Reference: January 2025 | Issue 1 | Vol 11 | Page 19
New study uncovers therapeutic inertia in the treatment of women with multiple sclerosis
A study has revealed significant therapeutic inertia in the treatment of women with multiple sclerosis (MS), highlighting gender disparities that could impact long-term health outcomes for women of childbearing age.
The findings, presented at the 40th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Denmark in September, suggest that concerns related to pregnancy may lead to delayed or reduced use of disease-modifying treatments (DMTs), even before pregnancy becomes a consideration.
In an extensive analysis of 22,657 patients with relapsing MS (74.2% women) who were on the French MS registry (OFSEP), researchers found that over a median follow-up of 11.6 years, women had a significantly lower probability of being treated with any DMT (OR 0.92; 95% CI 0.87-0.97) and were even less likely to be prescribed high-efficacy DMTs (HEDMTs) (OR 0.80; 95% CI 0.74-0.86).
The difference in DMT usage varied across different treatments and over time. Teriflunomide, fingolimod, and anti-CD20 therapies were significantly underused (OR 0.87; 95% CI 0.77-0.98: OR 0.78; 95% CI 0.70-0.86: and OR 0.80; 95% CI 0.72-0.80, respectively).
Interferon and natalizumab were initially used less frequently, but their usage equalised over time (OR 0.99; 95% CI 0.92-1.06: and OR 0.96; 95% CI 0.86-1.06, respectively). In contrast, glatiramer acetate and dimethyl fumarate initially showed similar use between genders, but eventually became more commonly prescribed to women (ORs 1.27; 95% CI 1.13-1.43: and OR 1.17; 95% CI 1.03-1.42, respectively).
The study further highlighted that the disparity in treatment emerged after two years of disease duration for DMTs and as early as one year for HEDMTs. Interestingly, this gender-based treatment gap did not significantly vary with patient age, indicating that therapeutic inertia
may persist regardless of the woman’s stage in life.
“These findings underscore the critical need to reassess how we make treatment decisions for women with MS, particularly those of childbearing age,” said Prof Sandra Vukusic, lead author of the study. “Women may not be receiving the most effective therapies at the optimal time, often due to concerns about pregnancy risks that may never materialise. The use of DMTs and HEDMTs is frequently limited by potential and unknown risks associated with pregnancy, as there is often insufficient data available when these drugs first
come to market.”
Both neurologists and patients contribute to this therapeutic inertia, many taking a precautionary approach and avoiding these treatments.
“The main impact of this inertia is the less effective control of disease activity during DMT-free periods, leading to the accumulation of lesions and an increased risk of long-term disability,” stressed Prof Vukusic. “This represents a real loss of opportunity for women, especially in an era where DMTs are so effective when used early.”
To address these challenges, the team recommends a multifaceted approach: “Empowering patients through education, improving the dissemination of recent findings, providing formal training for specialists, and actively collecting and analysing real-world data are essential steps to reducing therapeutic inertia and ensuring equity in treatment,” Prof Vukusic concluded.
Key biomarkers identified for predicting disability progression
A pioneering study presented at ECTRIMS 2024 has identified critical biomarkers that can predict the worsening of disability in MS. The breakthrough research has the potential to transform treatment strategies for millions of MS patients worldwide, paving the way for more personalised and effective treatment plans.
In this multicentre observational study, conducted across 13 hospitals in Spain and Italy, Dr Enric Monreal and his team found that elevated serum neurofilament light chain (sNfL) levels at the onset of MS can predict both relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA).
Additionally, serum glial fibrillary acidic protein (sGFAP) levels correlate with PIRA in patients with low levels of sNfL.
The study analysed blood samples from 725 MS patients collected within 12 months of disease onset. Using the Single Molecule Array (SIMOA) technique, researchers assessed the prognostic value of sNfL and sGFAP levels to predict RAW and PIRA.
Key findings reveal that higher sNfL levels are associated with a 45 per cent increased risk of RAW and a 43 per cent increased risk of PIRA. Patients with high sNfL levels often did not respond well to standard DMTs, but showed significant benefits from HEDMTs, such as natalizumab, alemtuzumab, ocrelizumab, rituximab, and ofatumumab.
In contrast, patients with high sGFAP and low sNfL levels experienced an 86 per cent increased risk of PIRA. This group did not respond to current DMTs.
Interestingly, while sGFAP is known to be associated with progression, high sNfL levels limited the ability of sGFAP to predict this outcome. Specifically, sGFAP values were predictive of PIRA only in patients with low sNfL levels.
“The identification of sNfL and sGFAP as predictive biomarkers allows us to tailor treatment strategies for MS patients more effectively,” said Dr Monreal, a researcher in MS at Ramón y Cajal University Hospital in Madrid and first author of the study. “Patients with low levels of both biomarkers had a good prognosis and could be treated with injectable or oral DMTs. However, high sNfL levels indicate a need for HEDMTs to prevent disability worsening, while patients with high sGFAP levels and low values of sNfL may require new therapeutic approaches.
“These distinct pathways in MS have significant therapeutic implications, as current DMTs primarily target the peripheral adaptive immune system without affecting CNS immunity. Therefore, identifying patients with higher levels of peripheral inflammation is crucial for preventing disability and improving patient outcomes.”
The results of this study underscore the critical need for personalised treatment approaches to effectively manage the millions of people affected by MS worldwide, many of whom have chronic disability that significantly impacts their quality of life, said Dr Monreal.
Ancestry-specific genetic variants linked to multiple sclerosis risk, new study shows
A landmark study has uncovered novel ancestry-specific genetic variants linked to MS, offering new insights that could reshape treatment approaches for diverse populations affected by the disease. The research, presented at ECTRIMS 2024, is the result of efforts by the Alliance for Research in Hispanic MS (ARHMS) Consortium and is the first large-scale study to identify ancestry-specific genetic effects for MS risk.
In a comprehensive analysis of over 7,000 individuals from self-reported Hispanic (n=4,313; 2,201 MS, 2,112 controls) and African American (n=3,085; 1,584 MS, 1,501 controls) backgrounds, researchers discovered key genetic loci on chromosome 13 associated with MS risk. The findings highlight the potential of ancestry-informed genetic studies to uncover previously unidentified risk factors for MS and to improve the precision of fine-mapping efforts across different racial and ethnic groups.
A novel genetic locus – 13q14.2 – was identified, specifically within African haplotypes. The variant, rs3803245, is located in a region of the chromosome that is highly open to certain proteins in T cells, suggesting this region may serve as a regulatory area in T cells, which are crucial in the pathology of MS.
At locus 1p35.2, the research identified two distinct genetic variants associated with MS risk – one specific to Native American haplotypes and the other to European haplotypes. The Native American variant, rs145088108, significantly increased the risk of MS in Hispanics and African Americans (OR 2.05), compared to the European variant, rs10914539 (OR 1.37) (European cohort = 15,000 MS and 27,000 controls).
Dr Jacob McCauley, Professor at the University of Miami Miller School of Medicine and leader of the study, explained: “The variant found in Native American genetic signatures changes the structure of a protein, which might explain why it is more strongly linked to MS risk. In contrast, the variant found in European genetic signatures is in a non-coding part of the gene, making it less clear how it contributes to the disease.”
Through a trans-ethnic meta-analysis, the researchers achieved high-resolution fine-mapping of seven previously identified MS risk loci. “The variants identified within these loci could pave the way for new targeted treatments for MS, some of which may be population-specific. Refining the focus on these regions is highly valuable and, with further replication, there is potential for discovering new drug targets in the future,” Dr McCauley elaborated.
“While we anticipated some level of genetic diversity, the identification of African and Native American-specific alleles influencing MS risk is both exciting and encouraging. As our cohort grows, we expect to discover even more ancestry-specific alleles that could be critical for understanding phenotypic diversity and addressing health disparities in MS.
“The study also highlights the importance of considering gene-environment interactions in future research. While the identified variants were largely population-specific, the researchers emphasised the need to explore how environmental and lifestyle factors might interact with these and other genetic variants to influence MS risk. This is especially relevant in diverse populations with varying socioeconomic backgrounds and diets.
Moving forward, Dr McCauley and colleagues of the ARHMS Consortium plan to conduct functional studies to determine the causal pathways associated with the fine-mapped variants and to expand their cohorts to discover additional ancestry-specific variants.
Early initiation of monoclonal antibodies in children with MS
New research presented at ECTRIMS 2024 reveals that initiating monoclonal antibody therapy during childhood, rather than delaying treatment until early adulthood, significantly reduces long-term disability in MS patients.
The study, which utilised data from the French and Italian MS Register as well as the global MSBase Registry, analysed the outcomes of 282 patients with paediatric-onset MS who began experiencing symptoms before the age of 18 years. Patients were divided into two groups based on when they initiated monoclonal antibody treatment: Either between the ages of 12-17 or 20-22 years.
To ensure comparability between the groups, the researchers used inverse probability treatment weighting based on propensity scores, which accounted for baseline differences in factors, such as sex, age at symptom onset, time from onset to clinically definite MS, and the number of relapses. This approach enabled a clear assessment of how the timing of initiating high-efficacy therapy affects disability outcomes from the age of 23 years.
Using the Expanded Disability Status Scale (EDSS) to measure and monitor disability progression in MS, the study showed that patients who began treatment between the ages of 12 and 17 years (39% of the study group) had a mean absolute increase of 0.40 points on the EDSS compared to a 0.95-point increase in those who started treatment later (61%).
Between the ages of 23 and 27 years, the increase in EDSS scores from baseline was 0.57 points lower in the early treatment group compared to the late treatment group. The benefits of early treatment persisted throughout the median follow-up period of 10.8 years.
Dr Sifat Sharmin, research fellow in the Clinical Outcomes Research (CORe) Unit at the University of Melbourne and leader of the study, said the study highlights the critical importance of early intervention in paediatric-onset MS. “The substantially lower risk of progressing to higher disability levels in the early treatment group was particularly evident in the moderate disability range, where further progression was reduced by up to 97 per cent.”
Currently, regulatory restrictions, due to limited evidence of the efficacy, safety, and impact of monoclonal antibodies on children’s development, often delay access to these treatments for paediatric-onset MS patients until adulthood.
“These findings are a strong argument for rethinking current treatment guidelines,” Dr Sharmin maintained. “By allowing earlier access to effective treatments, we can significantly enhance the quality of life for children with MS and reduce the burden of long-term disability.”
Looking ahead, the research team are dedicated to generating further evidence to support the proactive treatment of paediatric-onset MS, with a particular focus on assessing the long-term risks of immunosuppressive therapies in this population.
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