Some disease-modifying treatments (DMTs) for multiple sclerosis (MS) increase the risk of infection, but it remains unknown how the risk compares between trials and observational studies.

To assess the current state of observational research on the risk of infection in people with MS and using DMTs.

PubMed and Embase were searched for observational studies published on or before 4 April 2023 describing infection in people with MS, with a comparison of at least 1 DMT to no DMT or another DMT. We examined which DMT contrasts and types of infection were studied and how often; and compared observational results of the most frequently studied DMT to trial data from a network meta-analysis.

Out of 5373 search records 22 papers were eligible, of which 5 reported relative risks (RRs). In total, 9 DMTs were studied. Out of 45 possible contrasts, 9 were not studied, and 19 once. The most assessed specific type of infection was neurological (n = 11/22 studies). Natalizumab was the most studied DMT contrasting 7 other DMTs or no DMT, with 12 RRs reported. Point estimates of the RRs (compared to no DMT) for respiratory and urinary tract infections were in opposite direction compared to trial data.

Observational study data on the risk of infection in people with MS on DMT are sparse. The growing availability of real-world data on MS and DMT use provides an opportunity to study specific infections on DMT, which is particularly valuable to populations underrepresented in trials.

Advances in multiple sclerosis (MS) have not translated into equitable improvements in MS treatment or outcomes among minoritized people. Our objective was to determine whether a health system intervention designed to increase use of highly efficacious treatments (HETs) was implemented equitably and led to similar improvements in MS outcomes across racial and ethnic groups.

We designed and implemented an MS treatment algorithm that aligns a person's risk of disability with appropriately efficacious disease-modifying therapies (DMTs) and incorporates social determinants of health and patient preferences that can adversely affect adherence but does not include race or ethnicity. We used Kaiser Permanente Southern California's electronic health record to conduct a trend study of DMT utilization and annual relapse rates (ARRs) stratified by race and ethnicity before (2009-2011) and during (2012-2023) implementation of the treatment algorithm.

We identified 6,119 (978 Black, 1741 Hispanic, 3,400 White) DMT-treated patients with MS (mean age = 50.1 years, 75.4% female) during the study period. Before implementation, Hispanic DMT-treated patients had significantly higher ARRs per 1,000 person-years (PY) (245.1, 95%CI 205.5-284.8) compared with White DMT-treated patients (156.3, 95%CI 137.8-174.7). Black people had higher ARRs compared with White people before and during early implementation, but this difference was significant only in 2015. Over the 12 years of implementation, the increase in HET use (primarily rituximab) among DMT-treated patients with MS was highest among Hispanic people, followed by Black and White people (89.3%, 87.4%, and 82.9% in 2023, respectively). The corresponding decline in age-adjusted and sex-adjusted ARR (linear spline regression) was greatest among Hispanic (90%, 95% CI 89%-91%), followed by White (86%, 95% CI 85%-87%) and Black (82%, 95% CI 80%-84%) DMT-treated patients between 2011 and 2023. By 2023, no clinically significant difference in ARR between groups remained (35.5, 19.0, and 18.1 per 1,000 PY for Hispanic, Black, and White people, respectively).

Implementation of our novel health system intervention led to marked and equitable improvements in HET use and relapse rate reduction among Hispanic, Black, and White DMT-treated patients with MS. This indicates that implementing an algorithmic approach to increase HET use, particularly an affordable one, rituximab, can reduce racial and ethnic disparities in MS outcomes.

Multiple sclerosis (MS) is a chronic autoimmune-mediated neurodegenerative disease characterized by inflammation, demyelination, and axonal/neuronal damage in the central nervous system. In Portugal, the prevalence of MS is approximately 64.4 per 100 000 individuals. It is typically diagnosed in young adults aged 30 to 40, with a higher incidence in women, although it can also affect children/adolescents and the elderly. Recent advances in MS treatment include the development and approval of several new disease-modifying therapies (DMTs) such as ocrelizumab, cladribine, siponimod, and others, thus expanding options for relapsing-remitting MS (RRMS). However, the options for progressive forms of MS remain limited. In Portugal, MS management strategies, guided by the 2015 recommendations of the Directorate-General of Health and the Portuguese medicines agency, need updating to incorporate recent scientific evidence and clinical expertise. The aim of this manuscript is to highlight gaps in current Portuguese MS treatment algorithms and propose enhancements aligned with global standards, thus improving treatment selection and patient outcomes in the Portuguese healthcare system. Developed by nine Portuguese neurology experts from the Portuguese Multiple Sclerosis Study Group, this document not only provides evidence and clinical practice-based recommendations but also includes DMT algorithms tailored for various MS subtypes, including radiologically and clinically isolated syndromes, RRMS, progressive MS, and specific situations in MS treatment such as pediatric-onset MS, late-onset MS, pregnancy and breastfeeding. This document provides evidence- and clinical practice-based recommendations to optimize decision-making during MS management in Portuguese centers. The experts aim to prompt the urgent revision of national MS treatment frameworks, incorporating the latest advancements in MS research and international guidelines, to reduce the socio-economic burden on the national healthcare system and improve the long-term health outcomes of MS patients.

Current multiple sclerosis (MS) treatments reduce relapse activity but have limited impact on disease progression. Clinical trials targeting progression often fail because of insufficient understanding of its underlying mechanisms. This study analyzed a clinically well-characterized MS autopsy cohort from the Netherland Brain Bank (186 individuals) from which we selected donors exhibiting opposite disease trajectories of slow versus rapid progression. We performed extensive unbiased histology and spatial transcriptomics, which unveiled a distinct MS lesion type marked by an extensive myeloid cell rim with cellular and transcriptional signatures of innate immune activation, inflammatory cytokine production, unfolded protein response and apoptosis. Presence of this particular lesion type was linked to rapid disease progression. An independent translocator protein 18-kDa positron emission tomography study (114 individuals) validates the association between lesions with a broad myeloid cell rim and disease progression in individuals with MS. Our findings offer crucial insights into the mechanisms behind MS progression, identifying broad rim lesions as a biomarker for rapid disease progression and potentially guiding patient selection for future therapeutic trials targeting central nervous system intrinsic inflammation.

Cerebrospinal fluid (CSF) oligoclonal IgM bands (OCMBs) have been suggested as prognostic biomarkers in MS, but serum OCMBs meaning is still uncertain.

We aimed to assess frequency and clinical relevance of all OCMB patterns.

In this retrospective cohort study, 136 paired sera-CSF from consecutive persons with MS (pwMS) were tested in 2 centers for OCMBs using isoelectric focusing-immunoblotting. Active disease was defined as clinical or radiological relapse occurring during two-year follow-up. Predictors of active disease were analyzed with logistic regressions and Kaplan-Meier survival curves.

OCMBs were found in 6.6 % of pwMS as unique-to-CSF (pattern #2), and in 20.6 % as identical in serum-CSF (pattern #4), without between-cohort difference. Active disease was more frequent in those with pattern #2 (88.9 %) and #4 (64.3 %) than in those OCMB-negative (33.3 %, p < 0.001). In multivariate analysis, pattern #2 (OR: 15.9; 95 % CI [1.8-136]), and pattern #4 (OR: 3.3 95 % CI [1.3-8.3]) were independent predictors of active disease. In survival analysis, pattern #2 (p < 0.001) and #4 (p = 0.017) predicted radiological relapses.

Our data confirm that CSF OCMB marks poor prognosis in MS. However, both OCMB pattern #4 and pattern #2, with different strength prediction, might be useful to stratify pwMS deserving more aggressive treatments, although the stratification could be achieved in the near future with more standardized and easily measurable biomarkers (e.g., serum neurofilaments).

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and degenerative disease of the central nervous system. There were 33 335 people with MS in Australia in 2021 and 2917 in New Zealand in 2006 and the prevalence and incidence are increasing with time. Although new treatments have substantially improved outcomes in recent decades, the treatment landscape has become increasingly complex due to the expanding number of disease-modifying therapies (DMTs) and associated safety considerations.

A total of 80 consensus recommendations were developed on the current best-practice management of MS in Australia and New Zealand. Part 1 of these guidelines outlines the consensus recommendations covering domains including DMT counselling and selection, pre-DMT assessments, monitoring disease activity on DMT, switching DMT, and discontinuing DMT. The remaining recommendations are outlined in Part 2, encompassing risk mitigation strategies during treatment with DMT, managing DMT in special situations (including pregnancy, postpartum, breastfeeding, active infection including COVID-19, and malignancy), general lifestyle measures, acute MS relapses, and symptomatic treatments for MS.

This two-part position statement provides a practical resource for clinicians on current best-practice consensus recommendations for managing adults (≥ 18 years old) with MS in the Australian and New Zealand health care settings. It outlines the 14 DMTs currently available through the Australian Pharmaceutical Benefits Scheme and eight through the New Zealand Pharmaceutical Schedule, including the unique efficacy, safety and monitoring considerations of each. Through these guidelines, we aim to support safe, timely and effective management of patients with MS in Australia and New Zealand.

Early use of high-efficacy therapies (EHT) in multiple sclerosis (MS) is a promising but novel treatment strategy. Its adoption in Germany's MS care warrants further research.

This study assessed treatment initiation patterns among newly diagnosed MS patients in Germany (2017-2022).

This is a retrospective observational study.

Claims data from 4.5 million individuals insured by German statutory health insurance included 1448 newly diagnosed MS patients from 2017 to 2022. Patients were identified by International Statistical Classification of Diseases and Related Health Problems, 10th revision, German modification (ICD-10-GM) code G35 - in two different quarters of the same year, and a disease-modifying therapy (DMT) prescription, with no prior MS diagnosis or DMT prescription in the preceding 2 years. DMTs were categorized according to German Society of Neurology S2k guidelines: category 1 (low-efficacy), category 2 (moderate-efficacy) and category 3 (high-efficacy).

Of patients initiating treatment, 77.1% started with category 1, 8.1% with category 2 and 14.8% with category 3 DMTs. From 2017 to 2022, category 1 initiations declined by 7.6% points (pp), while categories 2 and 3 initiations increased by 2.8 and 4.8 pp, respectively. Escalation to category 3 occurred in 10.5% of category 1/2 starters, with 31.5% taking over 2 years. De-escalation to category 1/2 occurred in 3.3% of category 3 starters.

Real-world data highlight a shift towards EHT in MS care.

Multiple sclerosis (MS) is a complex, neurodegenerative and autoimmune disease with a multifactorial etiology. Epigenetic changes can influence the onset and development of the disease, and miRNAs, small RNAs that play a key role in post-transcriptional gene regulation, act as important modulators of the inflammatory process and the central nervous system´s response. The objective of this work is to compare and identify the expression of the miR-143/145 cluster, namely miR-143-5p and miR-145-5p. For this purpose, the expression of two mature miRNAs was determined in the serum of 80 patients with relapsing-remitting multiple sclerosis (RRMS) under different treatments and 60 healthy control subjects (HCS). Total miRNA was isolated from serum and subjected to quantitative PCR analysis (qPCR). In addition, an in silico analysis focused on the molecules affected by the disease was performed. It was found that miR-143-5p is upregulated in patients with RRMS (mean (m)= 0.74) compared to HCS (m = 1.50), while miR-145-5p is significantly downregulated in RRMS (m = 0.32) compared to HCS (m = 2.26). Furthermore, miR-143-5p expression may vary with treatment and exhibit sexual dimorphism, whereas miR-145 expression is primarily pathology-dependent. For in silico analysis, we proposed a new modified C-score that integrates several computational tools. This analysis indicates that GSTM3 and MMP9, which have been previously studied in MS, are the primary targets of miR-143-5p and miR-145-5p, respectively. In conclusion, the differential expression of these miRNAs underscores their possible sensitizing role in pathogenesis, suggesting that these two miRNAs, along with others, may be further explored in unraveling new pathophysiological pathways for treatment response in MS.

Anorectal fistulas remain one of the most challenging conditions in colorectal surgery and require precise anatomical knowledge for successful management. This comprehensive review synthesizes the current evidence on the anatomical foundations of fistula development and treatment, particularly focusing on the cryptoglandular hypothesis and its clinical implications. A systematic analysis of the recent literature has examined the relationship between anatomical structures and fistula formation, classification systems, diagnostic modalities, and therapeutic approaches. The review revealed that anatomical considerations fundamentally influence treatment outcomes, with modern imaging techniques achieving up to 98% accuracy in delineating fistula anatomy. Key findings demonstrate that surgical success rates vary significantly based on anatomical complexity: 92-97% for simple fistulas versus 40-95% for complex cases using sphincter-sparing techniques. Emerging minimally invasive approaches and regenerative therapies, including mesenchymal stem cells, show promising results with 50-60% healing rates in complex cases. Special considerations are needed for complex cases such as Crohn's disease-related and rectovaginal fistulas. This review provides surgeons with an evidence-based framework for selecting optimal treatment strategies based on anatomical considerations, emphasizing the importance of preserving the anal sphincter function while achieving complete fistula eradication. Integrating advanced imaging, surgical techniques, and emerging therapies offers new possibilities for improving patient outcomes. This review aimed to bridge the gap between anatomical knowledge and practical surgical application, enhance clinical decision-making, and improve patient outcomes in anorectal fistula management.

Predicting treatment response and disease progression in multiple sclerosis (MS) is challenging. Treatment Response Scoring Systems (TRSS) are potentially useful, but their utility in patients receiving high-efficacy therapies and very high-efficacy therapies (HET/vHET) remains unclear.

This study aimed to evaluate the performance of TRSS in patients treated with HET/vHET.

We retrospectively studied MS patients treated with HET/vHET in an MS specialized centre. TRSS, including the Rio Score, modified Rio Score and MAGNIMS score, were applied to assess response to treatment. We evaluated the predictive value of the TRSS on disease activity and disability progression.

TRSS effectively predicted disease activity and progression of disability in patients treated with HET/vHET. Patients with high TRSS scores at 12 months post-HET/vHET initiation had a significantly increased risk of relapses, new lesions on magnetic resonance imaging (MRI) scans and progression of disability at 4 years.

Our findings highlight the importance of personalized treatment strategies in MS. TRSS are valuable tools for monitoring treatment response, guiding clinical decision-making and optimizing patient care.

Background and Objectives: This study aims to identify cardiovascular risk factors among 91 patients with multiple sclerosis in Bucharest, Romania, using data from medical records and a self-administered questionnaire. Materials and Methods: The research focuses on smoking status, body mass index, blood sugar, cholesterol, triglycerides, blood pressure, and renal function. The average age of the patients was 42.90 ± 10.60 years, and 74.73% were female. The average BMI was 23.89 kg/m2 ± 4.74 kg/m2 (lower than in the general population), with 41.76% of patients having a BMI outside normal limits. The majority were former smokers (35.87%), followed by non-smokers (28.26%), and the fewest were smokers of more than 20 cigarettes/day (7.61%). The average total cholesterol was 198.48 ± 38.56 mg/dL, triglycerides were 114.22 mg/dL ± 76.2281 mg/dL, and blood glucose was 97.54 ± 36.58 mg/dL. While 25.27% of the patients had fasting blood glucose > 126 mg/dL, only five patients were diagnosed with DM. The average blood pressure was 137.5165 ± 19.5047 mmHg, with only 11 patients diagnosed with HTA. Results: The study found an average cardiovascular risk of 6.6133% ± 7.1412%, with higher values among males, rural patients, those with secondary-progressive MS, and those with a disease progression >10 years (after age adjustment). Conclusions: The study underscores the importance of identifying and combating cardiovascular risk factors in patients with multiple sclerosis.

The associations between the monthly rate of topological property change (mrTPC) in the structural and functional connectivity network (SCN, FCN) and achieving no evidence of disease activity (NEDA) in relapsing-remitting multiple sclerosis (RRMS) patients taking oral disease-modifying therapies (DMTs) remain insufficiently explored.

This was a retrospective study conducted with RRMS patients treated with oral DMTs or untreated between January 2019 and June 2023. All participants underwent baseline and follow-up clinical evaluations and MRI scans. Initially, NEDA statuses of all participants were assessed. Then, the mrTPCs from SCN and FCN were calculated. Finally, the baseline characteristics and mrTPCs were inserted into logistic regression models to explore their associations with achieving NEDA status.

A total of 58 RRMS patients were included, with 46 in the treated group and 12 in the untreated group. A greater percentage of treated RRMS patients achieved NEDA3+ (60.87 % vs. 25.00 %) or NEDA4+ (21.74 % vs. 8.33 %) statuses. Patients with oral DMTs (P = 0.032) and lower contrast-enhancing lesions (CELs) count (P = 0.009) were more likely to achieve NEDA3+ status. Nomograms based on the mrTPCs revealed SCN_NLe_SMA.R (P = 0.042) and FCN_NLe_PCL.L (P = 0.050) were significant for the NEDA3 or NEDA 4 model. Both the above models performed well (AUC: 0.756 and 0.722, respectively).

Specifically altered mrTPC was linked to NEDA status in RRMS patients on oral DMTs. Although the specific mechanisms for each NEDA status may differ and need further investigation, these findings can help clinicians personalize RRMS treatment and monitoring.

In recent years, significant progress has been made in immune demyelinating disorders, particularly regarding early diagnosis and disease-modifying drugs (DMDs). Despite advancements, socioeconomic factors in many Latin American countries present unique challenges that impede the proper identification and management of these disorders.

The updated consensus from the Central American and Caribbean working group strives to enhance the management of Multiple Sclerosis (MS), Neuromyelitis Optica Spectrum Disorder (NMOSD), and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD) by offering a framework for incorporating available treatment into clinical practice.

The authors conducted an extensive bibliographic search and followed a consensus process that included input from forum members to present a new, revised, and finalized report.

The consensus, endorsed by over 70% of members, covers the application of DMDs, biologic agents, glucocorticoids, definitions of therapeutic failure, patient monitoring, cessation of treatment, prognosis, therapy use during pregnancy and lactation, and vaccination in patients initiating or on DMDs or biologic treatments.

The revised consensus and guidelines aim to enhance long-term outcomes in these regions by assisting patients, regulatory bodies, healthcare providers, and policymakers.

We aimed to characterize the brain abnormalities that are associated with the cognitive and physical performance of patients with relapsing-remitting multiple sclerosis (RRMS) using a deep learning algorithm.

Three-dimensional (3D) nnU-Net was employed to calculate a novel spatial abnormality map by T1-weighted images and 281 RRMS patients (Dataset-1, male/female = 101/180, median age [range] = 35.0 [17.0, 65.0] years) were categorized into subtypes. Comparison of clinical and MRI features between RRMS subtypes was conducted by Kruskal-Wallis test. Kaplan-Meier analysis was conducted to investigate disability progression in RRMS subtypes. Additional validation using two other RRMS datasets (Dataset-2, n = 33 and Dataset-3, n = 56) was conducted.

Five RRMS subtypes were identified: (1) a Frontal-I subtype showing preserved cognitive performance and mild physical disability, and low risk of disability worsening; (2) a Frontal-II subtype showing low cognitive scores and severe physical disability with significant brain volume loss, and a high propensity for disability worsening; (3) a temporal-cerebellar subtype demonstrating lowest cognitive scores and severest physical disability among all subtypes but remaining relatively stable during follow-up; (4) an occipital subtype demonstrating similar clinical and imaging characteristics as the Frontal-II subtype, except a large number of relapses at baseline and preserved cognitive performance; and (5) a subcortical subtype showing preserved cognitive performance and low physical disability but a similar prognosis as the occipital and Frontal-II subtypes. Additional validation confirmed the above findings.

Spatial abnormality maps can explain heterogeneity in cognitive and physical performance in RRMS and may contribute to stratified management.

Question Can a deep learning algorithm characterize the brain abnormalities associated with the cognitive and physical performance of patients with RRMS? Findings Five RRMS subtypes were identified by the algorithm that demonstrated variable cognitive and physical performance. Clinical relevance The spatial abnormality maps derived RRMS subtypes had distinct cognitive and physical performances, which have a potential for individually tailored management.

Multiple sclerosis (MS) is a chronic inflammatory condition that causes lesions leading to both physical and psychological impairments, significantly affecting daily life. Therapeutic education has been identified as a valuable approach in managing chronic diseases, including MS. This study aims to develop a structured therapeutic education protocol specifically for MS patients, with the goal of demonstrating its positive effects on quality of life. This prospective, descriptive study will examine the effects of a therapeutic education program on the quality of life in MS patients. The study will be conducted at Rabat University Hospital's Physical Medicine and Rehabilitation and Neurology departments. Participants will undergo individualized educational sessions and interactive workshops. Evaluations will be performed at baseline, 3 months, and 6 months using the Multiple Sclerosis Quality of Life-54 (MSQOL-54) and the Measure of Urinary Handicap (M.H.U) scale. Effective management of MS necessitates personalized care strategies, including therapeutic education, which can enhance patient knowledge, self-management, and overall quality of life. This study aims to provide insights into how structured educational interventions can impact MS management and patient outcomes. This study protocol outlines an investigation into a therapeutic education program for MS patients. By addressing disease understanding, symptom management, and psychosocial support, the program seeks to improve patients' quality of life. Future research should assess the long-term effects of such interventions and compare their efficacy with other MS management approaches.

Background: The prognosis of people with multiple sclerosis (MS) has improved substantially in recent decades due to advances in diagnosis and treatment. Due to the unpredictable course and heterogenous treatment response in MS, there is a clear need for biomarkers that reflect disease activity in the clinical follow-up of these patients. We conducted a systematic review with Bayesian network meta-analysis with the aim of analyzing the effects of physical exercise on neurofilaments (NfL) and glial fibrillary acidic protein (GFAP) levels in patients with MS. Methods: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, starting with a PICO (patient/population, intervention, comparison, and outcome) question: what are the clinical effects of physical exercise (with independence of the type) on NfL and/or GFAP levels in patients with MS compared with other interventions or no intervention whatsoever? A systematically comprehensive literature search was conducted from January to March 2024 to identify original studies that answered the PICO question, using the main data sources. The quality of the studies included was assessed using the Quality Index of Downs & Black. For studies included in the systematic review that followed a randomized controlled trial (RCT) design, the methodological quality of each paper was assessed using the Physiotherapy Evidence Database (PEDro) Scale. Risk of bias was also explored by two independent reviewers. Finally, all articles were classified according to the levels of evidence and grades of recommendation for diagnosis studies established by the Oxford Center for Evidence-Based Medicine. For continuous outcome measures with enough comparisons and a methodological quality greater than or equal to good according to the PEDro scale, a Bayesian network meta-analysis (NMA) was applied. The statistical analyses were performed in R (version 4.1.3, R Core Team 2023) using the "BUGSnet" and "gemtc" packages. Bayesian NMA can be used to obtain a posterior probability distribution of all the relative treatment effects, which allows us to quantify the uncertainty of parameter estimates and to rank all the treatments in the network. Results: Eight studies were included in this systematic review and six articles in the NMA, and they were appraised for quality. The characteristics of the included studies, types of training and described protocols, methodological quality, risk of bias, and clinical effects on the studied biomarkers were outlined. Qualitative synthesis, effects of different exercise modalities in NfL with the Bayesian NMA, selection of the final model and model assessment, and ranking of interventions are also shown. Conclusions: Our findings indicated that moderate-intensity exercise is more likely to reduce NfL concentration compared to high-intensity exercise, and, in turn, high-intensity exercise is more likely to reduce NfL concentration than low-intensity exercise. However, the effects of high-intensity exercise on GFAP levels were inconclusive.

Epidemiological data of pediatric-onset multiple sclerosis (POMS) in the Middle East is limited.

To determine the demographic and clinical characteristics of POMS in Kuwait.

A retrospective study was conducted to assess the clinical characteristics of multiple sclerosis (MS) patients who disease onset started at age < 18 years and fulfilled the International Pediatric MS Study Group (IPMSSG) criteria for MS.

Of 249 POMS who were assessed, 70.3 % were female. The mean age at onset was 15.06 +11.78 years. Brainstem / cerebellar manifestation (34.9 %) were the most frequent presentation at onset of disease, followed by spinal (29.3 %) and visual pathway (27.3 %) symptoms. At the last follow-up visits, most of the patients (83.5 %) remained in a relapsing-remitting phenotype. The annual relapse rate (ARR) was 0.18 throughout the first 2 years while on treatment. At the baseline visit, the 51.4 % of the cohort-initiated platform therapies. Breakthrough disease (36.1 %) and adverse events (9.6 %) were the most common indications to escalate or switch to other disease-modifying drugs (DMTs).

Most POMS patients continued to be in a relapsing phenotype in our longitudinal study. Disease breakthrough is common in POMS especially when using platform therapies.

The potential for combining serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels to predict worsening disability in multiple sclerosis remains underexplored. We aimed to investigate whether sNfL and sGFAP values identify distinct subgroups of patients according to the risk of disability worsening and their response to disease-modifying treatments (DMTs). This multicentre study, conducted across 13 European hospitals, spanned from 15 July 1994 to 18 August 2022, with follow-up until 26 September 2023. We enrolled patients with multiple sclerosis who had serum samples collected within 12 months from disease onset and before initiating DMTs. Multivariable regression models were used to estimate the risk of relapse-associated worsening (RAW), progression independent of relapse activity (PIRA) and Expanded Disability Status Scale (EDSS) score of 3. Of the 725 patients included, the median age was 34.2 (interquartile range, 27.6-42.4) years, and 509 patients (70.2%) were female. The median follow-up duration was 6.43 (interquartile range, 4.65-9.81) years. Higher sNfL values were associated with an elevated risk of RAW [hazard ratio (HR) of 1.45; 95% confidence interval (CI) 1.19-1.76; P < 0.001], PIRA (HR of 1.43; 95% CI 1.13-1.81; P = 0.003) and reaching an EDSS of 3 (HR of 1.55; 95% CI 1.29-1.85; P < 0.001). Moreover, higher sGFAP levels were linked to a higher risk of achieving an EDSS score of 3 (HR of 1.36; 95% CI 1.06-1.74; P = 0.02) and, in patients with low sNfL values, to PIRA (HR of 1.86; 95% CI 1.01-3.45; P = 0.04). We also examined the combined effect of sNfL and sGFAP levels. Patients with low sNfL and sGFAP values exhibited a low risk of all outcomes and served as a reference. Untreated patients with high sNfL levels showed a higher risk of RAW, PIRA and reaching an EDSS of 3. Injectable or oral DMTs reduced the risk of RAW in these patients but failed to mitigate the risk of PIRA and reaching an EDSS of 3. Conversely, high-efficacy DMTs counteracted the heightened risk of these outcomes, except for the risk of PIRA in patients with high sNfL and sGFAP levels. Patients with low sNfL and high sGFAP values showed an increased risk of PIRA and achieving an EDSS of 3, which remained unchanged with either high-efficacy or other DMTs. In conclusion, evaluating sNfL and sGFAP levels at disease onset in multiple sclerosis might identify distinct phenotypes associated with diverse immunological pathways of disability acquisition and therapeutic response.

The number of disease-modifying therapies (DMTs) approved for the treatment of multiple sclerosis (MS) has greatly increased in recent decades, leading to higher treatment complexity. DMTs can differ in mode and frequency of administration, benefit-risk profile, and associated costs. Patients with MS contend not only with the burden of their chronic disease but also with the treatment burden of their MS therapy. Adhering to dosing schedules and infusion appointments can be difficult for busy, working-age patients or those with limited access to transportation. Patients and healthcare professionals (HCPs) may have differing priorities, concerns, and preferences when selecting treatment, potentially affecting treatment satisfaction and, importantly, adherence. Additionally, patients face direct and indirect costs related to treatment. These factors can all contribute to a high treatment burden on patients, impacting their quality of life and potentially leading to worse patient outcomes. HCPs, patients, and caregivers must work together to alleviate treatment burden through effective communication, shared decision-making, appreciating each other's perspectives, and additional HCP support. Consideration of treatment burden into clinical guidelines is also warranted. In this review, we examine key factors impacting treatment burden for patients with MS, with a focus on the patient perspective as provided by our patient authors, and provide strategies to minimize treatment burden.

Spinal cord lesions in multiple sclerosis (MS) have considerable impact on disability. High-efficacy disease-modifying treatments (hDMTs) are associated with greater reduction of relapses and new brain lesions compared to low-efficacy treatments (lDMTs). Knowledge on the impact of DMTs on cord lesion formation is limited as these outcome measures were not included in MS treatment trials. This study aims to investigate whether hDMTs reduce the formation of cord lesions more effectively than lDMTs.

Patients with relapse-onset MS, a cord magnetic resonance imaging (MRI) within 6 months before/after initiation of their first DMT and ≥1 cord MRI at follow-up (interval > 6 months) were extracted from the MSBase registry (ACTRN12605000455662). Patients treated with hDMTs ≥90% or lDMTs ≥90% of follow-up duration were considered the hDMT and lDMT groups, respectively. Matching was performed using propensity scores. Cox proportional hazards models were used to estimate the hazards of new cord lesions, brain lesions and relapses.

Ninety-four and 783 satisfied hDMT and lDMT group criteria, respectively. Seventy-seven hDMT patients were matched to 184 lDMT patients. In the hDMT group there was no evidence of reduction of new cord lesions (hazard ratio [HR] 0.99 [95% CI 0.51, 1.92], p = 0.97), while there were fewer new brain lesions (HR 0.22 [95% CI 0.10, 0.49], p < 0.001) and fewer relapses (HR 0.45 [95% CI 0.28, 0.72], p = 0.004).

A potential discrepancy exists in the effect of hDMTs over lDMTs in preventing spinal cord lesions versus brain lesions and relapses. While hDMTs provided a significant reduction for the latter when compared to lDMTs, there was no significant reduction in new spinal cord lesions.

Recent advances in multiple sclerosis (MS) management have shifted perspectives on treatment strategies, advocating for the early initiation of high-efficacy disease-modifying therapies (heDMTs). This perspective review discusses the rationale, benefits, and challenges associated with early heDMT initiation, reflecting on the obsolescence of the traditional "first-line" and "second-line" treatment classifications. The article emerges from the last update of the consensus document of the Spanish Society of Neurology on the treatment of MS. During its development, there was a recognized need to further discuss the concept of treatment lines and the early use of heDMTs. Evidence from randomized controlled trials and real-world studies suggests that early heDMT initiation leads to improved clinical outcomes, including reduced relapse rates, slowed disease progression, and decreased radiological activity, especially in younger patients or those in early disease stages. Despite the historical belief that heDMTs involve more risks and adverse events compared to moderate-efficacy DMTs (meDMTs), some studies have reported comparable safety profiles between early heDMTs and meDMTs, though long-term safety data are still lacking. The review also addresses the need for a personalized approach based on patient characteristics, prognostic factors, and preferences, explores the importance of therapeutic inertia, and highlights the evolving landscape of international and national guidelines that increasingly advocate for early intensive treatment approaches. The article also addresses the challenges of ensuring access to these therapies and the importance of further research to establish long-term safety and effectiveness of DMTs in MS.

Isolated value of MRI metrics in relapsing multiple sclerosis (RMS) as a surrogate marker of response to disease-modifying treatment (DMT) and, thus, as decision criteria for DMT escalation in the absence of clinical signs of disease activity is still a matter of debate. The aim of this study was to investigate whether DMT escalation based on isolated MRI activity affects clinical outcome.

Combining data from 5 MS centers in Austria and Switzerland, we included patients with RMS aged at least 18 years who (1) had initiated first-line, low-to-moderate-efficacy DMT (interferon β, glatiramer acetate, teriflunomide, or dimethyl fumarate) continued for ≥12 months, (2) were clinically stable (no relapses or disability progression) on DMT for 12 months, (3) had MRI at baseline and after 12 months on DMT, and (4) had available clinical follow-up for ≥2 years after the second MRI. The primary endpoint was occurrence of relapse during follow-up. The number of new T2 lesions (T2L) and DMT strategy (continuing low-/moderate-efficacy DMT vs escalating DMT) were used as covariates in regression analyses.

A total of 131 patients with RMS, median age of 36 (25th-75th percentiles: 29-43) years, 73% women, were included and observed over a median period of 6 (5-9) years after second MRI. Sixty-two (47%) patients had relapse. Patients who continued first-line DMT had a 3-fold increased risk of relapse given 2 new T2L (hazard ratio [HR] 3.2, lower limit [LL] of 95% CI: 1.5) and a 4-fold increased risk given ≥3 new T2L (HR 4.0, LL-CI: 2.1). Escalation of DMT lowered the risk of relapse in patients with 2 new T2L by approximately 80% (HR 0.2, upper limit [UL] of 95% CI: 1.3) and with ≥3 new T2L by 70% (HR 0.3, UL-CI: 0.8). In case of only 1 new T2L, the increased risk of relapse and the treatment effect did not reach statistical significance of 5%.

In our real-world cohort of patients clinically stable under low-to-moderate-efficacy DMT, escalation of DMT based on isolated MRI activity decreased risk of further relapse when at least 2 new T2L had occurred.

This study provides Class III evidence that clinically stable patients with MS on low-/moderate-efficacy DMT with ≥3 new T2L on MRI who escalate DMT have a reduced risk of relapse and Expanded Disability Status Scale progression.

Clinicians frequently rely on relapse counts, T2 MRI lesion load (T2L) and Expanded Disability Status Scale (EDSS) scores to guide treatment decisions for individuals diagnosed with multiple sclerosis (MS). This study evaluates how these factors, along with age and sex, influence prognosis during treatment with teriflunomide (TFL).

We conducted a nationwide cohort study using data from the Danish Multiple Sclerosis Registry.Eligible participants had relapsing-remitting MS or clinically isolated syndrome and initiated TFL as their first treatment between 2013 and 2019. The effect of age, pretreatment relapses, T2L and EDSS scores on the risk of disease activity on TFL were stratified by sex.

In total, 784 individuals were included (57.4% females). A high number of pretreatment relapses (≥2) was associated with an increased risk of disease activity in females only (OR and (95% CI): 1.76 (1.11 to 2.81)). Age group 50+ was associated with a lower risk of disease activity in both sexes (OR females=0.28 (0.14 to 0.56); OR males=0.22 (0.09 to 0.55)), while age 35-49 showed a different impact in males and females (OR females=0.79 (0.50 to 1.23); OR males=0.42 (0.24 to 0.72)). EDSS scores and T2L did not show any consistent associations.

A high number of pretreatment relapses was only associated with an increased risk of disease activity in females, while age had a differential impact on the risk of disease activity according to sex. Clinicians may consider age, sex and relapses when deciding on TFL treatment.

Treatment decisions for persons with relapsing-remitting multiple sclerosis (RRMS) rely on clinical and radiological disease activity, the benefit-harm profile of drug therapy, and preferences of patients and physicians. However, there is limited evidence to support evidence-based personalized decision-making on how to adapt disease-modifying therapy treatments targeting no evidence of disease activity, while achieving better patient-relevant outcomes, fewer adverse events, and improved care. Serum neurofilament light chain (sNfL) is a sensitive measure of disease activity that captures and prognosticates disease worsening in RRMS. sNfL might therefore be instrumental for a patient-tailored treatment adaptation. We aim to assess whether 6-monthly sNfL monitoring in addition to usual care improves patient-relevant outcomes compared to usual care alone.

Pragmatic multicenter, 1:1 randomized, platform trial embedded in the Swiss Multiple Sclerosis Cohort (SMSC). All patients with RRMS in the SMSC for ≥ 1 year are eligible. We plan to include 915 patients with RRMS, randomly allocated to two groups with different care strategies, one of them new (group A) and one of them usual care (group B). In group A, 6-monthly monitoring of sNfL will together with information on relapses, disability, and magnetic resonance imaging (MRI) inform personalized treatment decisions (e.g., escalation or de-escalation) supported by pre-specified algorithms. In group B, patients will receive usual care with their usual 6- or 12-monthly visits. Two primary outcomes will be used: (1) evidence of disease activity (EDA3: occurrence of relapses, disability worsening, or MRI activity) and (2) quality of life (MQoL-54) using 24-month follow-up. The new treatment strategy with sNfL will be considered superior to usual care if either more patients have no EDA3, or their health-related quality of life increases. Data collection will be embedded within the SMSC using established trial-level quality procedures.

MultiSCRIPT aims to be a platform where research and care are optimally combined to generate evidence to inform personalized decision-making in usual care. This approach aims to foster better personalized treatment and care strategies, at low cost and with rapid translation to clinical practice.

ClinicalTrials.gov NCT06095271. Registered on October 23, 2023.

Multiple sclerosis treatment strategies are changing in the Czech Republic. According to data from 2013-2021, the proportion of patients starting high-efficacy disease-modifying therapies is increasing. In this survey, we describe the actual data trends in multiple sclerosis (MS) patients beginning their first disease‑modifying therapies (DMTs) from 2013 to 2021. The secondary objective was to present the history, data collection, and scientific potential of the Czech National MS registry (ReMuS).

First, using descriptive statistics, we analysed the data for patients starting their first DMTs, either platform (including dimethyl fumarate) or high-efficacy DMTs (HE-DMTs), for each successive year. Second, a detailed description of the history, data collection, completeness, quality optimising procedures, and legal policies of ReMuS is provided.

Based on the dataset from December 31, 2021, the total number of monitored patients with MS in ReMuS increased from 9,019 in 2013 (referred from 7 of 15 MS centres) to 12,940 in 2016 (referred from all 15 Czech MS centres) to 17,478 in 2021. In these years, the percentage of patients treated with DMTs in the registry ranged from 76 to 83%, but the proportion of patients treated with HE-DMTs changed from 16.2% in 2013 to 37.1% in 2021. During the follow-up period, a total of 8,491 treatment-naive patients received DMTs. The proportion of patients (all MS phenotypes) starting HE-DMTs increased from 2.1% in 2013 to 18.5% in 2021.

Patient registries, including ReMuS, provide an essential quality data source, especially in light of the increasing percentage of patients on HE-DMTs. Although early initiation of HE-DMT can provide considerable benefits, it also carries greater potential risks. Consistent long-term follow-up of patients in real‑world clinical practice, which only registries allow, is therefore crucial to evaluate the efficacy and safety of therapeutic strategies, for epidemiological research and to assist decision making by healthcare providers and regulatory bodies.

In the majority of cases, multiple sclerosis (MS) is characterized by reversible episodes of neurological dysfunction, often followed by irreversible clinical disability. Accurate diagnostic criteria and prognostic markers are critical to enable early diagnosis and correctly identify patients with MS at increased risk of disease progression. The 2017 McDonald diagnostic criteria, which include magnetic resonance imaging (MRI) as a fundamental paraclinical tool, show high sensitivity and accuracy for the diagnosis of MS allowing early diagnosis and treatment. However, their inappropriate application, especially in the context of atypical clinical presentations, may increase the risk of misdiagnosis. To further improve the diagnostic process, novel imaging markers are emerging, but rigorous validation and standardization is still needed before they can be incorporated into clinical practice. This Series article discusses the current role of MRI in the diagnosis and prognosis of MS, while examining promising MRI markers, which could serve as reliable predictors of subsequent disease progression, helping to optimize the management of individual patients with MS. We also explore the potential of new technologies, such as artificial intelligence and automated quantification tools, to support clinicians in the management of patients. Yet, to ensure consistency and improvement in the use of MRI in MS diagnosis and patient follow-up, it is essential that standardized brain and spinal cord MRI protocols are applied, and that interpretation of results is performed by qualified (neuro)radiologists in all countries.

To evaluate CSF inflammatory markers with accumulation of cortical damage as well as disease activity in patients with early relapsing-remitting MS (RRMS).

CSF levels of osteopontin (OPN) and 66 inflammatory markers were assessed using an immune-assay multiplex technique in 107 patients with RRMS (82 F/25 M, mean age 35.7 ± 11.8 years). All patients underwent regular clinical assessment and yearly 3T MRI scans for 2 years while 39 patients had a 4-year follow-up. White matter lesion number and volume, cortical lesions (CLs) and volume, and global cortical thickness (CTh) were evaluated together with the 'no evidence of disease activity' (NEDA-3) status, defined by no relapses, no disability worsening, and no MRI activity, including CLs.

The random forest algorithm selected OPN, CXCL13, TWEAK, TNF, IL19, sCD30, sTNFR1, IL35, IL16, and sCD163 as significantly associated with changes in global CTh. OPN and CXCL13 were most related to accumulation of atrophy after 2 and 4 years. In a multivariate linear regression model on CSF markers, OPN (p < 0.001), CXCL13 (p = 0.001), and sTNFR1 (p = 0.024) were increased in those patients with accumulating atrophy (adjusted R-squared 0.615). The 10 markers were added in a model that included all clinical, demographic, and MRI variables: OPN (p = 0.002) and IL19 (p = 0.022) levels were confirmed to be significantly increased in patients developing more CTh change over the follow-up (adjusted R-squared 0.619). CXCL13 and OPN also revealed the best association with NEDA-3 after 2 years, with OPN significantly linked to disability accumulation (OR 2.468 [1.46-5.034], p = 0.004) at the multivariate logistic regression model.

These data confirm and expand our knowledge on the prognostic role of the CSF inflammatory profile in predicting changes in cortical pathology and disease activity in early MS. The data emphasize a crucial role of OPN.

The hit-hard-and-early (HHAE) strategy where treatment is initiated with high-efficacy therapies opposed to low-efficacy therapies presents a potential paradigm shift in multiple sclerosis (MS) management. This study aimed to assess the adoption of the HHAE strategy in Germany and the United States (US) from 2020 to 2022 based on real-world data.

The analysis was based on longitudinal, patient-level data from Germany and the US. For Germany, data was extracted from the Permea platform covering approximately 44 % of all German community pharmacy dispensing. For the US, data from the Komodo Healthcare Map™ was utilized, covering medical benefit data from around 88 % of the US patient population. Patients ≥18 years old and who had at least 2 prescriptions for MS-related disease-modifying drugs (DMDs) between January 2020 and December 2022 were included. To approximate therapy beginners, a washout period of one year before treatment start was applied, excluding all patients who had an MS-related DMD prescription or claim in 2019. Cohort entry date was the day of the first MS-related DMD dispense or claim. DMDs were classified as high-efficacy and low-efficacy based on the Multiple Sclerosis Therapy Consensus Group (MSTCG). Group differences were assessed with two-sided χ2-square and t-tests.

29,604 MS therapy beginners were identified in the German and 49,791 MS therapy beginners were identified in the US dataset. 29.6 % of MS therapy beginners in Germany and 61.6 % in the US followed the HHAE strategy. Between 2020 and 2022, a significant 14 % increase in the HHAE strategy was observed in both countries (p < 0.0001). High-efficacy therapy beginners switched from their initially prescribed therapy less frequently than low-efficacy therapy beginners: 6.9 % of high-efficacy vs. 19.5 % of low-efficacy therapy beginners in Germany (p < 0.0001) and 5.5 % of high-efficacy vs. 25.0 % low-efficacy therapy beginners in the US (p < 0.0001) switched from their first prescribed DMD.

Between 2020 and 2022, the adoption of the HHAE strategy increased in both countries, with the US exhibiting nearly double the adoption rates. High-efficacy therapy beginners were less likely to switch from their initially prescribed medication than low-efficacy therapy beginners. Real world evidence can provide valuable insights into rapidly changing treatment patterns in patients with MS.

Multiple sclerosis (MS) is a multifaceted neurological condition characterized by challenges in timely diagnosis and personalized patient management. The application of Artificial Intelligence (AI) to MS holds promises for early detection, accurate diagnosis, and predictive modeling. The objectives of this study are: 1) to propose new MS trajectory descriptors that could be employed in Machine Learning (ML) regressors and classifiers to predict patient evolution; 2) to explore the contribution of ML models in discerning MS trajectory descriptors using only baseline Magnetic Resonance Imaging (MRI) studies. This study involved 446 MS patients who had a baseline MRI, at least two measurements of Expanded Disability Status Scale (EDSS), and a 1-year follow-up. Patients were divided into two groups: 1) for model development and 2) for evaluation. Three descriptors: β1, β2, and EDSS(t), were related to baseline MRI parameters using regression and classification XGBoost models. Shapley Additive Explanations (SHAP) analysis enhanced model transparency by identifying influential features. The results of this study demonstrate the potential of AI in predicting MS progression using the proposed patient trajectories and baseline MRI scans, outperforming classic Multiple Linear Regression (MLR) methods. In conclusion, MS trajectory descriptors are crucial; incorporating AI analysis into MRI assessments presents promising opportunities to advance predictive capabilities. SHAP analysis enhances model interpretation, revealing feature importance for clinical decisions.