Teriflunomide is a once-daily, oral disease-modifying therapy (DMT) for relapsing forms of multiple sclerosis (MS). We studied clinical outcomes in a real-world setting involving a population-based ...large cohort of unselected patients enrolled in The Danish Multiple Sclerosis Registry (DMSR) who started teriflunomide treatment between 2013-2019.
This was a complete nationwide population-based cohort study with prospectively enrolled unselected cases. Demographic and disease-specific patient parameters related to treatment history, efficacy outcomes, and discontinuation and switching rates among other clinical variables were assessed at baseline and during follow-up visits.
A total of 3239 patients (65.4% female) started treatment with teriflunomide during the study period, 56% of whom were treatment-naïve. Compared to previously treated patients, treatment-naïve patients were older on average at disease onset, had a shorter disease duration, a lower Expanded Disability Status Scale score at teriflunomide treatment start and more frequently experienced a relapse in the 12 months prior to teriflunomide initiation. In the 3001 patients initiating teriflunomide treatment at least 12 months before the cut-off date, 72.7% were still on treatment one year after treatment start. Discontinuations in the first year were due mainly to adverse events (15.6%). Over the full follow-up period, 47.5% of patients discontinued teriflunomide treatment. Sixty-three percent of the patients treated with teriflunomide for 5 years were relapse-free, while significantly more treatment-naïve versus previously treated patients experienced a relapse during the follow-up (p<0.0001). Furthermore, 85% of the patients with available data were free of disability worsening at the end of follow-up.
Solid efficacy and treatment persistence data consistent with other real-world studies were obtained over the treatment period. Treatment outcomes in this real-world scenario of the population-based cohort support previous findings that teriflunomide is an effective and generally well-tolerated DMT for relapsing MS patients with mild to moderate disease activity.
Objective:
To investigate clinical outcomes in a real-world setting in the complete population-based cohort of alemtuzumab-treated MS patients in Denmark.
Methods:
Data were retrieved from The Danish ...Multiple Sclerosis Registry between 2009 and 2019. Demographic and disease-specific patient parameters related to treatment history, efficacy, and safety outcomes were assessed at baseline and during follow-up visits.
Results:
A total of 209 patients (78% female) started treatment with alemtuzumab during the study period with 3.1 ± 1.4 years follow-up. After 2 years, 75% of patients were relapse-free compared to 48% the year before alemtuzumab (p < 0.001). The annual number of relapses was reduced by 69% in year 4 compared with the year prior alemtuzumab. More active disease before alemtuzumab increased the annual hazard rate for relapse (HR: 2.88, p < 0.001). The Expanded Disability Status Scale (EDSS) score remained stable or improved in 81% of patients after 2 years. The need for an additional treatment course was associated with higher number of relapses in the year before alemtuzumab (odds ratio (OR) = 1.95, p = 0.001).
Conclusion:
In a country with primarily escalation strategy, relapse rate reduction was maintained for 5 years, and EDSS stabilized/improved in majority of patients. Higher relapse rate 1 year before alemtuzumab increased the odds for additional courses. Novel serious AEs were not observed.
Cladribine tablet therapy is an efficacious treatment for multiple sclerosis (MS). Recently, we showed that one year after the initiation of cladribine treatment, T and B cell crosstalk was impaired, ...reducing potentially pathogenic effector functions along with a specific reduction of autoreactivity to RAS guanyl releasing protein 2 (RASGRP2). In the present study we conducted a longitudinal analysis of the effect of cladribine treatment in patients with RRMS, focusing on the extent to which the effects observed on T and B cell subsets and autoreactivity after one year of treatment are maintained, modulated, or amplified during the second year of treatment.
In this case-control 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 52 (W52), 60 (W60), 72 (W72) and 96 (W96) weeks, were measured using flow cytometry. Autoreactivity was assessed using a FluoroSpot assay.
We found a substantial reduction in circulating memory B cells and proinflammatory B cell responses. Furthermore, we observed reduced T cell responses to autoantigens possibly presented by B cells (RASGRP2 and a-B crystallin (CRYAB)) at W52 and W96 and a further reduction in responses to the myelin antigens myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) after 96 weeks.
We conclude that the effects of cladribine observed after year one are maintained and, for some effects, even increased two years after the initiation of a full course of treatment with cladribine tablets.
Background:
Dimethyl fumarate (DMF) is a disease-modifying therapy used for patients with relapsing-remitting multiple sclerosis (RRMS). B cells are important contributors to the pathogenesis of ...RRMS, where they regulate the inflammatory immune responses and participate in development of lesions in the central nervous system (CNS). The impact of DMF on B cell subpopulations remains incompletely understood.
Objectives:
In this study, we evaluated the effects of DMF on B cell subpopulations and their effector functions.
Methods:
Blood from 21 DMF-treated and 18 untreated patients with RRMS was analyzed by flow cytometry.
Results:
We found that DMF reduces the frequency of circulating antigen–experienced B cells, a reduction likely related to a reduced frequency of follicular helper T (TFH) cells and an increased frequency of follicular regulatory T (TFR) cells. Studying the impact of monomethyl fumarate (MMF), the primary metabolite of DMF, on B cell effector function in vitro showed that MMF increased the frequency of transforming growth factor (TGF)-β-producing B cells and decreased the frequency of B cells secreting lymphotoxin (LT)-α, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and to a lesser extent IL-10.
Conclusion:
In summary, these data suggest an anti-inflammatory role of DMF and its metabolite MMF on the B cell compartment.
The endocannabinoid system (ECS) has been found altered in patients with multiple sclerosis (MS). However, whether the ECS alteration is present in the early stage of MS remains unknown. First, we ...aimed to compare the ECS profile between newly diagnosed MS patients and healthy controls (HCs). Next, we explored the association of the ECS, biomarkers of inflammation, and clinical parameters in newly diagnosed MS patients.
Whole blood gene expression of ECS components and levels of endocannabinoids in plasma were measured by real-time quantitative polymerase chain reaction and ultra-high-pressure liquid chromatography-mass spectrometry, respectively, in 66 untreated MS patients and 46 HCs.
No differences were found in the gene expression or plasma levels of the selected ECS components between newly diagnosed MS patients and HCs. Interferon-γ, encoded by the gene IFNG, correlated positively (ρ = 0.60) with the expression of G protein-coupled receptor 55 (GPR55), and interleukin1β (IL1B) correlated negatively (ρ = -0.50) with cannabinoid receptor 2 (CNR2) in HCs.
We found no alteration in the peripheral ECS between untreated patients with MS and HC. Furthermore, our results indicate that the ECS has a minor overall involvement in the early stage of MS on inflammatory markers and clinical parameters when compared with HCs.
Multiple sclerosis (MS) leads to physical and cognitive disability, which in turn impacts the socioeconomic status of the individual. The altered socioeconomic trajectory combined with the critical ...role of aging in MS progression could potentially lead to pronounced differences between MS patients and the general population. Few nations have the ability to connect long-term clinical and socioeconomic data at the individual level, and Denmark's robust population-based registries offer unique insights. This study aimed to examine the socioeconomic aspects of elderly Danish MS patients in comparison to matched controls from the general population.
A nationwide population-based study in Denmark was conducted, comprising all living MS patients aged 50 years or older as of 1 January 2021. Patients were matched 1:10 based on sex, age, ethnicity, and residence with a 25% sample of the total Danish population. Demographic and clinical information was sourced from the Danish Multiple Sclerosis Registry, while socioeconomic data were derived from national population-based registries containing details on education, employment, social services, and household characteristics. Univariate comparisons between MS patients and matched controls were then carried out.
The study included 8,215 MS patients and 82,150 matched individuals, with a mean age of 63.4 years (SD: 8.9) and a 2:1 female-to-male ratio. For those aged 50-64 years, MS patients demonstrated lower educational attainment (high education: 28.3 vs. 34.4%,
< 0.001) and fewer received income from employment (46.0 vs. 78.9%,
< 0.001), and working individuals had a lower annual income (48,500 vs. 53,500€,
< 0.001) in comparison to the controls. Additionally, MS patients within this age group were more likely to receive publicly funded practical assistance (14.3 vs. 1.6%,
< 0.001) and personal care (10.5 vs. 0.8%,
< 0.001). Across the entire population, MS patients were more likely to live alone (38.7 vs. 33.8%,
< 0.001) and less likely to have one or more children (84.2 vs. 87.0%,
< 0.001).
MS presents significant socioeconomic challenges among the elderly population, such as unemployment, reduced income, and increased dependence on social care. These findings underscore the pervasive impact of MS on an individual's life course, extending beyond the clinical symptoms of cognitive and physical impairment.
Alemtuzumab is a monoclonal antibody targeting CD52 on the surface of immune cells, approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS). The purpose of this study was ...to analyze the repopulation of peripheral lymphocytes following alemtuzumab-induced lymphocyte depletion and investigate associations with disease activity and development of secondary autoimmunity. For this, blood samples were collected two years after initiation of alemtuzumab treatment and lymphocytes were subjected to a comprehensive flow cytometry analysis. Included in the study were 40 patients treated with alemtuzumab and 40 treatment-naïve patients with RRMS. Disease activity and development of secondary autoimmune disease was evaluated after three years of treatment. Our study confirms that alemtuzumab treatment profoundly alters the circulating lymphocyte phenotype and describes a reconstituted immune system characterized by T cell activation/exhaustion, an increased regulatory control of IL-17 producing effector T cells and CD20
+
T cells, and a reduced control of B cells. There were no obvious associations between immune cell subsets and disease activity or development of secondary autoimmune disease during treatment with alemtuzumab. Our results indicate that the reconstituted immune response is skewed towards a more effective regulatory control of MS-associated proinflammatory T cell responses. Also, the enlarged pool of naïve B cells together with the apparent decrease in control of B cell activity may explain why alemtuzumab-treated patients retain the ability to mount a humoral immune response towards new antigens.
Numerous cytokines are implicated in the immunopathogenesis of multiple sclerosis (MS), but studies are often limited to whole blood (WB) or peripheral blood mononuclear cells (PBMCs), thereby ...omitting important information about the cellular origin of the cytokines. Knowledge about the relation between blood and cerebrospinal fluid (CSF) cell expression of cytokines and the cellular source of CSF cytokines is even more scarce.
We studied gene expression of a broad panel of cytokines in WB from relapsing-remitting multiple sclerosis (RRMS) patients in remission and healthy controls (HCs). Subsequently we determined the gene expression of the dysregulated cytokines in isolated PBMC subsets (CD4+, CD8+T-cells, NK-cells, B-cells, monocytes and dendritic cells) from RRMS patients and HCs and in CSF-cells from RRMS patients in clinical relapse and non-inflammatory neurological controls (NIND).
RRMS patients had increased expression of IFN-gamma (IFNG), interleukin (IL) 1-beta (IL1B), IL7, IL10, IL12A, IL15, IL23, IL27, lymphotoxin-alpha (LTA) and lymphotoxin-beta (LTB) in WB. In PBMC subsets the main sources of pro-inflammatory cytokines were T- and B-cells, whereas monocytes were the most prominent source of immunoregulatory cytokines. In CSF-cells, RRMS patients had increased expression of IFNG and CD19 and decreased expression of IL10 and CD14 compared to NINDs. CD19 expression correlated with expression of IFNG, IL7, IL12A, IL15 and LTA whereas CD14 expression correlated with IL10 expression.
Using a systematic approach, we show that expression of pro-inflammatory cytokines in peripheral blood primarily originates from T- and B-cells, with an important exception of IFNG which is most strongly expressed by NK-cells. In CSF-cell studies, B-cells appear to be enriched in RRMS and associated with expression of pro-inflammatory cytokines; contrarily, monocytes are relatively scarce in CSF from RRMS patients and are associated with IL10 expression. Thus, our findings suggest a pathogenetic role of B-cells and an immunoregulatory role of monocytes in RRMS.
A patient with motor conversion disorder presented with a functional paresis of the left hand. After exclusion of structural brain damage, she was repeatedly examined with whole-brain functional ...magnetic resonance imaging, while she performed visually paced finger-tapping tasks. The dorsal premotor cortex showed a bilateral deactivation in the acute-subacute phase. Recovery from unilateral hand paresis was associated with a gradual increase in task-based activation of the dorsal premotor cortex bilaterally. The right medial prefrontal cortex displayed the opposite pattern, showing initial task-based activation that gradually diminished with recovery. The inverse dynamics of premotor and medial prefrontal activity over time were found during unimanual finger-tapping with the affected and non-affected hand as well as during bimanual finger-tapping. These observations suggest that reduced premotor and increased medial prefrontal activity reflect an effector-independent cortical dysfunction in conversion paresis which gradually disappears in parallel with clinical remission of paresis. The results link the medial prefrontal and dorsal premotor areas to the generation of intentional actions. We hypothesise that an excessive ‘veto’ signal generated in medial prefrontal cortex along with decreased premotor activity might constitute the functional substrate of conversion disorder. This notion warrants further examination in a larger group of affected patients.
•We mapped finger-tapping activity in a patient recovering from conversion paresis.•Activity of dorsal premotor cortex gradually emerged during repeated fMRI sessions.•Conversely, medial prefrontal activity tapered off with recovery from paresis.•The pattern was also expressed during finger-tapping with the non-affected hand.•It may represent a substrate of cortical dysfunction in conversion disorder.
There is an unmet need in multiple sclerosis (MS) therapy for treatments to stop progressive disability. The development of treatments may be accelerated if novel biomarkers are developed to overcome ...the limitations of traditional imaging outcomes revealed in early phase trials. In January 2019, the International Progressive MS Alliance convened a standing expert panel to consider potential tissue fluid biomarkers in MS in general and in progressive MS specifically. The panel focused their attention on neurofilament light chain (NfL) in serum or plasma, examining data from both relapsing and progressive MS. Here, we report the initial conclusions of the panel and its recommendations for further research. Serum NfL (sNfL) is a plausible marker of neurodegeneration that can be measured accurately, sensitively, and reproducibly, but standard procedures for sample processing and analysis should be established. Findings from relapsing and progressive cohorts concur and indicate that sNfL concentrations correlate with imaging and disability measures, predict the future course of the disease, and can predict response to treatment. Importantly, disease activity from active inflammation (i.e., new T2 and gadolinium-enhancing lesions) is a large contributor to sNfL, so teasing apart disease activity from the disease progression that drives insidious disability progression in progressive MS will be challenging. More data are required on the effects of age and comorbidities, as well as the relative contributions of inflammatory activity and other disease processes. The International Progressive MS Alliance is well positioned to advance these initiatives by connecting and supporting relevant stakeholders in progressive MS.
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