title: Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses.
abstract: Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials.
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK. Electronic address: g.giovannoni@qmul.ac.uk.
authors.forename: Gavin
authors.initials: G
authors.lastname: Giovannoni
authors.affiliation: Department of Biostatistics, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA. Electronic address: cutterg@uab.edu.
authors.forename: Gary
authors.initials: G
authors.lastname: Cutter
authors.affiliation: Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy. Electronic address: mariapia.sormani@unige.it.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Sormani
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland. Electronic address: shibeshih.belachew@roche.com.
authors.forename: Shibeshih
authors.initials: S
authors.lastname: Belachew
authors.affiliation: Biogen, Cambridge, MA, USA. Electronic address: robert.hyde@biogen.com.
authors.forename: Robert
authors.initials: R
authors.lastname: Hyde
authors.affiliation: Biogen, Cambridge, MA, USA. Electronic address: harold.koendgen@gmail.com.
authors.forename: Harold
authors.initials: H
authors.lastname: Koendgen
authors.affiliation: Teva Pharmaceuticals, Netanya, Israel. Electronic address: Volker.Knappertz@tevapharm.com.
authors.forename: Volker
authors.initials: V
authors.lastname: Knappertz
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. Electronic address: davorka.tomic@novartis.com.
authors.forename: Davorka
authors.initials: D
authors.lastname: Tomic
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. Electronic address: david.leppert@novartis.com.
authors.forename: David
authors.initials: D
authors.lastname: Leppert
authors.affiliation: University of Mississippi Medical Center, Jackson, MS, USA. Electronic address: rherndon@umc.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Herndon
authors.affiliation: NMR Research Unit, Queen Square MS Centre, Department of Neuroinflammation, UCL Institute of Neurology, Queen Square, London, UK. Electronic address: c.wheeler-kingshott@ucl.ac.uk.
authors.forename: Claudia A M
authors.initials: CAM
authors.lastname: Wheeler-Kingshott
authors.affiliation: NMR Research Unit, Queen Square MS Centre, Department of Neuroinflammation, UCL Institute of Neurology, Queen Square, London, UK; NIHR University College Hospitals Biomedical Research Centre (BRC), UK. Electronic address: o.ciccarelli@ucl.ac.uk.
authors.forename: Olga
authors.initials: O
authors.lastname: Ciccarelli
authors.affiliation: Wolfson Institute for Biomedical Research, UCL, London, UK. Electronic address: d.selwood@ucl.ac.uk.
authors.forename: David
authors.initials: D
authors.lastname: Selwood
authors.affiliation: Merck, Aubonne, Switzerland. Electronic address: elisabetta.verdun-di-cantogno@merckgroup.com.
authors.forename: Elisabetta Verdun
authors.initials: EV
authors.lastname: di Cantogno
authors.affiliation: Merck, Aubonne, Switzerland. Electronic address: ali-frederic.ben-amor@merckgroup.com.
authors.forename: Ali-Frederic
authors.initials: AF
authors.lastname: Ben-Amor
authors.affiliation: Department of Medicine, Imperial College, London, UK. Electronic address: p.matthews@imperial.ac.uk.
authors.forename: Paul
authors.initials: P
authors.lastname: Matthews
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK. Electronic address: d.carassiti@qmul.ac.uk.
authors.forename: Daniele
authors.initials: D
authors.lastname: Carassiti
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK. Electronic address: david.baker@qmul.ac.uk.
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK. Electronic address: k.schmierer@qmul.ac.uk.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schmierer
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D006801:Humans; D020528:Multiple Sclerosis, Chronic Progressive / Q000175:diagnosis / Q000188:drug therapy / Q000503:physiopathology*
keywords: Asynchronous progressive multiple sclerosis; Axonopathy; Length-dependent; Multiple sclerosis; Progressive multiple sclerosis; Therapeutic lag