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ECTRIMS Bulletin June 2024


min read

Latest developments in MS research:

  • Learn how STING activation regulates the neuronal inflammatory stress response in individuals with MS.
  • Know more about therapy discontinuation in older people with MS.
  • Read about the two-hit hypothesis proposed for MS pathogenesis.

These noteworthy MS news highlights and more are included in our recently published ECTRIMS Bulletins – a 30-day snapshot of global news and publications on MS research, treatment, and care.
 
ECTRIMS Bulletins can be sent to you every month, delivered straight to your inbox, via our free subscription service. Simply select all “topics” that are of interest to you, and when one of those appears in our news and publication cycle, you’ll be sure to hear from us.

Pathogenesis

STING orchestrates the neuronal inflammatory stress response in multiple sclerosis
 
Cell | 14 June 2024

What are the mechanisms underlying the interplay between inflammation and neurodegeneration in MS? Throughout the course of MS, neurons are constantly challenged by chronic inflammation, resulting in neurodegeneration. Neurons play an active role in the process of neuroinflammation, modulating immune responses. When sensing inflammatory cues like cytokines and glutamate, neurons can launch a neuronal inflammatory stress response (NISR). The present study identifies the neural stimulator of interferon genes (STING) as a central regulator in the process resulting in inflammation-induced neurodegeneration. Only during inflammation, both in humans and mice, STING is expressed in neurons in the central nervous system (CNS) in response to continuous interferon-γ (IFNγ) exposure – a cytokine present in abundance in the CNS of individuals with MS. Initially, STING is retained at the endoplasmic reticulum (ER) through binding to the stromal interaction molecule 1 (STIM1). It then detaches from STIM1 due to glutamate excitotoxicity and travels to the Golgi apparatus. This detachment activates STING, leading to autophagic degradation of glutathione peroxidase 4 (GPX4) and ferroptosis. Interestingly, using STING antagonists in mice with experimental autoimmune encephalomyelitis (EAE) protected them from neural loss and ameliorated the disease course.

Reconciling lesions, relapses and smouldering associated worsening: A unifying model for multiple sclerosis pathogenesis 

Multiple Sclerosis and Related Disorders | August 2024

The authors propose a unifying model for multiple sclerosis pathogenesis. The two-hit hypothesis suggests that relapse associated worsening (RAW) and smouldering associated worsening (SAW) are not only parallel processes that can coexist, to varying extents, and contribute to disease outcome in individuals with MS. RAW and SAW might influence the severity of each other. The authors postulate that cortical lesions burden, radiologically observed changes in normal appearing white matter, and demyelinating white matter lesions interact systematically. Longitudinal analyses of MRI datasets are needed to investigate this hypothesis.

Therapeutics

High-efficacy therapy discontinuation vs continuation in patients 50 years and older with nonactive MS

JAMA Neurology | May 2024

Is it possible to discontinue a high-efficacy therapy (HET) in individuals of 50 years and older with nonactive MS, without increasing the risk of rebound? The authors of the present study analyse data from 1620 individuals over 50 years old with relapsing-remitting MS from the Observatoire Français de la Sclérose en Plaques (OFSEP) database. All patients were treated with HET – 1452 continued the treatment and 168 stopped it – and were stable for at least two years. After the propensity score matching, 154 individuals were retained in each group, i.e. continuation vs. discontinuation. The main outcome investigated was the time to first relapse.
The risk of relapse between the groups differed according to the DMTs discontinued. In fact, individuals with MS who stopped natalizumab had a probability of having a first relapse after 1-year follow-up of 33.6% (with a peak of relapses observed between 0 and 4 months after discontinuation). Individuals who stopped fingolimod had a probability of a first relapse at 1 year of 16.3%. On the contrary, stopping an anti-CD20 therapy did not increase the risk of rebound, compared to individuals who continued.                                                                                                                                                        

Clinical

Reliability parameters of the Timed 25-Foot-Walk (T25FW) in patients with Multiple Sclerosis: lower walking speed is associated with greater Smallest Detectable Change

Multiple Sclerosis and Related Disorders | 15 June 2024

Reliability refers to the consistency of a test over time. A reliable test yields similar scores when repeated in the same, standardised context. The present study aimed to assess the reliability of the Timed 25-Foot Walk (T25FW) in individuals with MS. The T25FW measures the time a patient takes to walk 25 feet (7.62 meters) safely but as quickly as possible. A total of 118 individuals with MS completed the test twice, with a one-year interval, in the same room at the Department of Physiotherapy of the Alrijne Hospital in Leiden. At the end of the second measurement, all patients were asked whether they noted changes in their walking speed compared to the previous time they performed the test. This question served to include in the study only those individuals who felt stable between the two tests. The 73 individuals with MS who reported no change completed the first test in 4.7 seconds and the follow-up test in 4.9 seconds. The T25FW demonstrated sufficient reliability. However, for individuals with MS with a lower walking speed, the smallest detectable change – the minimal change that can be confidently detected by a measurement – was higher. Further research would be needed to assess the test-retest reliability of T25FW in individuals with lower walking speed.