Mie Reith Mahler

Background: Multiple sclerosis (MS) monitoring often relies on traditional methods like the expanded disability status scale (EDSS) and magnetic resonance imaging, which may not fully reflect patients’ health. Patient-reported outcomes (PROs) provide valuable insights into patients’ experiences of their disease. Objectives: This study evaluated the Danish implementation of PROs for people with MS (PwMS) 3 years post-launch, comparing clinical and demographic characteristics between PRO users and non-users, and assessing PRO adherence. Results: As of 1 January 2025, 2121 PwMS had signed up for PRO, compared to 14,125 who did not. PRO users were younger (mean age 50.6 vs. 53.2 years), more frequently female (73.6% vs. 68.0%), had a shorter disease duration (15.1 vs. 16.4 years), and were more likely to be on high-efficacy disease-modifying therapies (75.6% vs. 62.2%). Additionally, fewer PRO users had low EDSS scores (6, 16.5% vs. 18.9%). Most enrolled patients lived in Region Hovedstaden (75.1%). Conclusion: The study highlights differences in profile between PRO users and non-users, demonstrating the PRO platform's adaptability across different ages and disability levels in PwMS. However, these findings also highlight potential implementation challenges and emphasize the need for sustained commitment to support long-term use of PRO.

Background and Objective: High‐efficacy (HE) disease‐modifying therapies (DMT) are increasingly used to treat multiple sclerosis (MS). Concerns arise when considering the decreasing efficacy and increasing risk of adverse events in aging patients. We aimed to describe disease activity and treatment trajectories in patients with MS who de‐escalated from an HE DMT to an moderate‐efficacy (ME) DMT.Methods: We performed a cohort study based on data from the Danish Multiple Sclerosis Registry (DMSR) including patients with relapsing–remitting MS (RRMS), who switched from an HE DMT to an ME DMT as defined by Danish authorities. We included patients from October 2007 to July 2023. Median follow‐up time was 0.8 years (IQR 0.3–2.5).Results: In total 333 patients (76.0% females, mean age: 45.1 years) de‐escalated for various reasons. Most patients de‐escalated from natalizumab or fingolimod (43.8% and 42.0%, respectively) to dimethyl fumarate (47.5%). At 2 years after de‐escalation, the cumulative risk of relapse was 38% (95% CI 31–44) and 53% (95% CI 46–60) for inflammatory disease activity (relapses and/or radiological disease activity). Age (HR 0.96, 95% CI 0.94–0.98) and inflammatory disease activity prior to de‐escalation (HR 2.05, 95% CI 1.45–2.91) were associated with inflammatory disease activity post de‐escalation.Discussion: De‐escalation from primarily natalizumab and fingolimod did not effectively ensure disease stability in this cohort. Younger age and inflammatory disease activity prior to de‐escalation were risk factors for inflammatory disease activity post de‐escalation, which can help guide future studies on de‐escalation.

Currently, there are limited therapeutic options for patients with non-active secondary progressive multiple sclerosis. Therefore, real-world studies have investigated differences between patients with relapsing-remitting multiple sclerosis, non-active secondary progressive multiple sclerosis and active secondary progressive multiple sclerosis. Here, we explore patterns and predictors of transitioning between these phenotypes. We performed a cohort study using data from The Danish Multiple Sclerosis Registry. We included patients with a relapsing-remitting phenotype, registered changes to secondary progressive multiple sclerosis and subsequent transitions between relapsing and non-relapsing secondary progressive multiple sclerosis, which was defined by the presence of relapses in the previous 2 years. We analysed predictors of transitioning from relapsing-remitting multiple sclerosis to relapsing and non-relapsing secondary progressive multiple sclerosis, as well as between the secondary progressive states using a multi-state Markov model. We included 4413 patients with relapsing-remitting multiple sclerosis. Within a median follow-up of 16.2 years, 962 were diagnosed with secondary progressive multiple sclerosis by their treating physician. Of these, we classified 729 as non-relapsing and 233 as relapsing secondary progressive multiple sclerosis. The risk of transitioning from relapsing-remitting to non-relapsing secondary progressive multiple sclerosis included older age (hazard ratio per increase of 1 year in age: 1.044, 95% confidence interval: 1.035–1.053), male sex (hazard ratio for female: 0.735, 95% confidence interval: 0.619–0.874), fewer relapses (hazard ratio per each additional relapse: 0.863, 95% confidence interval: 0.823–0.906), higher expanded disability status scale (hazard ratio per each additional point: 1.522, 95% confidence interval: 1.458–1.590) and longer time on disease-modifying therapies (hazard ratio per increase of 1 year in treatment, high-efficacy disease-modifying therapy: 1.095, 95% confidence interval: 1.051–1.141; hazard ratio, moderate-efficacy disease-modifying therapy: 1.073, 95% confidence interval: 1.051–1.095). We did not find significant predictors associated with the transition from relapsing secondary progressive multiple sclerosis to non-relapsing secondary progressive multiple sclerosis, whereas older age (hazard ratio per increase of 1 year in age: 0.956, 95% confidence interval: 0.942–0.971) prevented the transition from non-relapsing secondary progressive multiple sclerosis to relapsing secondary progressive multiple sclerosis. Our study suggests that transitioning from relapsing-remitting multiple sclerosis to non-relapsing secondary progressive multiple sclerosis depends on well-known factors affecting diagnosing secondary progressive multiple sclerosis. Further transitions between non-relapsing and relapsing secondary progressive multiple sclerosis are only affected by age. These findings add to the knowledge of non-active secondary progressive multiple sclerosis, a patient group with unmet needs in terms of therapies.

Background 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). Methods 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. Results 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. Conclusion 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.

Objectives: B cells are important in the pathogenesis of multiple sclerosis. It is yet unknown which subsets may be involved, but atypical B cells have been proposed as mediators of autoimmunity. In this study, we investigated differences in B‐cell subsets between controls and patients with untreated and anti‐CD20‐treated multiple sclerosis.Methods: We recruited 155 participants for an exploratory cohort comprising peripheral blood and cerebrospinal fluid, and a validation cohort comprising peripheral blood. Flow cytometry was used to characterize B‐cell phenotypes and effector functions of CD11c⁺ atypical B cells.Results: There were no differences in circulating B cells between controls and untreated multiple sclerosis. As expected, anti‐CD20‐treated patients had a markedly lower B‐cell count. Of B cells remaining after treatment, we observed higher proportions of CD11c⁺ B cells and plasmablasts. CD11c⁺ B cells were expanded in cerebrospinal fluid compared to peripheral blood in controls and untreated multiple sclerosis. Surprisingly, the proportion of CD11c⁺ cerebrospinal fluid B cells was higher in controls and after anti‐CD20 therapy than in untreated multiple sclerosis. Apart from the presence of plasmablasts, the cerebrospinal fluid B‐cell composition after anti‐CD20 therapy resembled that of controls. CD11c⁺ B cells demonstrated a high potential for both proinflammatory and regulatory cytokine production.Interpretation: The study demonstrates that CD11c⁺ B cells and plasmablasts are less efficiently depleted by anti‐CD20 therapy, and that CD11c⁺ B cells comprise a phenotypically and functionally distinct, albeit heterogenous, B‐cell subset with the capacity of exerting both proinflammatory and regulatory functions.

Objective: Cladribine tablet therapy is an efficacious treatment for multiple sclerosis (MS), however, its mechanism of action on T and B cell subsets remains unclear. The purpose of this study was to investigate the treatment effects of cladribine on the peripheral pool of T and B cells subsets and reactivity toward central nervous system (CNS) antigens.Methods: In this cross‐sectional exploratory study, frequencies and absolute counts of peripheral T and B cell subsets and B cell cytokine production from untreated patients with relapsing–remitting MS (RRMS) and patients treated with cladribine for 1 year were measured using flow cytometry. Autoreactivity was assessed using a FluoroSpot assay.Results: We found that 1 year after initiation of cladribine treatment, a lower number of CD4⁺ T cells was persisting whereas CD19⁺ B cell counts were normalized compared to untreated patients with RRMS. Follicular helper T cells and their effecter subsets producing cytokines exerting distinct B cell helper activity were lower and, additionally, the peripheral B cell pool was skewed toward a naïve and anti‐inflammatory phenotype. Finally, reactivity to the recently identified CNS‐enriched autoantigen RAS guanyl‐releasing protein 2 (RASGRP2), but not to myelin basic protein and myelin oligodendrocyte glycoprotein, was lower in cladribine‐treated patients.Interpretation: Together, these investigations on T and B cell subsets suggest that cladribine treatment impairs the B–T cell crosstalk and reduces their ability to mediate pathogenic effector functions. This may result in specific reduction of autoreactivity to RASGRP2 which is expressed in B cells and brain tissue. ANN NEUROL 2023;94:518–530

Background and Objective To study whether dimethyl fumarate is superior to placebo in decreasing CSF concentrations of neurofilament light chain (NFL) in patients with primary progressive MS (PPMS). Methods In the double-blind, placebo-controlled phase 2 study dimethyl FUMArate treatment in Progressive Multiple Sclerosis (FUMAPMS), patients with PPMS were randomly assigned to treatment with 240 mg dimethyl fumarate or placebo in a 1:1 ratio for 48 weeks. The primary endpoint was change in concentration of NFL in the CSF. Secondary endpoints included other CSF biomarkers and clinical and MRI measures. Efficacy was evaluated for the full data set by multiple imputations to account for missing data. Safety was assessed for the full data set. Results Fifty-four patients (mean age 54.9 years [SD 6.1], median Expanded Disability Status Scale 4.0 [nterquartile range 4.0–6.0], disease duration 14.1 [SD 9.4], and 21 [39%] female) were randomized to either placebo (n = 27) or dimethyl fumarate (n = 27) therapy. At screening CSF concentrations, adjusted for age and sex, of NFL, myelin basic protein (MBP), soluble CD27, chitinase 3-like 1, and B-cell maturation antigen were higher than in a group of symptomatic controls. Twenty-six patients (96%) in the dimethyl fumarate group and 24 patients (89%) in the placebo group completed the randomized phase. Mean change in CSF concentrations of NFL did not differ between groups (mean difference 99 ng/L; 95% CI −292 to 491 ng/L). MBP in CSF decreased in the treatment group (−182 ng/L, 95% CI −323 to −41 ng/L compared with placebo). The difference observed in the multiple imputation data set was not significant in a per protocol analysis. This was nominally significant in the multiple imputation data set but not in the per protocol analysis This was not found in the per protocol analysis Other secondary and tertiary outcomes were not affected. Various infections, lymphopenia, flushing, and gastrointestinal side effects were more frequent in the dimethyl fumarate group. Serious adverse events were similar between groups. Discussion Dimethyl fumarate treatment for 48 weeks had no effect on any of the investigated efficacy measures in patients with PPMS. We did not observe adverse events not anticipated for dimethyl fumarate treatment. Trial Registration Information Clinicaltrials.gov identifier NCT02959658. Classification of Evidence This study provides Class I evidence that for patients with PPMS, dimethyl fumarate treatment has no effect on CSF NFL levels compared with placebo treatment.