Search

Background: The long-term effect of high efficacy disease modifying therapy (DMT) on neurodegeneration in people with multiple sclerosis (pwMS) is largely unknown. The aim of this study was to evaluate the long-term effect of natalizumab (NTZ) or fingolimod (FTY) therapy on the evolution of brain atrophy compared to moderate efficacy DMT in a real-world clinical setting., Methods: A total of 438 pwMS with 2,439 MRI exams during treatment were analyzed: 252 pwMS treated with moderate efficacy DMT, 130 with NTZ and 56 with FTY. Evolution of brain atrophy was analyzed over an average follow-up of 6.6 years after treatment initiation. Brain segmentation was performed on clinical 3D-FLAIRs using SynthSeg and regional brain volume changes over time were compared between the treatment groups., Results: Total brain, white matter and deep gray matter atrophy rates did not differ between moderate efficacy DMTs, NTZ and FTY. Annualized ventricle growth rates were lower in pwMS treated with NTZ (1.1 %/year) compared with moderate efficacy DMT (2.4 %/year, p < 0.001) and similar to FTY (2.0 %/year, p = 0.051). Cortical atrophy rates were lower in NTZ (-0.08 %/year) compared with moderate efficacy DMT (-0.16 %/year, p = 0.048)., Conclusion: In a real-world clinical setting, pwMS treated with NTZ had slower ventricular expansion and cortical atrophy compared to those treated with moderate efficacy DMT., Competing Interests: Declaration of competing interest E.M.M. Strijbis, E.M.E. Coerver, Z.L.E. van Kempen and B. Jasperse have nothing to disclose. S. Noteboom is supported by research grants from Atara Biotherapeutics, Merck and Biogen. J. Killestein reports grants from Biogen, Novartis, TEVA, Bayer Schering Pharma, Glaxo Smith Kline, Merck, Genzyme and Roche. H. Vrenken has received research grants from Pfizer, Merck Serono, Novartis, and Teva, speaker honoraria from Novartis, and consulting fees from Merck Serono; all funds were paid directly to his institution. M.M. Schoonheim serves on the editorial board of Neurology and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS and ZonMW (Vidi grant, project number 09150172010056) and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, EIP, Sanofi, MedDay and Merck. M.D. Steenwijk is supported by research grants from Atara Biotherapeutics, Merck and Biogen., (Copyright © 2024. Published by Elsevier B.V.)

Background: Focal inflammatory disease activity in relapsing-remitting multiple sclerosis (RRMS) diminishes with increasing age. Here we use patient-level data from randomised controlled trials (RCTs) of natalizumab treatment in RRMS to investigate the association of age and inflammatory disease activity., Methods: We used patient-level data from the AFFIRM (natalizumab vs placebo in relapsing-remitting MS, NCT00027300) and SENTINEL (natalizumab plus interferon beta vs interferon beta in relapsing remitting MS, NCT00030966) RCTs. We determined the proportion of participants developing new T2 lesions, contrast-enhancing lesions (CELs) and relapses over 2 years of follow-up as a function of age, and investigated the association of age with time to first relapse using time-to-event analyses., Results: At baseline, there were no differences between age groups in T2 lesion volume and number of relapses in the year before inclusion. In SENTINEL, older participants had a significantly lower number of CELs. During both trials, the number of new CELs and the proportion of participants developing new CELs were significantly lower in older age groups. The number of new T2 lesions and the proportion of participants with any radiological disease activity during follow-up were also lower in older age groups, especially in the control arms., Conclusions: Older age is associated with a lower prevalence and degree of focal inflammatory disease activity in treated and untreated RRMS. Our findings inform the design of RCTs, and suggest that patient age should be taken into consideration when deciding on immunomodulatory treatment in RRMS., Competing Interests: Competing interests: EMS, EC, JC, JM and ZLEvK report no disclosures. JK received grants from Biogen, Novartis, TEVA, Bayer Schering Pharma, GlaxoSmithKline, Merck, Genzyme and Roche. PR received consulting and/or speaking honoraria from Alexion, Biogen, Celgene, Roche, Sanofi Genzyme, Viela and EMD Serono. JDB received honoraria from serving on the scientific advisory board and speaker’s bureau of Biogen, Celgene, EMD Serono, Genentech and Novartis. He has received research support from AbbVie, Alexion, Alkermes, Biogen, Celgene, Sanofi Genzyme, Genentech, Novartis and TG Therapeutics. GC served on data and safety monitoring boards: AstraZeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Horizon Pharmaceuticals, Hisun Pharmaceuticals, Mapi Pharmaceuticals, Merck, Merck/Pfizer, Opko Biologics, OncoImmune, Neurim, Novartis, Ophazyme, Sanofi-Aventis, Reata Pharmaceuticals, Teva Pharmaceuticals, VielaBio, Vivus, NHLBI (Protocol Review Committee), NICHD (OPRU oversight committee); consulting or advisory boards: Biodelivery Sciences International, Biogen, Click Therapeutics, Genzyme, Genentech, GW Pharmaceuticals, Immunic, Klein-Buendel Incorporated, Medimmune, Medday, Neurogenesis, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion/Cerexis Pharmaceuticals, Roche, TG Therapeutics. GC is employed by the University of Alabama at Birmingham and President of Pythagoras, a private consulting company located in Birmingham, Alabama, USA. MK received consulting fees and travel support from Biogen, Novartis, Roche, Sanofi Genzyme and EMD Serono., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: Inflammatory disease activity in multiple sclerosis (MS) decreases with advancing age. Previous work found a decrease in contrast-enhancing lesions (CELs) with age. Here, we describe the relation of age and magnetic resonance imaging (MRI) measures of inflammatory disease activity during long-term follow-up in a large real-world cohort of people with relapse onset MS., Methods: We investigated MRI data from the long-term observational Amsterdam MS cohort. We used logistic regression models and negative binomial generalized estimating equations to investigate the associations between age and radiological disease activity after a first clinical event., Results: We included 1063 participants and 10,651 cranial MRIs. Median follow-up time was 6.1 years (interquartile range = 2.4-10.9 years). Older participants had a significantly lower risk of CELs on baseline MRI (40-50 years vs. <40 years: odds ratio [OR] = 0.640, 95% confidence interval [CI] = 0.45-0.90; >50 years vs. <40 years: OR = 0.601, 95% CI = 0.33-1.08) and a lower risk of new T2 lesions or CELs during follow-up (40-50 years vs. <40 years: OR = 0.563, 95% CI = 0.47-0.67; >50 years vs. <40 years: OR = 0.486, 95% CI = 0.35-0.68)., Conclusions: Greater age is associated with a lower risk of inflammatory MRI activity at baseline and during long-term follow-up. In patients aged >50 years, a less aggressive treatment strategy might be appropriate compared to younger patients., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: It is not known if and when first-line disease modifying therapy (DMT) can safely be discontinued in relapse onset multiple sclerosis (MS) patients., Objectives: To investigate the characteristics of patients who discontinued first-line DMT, and the occurrence of clinical and radiological inflammatory disease activity after discontinuation., Methods: We collected clinical and MRI parameters from patients with relapse onset MS in the MS Center Amsterdam and Rijnstate Hospital Arnhem who discontinued first-line DMT with no intention of restarting or switching treatment., Results: In total, 130 patients were included in the analyses. After discontinuation, 78 patients (60%) experienced disease activity. Sixty-three patients (48.5%) showed MRI activity after DMT discontinuation, 40 patients (30.8%) experienced relapse(s), and 29 patients (22.3%) restarted DMT. Higher age at DMT discontinuation was associated with a lower risk of MRI activity (45 -55 vs. <45 years: OR 0.301, p = 0.007, >55 vs. <45 years, OR: 0.296, p = 0.044), and with a lower risk of relapse(s) after discontinuation (45-55 vs. <45 years: OR=0.495, p = 0.106, >55 vs. <45 years: OR=0.081, p = 0.020)., Conclusion: Higher age at first-line DMT discontinuation is associated with lower risk and severity of radiological disease activity in MS, and a lower risk of relapse(s) after discontinuation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Background: Clinical measures in multiple sclerosis (MS) face limitations that may be overcome by utilising smartphone keyboard interactions acquired continuously and remotely during regular typing., Objective: The aim of this study was to determine the reliability and validity of keystroke dynamics to assess clinical aspects of MS., Methods: In total, 102 MS patients and 24 controls were included in this observational study. Keyboard interactions were obtained with the Neurokeys keyboard app. Eight timing-related keystroke features were assessed for reliability with intraclass correlation coefficients (ICCs); construct validity by analysing group differences (in fatigue, gadolinium-enhancing lesions on magnetic resonance imaging (MRI), and patients vs controls); and concurrent validity by correlating with disability measures., Results: Reliability was moderate in two (ICC = 0.601 and 0.742) and good to excellent in the remaining six features (ICC = 0.760-0.965). Patients had significantly higher keystroke latencies than controls. Latency between key presses correlated the highest with Expanded Disability Status Scale ( r  = 0.407) and latency between key releases with Nine-Hole Peg Test and Symbol Digit Modalities Test (ρ = 0.503 and r  = -0.553, respectively), p s < 0.001., Conclusion: Keystroke dynamics were reliable, distinguished patients and controls, and were associated with clinical disability measures. Consequently, keystroke dynamics are a promising valid surrogate marker for clinical disability in MS.

Ocrelizumab is often used as an alternative therapy in natalizumab-treated MS patients at risk for progressive multifocal leukoencephalopathy (PML). Our objective was to assess efficacy and safety of JC-virus positive patients switching (either directly or indirectly) from natalizumab to ocrelizumab. Forty-two patients were included from an observational cohort (median follow-up 21 months). No evidence of disease activity was found in 83% of direct switchers and 50% of indirect switchers. Two direct switchers were diagnosed with carry-over PML. Our data support a direct switch for adequate disease suppression, although carry-over PML illustrates the dilemma when choosing between a direct or indirect switch., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: Z.Y.G.J.v.L, A.A.T., E.A.J.W., E.M.M.S., N.F.K., B.M. and Z.L.E.K. have no conflicts of interest. F.B. acts as a consultant to Biogen Idec, Janssen Alzheimer Immunotherapy, Bayer Schering, Merck Serono, Roche, Novartis, Genzyme and Sanofi-aventis; he has received sponsorship from EU-H2020, NWO, SMSR, EU-FP7, TEVA, Novartis and Toshiba; he is on the editorial board of Radiology, Brain, Neuroradiology, Multiple Sclerosis Journal (MSJ) and Neurology; he is supported by the NIHR biomedical research centre at UCLH. C.E.T. has served on advisory boards for Roche, has received nonfinancial support in the form of research consumables from ADx NeuroSciences and Euroimmun, and has performed contract research or received grants from Probiodrug, Biogen, Esai, Toyama, Janssen Prevention Center, Boehringer, Axon Neuroscience, EIP Pharma, PeopleBio, and Roche. J. Killestein reports has accepted speaker and consulting fees from Merck, Biogen, TEVA, Sanofi, Genzyme, Roche, and Novartis., (© The Author(s) 2021.)