MSFrontier

Why MS progresses

What drives worsening without relapses, and what slows it?

In short

Disability can keep worsening even when relapses have stopped. This is called progression, and it is the main cause of long-term disability.

Most medicines that stop relapses do little against it, so it is the biggest unmet need in MS.

The leading explanations are inflammation trapped inside the brain, nerve fibres running short of energy and repair that fails with age. Only a few medicines have slowed progression in trials.

Background in MS in depth

Hypotheses by status

  • Confirmed 5
  • Supported by one trial 3
  • Promising 6
  • Mixed 4
  • Results pending 17
  • Being tested 66
  • Failed early 16
  • Disproven 7
  • No clear answer 74
198
Hypotheses
34
Trials recruiting
19
Phase 3 running
2
Readouts in 90 days

Most recent results

  • O'HAND
    Phase 3Main goal metvs placebo2026
  • MS-STAT2
    Phase 3Main goal not metvs placebo2026
  • MS-SMART
    Phase 2Main goal not metvs placebo2026

Next readouts

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How the damage happens: two compartments

A useful research distinction is between peripheral immune activity and inflammation within the central nervous system. These processes interact rather than acting as two entirely separate causes of damage.[1][5]

The HERMES randomised trial showed that rituximab, which depletes CD20-positive B cells, reduced gadolinium-enhancing MRI lesions and relapses in relapsing MS. This provided clinical evidence that B cells take part in MS disease activity.[6]

Some lesions remain chronically active at their edges, involving microglia, lymphocytes and astrocytes. A subset have paramagnetic rims visible on specialised MRI. These rims are being studied as markers of chronic active lesions.[4][1][8]

What has been tried in progressive MS →

Why MS progresses: the leading hypotheses

Several interacting mechanisms have been proposed to explain progression. Their relative importance may differ between people and across the course of MS.[1][5]

Compartmentalised inflammation is one leading explanation. Immune cells in the central nervous system and activated microglia around chronic lesions may sustain injury despite control of new inflammatory activity. Tissue studies support this, although progression may not have the same cause in everyone.[1][4]

Persistent EBV is another possibility under investigation. The evidence linking infection to the onset of MS is much stronger than the evidence that ongoing viral activity drives progression. Vaccines and antivirals are ways of testing the difference.[2][3][9]

Demyelinated axons face increased energy demands, while mitochondrial dysfunction can limit the energy available. This mismatch is one proposed contributor to nerve-fibre loss in progressive MS.[5]

Age-related changes in oligodendrocyte precursor cells, which can mature into myelin-forming cells, may reduce repair capacity. Studies in aged animals support this, and early human trials are testing repair-related measures rather than establishing restored function.[7]

References

  1. [1]Kuhlmann et al. · Multiple sclerosis progression: time for a new mechanism-driven framework (2023)
  2. [2]Bjørnevik et al. · Longitudinal analysis of Epstein-Barr virus and MS (2022)
  3. [3]Lanz et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature, 2022
  4. [4]Absinta et al. A lymphocyte–microglia–astrocyte axis in chronic active multiple sclerosis. Nature, 2021
  5. [5]Mahad, Trapp and Lassmann. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurology, review (2015)
  6. [6]Hauser et al. B-cell depletion with rituximab in relapsing–remitting multiple sclerosis (HERMES). NEJM, 2008
  7. [7]Neumann et al. Metformin restores CNS remyelination capacity by rejuvenating aged stem cells. Cell Stem Cell, 2019
  8. [8]Absinta et al. Association of chronic active multiple sclerosis lesions with disability in vivo. JAMA Neurology (2019)
  9. [9]ClinicalTrials.gov. Therapeutic EBV vaccine mRNA-1195 in MS, NCT06735248

Background in MS in depth

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