This unique webinar explored four groundbreaking abstracts presented at ECTRIMS 2024. An expert panel chaired by Professor Frauke Zipp from the University of Mainz and Dr Robert Hoepner from the University Hospital of Bern, offered an in-depth analysis of the latest advancements in MS research and treatment.
Dr Sifat Sharmin from the University of Melbourne initiated the discussion by highlighting the critical importance of early intervention with high-efficacy therapies in children with MS. Children experience 2-3 times more relapses than adults [1]. Although they recover better, it has also been observed that a higher annualised relapse rate increases the risk of worsening disability [2].
To date, only fingolimod is approved to be used in children with MS. However, from the age of 18 the range of available high-efficacy therapies extends. The risk of worsening disability is higher in individuals with MS treated with low-efficacy therapies. Therefore, Dr Sharmin explores the opportunity to start earlier high-efficacy therapies during childhood. The findings indicate that high-efficacy therapies with ocrelizumab, rituximab, or natalizumab initiated between 12 and 22 years old and continued for at least 6 months are associated with a reduction in disability at 23 years old and beyond. The data were collected from three registries: Italian MS and Related Disorders Register, French MS Registry (OFSEP) and MS Base Registry. Professor Zipp raised an important concern about the safety of these therapies. And Dr Sharmin responded by noting that 12 individuals had discontinued treatment due to safety concerns or lack of efficacy. However, no further data on safety were available, highlighting the need for future longitudinal studies to explore this issue in greater depth.
The webinar then continued with Dr Enric Monreal from the University Hospital Ramón y Cajal, who discussed the importance of serum neurofilament light chain (sNfL) levels in predicting long-term disability in individuals with MS. sNfL levels rise after axonal injury, and levels above 10 pg/mL were associated with an increased risk of 6-month disability worsening and an Expanded Disability Status Scale (EDSS) of 3 [3]. Furthermore, in a multicenter observational study, involving 13 hospitals in Spain and Italy, Dr Monreal and his colleagues found that increased sNfL levels at MS onset can predict relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) [4]. Moreover, higher serum glial fibrillary acidic protein (sGFAP) concentration, released by reactive astrocytes following injury, was associated with non-active progression in individuals with low sNfL levels.
Dr Monreal concluded that in individuals with MS and low levels of sNfL and sGFAP within the first year of MS onset, any disease-modifying treatment (DMT) can be considered, as they are at low risk for inflammation and the development of RAW and PIRA. However, individuals with elevated sNfL score are good candidate for early use of high-efficacy DMTs to reduce the risk of PIRA linked to underlying inflammation and, especially, the risk of RAW. Individuals with high levels of sGFAP and low levels of sNfL could use any treatment because they have lower inflammation. In this last instance, the risk for RAW might be reduced, but the risk for PIRA would not be affected. Professor Zipp asked what elements might drive the choice of treatment, when magnetic resonance imaging (MRI), clinical prognostic markers, and measurements of sNfL and sGFAP are available. Dr Monreal suggested that it depends on how elevated the sNfL and sGFAP levels are, as sNfL concentration provide a quantitative estimation of ongoing inflammation.
Dr Ashley Beecham from the University of Miami took the stage to present a fascinating genetic study [5]. Historically, ancestrally diverse populations have been underrepresented in genetic research, which limits a full understanding of the genetic architecture of the disease. This lack of representation exacerbates health inequalities and renders the translation of genetic findings into clinical practice incomplete.
In a multi-ethnic cohort of approximately 8,000 individuals from self-reported Hispanic and African American backgrounds, researchers identified key genetic loci associated with MS risk. Dr Beecham and her colleagues identified novel population-specific risk alleles that may contribute to the diverse manifestation of MS across racial and ethnic groups. They demonstrated the presence of novel population-specific risk alleles, even within previously identified MS loci, and finally demonstrated the utility of a trans-ethnic approach for fine-mapping of risk loci, enabling the identification of both ancestry-specific and cosmopolitan alleles with coding and regulatory potential. These studies hold great promise for advancing treatment and prevention strategies in diverse ancestral populations.
Dr Antoine Gavoille from the University Hospital Center of Lyon then addressed the issue of therapeutic inertia in women with MS [6]. Therapeutic inertia is defined as the failure to initiate or intensify therapy when treatment goals are not met. Dr Gavoille emphasised that women of childbearing age with MS are often under-treated compared to men with similar disease severity. An analysis of over 22,000 individuals with relapsing MS in the French MS registry (OFSEP) revealed that women were significantly less likely than men to be treated with any DMT and were even less likely to receive high-efficacy DMTs.
This discrepancy may stem from concerns about exposing women of childbearing age to certain DMTs, in consideration of a possible future pregnancy. As a result, many women are not receiving the most effective therapies at the optimal time. Dr Hoepner stressed that, in the current era, these gaps and disparities are unacceptable. Dr Gavoille called for more data on the use of DMTs during pregnancy and emphasised the urgency of transforming this data into practical recommendations for healthcare providers.
References
[1] Benson LA et al. Multiple Sclerosis and Related Disorders 2014; 3(2): 186-193.
[2] Sharmin S et al. The Lancet Child & Adolescent Health 8.5 (2024): 348-357. Presented at ECTRIMS 2024.
[3] Monreal E et al. JAMA Neurol. 2023; 80(4): 397-403.
[4] Serum neurofilament light chain and glial fibrillary acidic protein levels at disease onset unveil immunologic pathways of disability acquisition in multiple sclerosis, Monreal E et al. (2024). Presented at ECTRIMS 2024.
[5] Novel ancestry-specific and putative causal genetic variants for multiple sclerosis identified by an ancestry-informed regression and trans-ethnic fine-mapping analysis, McCauley JL et al. (2024). Presented at ECTRIMS 2024.
[6] Is there therapeutic inertia in women with MS? Vukusic S et al. (2024). Presented at ECTRIMS 2024.