Latest developments in MS research:
- Learn about association between anti-CD20 therapies and COVID-19 severity among patients with relapsing-remitting and progressive MS
- Read about the genetic basis of MS severity
- Review findings from the ocrelizumab randomised, double-blind phase 3 clinical trials
These noteworthy MS news highlights and more are included in our recently published ECTRIMS Bulletins – a 30-day snapshot of global news & publications on MS research, treatment and care.
ECTRIMS Bulletins 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 & publication cycle you’ll be sure to hear from us.
Clinical
Association Between Anti-CD20 Therapies and COVID-19 Severity Among Patients with Relapsing-Remitting and Progressive Multiple Sclerosis
This study aimed to assess the association between anti-CD20 therapies and COVID-19 severity in individuals with relapsing-remitting MS (RRMS) and progressive MS (PMS). Overall, 1400 individuals, 971 with RRMS and 429 with PMS, were included in the study. In a weighted analysis, 13.4% of patients with RRMS treated with anti-CD20 therapies had severe COVID-19, compared to 2.9% who did not receive anti-CD20 therapies (adjusted odds ratio [OR]: 5.20; 95% CI: 2.78–9.71); anti-CD20 treatment was therefore associated with increased risk of severe COVID-19. Among patients with PMS, 19.0% of patients treated with anti-CD20 had severe COVID-19 compared to 15.5% of those who did not receive anti-CD20 therapies (adjusted OR: 1.28; 95% CI: 0.76–2.16); therefore, there was no association between anti-CD20 treatment and severe COVID-19.
Associations among stressors across the lifespan, disability, and relapses in adults with multiple sclerosis
Brain and Behavior | 21 May 2023
Stress and hardship during childhood, adolescence and adulthood have been hypothesised to affect the present and future health and well-being of individuals with MS. This study measured lifetime stressors and assessed their impacts on disability and relapse burden changes since COVID-19 onset (March 2020) in 713 participants, the majority of whom were female and had RRMS. Findings from the study revealed that, while childhood and adulthood stressors contributed significantly to disability, only adulthood stressors contributed significantly to relapse burden changes since COVID-19 onset.
Pathogenesis
Locus for severity implicates CNS resilience in progression of multiple sclerosis
This genome-wide association study aimed to provide insight into the potential mechanisms involved in the progression of MS. The initial study was conducted in 12,584 cases and replicated in a further 9,805 cases. The investigators identified a significant association with rs10191329 in the DYSF–ZNF638 locus, the risk allele of which is associated with a median shortening of 3.7 years in the time to requiring a walking aid in homozygous carriers and with increased brainstem and cortical pathology in brain tissue. These findings suggest a key role for CNS resilience in determining outcome in MS.
Not all roads lead to the immune system: the genetic basis of multiple sclerosis severity
Using prospectively obtained data from MSBase, the largest international MS registry, this study assembled a cohort of deeply phenotyped individuals of European ancestry with relapse-onset MS. The investigators conducted an unbiased genome-wide association study, and utilised machine learning approaches, to assess the genetic contribution to longitudinally defined MS severity phenotypes in 1813 individuals. No genetic variants of moderate to large effect sizes that met genome-wide significance thresholds were identified. However, the top variants in the GWAS analyses were significantly associated with time to key EDSS milestones (EDSS 3 and EDSS 6). Gene set enrichment analyses demonstrated that severity was regulated by CNS signals. Using a machine learning approach incorporating genetic, clinical and demographic data, the authors demonstrated that they could accurately predict disease severity AUC 0.84 (95% CI 0.79-0.88) outperforming clinical and demographic data alone AUC 0.54 (95% CI 0.48, 0.60).
Association of Arachidonic Acid-Derived Lipid Mediators with Disease Severity in Patients with Relapsing and Progressive Multiple Sclerosis
Excessive activation of lipid mediator pathways has been postulated to play a role in the complex pathogenesis of MS. This study assessed the association between omega-3 and omega-6 fatty acids and clinical, biochemical and magnetic resonance imaging (MRI)-based parameters in both individuals with MS (170 with relapsing-remitting MS, 115 with progressive MS) and 125 healthy volunteers. Elevated levels of specific products of the arachidonic acid pathway were found to be associated with neurodegenerative processes, particularly in individuals with progressive MS, highlighting the potential relevance of omega-6 fatty acids in disease pathogenesis.
Imaging and Non-imaging Biomarkers
Blood neurofilament light levels predict non-relapsing progression following anti-CD20 therapy in relapsing and primary progressive multiple sclerosis: findings from the ocrelizumab randomised, double-blind phase 3 clinical trials
Neurofilament light chain (NfL) is associated with relapsing MS activity and has been postulated to have prognostic ability for future relapse-related disease progression. This study aimed to assess whether NfL was also predictive of non-relapse-related MS progression. In individuals with RRMS without disease activity, and in all individuals with primary progressive MS (PPMS), higher baseline NfL was prognostic for greater whole brain and thalamic atrophy, greater volume expansion of slowly expanding lesions and clinical progression. Ocrelizumab treatment significantly reduced NfL levels, consistent with its effects on acute disease activity and disability progression. However, persistently elevated NfL levels were observed in a subgroup of individuals receiving ocrelizumab treatment – demonstrating the potential clinical utility of NfL as a predictive biomarker for increased risk of clinical progression.
miRNA 548a-3p as biomarker of NEDA-3 at 2 years in multiple sclerosis patients treated with fingolimod
Over the last decade, different microRNA (miRNA) expression patterns have been associated with treatment responses in MS, resulting in increasing interest in the potential role of miRNAs as treatment response biomarkers. This study evaluated serum miRNAs as biomarkers of No Evidence of Disease Activity (NEDA-3) at 2 years in patients with RRMS treated with fingolimod. Findings from the study demonstrated differences in miR-548a-3p expression at 6 months after fingolimod initiation in patients with MS who achieved NEDA-3 at 2 years. These results provide class III evidence of the use of miR-548a-3p as a biomarker of NEDA-3 in patients treated with fingolimod.
Several serum lipid metabolites are associated with relapse risk in paediatric-onset multiple sclerosis
Multiple Sclerosis Journal | 18 May 2023
Alterations in lipid metabolites in individuals with MS might be of prognostic interest due to their various roles in the brain such as acting as an energy source, being a component of cellular membranes and serving as bioactive molecules. This study aimed to determine whether alterations in serum lipid metabolites were associated with the risk of relapse and disability in children with MS. The investigators concluded that in children with MS, acylcarnitines and polyunsaturated fatty acids were associated with higher relapse rates and Expanded Disability Status Scale (EDSS) scores, while serum phosphatidylethanolamines, plasmalogens and primary bile acid metabolites were associated with lower relapse rates and EDSS scores.
Therapeutics
Risk of new disease activity in patients with multiple sclerosis who continue or discontinue disease-modifying therapies (DISCOMS): a multicentre, randomised, single-blind, phase 4, non-inferiority trial
The multicentre, randomised, controlled, rater-blinded, phase 4, non-inferiority DISCOMS trial aimed to determine whether the risk of disease recurrence is increased in older (>55 years) patients with MS and no recent disease activity who discontinue DMT compared to those who remain on DMT. A total of 259 individuals with MS were enrolled, with 128 assigned to continue DMT and 131 to discontinue treatment. The difference in event rates between the two groups was 7·5 percentage points (95% CI 0·6–15·0), with similar rates of adverse events in each group. The investigators were unable to conclude whether DMT discontinuation is non-inferior to continuation in individuals with MS >55 years old.
Initiation Patterns of Disease-Modifying Therapies for Multiple Sclerosis Among US Adults and Children, 2001 Through 2020
This cross-sectional study examined the impact of increasing availability of disease-modifying therapies (DMTs) for MS on real-world prescribing patterns between 2001 and 2020. Significant changes in DMT prescribing patterns were noted over this 20-year period, with a decline in the use of injectable therapies following the introduction of oral agents. Between 2019 and 2020, dimethyl fumarate was the most commonly initiated DMT in adults (23.3% to 27.2% of all initiations), while in children fingolimod was the most commonly initiated (34.8% to 68.8%). The cause underlying this shift in prescribing patterns is not definitively known but may reflect several factors, including convenience of administration, direct-to-consumer advertising or insurance restrictions.
A systematic review of the safety and efficacy of monoclonal antibodies for progressive multiple sclerosis
International Immunopharmacology | July 2023
This systematic review evaluated the available evidence regarding monoclonal antibody treatment for PMS. After examining evidence from 13 clinical trials investigating monoclonal antibodies (ocrelizumab, natalizumab, rituximab and alemtuzumab) in individuals with PMS, the authors concluded that ocrelizumab was the most efficient monoclonal antibody for primary PMS, and significantly reduced clinical disease progression measures. In contrast, the results for rituximab showed significant changes for only some endpoints on MRI and clinical measures. Natalizumab decreased the relapse rate and improved MRI features for secondary PMS patients, but not clinical endpoints, and studies on alemtuzumab revealed conflicting outcomes, with improvements observed in MRI endpoints but clinical worsening in patients.
Long-term results of autografting persons with multiple sclerosis are better in those not exposed to prior disease-modifying therapies
Multiple Sclerosis and Related Disorders | July 2023
Autologous haematopoietic stem cell transplantation (aHSCT) can change the natural history of MS. This study analysed whether aHSCT should be performed early in the course of the disease or after failure of other therapies. The investigators studied the long-term results of aHSCT in 1132 individuals with MS who were given, or not given, immunosuppressive DMT prior to transplantation. The EDSS score typically indicated disease worsening in patients before the aHSCT, but was stabilised at 3 years post-transplant in individuals with prior exposure to DMT. In contrast, individuals who had not received prior DMT demonstrated significant improvements in EDSS score. The findings from this study indicated a positive response in all patients receiving aHSCT, but significantly superior outcomes in those without prior DMT exposure.
Evaluating the efficacy and safety of transitioning patients with multiple sclerosis from natalizumab to ocrelizumab (OCTAVE)
Multiple Sclerosis Journal | 15 June 2023
This study evaluated the safety and efficacy of ocrelizumab in 43 individuals with clinically and radiographically stable RRMS previously treated with natalizumab. Two individuals in the study relapsed while on ocrelizumab, one at month 9 and the other at month 12, without changes on brain MRI. Two additional patients had new brain MRI lesions detected at month 3, with no new symptoms. The investigators concluded that clinical and MRI stability are observed in most individuals with RRMS who transition from natalizumab to ocrelizumab.
Rituximab vs Ocrelizumab in Relapsing-Remitting Multiple Sclerosis
This multicentre cohort study examined whether rituximab is non-inferior to ocrelizumab in preventing relapses and disability in patients with RRMS. Outcomes were assessed in 710 individuals with MS treated with ocrelizumab and 186 treated with rituximab. The main outcome measure was a non-inferiority comparison of annualised rate of relapses, ARRs. Over a pairwise censored mean follow-up of 1.4 years, the ARR ratio was higher in individuals with MS treated with rituximab compared with ocrelizumab, demonstrating that rituximab was not non-inferior, and was associated with a higher risk of relapses, than ocrelizumab.
Comparison Between Dimethyl Fumarate, Fingolimod, and Ocrelizumab After Natalizumab Cessation
The objective of this cohort study, conducted in 1386 individuals with RRMS, was to compare the effectiveness and persistence of treatment with dimethyl fumarate, fingolimod and ocrelizumab following natalizumab discontinuation. Discontinuation of natalizumab has been shown to be associated with a risk of rebound disease activity, and so there is a need to identify the optimal switch DMT strategy after natalizumab to limit the risk of severe relapses. In this study, a switch to ocrelizumab was associated with the lowest annualised relapse and discontinuation rates, and the longest time to first relapse, compared with dimethyl fumarate and fingolimod.