Latest developments in MS research:
- Read about the causal association between vitamin D receptor binding at a locus and multiple sclerosis among Europeans.
- Learn about the Consensus Statement that aims to guide the radiological definition and measurement of chronic active lesions.
- Know more about the prevalence of comorbidities in people with MS enrolled in phase-III clinical trials.
These noteworthy MS news highlights and more are included in our recently published ECTRIMS Research Updates – a 30-day snapshot of global news and publications on MS research, treatment, and care.
ECTRIMS Research Updates can be sent to you every month, delivered straight to your inbox, via our free subscription service. Simply select all “topics” that are of interest to you, and when one of those appears in our news and publication cycle, you’ll be sure to hear from us.
Genetics
Evidence supports a causal association between allele-specific vitamin D receptor binding and multiple sclerosis among Europeans
This study explores the mechanisms which might explain the link between vitamin D pathways and the pathogenesis of multiple sclerosis (MS). The authors conducted a Mendelian Randomisation study to investigate the causal associations between vitamin D receptor (VDR) binding at a locus, 25-hydroxyvitamin D (25(OH)D) serum levels, and MS risk. Genetic instrumental variables (GIVs) were used for both VDR-binding variant (VDR-BV) and serum 25(OH)D. Dr. Adams and colleagues analysed genetic data from 13,589 people with MS and 38,887 controls of European ancestry from the Swedish Human OMNI, the Swedish GSA, the UK Biobank study, and Kaiser Permanente Northern California. Key results revealed that two VDR-BVs – rs2881514 and rs2531804 – were independently associated with MS susceptibility. rs2881514 was associated with an increased risk of MS and rs2531804 with a decreased risk of MS. Interestingly, there was evidence of interaction – not significant after correcting for multiple testing – between rs2881514 and a 25(OH)D GIV. This implies an effect on 25(OH)D levels. In particular, the direction of the association showed an interaction between increased VDR binding at rs2881514 and decreased bioavailability of 25(OH)D, determining an increased risk of MS. The authors demonstrated, for the first time, a causal association between rs2881514 and MS, potentially mediated by 25(OH)D. The results corroborate the hypothesis that genetic variations in individual VDR binding sites, followed by alterations in gene transcription and expression of vitamin D, contributes to MS.
Expression profiling of cerebrospinal fluid identifies dysregulated antiviral mechanisms in multiple sclerosis
The study presents in-depth analyses of the cerebrospinal fluid (CSF) transcriptome, aiming to identify the precise nature of the dysregulation in immune networks in individuals with multiple sclerosis (MS). Dr. Ban and colleagues conducted a high-resolution single-cell analysis of 92,732 cells from the CSF of 33 patients living with MS and 48 patients with other neurological diseases from the Cambridge University Hospital. The authors identified in patients with MS an increased proportion of an uncommon CD8+ T cell population in patients with MS, characterised by upregulation of inhibitory receptors – HAVCR2 and TIGIT. Furthermore, a Multi-Omics Factor Analysis (MOFA) revealed several factors showing altered expression associated with MS – in T cells and myeloid cells. Moreover, Dr. Ban and colleagues conducted the first single-cell expression quantitative trait loci (eQTL) analysis in CSF. They identified two eQTLs in CD8+ T cells related with MS susceptibility in genes associated to controlling viral responses – ZC3HAV1 and IFITM2, while no significant enrichment was identified in viral genomes in the CSF of patients with MS. Overall, the study suggests that alterations in viral control mechanisms may play a key role in the development of MS.
Clinical
Clinical impact of gender and age at onset on disease trajectory in primary progressive multiple sclerosis patients
Multiple Sclerosis Journal I 21 January 2024
This observational study analyses data from a cohort of the “RelevarEM” registry, that collects information on multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) in Argentina. The authors aimed to explore the clinical impact of gender and age at onset on the course of the disease in 125 patients with primary progressive multiple sclerosis. They observed no significant difference between males and females in the average annual increase of the Expanded Disability Status Scale (EDSS) scores. Furthermore, the rate of disease progression did not change significantly in relation to age at onset.
Investigating the Prevalence of Comorbidity in Multiple Sclerosis Clinical Trial Populations
The International Advisory Committee on Clinical Trials in MS has recommended to investigate comorbidities in multiple sclerosis (MS) in clinical trials. Moreover, the Food and Drug Administration (FDA) has emphasised the importance of broadening the range of baseline characteristics in phase-III clinical trials to better understand the benefits and risks of treatments in real-world populations. Following these recommendations, the present study aims to explore the prevalence of comorbid conditions in people with MS enrolled in phase-III clinical trials. The authors analyse the comorbidity status of 17,926 individuals with MS who participated to 17 phase-III clinical trials. Almost half of the patients – 46,5% – had one or more comorbidities. The most prevalent comorbid conditions were depression, hypertension, migraine, anxiety, and dyslipidemia. Over time, the prevalence of most comorbidities decreased or remained stable, while the prevalence of diabetes and hypertension increased. Migraine was more prevalent in female and younger participants, whereas hypertension, hyperlipidemia and diabetes were more prevalent among older participants. About 17% of the participants showed multiple chronic conditions. Cardiometabolic and mental conditions represented the most frequently observed dyad, while 3 cardiometabolic conditions represented the most frequent triad. Older age was more frequently associated with comorbidities.
Imagining chronic active lesions in multiple sclerosis: a consensus statement
The North American Imagining in Multiple Sclerosis Cooperative developed a Consensus Statement that aims to guide the radiological definition and measurement of chronic active lesions (CAL). CAL are a relevant manifestation of chronic inflammation in MS and are implicated in non-relapsing biological progression. The Consensus Statement proposes the following as promising candidate biomarkers of CAL: 1) paramagnetic rim lesions (PRL) on susceptibility-sensitive MRI sequences, 2) slowly expanding lesions (SEL) identified in magnetic resonance imaging (MRI) on T1 and T2-weighted scans, and 3) 18-kDa translocator protein (TSPO)-positive lesions on positron emission tomography (PET).
Therapeutics
Inhibition of CD40L with Frexalimab in Multiple Sclerosis
The New England Journal of Medicine I 15 February 2024
Persons with multiple sclerosis have elevated levels of soluble CD40L that highly correlate with disability. Clinical and pathological studies have indicated the inhibition of the CD40-CD40L pathway as a potential therapeutic strategy to treat multiple sclerosis (MS). Frexalimab is a second-generation anti-CD40L monoclonal antibody, Fc-engineered to avoid risks of thromboembolic events. The present study reports the results of a phase-2 trial of frexalimab – double-blind, randomised, placebo-controlled – involving 125 individuals with relapsing remitting multiple sclerosis and a mean age of 36.6 years. A group of participants received 1200 mg of frexalimab intravenously every 4 weeks; a group received 300 mg of frexalimab subcutaneously every 2 weeks and two groups received matching placebos. The number of new gadolinium-enhancing T1-weighted lesions identified with magnetic resonance imagining at week 12 were reduced in the groups who received the treatment compared to those who received placebo. The adjusted mean number of new gadolinium-enhancing T1-weighted lesions at week 12 relative to week 8 was 0.2 in the 1200-mg group and 0.3 in the 300-mg group, as compared to 1.4 in the placebo group. The adjusted mean number of new or enlarging T2-weighted lesions at week 12 was 0.3 in the 1200-mg group and 0.5 in the 300-mg group, compared to 3.5 in the placebo group. At week 24, the counts of gadolinium-enhancing T1-weighted lesions and new and enlarging T2-weighted lesions remained low among participants who continued the frexalimab treatment. The most common adverse events were COVID-19 and headaches.
Review
Immunomodulators and immunosuppressants for relapsing‐remitting multiple sclerosis: a network meta‐analysis
Cochrane Database of Systematic Reviews I 4 January 2024
A large armamentarium of disease-modifying treatments (DMTs) is today available to treat people with relapsing-remitting multiple sclerosis (RRMS). Each of these therapies slows disability accrual and decreases relapses compared to absence of treatment. This review aims to investigate the relative benefit of each treatment for people with RRMS. Fifty studies published until August 2022 were included – 50% were placebo-controlled and 68% sponsored by pharmaceutical companies – with a total of 36,541 adults with RRMS treated with a DMT for at least 1 year. Based on high certainty of evidence, results suggest that, compared to placebo, a 2-year treatment with natalizumab, cladribine or alemtuzumab was more effective in decreasing the frequency of relapses than the other DMTs included in this analysis. Based on moderate certainty of evidence, the authors indicate that a treatment of natalizumab can be effective in slowing disability progression after 24 months.