Latest developments in MS research:
- Read about how to improve acute risk stratification when people first report having optic neuritis by applying a genetic risk score model.
- Learn about a key mitochondrial mechanism that sustains the activation of microglia and consequent neurotoxicity.
- Know more about spinal cord lesions in multiple sclerosis.
These noteworthy MS news highlights and more are included in this month’s 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.
Biomarkers
Cerebrospinal fluid mtDNA concentrations are increased in multiple sclerosis and were normalized after intervention with autologous hematopoietic stem cell transplantation
Multiple Sclerosis and Related Disorders I April 2024
The study suggests that cell-free mitochondrial DNA (mtDNA) in cerebrospinal fluid (CSF) can be considered a potential biomarker for monitoring inflammatory activity and treatment response in multiple sclerosis (MS). Levels of mtDNA were elevated in the CSF of 48 patients with MS, compared to 32 healthy controls, before autologous hematopoietic stem cell transplantation (aHSCT) – a potent treatment for MS. The levels of mtDNA were normalised after intervention with aHSCT. The study also shows that baseline concentrations of cell-free mtDNA correlates with clinical measures of MS, including CSF mononuclear cell counts, levels of immunoglobulin G (IgG) and M (IgM), scores at the Expanded Disability Status Scale (EDSS) and number of relapses in the year before.
Reviews
Practical considerations for managing pregnancy in patients with multiple sclerosis
The review provides an overview of recommendations and guidelines by the US Food and Drug Administration (FDA), European Medicines Agency (EMA) and Health Canada on how to manage treatment during pregnancy and breastfeeding in patients with MS. 1) Most DMTs should be stopped before conception or pregnancy due to possible effects on the foetus. However, the B-cell-depleting group of monoclonal antibodies have properties that can be leveraged to maximise their therapeutics benefits during pregnancy. Conversations about the intention to have a family should start as early as possible. When a patient wishes to become pregnant, planning should be recommended to have the time to adjust DMTs. 2) Women with MS can undergo fertility treatments. 3) MS does not seem to affect pregnancy outcomes. 4) MS should not impact the way the mother wishes to deliver. 4) During the first few months after delivery, patients with MS need to be closely monitored, due to an increased risk of postpartum depression. After the delivery, it is recommended to women with MS to undergo a pelvic floor physiotherapy. Re-starting DMTs early postpartum can also be helpful to reduce the risk of relapses. 5) Women with MS who want to breastfeed should be encouraged to do so. Discussions about family planning should be solicited as early as possible and regularly. A risk/benefit analysis will often be needed when managing the treatment during pregnancy and breastfeeding.
Genetics
Applying a genetic risk score model to enhance prediction of future multiple sclerosis diagnosis at first presentation with optic neuritis
Nature Communications I 28 February 2024
Using data from the UK Biobank, this study highlights the possibility to use a combined model to improve acute risk stratification when people first report having optic neuritis. Optic neuritis (ON) typically presents as a subacute vision loss in one eye or both eyes. Half of patients with ON are eventually diagnosed with multiple sclerosis (MS). It may be very important to differentiate people with ON at low risk from those at high risk of developing MS, to support neurologists in a time-critical decision. Indeed, while people with ON at low future MS risk may benefit from urgent corticosteroids, people at high future MS risk may benefit from early disease-modifying therapy (DMT). The authors show that combining an MS-genetic risk score with demographic factors that can increase MS risk – age at ON onset and sex – can significantly enhance prediction of future MS at first presentation with ON. The results were also replicated across two large datasets – Geisinger from USA and FinnGen from Finland.
Therapeutics
Comparative effectiveness of natalizumab, fingolimod, and injectable therapies in paediatric-onset multiple sclerosis
This retrospective cohort study aims to compare the effectiveness of natalizumab, fingolimod and injectable DMTs – interferonbeta and glatiramer acetate – in patients with paediatric-onset multiple sclerosis (POMS). The authors analyse real-world clinical data of 1,218 individuals with POMS from the MSBase registry. All the patients started the treatment with an injectable DMT, fingolimod, or natalizumab between 2006 and 2021. At year 1, 2 and 5, the proportion of relapse-free patients was highest with natalizumab, followed by fingolimod and injectable DMTs. The risk of relapse was significantly lower in patients treated with natalizumab than patients treated with injectable DMTs or fingolimod, and in patients treated with fingolimod compared to patients treated with injectable DMTs. The results are consistent with previous studies on the efficacy of natalizumab and fingolimod in individuals with MS with adult-onset.
Safety and efficacy of extended versus standard interval dosing of natalizumab in multiple sclerosis patients: a systematic review and meta-analysis
Acta Neurologica Belgica I 8 March 2024
This meta-analysis on 14 studies aims to evaluate the efficacy and safety of natalizumab in patients with multiple sclerosis under extended interval dosing – 5 to 8 weeks. The standard dose of interest of the study was 300mg of natalizumab given by intravenous infusion. The study showed the non-inferiority of the extended interval dosing of natalizumab compared to the standard interval dosing. No significant difference between extended and standard interval dosing was found in all the outcomes of interest – risk of clinical relapses, risk of new or newly enlarging lesions identified with the magnetic resonance imaging (MRI), change in the Expanded Disability Status Scale (EDSS). Furthermore, increasing the interval dosing did not reduce the risk of developing progressive multifocal leukoencephalopathy (PML). However, drawing conclusions about the effect on PML risk is difficult, due to the small numbers of events.
Pathogenesis
Mitochondrial complex I activity in microglia sustains neuroinflammation
The study identifies a key mitochondrial mechanism that sustains the activation of microglia and neurotoxic damage. Persistently activated myeloid cells are a source of neurotoxic factors in multiple sclerosis (MS). The authors show that, when the inflammation of central nervous system becomes chronic, microglia show a depletion of phosphocreatine and reduced levels of adenosine triphosphate (ATP). This may be linked to a decreased antioxidant and inflammasome response. Using fluorescence-activated cell sorting (FACS), microglia were isolated from the spinal cord of mice with experimental autoimmune encephalomyelitis (EAE) – a model of a disease that is MS-like – during the acute and the chronic stage. It was observed that in the chronic stage microglia presented with decreased levels of itaconate – an inhibitor of mitochondrial complex II (CII) – and a change of their mitochondrial function. The authors propose that increased CII activity in particular conditions can boost reverse electron transport (RET) through mitochondrial complex I activity in microglia. Importantly, in mice it is possible to block complex I activity in microglia to prevent neurotoxicity.
The prevalence and topography of spinal cord demyelination in multiple sclerosis: a retrospective study
Acta Neuropathologica I 9 March 2024
This retrospective study investigates cervical, thoracic, and lumbar spinal cord tissue from a post-mortem cohort of 119 cases of multiple sclerosis (MS) obtained from the UK MS Tissue Bank. The authors found at least one lesion in the spinal cord in 76.5% of the cases, mostly inflammatory. The lesions were observed at different levels of the spinal cord: 177 lesions were cervical, 152 thoracic, and 131 lumbar, for a total of 460 lesions. Most typically, the lesions affected the posterior and lateral white matter columns. The study shows that spinal cord lesions are common in MS and highly inflammatory.