Multiple sclerosis progression: time for a new mechanism-driven framework

The Lancet Neurology, Journal Year: 2022, Volume and Issue: 22(1), P. 78 - 88

Published: Nov. 18, 2022

Language: Английский

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Early use of high-efficacy disease‑modifying therapies makes the difference in people with multiple sclerosis: an expert opinion

Journal of Neurology, Journal Year: 2022, Volume and Issue: 269(10), P. 5382 - 5394

Published: May 24, 2022

Abstract Multiple sclerosis (MS) is a chronic and progressive neurological disease that characterized by neuroinflammation, demyelination neurodegeneration occurring from the earliest phases of may be underestimated. MS patients accumulate disability through relapse-associated worsening or progression independent relapse activity. Early intervention with high-efficacy disease-modifying therapies (HE-DMTs) represent best window opportunity to delay irreversible central nervous system damage MS-related hindering underlying heterogeneous pathophysiological processes contributing progression. In line this, growing evidence suggests early use HE-DMTs associated significant greater reduction not only inflammatory activity (clinical relapses new lesion formation at magnetic resonance imaging) but also progression, in terms accumulation clinical compared delayed HE-DMT escalation strategy. These beneficial effects seem acceptable long-term safety risks, thus configuring this treatment approach as most positive benefit/risk profile. Accordingly, it should mandatory treat people case prognostic factors suggestive aggressive disease, advisable offer an after diagnosis, taking into account drug profile, severity, and/or radiological activity, patient-related factors, including possible comorbidities, family planning, patients’ preference agreement EAN/ECTRIMS AAN guidelines. Barriers for include concerns safety, challenges management initiation monitoring, negative preferences, restricted access according guidelines regulatory rules, sustainability. However, these barriers do apply each none appear insuperable.

Language: Английский

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Harmonizing Definitions for Progression Independent of Relapse Activity in Multiple Sclerosis

JAMA Neurology, Journal Year: 2023, Volume and Issue: 80(11), P. 1232 - 1232

Published: Oct. 2, 2023

Emerging evidence suggests that progression independent of relapse activity (PIRA) is a substantial contributor to long-term disability accumulation in relapsing-remitting multiple sclerosis (RRMS). To date, there no uniform agreed-upon definition PIRA, limiting the comparability published studies.

Language: Английский

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Cellular architecture of evolving neuroinflammatory lesions and multiple sclerosis pathology

Cell, Journal Year: 2024, Volume and Issue: 187(8), P. 1990 - 2009.e19

Published: March 20, 2024

Multiple sclerosis (MS) is a neurological disease characterized by multifocal lesions and smoldering pathology. Although single-cell analyses provided insights into cytopathology, evolving cellular processes underlying MS remain poorly understood. We investigated the dynamics of modeling temporal regional rates progression in mouse experimental autoimmune encephalomyelitis (EAE). By performing spatial expression profiling using situ sequencing (ISS), we annotated neighborhoods found centrifugal evolution active lesions. demonstrated that disease-associated (DA)-glia arise independently are dynamically induced resolved over course. Single-cell mapping human archival spinal cords confirmed differential distribution homeostatic DA-glia, enabled deconvolution inactive sub-compartments, identified new lesion areas. establishing resource neuropathology at resolution, our study unveils intricate MS.

Language: Английский

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The neuropathobiology of multiple sclerosis

Nature reviews. Neuroscience, Journal Year: 2024, Volume and Issue: 25(7), P. 493 - 513

Published: May 24, 2024

Language: Английский

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Determinants and Biomarkers of Progression Independent of Relapses in Multiple Sclerosis

Annals of Neurology, Journal Year: 2024, Volume and Issue: 96(1), P. 1 - 20

Published: April 3, 2024

Clinical, pathological, and imaging evidence in multiple sclerosis (MS) suggests that a smoldering inflammatory activity is present from the earliest stages of disease underlies progression disability, which proceeds relentlessly independently clinical radiological relapses (PIRA). The complex system pathological events driving "chronic" worsening likely linked with early accumulation compartmentalized inflammation within central nervous as well insufficient repair phenomena mitochondrial failure. These mechanisms are partially lesion-independent differ those causing formation new focal demyelinating lesions; they lead to neuroaxonal dysfunction death, myelin loss, glia alterations, finally, neuronal network outweighing (CNS) compensatory mechanisms. This review aims provide an overview state art neuropathological, immunological, knowledge about underlying activity, focusing on possible biomarkers their translation into practice. ANN NEUROL 2024;96:1-20.

Language: Английский

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Multiple sclerosis: emerging epidemiological trends and redefining the clinical course

The Lancet Regional Health - Europe, Journal Year: 2024, Volume and Issue: 44, P. 100977 - 100977

Published: Aug. 23, 2024

SummaryMultiple sclerosis is a chronic, inflammatory, and neurodegenerative disease of the central nervous system major cause neurological disability in young adults. Its prevalence incidence are increasing, it has been estimated at over 2.8 million cases worldwide, addition to recent trends towards shift MS older ages, with peak estimates sixth decade life. Although historically relapsing progressive phases have considered separate clinical entities, evidence progression independent relapse activity (PIRA) led reconsideration multiple as continuum, which features variably coexist from earliest stages disease, challenging traditional view course. In this Series article, we provide an overview how description course epidemiological Europe evolved. For purpose, focus on concept PIRA, discussing its potential main mechanism by patients acquire disability, definition varies between studies, ongoing research field. We emphasise importance incorporating assessment hidden manifestations into patient management help uncover quantify PIRA phenomenon possible implications for future changes classification disease. At same time, insights overcoming challenges identifying defining adopting new understanding MS.

Language: Английский

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Using the Progression Independent of Relapse Activity Framework to Unveil the Pathobiological Foundations of Multiple Sclerosis

Neurology, Journal Year: 2024, Volume and Issue: 103(1)

Published: June 18, 2024

Progression independent of relapse activity (PIRA), a recent concept to formalize disability accrual in multiple sclerosis (MS) relapses, has gained popularity as potential clinical trial outcome. We discuss its shortcomings and appraise the challenges implementing it settings, experimental trials, research. The current definition PIRA assumes that acute inflammation, which can manifest relapse, neurodegeneration, manifesting progressive accrual, be disentangled by introducing specific time windows between onset relapses observed increase disability. term PIRMA (progression MRI activity) was recently introduced indicate absence both new brain spinal cord lesions. Assessing practice is highly challenging because necessitates frequent assessments scans. commonly assessed using Expanded Disability Status Scale, scale heavily weighted toward motor disability, whereas more granular assessment deterioration, including cognitive decline, composite measures or other tools, such digital would possess greater utility. Similarly, an outcome measure randomized trials also requires methodological considerations. underpinning pathobiology accumulation, not associated with may encompass chronic active lesions (slowly expanding paramagnetic rim lesions), cortical lesions, atrophy, particularly gray matter, diffuse focal microglial activation, persistent leptomeningeal enhancement, white matter tract damage. propose use understand main determinant observational, cohort studies, where regular scans are included, introduce "advanced-PIRMA" investigate contributions abovementioned processes, conventional advanced imaging. This supported knowledge reflects MS pathogenic mechanisms better than purely descriptors. Any residual remains unexplained after considering all these imaging, will highlight future research priorities help complete our understanding pathogenesis.

Language: Английский

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Smouldering‐Associated Worsening in Multiple Sclerosis: An International Consensus Statement on Definition, Biology, Clinical Implications, and Future Directions

Annals of Neurology, Journal Year: 2024, Volume and Issue: 96(5), P. 826 - 845

Published: July 25, 2024

Despite therapeutic suppression of relapses, multiple sclerosis (MS) patients often experience subtle deterioration, which extends beyond the definition "progression independent relapsing activity." We propose concept smouldering-associated-worsening (SAW), encompassing physical and cognitive symptoms, resulting from smouldering pathological processes, remain unmet targets. provide a consensus-based framework possible substrates manifestations MS, we discuss clinical, radiological, serum/cerebrospinal fluid biomarkers for potentially monitoring SAW. Finally, share considerations optimizing disease surveillance implications clinical trials to promote integration MS into routine practice future research efforts. ANN NEUROL 2024;96:826-845.

Language: Английский

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High-Dose Vitamin D in Clinically Isolated Syndrome Typical of Multiple Sclerosis

JAMA, Journal Year: 2025, Volume and Issue: unknown

Published: March 10, 2025

Importance Vitamin D deficiency is a risk factor for multiple sclerosis (MS) and associated with the of disease activity, but data on benefits supplementation are conflicting. Objective To evaluate efficacy high-dose cholecalciferol as monotherapy in reducing activity patients clinically isolated syndrome (CIS) typical MS. Design, Setting, Participants The D-Lay MS trial was parallel, double-blind, randomized placebo-controlled clinical 36 centers France. Patients were enrolled from July 2013 to December 2020 (final follow-up January 18, 2023). Untreated CIS aged 18 55 years duration less than 90 days, serum vitamin concentration 100 nmol/L, diagnostic magnetic resonance imaging (MRI) meeting 2010 criteria dissemination space or 2 more lesions presence oligoclonal bands recruited. Intervention 1:1 receive oral 000 IU (n = 163) placebo 153) every weeks 24 months. Main Outcomes Measures primary outcome measure defined occurrence relapse and/or MRI (new contrast-enhancing lesions) over months follow-up, also analyzed separate secondary outcomes. Results Of 316 participants (median [IQR] age, 34 [28-42] years; 70% women), analysis included 303 (95.9%) who took at least 1 dose study drug 288 (91.1%) ultimately completed 24-month trial. Disease observed 94 (60.3%) group 109 (74.1%) (hazard ratio [HR], 0.66 [95% CI, 0.50-0.87]; P .004), median time longer (432 vs 224 days; log-rank .003). All 3 outcomes reported significant differences favoring group: (89 [57.1%] 96 [65.3%]; HR, 0.71 0.53-0.95]; .02), new (72 [46.2%] 87 [59.2%]; 0.61 0.44-0.84]; .003), (29 [18.6%] 50 [34.0%]; 0.47 0.30-0.75]; .001). 10 showed no difference, including relapse, which occurred 28 (17.9%) 32 (21.8%) (HR, 0.69 0.42-1.16]; .16). similar subset 247 updated 2017 relapsing-remitting treatment initiation. Severe adverse events 17 13 group, none related cholecalciferol. Conclusions Relevance Oral significantly reduced early These results warrant further investigation, potential role pulse add-on therapy. Trial Registration ClinicalTrials.gov Identifier: NCT01817166

Language: Английский

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