial.

JAMA Neurol 2021 May;78(5):558-567

Neurology and Research Center for Clinical Neuroimmunology and Neuroscience Basel, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering University Hospital and University of Basel, Basel, Switzerland.

Importance: To our knowledge, the Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM) trial is the first phase 3 study comparing 2 oral disease-modifying therapies for relapsing multiple sclerosis (RMS).

Objective: To compare the efficacy of ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P1) modulator with teriflunomide, a pyrimidine synthesis inhibitor, approved for the treatment of patients with RMS.

Design, Setting, And Participants: This multicenter, double-blind, active-comparator, superiority randomized clinical trial enrolled patients from April 27, 2015, to May 16, 2019, who were aged 18 to 55 years and had been diagnosed with multiple sclerosis per 2010 McDonald criteria, with a relapsing course from the onset, Expanded Disability Status Scale (EDSS) scores of 0 to 5.5, and recent clinical or magnetic resonance imaging disease activity.

Interventions: Patients were randomized (1:1) to 20 mg of ponesimod or 14 mg of teriflunomide once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1P1 modulators and a follow-up period of 30 days.

Main Outcomes And Measures: The primary end point was the annualized relapse rate. The secondary end points were the changes in symptom domain of Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) at week 108, the number of combined unique active lesions per year on magnetic resonance imaging, and time to 12-week and 24-week confirmed disability accumulation. Safety and tolerability were assessed. Exploratory end points included the percentage change in brain volume and no evidence of disease activity (NEDA-3 and NEDA-4) status.

Results: For 1133 patients (567 receiving ponesimod and 566 receiving teriflunomide; median [range], 37.0 [18-55] years; 735 women [64.9%]), the relative rate reduction for ponesimod vs teriflunomide in the annualized relapse rate was 30.5% (0.202 vs 0.290; P < .001); the mean difference in FSIQ-RMS, -3.57 (-0.01 vs 3.56; P < .001); the relative risk reduction in combined unique active lesions per year, 56% (1.405 vs 3.164; P < .001); and the reduction in time to 12-week and 24-week confirmed disability accumulation risk estimates, 17% (10.1% vs 12.4%; P = .29) and 16% (8.1% vs 9.9; P = .37), respectively. Brain volume loss at week 108 was lower by 0.34% (-0.91% vs -1.25%; P < .001); the odds ratio for NEDA-3 achievement was 1.70 (25.0% vs 16.4%; P < .001). Incidence of treatment-emergent adverse events (502 of 565 [88.8%] vs 499 of 566 [88.2%]) and serious treatment-emergent adverse events (49 [8.7%] vs 46 [8.1%]) was similar for both groups. Treatment discontinuations because of adverse events was more common in the ponesimod group (49 of 565 [8.7%] vs 34 of 566 [6.0%]).

Conclusions And Relevance: In this study, ponesimod was superior to teriflunomide on annualized relapse rate reduction, fatigue, magnetic resonance imaging activity, brain volume loss, and no evidence of disease activity status, but not confirmed disability accumulation. The safety profile was in line with the previous safety observations with ponesimod and the known profile of other S1P receptor modulators.

Trial Registration: ClinicalTrials.gov Identifier: NCT02425644.
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http://dx.doi.org/10.1001/jamaneurol.2021.0405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008435PMC
May 2021

Disability improvement as a clinically relevant outcome in clinical trials of relapsing forms of multiple sclerosis.

Mult Scler 2021 Mar 26:13524585211000280. Epub 2021 Mar 26.

Research Center for clinical Neuroimmunology and Neuroscience Basel (RC2NB) and MS Center, Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital, University of Basel, Basel, Switzerland.

Background: Disease-modifying therapies (DMTs) can reduce the risk of disability worsening in patients with relapsing forms of multiple sclerosis (RMS). High-efficacy DMTs can lead to confirmed or sustained disability improvement (CDI and SDI).

Objective And Methods: Post hoc analyses of data from the TRANSFORMS, FREEDOMS, and FREEDOMS II trials and their extensions assessed the effects of fingolimod (0.5-1.25 mg/day) on stabilizing or improving disability over ⩽8 years in participants with RMS. CDI and SDI rates were compared between participants initially randomized to fingolimod, interferon (IFNβ-1a), or placebo.

Results: At 8 years' follow-up in TRANSFORMS, 35.1% (95% confidence interval [CI], 28.2%-43.1%) of assessed participants in the IFNβ-1a-fingolimod switch group and 41.9% (36.6%-47.6%) on continuous fingolimod experienced CDI; disability did not worsen in approximately 70%. Similar results were seen in the combined FREEDOMS population. Proportionally fewer TRANSFORMS participants achieved SDI in the IFNβ-1a-fingolimod switch group than on continuous fingolimod (5.4% [3.0%-9.5%] vs 14.2% [10.8%-18.4%],  = 0.01).

Conclusion: CDI and SDI are outcomes of interest for clinical trials and for long-term follow-up of participants with RMS. Monitoring CDI and SDI in addition to disability worsening may facilitate understanding of the therapeutic benefit of RMS treatments.
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http://dx.doi.org/10.1177/13524585211000280DOI Listing
March 2021

Safety and efficacy of daclizumab beta in patients with relapsing multiple sclerosis in a 5-year open-label study (EXTEND): final results following early termination.

Ther Adv Neurol Disord 2021 26;14:1756286420987941. Epub 2021 Feb 26.

Biogen, Cambridge, MA, USA.

Background: EXTEND (NCT01797965), an open-label extension study, evaluated the safety and efficacy of daclizumab beta in participants with relapsing multiple sclerosis (MS) who had completed the randomized DECIDE study.

Methods: Eligible participants who received either daclizumab beta or interferon beta-1a in DECIDE received daclizumab beta 150 mg subcutaneously every 4 weeks for up to 5 years in EXTEND, followed by 24 weeks of post-dosing follow-up. Safety and tolerability were evaluated, as were clinical efficacy and magnetic resonance imaging (MRI). EXTEND was terminated ahead of schedule by the sponsors.

Results: The total safety population ( = 1203) received at least one dose of daclizumab beta in EXTEND. In the DECIDE and EXTEND combined periods, the median number of doses of daclizumab beta was 53; median time on treatment was 196 weeks. By 24 September 2018, the end of the study, 110/1203 (9%) participants had completed the protocol-specified treatment period and 1101/1203 (92%) had experienced an adverse event (AE). The most commonly reported AEs were MS relapse, nasopharyngitis, and upper respiratory tract infection. Hepatic events (18%), cutaneous events (45%), and infections (62%) were common treatment-related AEs. The incidence of serious AEs was 29%, most commonly MS relapse and infections. The incidence of immune-mediated disorders was 2%; three of seven were encephalitis. Two of six deaths were considered treatment related. In participants who received continuous daclizumab beta throughout DECIDE and EXTEND, the treatment effects on clinical and MRI outcomes were maintained for up to 6 years.

Conclusion: Results from the combined DECIDE-EXTEND study elucidate outcomes of longer-term treatment with daclizumab beta in the clinical trial setting and underscore the importance of pharmacovigilance with immunomodulatory therapies in the real-world setting.
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http://dx.doi.org/10.1177/1756286420987941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934044PMC
February 2021

Risk of requiring a wheelchair in primary progressive multiple sclerosis: Data from the ORATORIO trial and the MSBase registry.

Eur J Neurol 2021 Mar 16. Epub 2021 Mar 16.

McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA.

Background And Purpose: Reaching Expanded Disability Status Scale (EDSS) ≥7.0 represents the requirement for a wheelchair. Here we (i) assess the effect of ocrelizumab on time to EDSS ≥7.0 over the ORATORIO (NCT01194570) double-blind and extended controlled periods (DBP+ECP), (ii) quantify likely long-term benefits by extrapolating results, and (iii) assess the plausibility of extrapolations using an independent real-world cohort (MSBase registry; ACTRN12605000455662).

Methods: Post hoc analyses assessing time to 24-week confirmed EDSS ≥7.0 in two cohorts of patients with primary progressive multiple sclerosis (baseline EDSS 3.0-6.5) were investigated in ORATORIO and MSBase.

Results: In the ORATORIO DBP+ECP, ocrelizumab reduced the risk of 24-week confirmed EDSS ≥7.0 (hazard ratio = 0.54, 95% confidence interval [CI]: 0.31-0.92; p = 0.022). Extrapolated median time to 24-week confirmed EDSS ≥7.0 was 12.1 and 19.2 years for placebo and ocrelizumab, respectively (7.1-year delay [95% CI: -4.3 to 18.4]). In MSBase, the median time to 24-week confirmed EDSS ≥7.0 was 12.4 years.

Conclusions: Compared with placebo, ocrelizumab significantly delayed time to 24-week confirmed wheelchair requirement in ORATORIO. The plausibility of the extrapolated median time to reach this milestone in the placebo group was supported by observed real-world data from MSBase. Extrapolated benefits for ocrelizumab over placebo could represent a truly meaningful delay in loss of ambulation and independence.
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http://dx.doi.org/10.1111/ene.14824DOI Listing
March 2021

Risk of requiring a walking aid after 6.5 years of ocrelizumab treatment in patients with relapsing multiple sclerosis: Data from the OPERA I and OPERA II trials.

Eur J Neurol 2021 Mar 16. Epub 2021 Mar 16.

McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.

Background And Purpose: Requiring a walking aid is a fundamental milestone in multiple sclerosis (MS), represented by an Expanded Disability Status Scale (EDSS) score ≥6.0. In the present study, we assess the effect of ocrelizumab (OCR) on time to EDSS score ≥6.0 in relapsing MS.

Methods: Time to EDSS score ≥6.0 confirmed for ≥24 and ≥48 weeks was assessed over the course of 6.5 years (336 weeks) in the double-blind period (DBP) and open-label extension (OLE) period of the OPERA I (NCT01247324) and OPERA II (NCT01412333) studies.

Results: Time to reach EDSS score ≥6.0 was significantly delayed in those initially randomized to OCR versus interferon. Over 6.5 years, the risk of requiring a walking aid confirmed for ≥24 weeks was 34% lower among those who initiated OCR earlier versus delayed treatment (average hazard ratio [HR] DBP + OLE 0.66, 95% confidence interval [CI] 0.45-0.95; p = 0.024); the risk of requiring a walking aid confirmed for ≥48 weeks was 46% lower (average HR DBP+OLE 0.54, 95% CI 0.35-0.83; p = 0.004).

Conclusion: The reduced risk of requiring a walking aid in earlier initiators of OCR demonstrates the long-term implications of earlier highly effective treatment.
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http://dx.doi.org/10.1111/ene.14823DOI Listing
March 2021

Myelin and axon pathology in multiple sclerosis assessed by myelin water and multi-shell diffusion imaging.

Brain 2021 07;144(6):1684-1696

Department of Medicine and Biomedical Engineering, Translational Imaging in Neurology Basel, University Hospital Basel and University of Basel, Basel, Switzerland.

Damage to the myelin sheath and the neuroaxonal unit is a cardinal feature of multiple sclerosis; however, a detailed characterization of the interaction between myelin and axon damage in vivo remains challenging. We applied myelin water and multi-shell diffusion imaging to quantify the relative damage to myelin and axons (i) among different lesion types; (ii) in normal-appearing tissue; and (iii) across multiple sclerosis clinical subtypes and healthy controls. We also assessed the relation of focal myelin/axon damage with disability and serum neurofilament light chain as a global biological measure of neuroaxonal damage. Ninety-one multiple sclerosis patients (62 relapsing-remitting, 29 progressive) and 72 healthy controls were enrolled in the study. Differences in myelin water fraction and neurite density index were substantial when lesions were compared to healthy control subjects and normal-appearing multiple sclerosis tissue: both white matter and cortical lesions exhibited a decreased myelin water fraction and neurite density index compared with healthy (P < 0.0001) and peri-plaque white matter (P < 0.0001). Periventricular lesions showed decreased myelin water fraction and neurite density index compared with lesions in the juxtacortical region (P < 0.0001 and P < 0.05). Similarly, lesions with paramagnetic rims showed decreased myelin water fraction and neurite density index relative to lesions without a rim (P < 0.0001). Also, in 75% of white matter lesions, the reduction in neurite density index was higher than the reduction in the myelin water fraction. Besides, normal-appearing white and grey matter revealed diffuse reduction of myelin water fraction and neurite density index in multiple sclerosis compared to healthy controls (P < 0.01). Further, a more extensive reduction in myelin water fraction and neurite density index in normal-appearing cortex was observed in progressive versus relapsing-remitting participants. Neurite density index in white matter lesions correlated with disability in patients with clinical deficits (P < 0.01, beta = -10.00); and neurite density index and myelin water fraction in white matter lesions were associated to serum neurofilament light chain in the entire patient cohort (P < 0.01, beta = -3.60 and P < 0.01, beta = 0.13, respectively). These findings suggest that (i) myelin and axon pathology in multiple sclerosis is extensive in both lesions and normal-appearing tissue; (ii) particular types of lesions exhibit more damage to myelin and axons than others; (iii) progressive patients differ from relapsing-remitting patients because of more extensive axon/myelin damage in the cortex; and (iv) myelin and axon pathology in lesions is related to disability in patients with clinical deficits and global measures of neuroaxonal damage.
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http://dx.doi.org/10.1093/brain/awab088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374972PMC
July 2021

Impact of complement activation on clinical outcomes in multiple sclerosis.

Ann Clin Transl Neurol 2021 04 1;8(4):944-950. Epub 2021 Mar 1.

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, 48149, Germany.

We determined activation profiles of the classical and alternative complement pathway in 39 treatment-naïve patients with early relapse-onset MS. Plasma concentrations of complement fragments were unchanged in MS compared to 32 patients with non-inflammatory neurological diseases. Profiles in patients experiencing clinical exacerbations did not differ from patients with stable disease and did not correlate with baseline EDSS, numbers of T2 lesions and time to second relapse. Long-term EDSS outcomes 4 years after diagnosis did not significantly correlate with baseline complement levels. These data do not support the use of complement activation products as biomarkers for disease activity in early MS.
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http://dx.doi.org/10.1002/acn3.51334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045986PMC
April 2021
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