Deciphering Multiple Sclerosis Progression

Meca-Lallana, Virginia; Berenguer‐Ruiz, Leticia; Polo, J. Carreres; Eichau-Madueño, Sara; Ferrer-Lozano, Jaime; Forero, Lucía; Higueras, Yolanda; Lara, Nieves Téllez; Vidal-Jordana, Ángela; Pérez‐Miralles, Francisco

doi:10.3389/fneur.2021.608491

Cited by 19 publications

(26 citation statements)

References 133 publications

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“…Clearly, these biomarkers are of value in this context. Indeed, generally in future studies evaluating aHSCT, these more sensitive monitoring tools would be of great value to outcome data, as well as establishing whether alterations in oligoclonal band (OCB) or glial fibrillary acidic protein (GFAP) production occurs following transplantation, particularly when compared to a control group [ 111 ].…”

Section: Monitoring the Efficacy Of Transplantmentioning

confidence: 99%

The current standing of autologous haematopoietic stem cell transplantation for the treatment of multiple sclerosis

et al. 2022

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Autologous haematopoietic stem cell transplantation (aHSCT) is gaining traction as a valuable treatment option for patients affected by severe multiple sclerosis (MS), particularly the relapsing–remitting form. We describe the current literature in terms of clinical trials, observational and retrospective studies, as well as immune reconstitution following transplantation, with a focus on the conditioning regimens used for transplantation. The evidence base predominantly consists of non-randomised, uncontrolled clinical trials or data from retrospective or observational cohorts, i.e. very few randomised or controlled trials. Most often, intermediate-intensity conditioning regimens are used, with promising results from both myeloablative and lymphoablative strategies, as well as from regimens that are low and high intensity. Efficacy of transplantation, which is likely secondary to immune reconstitution and restored immune tolerance, is, therefore, not clearly dependent on the intensity of the conditioning regimen. However, the conditioning regimen may well influence the immune response to transplantation. Heterogeneity of conditioning regimens among studies hinders synthesis of the articles assessing post-aHSCT immune system changes. Factors associated with better outcomes were lower Kurtzke Expanded Disability Status Scale, relapsing–remitting MS, younger age, and shorter disease duration at baseline, which supports the guidance for patient selection proposed by the European Society for Blood and Marrow Transplantation. Interestingly, promising outcomes were described for patients with secondary progressive MS by some studies, which may be worth taking into account when considering treatment options for patients with active, progressive disease. Of note, a significant proportion of patients develop autoimmune disease following transplantation, with alemtuzumab-containing regimens associated with the highest incidence.

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Section: Monitoring the Efficacy Of Transplantmentioning

confidence: 99%

The current standing of autologous haematopoietic stem cell transplantation for the treatment of multiple sclerosis

et al. 2022

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“…Stratification on age is also a relevant evaluation, as MS is a long-term condition and younger patients typically have a less severe form of the disease. As the disease progresses, it can evolve from relapse-remitting to a progressive state (Meca-Lallana et al, 2021), which is often accompanied by an increase in symptom severity. Our age buckets were chosen based on expert input on what would be most clinically useful.…”

Section: Subgroup Resultsmentioning

confidence: 99%

Disability prediction in multiple sclerosis using performance outcome measures and demographic data

Roy¹,

Mincu²,

Proleev³

et al. 2022

Preprint

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Literature on machine learning for multiple sclerosis has primarily focused on the use of neuroimaging data such as magnetic resonance imaging and clinical laboratory tests for disease identification. However, studies have shown that these modalities are not consistent with disease activity such as symptoms or disease progression. Furthermore, the cost of collecting data from these modalities is high, leading to scarce evaluations. In this work, we used multi-dimensional, affordable, physical and smartphone-based performance outcome measures (POM) in conjunction with demographic data to predict multiple sclerosis disease progression. We performed a rigorous benchmarking exercise on two datasets and present results across 13 clinically actionable prediction endpoints and 6 machine learning models. To the best of our knowledge, * These authors contributed equally † Data used in the preparation of this article were obtained from the Multiple Sclerosis Outcome Assessments Consortium (MSOAC). As such, the investigators within MSOAC contributed to the design and implementation of the MSOAC Placebo database and/or provided placebo data, but did not participate in the analysis of the data or the writing of this report.

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“…An innovative design feature of study AB07002 is its use of EDSS repeated-measures GEE methodology for the primary efficacy outcome, as opposed to survival or disability progression analyses that consider a specific milestone. 25 The latter approaches ignore available data, both before and after reaching the milestone, do not consider differences between individual trajectories, and have a relatively low incidence of milestone attainment over 2 years in the placebo group. Conversely, GEE repeated-measure models, where observations are clustered within individuals, use all available information to generate a population-averaged interpretation of the data, which takes into account the fluctuating nature of EDSS over time (i.e., all detectable improvement and worsening).…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis

Vermersch

Brieva-Ruiz

Fox

et al. 2022

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesMasitinib is a selective tyrosine kinase inhibitor, targeting innate immune cells (mast cells and microglia) that are involved in the pathophysiology of progressive multiple sclerosis (MS). Study AB07002 assessed oral masitinib in patients with progressive MS who were progressing but not clinically active.MethodsThis randomized, double-blind, 2 parallel-group, placebo-controlled trial assessing 2 dose levels of masitinib vs equivalent placebo was conducted at 116 hospital clinics and specialized MS centers in 20 countries. Randomization (2:1) with minimization was performed centrally using an automated system. Patients, physicians, and outcome assessors remained masked to treatment group allocation. Patients with primary progressive MS (PPMS) or nonactive secondary progressive MS (nSPMS) without relapse for ≥2 years, aged 18–75 years, with baseline Expanded Disability Status Scale (EDSS) 2.0–6.0, and regardless of time from onset were treated for 96 weeks. The primary end point was overall EDSS change from baseline using repeated measures (generalized estimating equation, timeframe W12–W96, measured every 12 weeks), with positive values indicating increased clinical deterioration. Efficacy and safety were assessed in all randomly assigned and treated patients.ResultsA total of 611 patients were randomized; 301 in the masitinib 4.5 mg/kg/d parallel group and 310 in the uptitrated masitinib 6.0 mg/kg/d parallel group. Masitinib (4.5 mg/kg/d) (n = 199) showed significant benefit over placebo (n = 101) according to the primary end point, 0.001 vs 0.098, respectively, with a between-group difference of −0.097 (97% CI −0.192 to −0.002); p = 0.0256. Safety was consistent with masitinib's known profile (diarrhea, nausea, rash, and hematologic events), with no elevated risk of infection. Efficacy results from the independent uptitrated masitinib 6.0 mg/kg/d parallel group were inconclusive, and no new safety signal was observed.DiscussionMasitinib (4.5 mg/kg/d) can benefit people with PPMS and nSPMS. A confirmatory phase 3 study will be initiated to substantiate these data.Trial Registration InformationThe first participant was randomized to study AB07002 on August 25, 2011. The trial was registered with the European Clinical Trials Database (#EudraCT 2010-021219-17) on July 1, 2011 (clinicaltrialsregister.eu/ctr-search/trial/2010-021219-17/ES) and with ClinicalTrials.gov (#NCT01433497) on September 14, 2011 (clinicaltrials.gov/ct2/show/NCT01433497).Classification of EvidenceThis study provides Class II evidence that masitinib 4.5 mg/kg/d decreased progression of disability, measured by the EDSS, in adults with PPMS or patients with nSPMS (with no exacerbations in the last 2 years).

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Deciphering Multiple Sclerosis Progression

Cited by 19 publications

References 133 publications

The current standing of autologous haematopoietic stem cell transplantation for the treatment of multiple sclerosis

The current standing of autologous haematopoietic stem cell transplantation for the treatment of multiple sclerosis

Disability prediction in multiple sclerosis using performance outcome measures and demographic data

Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis

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