The radiologically isolated syndrome (RIS) currently represents the earliest detectable preclinical phase of multiple sclerosis (MS). Remarkable advancements have been recently made, including the ...identification of risk factors for disease evolution, revisions to the existing 2009 RIS criteria, and our understanding of the impact of early disease-modifying therapy use in the prevention/delay of symptomatic MS from two randomized clinical trials. Here, we discuss RIS in the context of the spectrum of MS, implications in the clinical management of individuals, and provide insights into future opportunities and challenges given the anticipated inclusion of asymptomatic MS in the formal definition of MS.
Objective
The radiologically isolated syndrome (RIS) represents the earliest detectable pre‐clinical phase of multiple sclerosis (MS). This study evaluated the impact of therapeutic intervention in ...preventing first symptom manifestation at this stage in the disease spectrum.
Methods
We conducted a multi‐center, randomized, double‐blinded, placebo‐controlled study involving people with RIS. Individuals without clinical symptoms typical of MS but with incidental brain MRI anomalies consistent with central nervous system (CNS) demyelination were included. Within 12 MS centers in the United States, participants were randomly assigned 1:1 to oral dimethyl fumarate (DMF) 240 mg twice daily or placebo. The primary endpoint was the time to onset of clinical symptoms attributable to a CNS demyelinating event within a follow‐up period of 96 weeks. An intention‐to‐treat analysis was applied to all participating individuals in the primary and safety investigations. The study is registered at ClinicalTrials.gov, NCT02739542 (ARISE).
Results
Participants from 12 centers were recruited from March 9, 2016, to October 31, 2019, with 44 people randomized to dimethyl fumarate and 43 to placebo. Following DMF treatment, the risk of a first clinical demyelinating event during the 96‐week study period was highly reduced in the unadjusted Cox proportional‐hazards regression model (hazard ratio HR = 0.18, 95% confidence interval CI = 0.05–0.63, p = 0.007). More moderate adverse reactions were present in the DMF (34 32%) than placebo groups (19 21%) but severe events were similar (DMF, 3 5%; placebo, 4 9%).
Interpretation
This is the first randomized clinical trial demonstrating the benefit of a disease‐modifying therapy in preventing a first acute clinical event in people with RIS. ANN NEUROL 2023;93:604–614
This multi‐center, randomized, double‐blinded trial by Okuda, et al. assessed the impact of dimethyl fumarate (DMF) in the time to onset of first clinical symptoms attributable to a central nervous system (CNS) demyelinating event within a follow‐up period of 96 weeks. Treatment with DMF resulted in over 80% risk reduction relative to placebo in the prevention of a first acute clinical event related to multiple sclerosis. A significant reduction in new and/or newly‐enlarging T2‐weighted hyperintense lesions was also observed.
Background and purpose
With the new highly active drugs available for people with multiple sclerosis (pwMS), vaccination becomes an essential part of the risk management strategy. We aimed to develop ...a European evidence‐based consensus for the vaccination strategy of pwMS who are candidates for disease‐modifying therapies (DMTs).
Methods
This work was conducted by a multidisciplinary working group using formal consensus methodology. Clinical questions (defined as population, interventions and outcomes) considered all authorized DMTs and vaccines. A systematic literature search was conducted and quality of evidence was defined according to the Oxford Centre for Evidence‐Based Medicine Levels of Evidence. The recommendations were formulated based on the quality of evidence and the risk–benefit balance.
Results
Seven questions, encompassing vaccine safety, vaccine effectiveness, global vaccination strategy and vaccination in subpopulations (pediatric, pregnant women, elderly and international travelers) were considered. A narrative description of the evidence considering published studies, guidelines and position statements is presented. A total of 53 recommendations were agreed by the working group after three rounds of consensus.
Conclusion
This first European consensus on vaccination in pwMS proposes the best vaccination strategy according to current evidence and expert knowledge, with the goal of homogenizing the immunization practices in pwMS.
Background:
With the new highly active drugs available for people with multiple sclerosis (pwMS), vaccination becomes an essential part of the risk management strategy
Objective:
To develop a ...European evidence-based consensus for the vaccination strategy of pwMS who are candidates for disease-modifying therapies (DMTs).
Methods:
This work was conducted by a multidisciplinary working group using formal consensus methodology. Clinical questions (defined as population, interventions, and outcomes) considered all authorized DMTs and vaccines. A systematic literature search was conducted and quality of evidence was defined according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. The recommendations were formulated based on the quality of evidence and the risk–benefit balance.
Results:
Seven questions, encompassing vaccine safety, vaccine effectiveness, global vaccination strategy and vaccination in sub-populations (pediatric, pregnant women, elderly and international travelers) were considered. A narrative description of the evidence considering published studies, guidelines, and position statements is presented. A total of 53 recommendations were agreed by the working group after three rounds of consensus.
Conclusion:
This first European consensus on vaccination in pwMS proposes the best vaccination strategy according to current evidence and expert knowledge, with the goal of homogenizing the immunization practices in pwMS.
Background:
Time matters in multiple sclerosis (MS). Irreversible neural damage and cell loss occur from disease onset. The MS community has endorsed a management strategy of prompt diagnosis, timely ...intervention and regular proactive monitoring of treatment effectiveness and disease activity to improve outcomes in people with MS.
Objectives:
We sought to develop internationally applicable quality standards for timely, brain health–focused MS care.
Methods:
A panel of MS specialist neurologists participated in an iterative, online, modified Delphi process to define ‘core’, ‘achievable’ and ‘aspirational’ time frames reflecting minimum, good and high care standards, respectively. A multidisciplinary Reviewing Group (MS nurses, people with MS, allied healthcare professionals) provided insights ensuring recommendations reflected perspectives from multiple stakeholders.
Results:
Twenty-one MS neurologists from 19 countries reached consensus on most core (25/27), achievable (25/27) and aspirational (22/27) time frames at the end of five rounds. Agreed standards cover six aspects of the care pathway: symptom onset, referral and diagnosis, treatment decisions, lifestyle, disease monitoring and managing new symptoms.
Conclusion:
These quality standards for core, achievable and aspirational care provide MS teams with a three-level framework for service evaluation, benchmarking and improvement. They have the potential to produce a profound change in the care of people with MS.
Background:
Yellow fever vaccine (YFV) is not advised for multiple sclerosis (MS) patients because of the potential risk of post-vaccine relapses.
Objective:
To assess the risk of relapsing-remitting ...multiple sclerosis (RR-MS) worsening after YFV.
Methods:
Non-interventional observational retrospective, exposed/non-exposed cohort study nested in the French national cohort including MS.
Results:
128 RR-MS were included. The 1-year annualized relapse rate (ARR) following YFV did not differ between exposed: 0.219 (0.420) and non-exposed subjects: 0.208 (0.521) (p = 0.92). Time to first relapse was not different between groups (adjusted hazard ratio (HR) = 1.33; 95% confidence interval (CI) = 0.53–3.30, p = 0.54).
Conclusion:
These results suggest that YFV does not worsen the course of RR-MS.
Background:
Counseling on pregnancy is still challenging, particularly regarding the use of disease-modifying treatments (DMTs). We are lacking long-term outcomes in children exposed to DMTs.
...Objectives:
This study aimed to set up a French pregnancy registry for women with multiple sclerosis (MS) and related disorders nested within the Observatoire Français de la Sclérose en Plaques (OFSEP) cohort.
Methods:
Prospective, observational, multicentric, epidemiological study in France. Neurological visits are organized according to routine practice. Data are collected on the OFSEP minimal datasheet. Auto-questionnaires on pregnancy are completed by patients at Months 5–6 and 8 during pregnancy, and Months 3, 6, and 12 postpartum. A specific survey on analgesia is completed by anesthesiologists. Pediatric data are collected from the child’s health book, where visits on Day 8, Month 9, and 24 are mandatory. Parents complete neurodevelopmental questionnaires at Year 1, Years 2 and 6.
Results:
The RESPONSE study started in August 2019. On 7 April 2023, 515 women were included. Baseline demographics are presented.
Conclusions:
RESPONSE will provide rich information on the global management of pregnancy in France and prospective data on children until the age of 6 years, exposed or not to a DMT, including data on neurodevelopment that can be compared to the general population.
Study funding:
EDMUS and ARSEP Foundation, Biogen, Roche.
Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) ...are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research.
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