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

Kuhlmann, Tanja; Moccia, Marcello; Coetzee, Timothy; Cohen, Jeffrey A.; Correale, Jorge; Graves, Jennifer; Marrie, Ruth Ann; Montalbán, Xavier; Yong, V. Wee; Thompson, Alan; Reich, Daniel S.; Amato, Maria Pia; Banwell, Brenda; Barkhof, Frederik; Chataway, Jeremy; Chitnis, Tanuja; Comı, Gıancarlo; Derfuss, Tobias; Finlayson, Marcia; Goldman, Myla D.; Green, Ari; Hellwig, Kerstin; Kos, Daphne; Miller, Aaron; Mowry, Ellen M.; Oh, Jiwon; Salter, Amber; Sormani, Maria Pia; Tintoré, Mar; Tremlett, Helen; Trojano, María; Walt, Anneke van der; Vukusic, Sandra; Waubant, Emmaunelle

doi:10.1016/s1474-4422(22)00289-7

Cited by 278 publications

(186 citation statements)

References 115 publications

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“…The availability of an MS-GRS combined model, in the context of undifferentiated ON, may help advance understanding of a clinically isolated syndrome, the forme fruste of ON in MS. Indeed, there is increasing recognition of MS clinical phenotypes falling on a continuum of disease severity and progression over time, 14 and further research is needed to determine whether individuals at high MS risk should be directed to MS services more rapidly, for consideration of disease modifying therapy.…”

Section: Discussionmentioning

confidence: 99%

“…There is unmet clinical need for a tool to improve acute risk strati cation, differentiating those at low future MS risk, who may bene t from urgent corticosteroids, from those at high future MS risk, who may bene t from earlier disease modifying therapy to reduce long term neurological disability. 14 Many autoimmune and autoin ammatory diseases including MS, are heritable, with recent large genome wide association studies (GWAS) identifying over 300 associated loci. The identi cation of strong, complex, human leukocyte antigen (HLA) class II associations, in addition to non-HLA associations offers the opportunity to aggregate MS genetic risk as a continuous MS genetic risk score (GRS).…”

Section: Introductionmentioning

confidence: 99%

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Applying a genetic risk score model to enhance prediction of future Multiple Sclerosis diagnosis at first presentation with optic neuritis: a cohort study in the UK Biobank

Oram

Loginovic

Ferrat

et al. 2022

Preprint

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Optic neuritis (ON) is associated with numerous immune-mediated inflammatory diseases. After presenting for the first time with undifferentiated ON, up to 50% per cent of patients are subsequently diagnosed with multiple sclerosis (MS), sometimes many years later. Differentiating MS-ON from non-MS-ON in the acute setting is challenging but important. Initial treatment of MS-ON and non-MS ON differs, with the latter often requiring urgent immunosuppression. Diagnostic delay in non-MS ON impacts final visual prognosis. Over 200 common genetic variants are associated with MS. We sought to establish whether integrating an MS genetic risk score (MS-GRS) improves prediction of future MS in undifferentiated ON. Using data from the United Kingdom Biobank we showed that combining MS-GRS with demographic risk factors significantly improves MS prediction in patients with undifferentiated ON. In a combined risk model including sex, age and MS-GRS, one standard deviation of MS risk score increased the Hazard of MS 1.3-fold (95% confidence interval 1.09-1.59, P<0.005). Participants stratified into quartiles of predicted MS risk developed incident MS during cumulative follow-up at rates varying from 3.8% (95% CI 1.2–8.6%, lowest risk quartile) to 41.7% (95% CI 33.1–50.6%, highest risk quartile). This study indicates that using a combined model in clinical practice might enhance individual MS risk stratification, paving the way for precision-based ON treatment and earlier introduction of MS disease-modifying therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Applying a genetic risk score model to enhance prediction of future Multiple Sclerosis diagnosis at first presentation with optic neuritis: a cohort study in the UK Biobank

Oram

Loginovic

Ferrat

et al. 2022

Preprint

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“…In addition, the regional sequence of the structural disconnections was not investigated for different phenotypes of MS such as CIS, RRMS, SPMS, and PPMS. A future study could investigate if the sequence of the structural disconnections differs for different phenotypes might be beneficial, however traditional clinical classifiers may not be relevant 51 . Presence or absence of treatment and type of treatments likely contribute to disability progression and the appearance of new lesions; this information was not included in the dEBM model.…”

Section: Limitationsmentioning

confidence: 99%

The sequence of regional structural disconnectivity due to multiple sclerosis lesions

Tozlu

Olafson

Jamison

et al. 2023

Preprint

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Objective: Prediction of disease progression is challenging in multiple sclerosis (MS) as the sequence of lesion development and retention of inflammation within a subset of chronic lesions is heterogeneous among patients. We investigated the sequence of lesion-related regional structural disconnectivity across the spectrum of disability and cognitive impairment in MS. Methods: In a full cohort of 482 patients, the Expanded Disability Status Scale was used to classify patients into (i) no or mild vs (ii) moderate or severe disability groups. In 363 out of 482 patients, Quantitative Susceptibility Mapping was used to identify paramagnetic rim lesions (PRL), which are maintained by a rim of iron-laden innate immune cells. In 171 out of 482 patients, Brief International Cognitive Assessment was used to identify subjects with cognitive impairment. Network Modification Tool was used to estimate the regional structural disconnectivity due to MS lesions. Discriminative event-based modeling was applied to investigate the sequence of regional structural disconnectivity due to all representative lesions across the spectrum of disability and cognitive impairment. Results: Structural disconnection in the ventral attention and subcortical networks was an early biomarker of moderate or severe disability. The earliest biomarkers of disability progression were structural disconnections due to PRL in the motor-related regions. Subcortical structural disconnection was an early biomarker of cognitive impairment. Interpretation: MS lesion-related structural disconnections in the subcortex is an early biomarker for both disability and cognitive impairment in MS. PRL-related structural disconnection in the motor cortex may identify the patients at risk for moderate or severe disability in MS.

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“…MS has long been considered an autoimmune disorder, and systemic immune-directed therapies can virtually eliminate clinical relapses, including their MRI counterparts, such as T2 signals or gadolinium-enhancing lesions, collectively referred to as disease activity. Similar therapies when prescribed for the progressive phase have little effect on disease course, independent of the effects on disease activity ( 2 ). Based on a review of approximately 200,000 Expanded Disability Status Scale (EDSS) transitions from more than 27,000 patients, Lublin et al concluded that, although relapses contribute to the accumulation of disability, primarily early on, progression in the absence of disease activity (referred to as PIRA) becomes the principal driver of disability accumulation in the progressive phase of the disease ( 3 ).…”

Section: Early Events In Multiple Sclerosis Drive Disabilitymentioning

confidence: 99%

“…One speculates whether stressed, mature OLs could be rescued and induced to restore axonal wrapping. In more chronic MS lesions, there is progressive loss of OLs and axons; active remyelination is rarely noted ( 2 ).…”

Section: Early Events In Multiple Sclerosis Drive Disabilitymentioning

confidence: 99%

Seeking neuroprotection in multiple sclerosis: an ongoing challenge

Antel¹,

Kennedy²

2023

Journal of Clinical Investigation

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Multiple sclerosis (MS) is an autoimmune disease of the CNS, featuring inflammation and demyelination with variable recovery. In this issue of the JCI , Kapell, Fazio, and authors address the potential for targeting neuron-oligodendrocyte potassium shuttling at the nodes of Ranvier as a neuroprotective strategy during inflammatory demyelination of the CNS in experimental MS. Their extensive and impressive study could serve as a template for defining the physiologic properties of a putative protective pathway. The authors examined MS features in existent disease models, investigated the impact of pharmacologic intervention, and evaluated its status in tissues from patients with MS. We await future studies that will tackle the challenge of translating these findings into a clinical therapy.

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

Cited by 278 publications

References 115 publications

Applying a genetic risk score model to enhance prediction of future Multiple Sclerosis diagnosis at first presentation with optic neuritis: a cohort study in the UK Biobank

Applying a genetic risk score model to enhance prediction of future Multiple Sclerosis diagnosis at first presentation with optic neuritis: a cohort study in the UK Biobank

The sequence of regional structural disconnectivity due to multiple sclerosis lesions

Seeking neuroprotection in multiple sclerosis: an ongoing challenge

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