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
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 continuum1,2. 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 volume1,2. 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.
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 progression4,5. 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 progression6-8. 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 activity9-11
- 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 content13,14
SEL and PRL measurements are now being employed to improve disease progression understanding in clinical trials in MS15,16
Detecting early progression is an unmet need in MS, both clinically and in research17,18. 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 validation17,19. 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.
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 immunoglobulins22,24,25. 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 receptors22,24.
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 observed28-32. 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
- Krieger SC, Cook K, De Nino S, Fletcher M. The topographical model of multiple sclerosis: A dynamic visualization of disease course. Neurology(R) Neuroimmunology & Neuroinflammation. 2016;3(5):e279.
- Krieger SC, Sumowski J. New insights into multiple sclerosis clinical course from the topographical model and functional reserve. Neurologic Clinics. 2018;36(1):13-25.
- Krieger SC, Antoine A, Sumowski JF. EDSS 0 is not normal: Multiple sclerosis disease burden below the clinical threshold. Multiple Sclerosis Journal. 2022:13524585221108297.
- Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nature Reviews Immunology. 2015;15:545-558.
- Li R, Patterson KR, Bar-Or A. Reassessing B cell contributions in multiple sclerosis. Nature immunol. 2018;19(7):696–707.
- Elliott C, Belachew S, Wolinsky JS, Hauser SL, Kappos L, Barkhof F, et al. Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis. Brain: A Journal of Neurology. 2019;142(9):2787-2799.
- Dal-Bianco A, Grabner G, Kronnerwetter C, Weber M, Höftberger R, Berger T, et al. Slow expansion of multiple sclerosis iron rim lesions: pathology and 7 T magnetic resonance imaging. Acta Neuropathologica. 2017;133(1):25-42.
- Absinta M, Sati P, Masuzzo F, Nair G, Sethi V, Kolb H, et al. Association of chronic active multiple sclerosis lesions with disability in vivo. JAMA Neurology. 2019;76(12):1474-1483.
- Venneti S, Lopresti BJ, Wiley CA. Molecular imaging of microglia/macrophages in the brain. Glia. 2013;61(1):10-23.
- Airas L, Rissanen E, Rinne JO. Imaging neuroinflammation in multiple sclerosis using TSPO-PET. Clin Transl Imaging. 2015;3:461-473.
- Giannetti P, Politis M, Su P, Turkheimer FE, Malik O, Keihaninejad S, et al. Increased PK11195-PET binding in normal-appearing white matter in clinically isolated syndrome. Brain. 2015;138(1):110-119.
- Dal-Bianco A, Schranzer R, Grabner G, Lanzinger M, Kolbrink S, Pusswald G, et al. Iron rims in patients with multiple sclerosis as neurodegenerative marker? A 7-tesla magnetic resonance study. Frontiers in Neurology. 2021;12:632749.
- Fox RJ, Sakaie K, Lee JC, Debbins JP, Liu Y, Arnold DL, et al. A validation study of multicenter diffusion tensor imaging: reliability of fractional anisotropy and diffusivity values. American Journal of Neuroradiology. 2012;33(4):695-700.
- Elliott C, Arnold DL, Chen H, Ke C, Zhu L, Chang I, et al. Patterning chronic active demyelination in slowly expanding/evolving white matter MS lesions. AJNR: American Journal of Neuroradiology. 2020;41(9):1584-1591.
- Calvi A, Clarke MA, Prados F, Chard D, Ciccarelli O, Alberich M, et al. Relationship between paramagnetic rim lesions and slowly expanding lesions in multiple sclerosis. Multiple Sclerosis Journal. 2022:13524585221141964.
- Pozzilli C, Pugliatti M, Vermersch P, Grigoriadis N, Alkhawajah M, Airas L, et al. Diagnosis and treatment of progressive multiple sclerosis: A position paper. European Journal of Neurology. 2023;30(1):9-21.
- Meca-Lallana V, Berenguer-Ruiz L, Carreres-Polo J, Eichau-Madueño S, Ferrer-Lozano J, Forero L, et al. Deciphering multiple sclerosis progression. Frontiers in Neurology. 2021;12:608491.
- Kalincik T, Cutter G, Spelman T, Jokubaitis V, Havrdova E, Horakova D, et al. Defining reliable disability outcomes in multiple sclerosis. Brain: A Journal of Neurology. 2015;138(Pt 11):3287-3298.
- Zhang Y, Taylor BV, Simpson Jr S, Blizzard L, van der Mei I. Patient-reported outcomes are worse for progressive-onset multiple sclerosis than relapse-onset multiple sclerosis, particularly early in the disease process. European Journal of Neurology. 2019;26(1):155-161.
- Zaratin P, Vermersch P, Amato MP, Brichetto G, Coetzee T, Cutter G, et al. The agenda of the global patient reported outcomes for multiple sclerosis (PROMS) initiative: Progresses and open questions. Multiple Sclerosis and Related Disorders. 2022;61:103757.
- Giovannoni G, Popescu V, Wuerfel J, Hellwig K, Iacobaeus E, Jensen MB, et al. Smouldering multiple sclerosis: the ‘real MS’. Therapeutic Advances in Neurological Disorders. 2022;15:175628642110667.
- Hendriks RW, Yuvaraj S, Kil LP. Targeting Bruton's tyrosine kinase in B cell malignancies. Nature Reviews Cancer. 2014;14(4):219-232.
- Cao T, Wang Z, Zhu X. The Immunomodulatory Functions of BTK Inhibition in the Central Nervous System. Journal of Inflammation Research. 2022;Volume 15:6427-6438.
- López-Herrera G, Vargas-Hernández A, González-Serrano ME, Berrón-Ruiz L, Rodríguez-Alba JC, Espinosa-Rosales F, et al. Brutonˈs tyrosine kinase-an integral protein of B cell development that also has an essential role in the innate immune system. Journal of Leukocyte Biology. 2014;95(2):243-250.
- Hartkamp L, Radstake T, Reedquist K. Bruton’s tyrosine kinase in chronic inflammation: from pathophysiology to therapy. International Journal of Interferon, Cytokine and Mediator Research. 2015:27.
- Rijvers L, Van Langelaar J, Bogers L, Melief M-J, Koetzier SC, Blok KM, et al. Human T-bet+ B cell development is associated with BTK activity and suppressed by evobrutinib. JCI Insight. 2022;7(16).
- Gruber RC, Chretien N, Dufault MR, Proto J, Zhang M, LaMorte M, et al. Central Effects of BTK Inhibition in Neuroinflammation (808). Neurology. 2020;94(15 Supplement):808.
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- Mangla A, Khare A, Vineeth V, Panday NN, Mukhopadhyay A, Ravindran B, et al. Pleiotropic consequences of Bruton tyrosine kinase deficiency in myeloid lineages lead to poor inflammatory responses. Blood. 2004;104(4):1191-1197.
- Takeshita H, Taniuchi I, Kato J, Watanabe T. Abrogation of autoimmune disease in Lyn-deficient mice by the mutation of the Btk gene. International Immunology. 1998;10(4):435-444.
- Jansson L, Holmdahl R. Genes on the X chromosome affect development of collagen-induced arthritis in mice. Clinical and Experimental Immunology. 2008;94(3):459-465.
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.
Developed by EPG Health for Medthority. This meeting content has been developed in collaboration with Merck KGaA, Darmstadt, Germany and expert faculty. EPG Health received funding from Merck KGaA, Darmstadt, Germany.
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US-NONNI-01350 | May 2023