Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses

Mult Scler Relat Disord. 2017 Feb;12:70-78. doi: 10.1016/j.msard.2017.01.007. Epub 2017 Jan 17.

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.

Keywords: Asynchronous progressive multiple sclerosis; Axonopathy; Length-dependent; Multiple sclerosis; Progressive multiple sclerosis; Therapeutic lag.

Publication types

  • Review

MeSH terms

  • Animals
  • Axons / physiology*
  • Humans
  • Multiple Sclerosis, Chronic Progressive / diagnosis
  • Multiple Sclerosis, Chronic Progressive / drug therapy
  • Multiple Sclerosis, Chronic Progressive / physiopathology*