THE UNSEEN PATHWAY

Disability accumulation is thought to be driven in part by smoldering neuroinflammation1,2

Originating in the CNS, smoldering neuroinflammation may be independent of acute neuroinflammation that drives relapses and acute lesions.1,2

Two concurrent neuroinflammatory pathways drive disease progression, resulting in disability accumulation from the onset of MS1,2:

.

Acute neuroinflammation:

  • Is driven in part by activated B cells and T cells derived from the periphery1,2
  • Results in relapses, acute lesions, and disability from incomplete relapse recovery1,2
.

Smoldering neuroinflammation:

  • Is driven primarily by pathogenic microglia found in the CNS1,2
  • Is a driver of both physical and cognitive disability accumulation1,2
.

Bruton’s Tyrosine Kinase (BTK) is expressed in both B cells and microglia and plays a critical role in neuroinflammation1

Peripheral B cells were thought to be the main driver of MS. Now we know that both B cells and microglia are involved3

BTK drives the pathogenic activation of B cells and regulates B-cell maturation, proliferation (NF-kB), autoantibody production, and cytokine secretion
BTK drives the pathogenic activation of microglia and proinflammatory cytokine secretion (eg, TNFα, IL-1β, IL-6)

BTK drives the pathogenic activation of both B cells and microglia1,4,5

See how progression occurs

Microglia can trigger neurotoxic pathways, producing proinflammatory cytokines, leading to disease progression and neurodegeneration, and ultimately disability accumulation6

Even in the earliest stages of MS, microglia often shift from a homeostatic state to a pathogenic one.2
 

Homeostatic Microglia


Homeostatic microglia play an important role in regulating myelination and remyelination, synaptic maintenance, blood-brain barrier permeability, and neurogenesis.7

Homeostatic microglia play an important role in phagocytosis, myelination/remyelination, and synapse monitoring and pruning

Pathogenic Microglia


Pathogenic microglia are associated with increased demyelination and inhibition of remyelination, increased blood-brain barrier permeability, and neurodegenerative processes.8-11

Pathogenic microglia are associated with increased blood-brain barrier permeability, increased phagocytosis and demyelination, release of proinflammatory cytokines, inhibition of remyelination, overactive synaptic pruning, neuronal disruption, and development of chronic lesions
smoldering match brain

Smoldering neuroinflammation that is driven by pathogenic microglia is associated with chronic active lesions, ongoing axonal injury, and neurodegeneration, resulting in disability accumulation12

Even when you can’t easily see them, processes driving disease progression resulting in disability accumulation are happening2,13

Neuroinflammatory drivers of disease progression impact all patients with MS.2,13

  • Neuroinflammatory drivers are active from the onset and continue regardless of whether patients have relapsing or progressive forms of the disease2,13
  • Beginning early in MS, smoldering neuroinflammation can be largely unseen and lead to disability accumulation2
  • Smoldering neuroinflammation starts and is ongoing even before the first relapse or acute lesion activity2

When “unseen” disease progression goes unaddressed, it can result in irreversible disability accumulation and damage that may negatively impact patients’ lives in several areas, including but not limited to14-17:

.

Cognition

.

Mood

.

Fatigue

.

Dexterity

.

Coordination
and Balance

.

Genitourinary
Symptoms

Patient reports are the key to detecting and acknowledging subtle changes in disability that may be difficult to detect due to the low sensitivity of standard metrics like the Expanded Disability Status Scale (EDSS). This scale reflects the level of damage that has already occurred and provides limited information about the underlying neurodegenerative processes.2,15,16

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References:

  1. Häusser-Kinzel S, Weber MS. The role of B cells and antibodies in multiple sclerosis, neuromyelitis optica, and related disorders. Front Immunol. 2019;10:201.
  2. Giovannoni G, Popescu V, Wuerfel J, et al. Smouldering multiple sclerosis: the ‘real MS’. Ther Adv Neurol Disord. 2022;15:17562864211066751. doi:10.1177/17562864211066751.
  3. Frisch ES, Pretzsch R, Weber MS. A milestone in multiple sclerosis therapy: monoclonal antibodies against CD20—yet progress continues. Neurotherapeutics. 2021;18(3):1602-1622.
  4. Hendriks RW. Drug discovery: new BTK inhibitor holds promise. Nat Chem Biol. 2011;7(1):4-5. 
  5. Keaney J, Gasser J, Gillet G, Scholz D, Kadiu I. Inhibition of Bruton's Tyrosine Kinase modulates microglial phagocytosis: therapeutic implications for Alzheimer's disease. J Neuroimmune Pharmacol. 2019;14(3):448-461.
  6. Correale J. The role of microglial activation in disease progression. Mult Scler. 2014;20(10):1288-1295.
  7. Sierra A, Paolicelli RC, Kettenmann H. Cien años de microglía: milestones in a century of microglial research. Trends Neurosci. 2019;42(11):778-792.
  8. Guerrero BL, Sicotte NL. Microglia in multiple sclerosis: friend or foe? Front Immunol. 2020;11:374. doi:10.3389/fimmu.2020.00374
  9. Luo C, Jian C, Liao Y, et al. The role of microglia in multiple sclerosis. Neuropsychiatr Dis Treat. 2017;13:1661-1667. doi:10.2147/NDT.S140634
  10. Cardozo PL, de Lima IBQ, Maciel EMA, Silva NC, Dobransky T, Ribeiro FM. Synaptic elimination in neurological disorders. Neuropsychiatr Dis Treat. 2017;13:1661-1667. doi:10.2147/NDT.S140634
  11. Schreiner TG, Romanescu C, Popescu BO. The blood-brain barrier—a key player in multiple sclerosis disease mechanisms. Biomolecules. 2022;12(4):538.
  12. Frischer JM, Weigand SD, Guo Y, et al. Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. Ann Neurol. 2015;78(5):710-721.
  13. Scalfari A. MS can be considered a primary progressive disease in all cases, but some patients have superimposed relapses - Yes. Mult Scler. 2021;27(7):1002-1004.
  14. Cree BAC, Hollenbach JA, Bove R, et al; University of California, San Francisco MS-Epic Team. Silent progression in disease activity-free relapsing multiple sclerosis. Ann Neurol. 2019;85(5):653-666.
  15. Ziemssen T, Derfuss T, de Stefano N, et al. Optimizing treatment success in multiple sclerosis. J Neurol. 2016;263(6):1053-1065.
  16. Lakin L, Davis BE, Binns CC, Currie KM, Rensel MR. Comprehensive approach to management of multiple sclerosis: addressing invisible symptoms—a narrative review. Neurol Ther. 2021;10(1):75-98.
  17. Halper J, Kennedy P, Miller CM, Morgante L, Namey M, Ross AP. Rethinking cognitive function in multiple sclerosis: a nursing perspective. J Neurosci Nurs. 2003;35(2):70-81.