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you are agreeing to our Cookie Policy | Continue JAMA Network HomeJAMA Neurology This Issue Views 2,357 Citations 0 60 Full Text Share Comment Original Investigation May 15, 2023 Comparative Effectiveness of Autologous Hematopoietic Stem Cell Transplant vs Fingolimod, Natalizumab, and Ocrelizumab in Highly Active Relapsing-Remitting Multiple Sclerosis Tomas Kalincik, MD, PhD1,2; Sifat Sharmin, PhD1,2; Izanne Roos, MBChB, PhD1,2; Mark S. Freedman, MD3; Harold Atkins, MD4; Joachim Burman, MD, PhD5; Jennifer Massey, MBBS, PhD6,7; Ian Sutton, MBBS, PhD6,8; Barbara Withers, MD, PhD7,9; Richard Macdonell, MD, PhD10,11; Andrew Grigg, MD, PhD11,12; Øivind Torkildsen, MD, PhD13; Lars Bo, MD, PhD13; Anne Kristine Lehmann, MD, PhD14; Eva Kubala Havrdova, MD, PhD15; Eva Krasulova, MD, PhD15; Marek Trněný, MD, PhD16; Tomas Kozak, MD, PhD17; Anneke van der Walt, MBBS, PhD18,19; Helmut Butzkueven, MBBS, PhD18,19; Pamela McCombe, MBBS20,21; Olga Skibina, MBBS18,22,23; Jeannette Lechner-Scott, MD, PhD24,25; Barbara Willekens, MD, PhD26,27; Elisabetta Cartechini, MD28; Serkan Ozakbas, MD29; Raed Alroughani, MD30; Jens Kuhle, MD, PhD31; Francesco Patti, MD32,33; Pierre Duquette, MD34; Alessandra Lugaresi, MD, PhD35,36; Samia J. Khoury, MD, PhD37; Mark Slee, MD, PhD38; Recai Turkoglu, MD39; Suzanne Hodgkinson, MD40; Nevin John, MD, PhD41,42; Davide Maimone, MD43; Maria Jose Sa, MD44; Vincent van Pesch, MD, PhD45,46; Oliver Gerlach, MD, PhD47,48; Guy Laureys, MD49; Liesbeth Van Hijfte, MD49; Rana Karabudak, MD50; Daniele Spitaleri, MD51; Tunde Csepany, MD, PhD52; Riadh Gouider, MD53,54; Tamara Castillo-Triviño, MD55; Bruce Taylor, MD, PhD56,57; Basil Sharrack, MD, PhD58; John A. Snowden, MD, PhD59; and the MSBase Study Group Collaborators; and the MSBase Study Group Authors Author Affiliations JAMA Neurol. 2023;80(7):702-713. doi:10.1001/jamaneurol.2023.1184 editorial comment iconEditorial Comment Key Points Question What is the comparative effectiveness of autologous hematopoietic stem cell transplant (AHSCT) vs individual most potent disease-modifying therapies for relapsing-remitting multiple sclerosis (MS), such as natalizumab or ocrelizumab? Findings In this observational comparative effectiveness study of 4915 individuals using a composite cohort from specialized MS centers and the MSBase international registry, the effectiveness of AHSCT was compared with 1 medium-efficacy and 2 high-efficacy disease-modifying therapies (fingolimod, natalizumab, and ocrelizumab) in patients with relapsing-remitting MS, high frequency of relapses, and moderate disability. Over 5 years, AHSCT was associated with substantially lower relapse rate than fingolimod and marginally lower relapse rate than natalizumab and was also associated with a higher rate of recovery from disability compared with fingolimod and natalizumab, but no evidence of difference in clinical outcomes between AHSCT and ocrelizumab was found at 3-year follow-up. Meaning The results indicate that in relapsing-remitting MS, the clinical effectiveness of AHSCT is considerably superior to fingolimod and marginally superior to natalizumab. Abstract Importance Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS). Objective To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials. Design, Setting, and Participants This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics. Exposure AHSCT vs fingolimod, natalizumab, or ocrelizumab. Main outcomes Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. Results Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730 [49.0%]), AHSCT (146 [87.4%]) was associated with marginally lower ARR (mean [SD], 0.08 [0.31] vs 0.10 [0.34]), similar risk of disability worsening (HR, 1.06; 95% CI, 0.54-2.09), and higher chance of disability improvement (HR, 2.68; 95% CI, 1.72-4.18) over 5 years. AHSCT (110 [65.9%]) and ocrelizumab (343 [49.0%]) were associated with similar ARR (mean [SD], 0.09 [0.34] vs 0.06 [0.32]), disability worsening (HR, 1.77; 95% CI, 0.61-5.08), and disability improvement (HR, 1.37; 95% CI, 0.66-2.82) over 3 years. AHSCT-related mortality occurred in 1 of 159 patients (0.6%). Conclusion In this study, the association of AHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effectiveness of AHSCT and ocrelizumab over a shorter available follow-up time.

Cladribine (2-chlorodeoxyadenosine, 2CdA) is one of the most effective disease-modifying drugs for multiple sclerosis (MS). Cladribine is a synthetic purine nucleoside analog that induces cell death of lymphocytes and oral cladribine treatment leads to a long-lasting disease stabilization, potentially attributable to immune reconstitution. In addition to its effects on lymphocytes, cladribine has been shown to have immunomodulatory effects on innate immune cells, including dendritic cells and monocytes, which could also contribute to its therapeutic efficacy. However, whether cladribine can modulate human macrophage/microglial activation or monocyte differentiation is currently unknown. The aim of this study was to determine the immunomodulatory effects of cladribine upon monocytes, monocyte-derived macrophages (MDMs) and microglia. We analyzed the phenotype and differentiation of monocytes from MS patients receiving their first course of oral cladribine both before and three weeks after the start of treatment. Flow cytometric analysis of monocytes from MS patients undergoing cladribine treatment revealed that the number and composition of CD14/CD16 monocyte subsets remained unchanged after treatment. Furthermore, after differentiation with M-CSF, such MDMs from treated MS patients showed no difference in gene expression of the inflammatory markers compared to baseline. We further investigated the direct effects of cladribine in vitro using human adult primary MDMs and microglia. GM-CSF-derived MDMs were more sensitive to cell death than M-CSF-derived MDMs. In addition, MDMs treated with cladribine showed increased expression of costimulatory molecules CD80 and CD40, as well as expression of anti-inflammatory, pro-trophic genes IL10 and MERTK, depending on the differentiation condition. Cladribine treatment in vitro did not modulate the expression of activation markers in human microglia. Our study shows that cladribine treatment in vitro affects the differentiation of monocytes into macrophages by modulating the expression of activation markers, which might occur similarly in tissue after their infiltration in the CNS during MS.

Additional file 1. SPIRIT 2013 checklist: recommended items to address in a clinical trial protocol and related documents.

In order to further investigate the molecular mechanisms that regulate oligodendrocyte (OC) survival, we utilized microarrays to characterize changes in OC gene expression after exposure to the cytokines neurotrophin3, insulin, or leukemia inhibitory factor (LIF) in vitro. We identified and validated the induction and secretion of the neuropeptide galanin in OCs, specifically in response to LIF. We next established that galanin is an OC survival factor and showed that autocrine or paracrine galanin secretion mediates LIF-induced OC survival in vitro. We also revealed that galanin is up-regulated in OCs in the cuprizone model of central demyelination, and that oligodendroglial galanin expression is significantly regulated by endogenous LIF in this context. We also showed that knock-out of galanin reduces OC survival and exacerbates callosal demyelination in the cuprizone model. These findings suggest a potential role for the use of galanin agonists in the treatment of human demyelinating diseases.

Cognitive dysfunction is common in patients with multiple sclerosis (MS). Saccadic eye movement paradigms such as antisaccades (AS) can sensitively interrogate cognitive function, in particular, the executive and attentional processes of response selection and inhibition. Although we have previously demonstrated significant deficits in the generation of AS in MS patients, the neuropathological changes underlying these deficits were not elucidated. In this study, 24 patients with relapsing–remitting MS underwent testing using an AS paradigm. Rank correlation and multiple regression analyses were subsequently used to determine whether AS errors in these patients were associated with: (i) neurological and radiological abnormalities, as measured by standard clinical techniques, (ii) cognitive dysfunction, and (iii) regionally specific cerebral white and gray‐matter damage. Although AS error rates in MS patients did not correlate with clinical disability (using the Expanded Disability Status Score), T2 lesion load or brain parenchymal fraction, AS error rate did correlate with performance on the Paced Auditory Serial Addition Task and the Symbol Digit Modalities Test, neuropsychological tests commonly used in MS. Further, voxel‐wise regression analyses revealed associations between AS errors and reduced fractional anisotropy throughout most of the cerebellum, and increased mean diffusivity in the cerebellar vermis. Region‐wise regression analyses confirmed that AS errors also correlated with gray‐matter atrophy in the cerebellum right VI subregion. These results support the use of the AS paradigm as a marker for cognitive dysfunction in MS and implicate structural and microstructural changes to the cerebellum as a contributing mechanism for AS deficits in these patients. Hum Brain Mapp 35:2310–2319, 2014. © 2013 Wiley Periodicals, Inc.

Supplemental Material for Early imaging predictors of longer term multiple sclerosis risk and severity in acute optic neuritis by Sanuji Gajamange Department of Medicine and Radiology, University of Melbourne, Australia Jim Stankovich Department of Neuroscience, Central Clinical School, Monash University, Australia Gary Egan Monash Biomedical Imaging, Monash University, Australia Trevor Kilpatrick The Florey Institute of Neuroscience and Mental Health, Australia Helmut Butzkueven, Joanne Fielding, Anneke van der Walt and Scott Kolbe in Multiple Sclerosis Journal – Experimental, Translational and Clinical

Supplemental Material for Early imaging predictors of longer term multiple sclerosis risk and severity in acute optic neuritis by Sanuji Gajamange Department of Medicine and Radiology, University of Melbourne, Australia Jim Stankovich Department of Neuroscience, Central Clinical School, Monash University, Australia Gary Egan Monash Biomedical Imaging, Monash University, Australia Trevor Kilpatrick The Florey Institute of Neuroscience and Mental Health, Australia Helmut Butzkueven, Joanne Fielding, Anneke van der Walt and Scott Kolbe in Multiple Sclerosis Journal – Experimental, Translational and Clinical