Welcome

Discover developments in tools for understanding multiple sclerosis (MS) and its progression, as presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2022:

• Watch an interview with Professor Stephen Krieger discussing his topographical model and its potential clinical implications
• Learn about his view of the clinical course of MS being a continuum
• Read about markers of central inflammation using imaging techniques
• Consider the importance of patient-reported outcomes
• Read a summary of Bruton’s tyrosine kinase (BTK) and MS

A new lexicon for the MS disease course

Professor Stephen Krieger, Professor of Neurology at Mount Sinai Hospital in New York, US, chaired and opened the acadeME MS symposium ‘New tools and challenges for multiple sclerosis.’ On the closing afternoon of the congress, Professor Krieger discussed his ideas regarding the re-thinking of MS disease course and progression. In his presentation, Professor Krieger described the old two-stage disease paradigm of MS that is now considered as two parallel processes and, how his topographical model depicts a disease continuum^1,2. Watch the video to see the interview and hear his explanation.

Professor Krieger’s topographical model considers clinically silent symptoms not always detected by traditional measures. While some symptoms reach above the ‘water’ threshold, such as relapses or quantified expanded disability status scale (EDSS), some remain as sub-threshold peaks. For example, T2 number and volume^1,2. The annual rate of brain volume loss is represented as water level descent, bringing some symptoms to the ‘surface’ over time (see the video below).

Professor Krieger’s recent study found sub-threshold deficits with EDSS-0 in people with MS when compared with healthy controls³. Although both had EDSS scores of 0, people with MS had deficits in tasks measuring balance and upper extremity coordination, including the timed 25-foot walk (T25FW) and the nine-hole peg test (NHPT), which in turn correlated with imaging markers. Therefore, Professor Krieger believes we should reconceptualize clinical thresholds and harness more sensitive clinical measurements. Watch the video of Professor Krieger’s interview to find out more.

So, should we be understanding MS progression as a continuum, rather than distinct clinical stages? New insights could improve outcomes for both health care professionals (HCPs) and people with MS alike.

Imaging and central inflammation

The symposium continued with a discussion on neuroimaging techniques used to detect inflammation. Both peripheral inflammation, driven by B cells, macrophages and T cells, and central inflammation, driven by microglia and B cells in the central nervous system (CNS), contribute towards disease progression^4,5. Paramagnetic rim lesions (PRLs) and slowly expanding lesions (SELs) measured with magnetic resonance imaging (MRI) are markers of chronic active lesions (CALs) and are associated with disease progression^6-8. SELs can be detected in vivo using longitudinal sequences of T1- and T2-weighted MRI⁶.

In addition, other imaging techniques are now being used to detect lesions.

• Positron emission tomography (PET) can detect microglial/macrophage activation which characterize lesion activity^9-11
• Sensitivity weighted imaging, sensitive to iron, can detect CALs due to iron-full microglia/macrophages at the lesion edge¹²
• Magnetization transfer ratio and diffusion tensor imaging radial diffusivity can be used to evaluate tissue integrity changes over time, through associations with myelin content^13,14

SEL and PRL measurements are now being employed to improve disease progression understanding in clinical trials in MS^15,16

The need for patient-reported outcomes

Detecting early progression is an unmet need in MS, both clinically and in research^17,18. Dr. Marcus D’Souza is a Senior Physician at the Department of Neurology and the Innovation Lab University Hospital in Basel, Switzerland. Dr. D’Souza, at the same symposium, said patient-reported outcomes (PROs) may have a role to play. PROs reflect evaluations directly from the patient, meaning they currently lack validation^17,19. However, PROs are convenient, provide novel insights and are sensitive to disease progression, even in early stages or for mild disabilities¹⁷. Therefore, PROs could be beneficial for detecting sub-threshold symptoms, also suggested by Professor Krieger¹⁷.

The multi-stakeholder PROs for MS (PROMS) initiative, jointly led by the European Charcot Foundation and the Multiple Sclerosis International Federation, aims to bring a unified understanding of PROs that can guide research, clinical management, and healthcare systems²⁰

Combining these into eHealth tools to integrate PROs in current practices could enable a holistic and personalized approach in detecting early MS progression.

BTK and MS

An emerging concept in the understanding of MS is that of ongoing CNS inflammation, also known as smoldering inflammation, which contributes to disease progression²¹.

Smoldering inflammation is distinct from the acute inflammation that underlies relapses. During a relapse, an influx of pathologically activated B and T lymphocytes, macrophages, and plasma cells crosses the blood-brain barrier leading to formation of acute focal inflammatory lesions⁴. In contrast, smoldering MS is driven by CNS-compartmentalized chronic inflammation in which activated microglia, macrophages, and astrocytes play a central role²¹. These cells secrete pro-inflammatory cytokines and reactive oxygen species which promote demyelination and neuroaxonal damage in both white and grey matter, leading to brain and spinal cord atrophy²¹.

BTK is a member of the Tec family of non-receptor tyrosine kinases known for its role as a key signaling molecule downstream of the B cell receptor (BCR)²². BTK-related signaling also participates in the cascade of autoimmunity and inflammation²³. In B cells, this kinase is an essential component of the B-cell receptor signaling pathway regulating proliferation, maturation, antigen presentation, and production of secreted immunoglobulins^22,24,25. In addition to B cells, BTK is also expressed in other immune cells, such as macrophages and microglia, downstream of various receptors including Fc, integrin, Toll-like and chemokine receptors^22,24.

Several lines of evidence support that BTK function is relevant in the pathophysiology of MS. First, BTK expression is increased in subsets of B cells from MS patients²⁶. Second, BTK is increased in microglia in and around MS lesions²⁷. Third, in preclinical experimental models of autoimmune disease in which BTK is genetically silent (BTK knockouts), less severe forms of disease are observed^28-32. BTK is therefore an interesting avenue for future research in MS and several clinical trials are now exploring this topic.

ECTRIMS 2022 provided novel insights on how we can better perceive, measure and combat disease progression in MS

References

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Stephen Krieger reports grants and research support from Biogen, BMS, Novartis and Sanofi, and received honoria or compensation for consultation from Biogen, Merck KGaA, Darmstadt, Germany, Genentech, Novartis, Octave, Genzyme/Sanofi and TG Therapeutics, and participates in a speaker’s bureau for Biogen, Merck KGaA, Darmstadt, Germany, Genentech, Novartis, Octave, Genzyme/Sanofi and TG Therapeutics.  

Marcus D’Souza received travel support from Novartis and Roche, and research support from the University Hospital Basel. Dr. D’Souza is CEO of Neurostatus-UHB AG.