• During the early stages of RRMS, pathophysiology is marked by important demyelination and a variable degree of axonal loss and reactive gliosis. People with RRMS present with focal inflammation and perivenular as well as parenchymal infiltrates of lymphocytes and macrophages1
  • The mechanisms of transition from RRMS to SPMS are not completely understood and the disease is thought to evolve as a continuum,2 but the inflammation that occurs in RRMS slowly lessens as the disease evolves into the progressive phase3


SPMS pathophysiology is incompletely understood, and no definitive imaging or laboratory test exist that are able to inform when the disease is progressive;4 possible mechanisms include:5


Cell icon for inflammation

Creation of microenvironment in the CNS leading to retainment of inflammatory cells

Brain question icon for neurodegeneration independent of inflmmation

Neurodegenerative process independent of inflammation

Brain degeneration icon for primary neurodegeneration with secondary inflammation

MS as a primarily neurodegenerative disease with inflammation occurring as a secondary response, amplifying progression

  • Evidence suggests inflammation does not stop in the progressive stage; conversely, it persists (at least within the CNS) behind a closed or repaired blood-brain barrier4
  • Ultimately, the accumulation of two kinds of inflammation contributes to irreversible CNS damage in SPMS: peripheral and trapped inflammation6–8


Graph representing the transition from RRMS to SPMS

Adapted from Dendrou et al, Nat Rev Immunol 2015 and Perez-Cerda et al, Mult Scler Demylineating Disor 2016.


Peripheral inflammation refers to the infiltration of peripheral lymphocytes in the CNS, triggering an immune response that damages the myelin and eventually leads to axonal loss9

Trapped inflammation describes immune cell infiltrates becoming trapped within the CNS behind an unaffected blood-brain barrier, forming lymph follicle-like aggregates in the meninges, leading to demyelination and neurodegeneration10


Peripheral inflammation

  • Previous research implies that peripheral inflammation may continue to play a significant role during the progressive phase4
    • As the disease progresses from the relapsing-remitting to secondary phase, circulating immune cells (B- and T-cells) temporarily damage the CNS6
    • Infiltration of immune cells and other inflammatory components therefore results in a more pronounced atrophy of the grey and white matter, reflecting the inflammatory response accumulated in the CNS6,9

Trapped inflammation

  • In addition, and independent of peripheral inflammation, trapped inflammation worsens the activation of CNS-resident immune cells once these cells cross the blood-brain barrier and are trapped6,7
  • As the disease progresses, B-cells create a compartmentalised group, inside the CNS and the blood-brain barrier5
  • Abnormal B-cell functions – including cytokine secretion, antibody production, antigen presentation, follicle-like structures formation and increased secretion of lymphotoxin, TNF-α, IL-6, or deficient secretion of regulatory cytokines – complements the disease, irrespective of the peripheral B-cell and immune function5
  • Meningeal inflammation has been characteristically described in SPMS, and it has been suggested that it may play a part in the development of disability4

*SPMS with active disease is defined as the presence of relapses and/or the occurrence of T1 or new or enlarging T2 lesions.11

CNS, central nervous system; RRMS, relapsing-remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis.


  1. Huang WJ, Chen WW, Zhang X. Exo Ther Med. 2017;13(6):3163–3166.
  2. Ziemssen T, Tolley C, Bennet B, et al. Mult Scler Relat Disord. 2020;38:101861.
  3. National MS Society. Diagnosing SPMS. Available at: https://www.nationalmssociety.org/What-is-MS/Types-of-MS/Secondary-progr.... Accessed November 2021.
  4. Plantone D, De Angelis F, Doshi A, Chataway J. CNS Drugs. 2016;30(6):517–526.
  5. Correale J, Gaitan MI, Yssraelit MC, Fiol MP. Brain. 2017;140(3):527–546.
  6. Dendrou CA et al. Nat Rev Immunol. 2015;15:545–558.
  7. Kutzelnigg A, Lucchinetti CF, Stadelmann C, et al. Brain. 2005;128(Pt 11):2705–2712.
  8. Lassman H, van Horssen J, Mahad D. Nat Rev Neurol. 2012;8(11):647–656.
  9. Murta V, Ferrari CC. Mol Cell Neurosci. 2013;(53):6–13.
  10. Perez-Cerda F, Sanchez-Gomez MV, Matute C. Mult Scler Demylineating Disor. 2016;1:1–8.
  11. Lublin FD, Reingold SC, Cohen JA, et al. Neurology. 2014;83(3):278–286.
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