Genetic and Biochemical Factors Related to the Risk and Disability Progression in Multiple Sclerosis

The aim of the study was to verify the association of clinical relapses and brain activity with disability progression in relapsing/remitting multiple sclerosis patients receiving disease-modifying treatments in Poland. Disability progression was defined as relapse-associated worsening (RAW), progression independent of relapse activity (PIRA), and progression independent of relapses and brain MRI Activity (PIRMA). Data from the Therapeutic Program Monitoring System were analyzed. Three panels of patients were identified: R0, no relapse during treatment, and R1 and R2 with the occurrence of relapse during the first and the second year of treatment, respectively. In the R0 panel, we detected 4.6% PIRA patients at 24 months (p < 0.001, 5.0% at 36 months, 5.6% at 48 months, 6.1% at 60 months). When restricting this panel to patients without brain MRI activity, we detected 3.0% PIRMA patients at 12 months, 4.5% at 24 months, and varying from 5.3% to 6.2% between 36 and 60 months of treatment, respectively. In the R1 panel, RAW was detected in 15.6% patients at 12 months and, in the absence of further relapses, 9.7% at 24 months and 6.8% at 36 months of treatment. The R2 group was associated with RAW significantly more frequently at 24 months compared to the R1 at 12 months (20.7%; p < 0.05), but without a statistical difference later on. In our work, we confirmed that disability progression was independent of relapses and brain MRI activity.

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Determinants of therapeutic lag in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458520981300 ◽

2021 ◽

pp. 135245852098130

Author(s):

Izanne Roos ◽

Emmanuelle Leray ◽

Federico Frascoli ◽

Romain Casey ◽

J William L Brown ◽

...

Keyword(s):

Multiple Sclerosis ◽

Expanded Disability Status Scale ◽

Disability Progression ◽

Delayed Onset ◽

Disease Characteristics ◽

Disability Status ◽

Male Sex ◽

Pre Treatment ◽

Patient Subgroups

Background: A delayed onset of treatment effect, termed therapeutic lag, may influence the assessment of treatment response in some patient subgroups. Objectives: The objective of this study is to explore the associations of patient and disease characteristics with therapeutic lag on relapses and disability accumulation. Methods: Data from MSBase, a multinational multiple sclerosis (MS) registry, and OFSEP, the French MS registry, were used. Patients diagnosed with MS, minimum 1 year of exposure to MS treatment and 3 years of pre-treatment follow-up, were included in the analysis. Studied outcomes were incidence of relapses and disability accumulation. Therapeutic lag was calculated using an objective, validated method in subgroups stratified by patient and disease characteristics. Therapeutic lag under specific circumstances was then estimated in subgroups defined by combinations of clinical and demographic determinants. Results: High baseline disability scores, annualised relapse rate (ARR) ⩾ 1 and male sex were associated with longer therapeutic lag on disability progression in sufficiently populated groups: females with expanded disability status scale (EDSS) < 6 and ARR < 1 had mean lag of 26.6 weeks (95% CI = 18.2–34.9), males with EDSS < 6 and ARR < 1 31.0 weeks (95% CI = 25.3–36.8), females with EDSS < 6 and ARR ⩾ 1 44.8 weeks (95% CI = 24.5–65.1), and females with EDSS ⩾ 6 and ARR < 1 54.3 weeks (95% CI = 47.2–61.5). Conclusions: Pre-treatment EDSS and ARR are the most important determinants of therapeutic lag.

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Study protocol: randomised controlled trial evaluating exercise therapy as a supplemental treatment strategy in early multiple sclerosis: the Early Multiple Sclerosis Exercise Study (EMSES)

BMJ Open ◽

10.1136/bmjopen-2020-043699 ◽

2021 ◽

Vol 11 (1) ◽

pp. e043699

Author(s):

Morten Riemenschneider ◽

Lars G Hvid ◽

Steffen Ringgaard ◽

Mikkel K E Nygaard ◽

Simon F Eskildsen ◽

...

Keyword(s):

Multiple Sclerosis ◽

Randomised Controlled Trial ◽

Usual Care ◽

Treatment Strategy ◽

Controlled Trial ◽

Treatment Strategies ◽

Control Group ◽

Disease Course ◽

Disability Progression ◽

Randomised Controlled

IntroductionIn the relapsing remitting type of multiple sclerosis (MS) reducing relapses and neurodegeneration is crucial in halting the long-term impact of the disease. Medical disease-modifying treatments have proven effective, especially when introduced early in the disease course. However, patients still experience disease activity and disability progression, and therefore, supplemental early treatment strategies are warranted. Exercise appear to be one of the most promising supplemental treatment strategies, but a somewhat overlooked ‘window of opportunity’ exist early in the disease course. The objective of this study is to investigate exercise as a supplementary treatment strategy early in the disease course of MS.Methods and analysisThe presented Early Multiple Sclerosis Exercise Study is a 48-week (plus 1-year follow-up) national multicentre single-blinded parallel group randomised controlled trial comparing two groups receiving usual care plus supervised high-intense exercise or plus health education (active control). Additionally, data will be compared with a population-based control group receiving usual care only obtained from the Danish MS Registry. The primary outcomes are annual relapse rate and MRI derived global brain atrophy. The secondary outcomes are disability progression, physical and cognitive function, MS-related symptoms, and exploratory MRI outcomes. All analyses will be performed as intention to treat.Ethics and disseminationThe study is approved by The Central Denmark Region Committees on Health Research Ethics (1-10-72-388-17) and registered at the Danish Data Protection Agency (2016-051-000001 (706)). All study findings will be published in scientific peer-reviewed journals and presented at relevant scientific conferences.Trial registration numberNCT03322761.

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Parity and disability progression in relapsing–remitting multiple sclerosis

Journal of Neurology ◽

10.1007/s00415-020-10093-1 ◽

2020 ◽

Vol 267 (12) ◽

pp. 3753-3762

Author(s):

Anat Achiron ◽

◽

Alon Ben-David ◽

Michael Gurevich ◽

David Magalashvili ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disability Progression ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis

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Interferon-beta and disability progression in relapsing-remitting multiple sclerosis

Clinical Neurology and Neurosurgery ◽

10.1016/j.clineuro.2013.09.024 ◽

2013 ◽

Vol 115 ◽

pp. S65-S69 ◽

Cited By ~ 13

Author(s):

Jelena Drulovic ◽

Jelena Kostic ◽

Sarlota Mesaros ◽

Irena Dujmovic Basuroski ◽

Nebojsa Stojsavljevic ◽

...

Keyword(s):

Multiple Sclerosis ◽

Interferon Beta ◽

Disability Progression ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis

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Repurposing Domperidone in Secondary Progressive MS

Neurology ◽

10.1212/wnl.0000000000011863 ◽

2021 ◽

pp. 10.1212/WNL.0000000000011863

Author(s):

Marcus W. Koch ◽

Kayla Sage ◽

Sharanjit Kaur ◽

Janet Kim ◽

Graziela Cerchiaro ◽

...

Keyword(s):

Multiple Sclerosis ◽

Adverse Events ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive Multiple Sclerosis ◽

Phase 2 ◽

Disability Progression ◽

Two Stage ◽

Serious Adverse Events ◽

Secondary Progressive ◽

Link Type

ObjectiveTo assess whether treatment with the generic drug domperidone can reduce the progression of disability in secondary progressive multiple sclerosis (SPMS), we conducted a phase 2 futility trial following the Simon two-stage design.MethodsWe enrolled patients in an open-label, Simon two-stage, single-center, phase 2, single-arm futility trial at the Calgary MS Clinic if they met the following criteria: age 18–60 years, SPMS, screening EDSS score of 4.0–6.5 and screening T25FW of 9 seconds or more. Patients received domperidone 10 mg QID for one year. The primary outcome was worsening of disability, defined as worsening of the T25FW performance by 20% or more at 12 months compared to at baseline. This trial is registered with ClinicalTrials.gov, number NCT02308137.ResultsBetween February 13, 2015 and January 3, 2020, 110 patients were screened, 81 received treatment, 64 completed follow-up, of whom 62 were analysed. The study did not meet its primary endpoint: 22 of 62 (35%) patients experienced significant worsening of disability, which is close to the expected proportion of 40%, and above the pre-defined futility threshold. Patients with higher prolactin levels during the study had a significantly lower risk of disability progression, which may warrant further investigation. Domperidone treatment was reasonably well tolerated, but adverse events occurred in 84% and serious adverse events in 15% of patients.ConclusionsDomperidone treatment could not reject futility in reducing disability progression in SPMS. The Simon two-stage trial model may be a useful model for phase 2 studies in progressive MS.Classification of evidenceThis study provides Class III evidence that in individuals with secondary progressive multiple sclerosis participating in a futility trial, domperidone treatment could not reject futility in reducing disability progression at 12 months.

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Cerebellar Dysfunction in Multiple Sclerosis: Considerations for Research and Rehabilitation Therapy

Neurorehabilitation and Neural Repair ◽

10.1177/15459683211065442 ◽

2021 ◽

pp. 154596832110654

Author(s):

Erin M. Edwards ◽

Nora E. Fritz ◽

Amanda S. Therrien

Keyword(s):

Multiple Sclerosis ◽

Motor Control ◽

Motor Impairment ◽

Future Research ◽

Disability Progression ◽

Cerebellar Dysfunction ◽

Motor Disability ◽

Rehabilitation Outcomes ◽

Critical Knowledge ◽

The Impact

Introduction. Cerebellar pathology is common among persons with multiple sclerosis (PwMS). The cerebellum is well recognized for its role in motor control and motor learning and cerebellar pathology in multiple sclerosis is associated with enhanced motor impairment and disability progression. The Problem. To mitigate motor disability progression, PwMS are commonly prescribed exercise and task-specific rehabilitation training. Yet, whether cerebellar dysfunction differentially affects rehabilitation outcomes in this population remains unknown. Furthermore, we lack rehabilitation interventions targeting cerebellar dysfunction. The Solution. Here, we summarize the current understanding of the impact of cerebellar dysfunction on motor control, motor training, and rehabilitation in persons with multiple sclerosis. Recommendations. Additionally, we highlight critical knowledge gaps and propose that these guide future research studying cerebellar dysfunction in persons with multiple sclerosis.

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