Immunology of relapse and remission in multiple sclerosis.

Eighty percent of individuals with multiple sclerosis (MS) initially develop a clinical pattern with periodic relapses followed by remissions, called relapsing-remitting MS (RRMS). This period of fluctuating disease may last for a decade or more. Clinical relapses reflect acute inflammation in the central nervous system (CNS), composed of the brain and spinal cord. Often, different anatomic areas in the CNS are involved each time a relapse occurs, resulting in varied clinical manifestations in each instance. Relapses are nearly always followed by some degree of remission, though recovery to baseline status before the flare is often incomplete. There are nine approved drugs for treatment of RRMS. The most potent drug for inhibiting relapses, the humanized anti-α4 integrin antibody known as Natalizumab, blocks homing of mononuclear cells to the CNS. The mechanisms of action of the approved drugs for RRMS provide a strong foundation for understanding the pathobiology of the relapse. Despite substantial progress in controlling relapses with the current armamentarium of medications, there is much to learn and ever more effective and safe therapies to develop.

Inhibition of CD40L with Frexalimab in Multiple Sclerosis.

BACKGROUND: The CD40-CD40L costimulatory pathway regulates adaptive and innate immune responses and has been implicated in the pathogenesis of multiple sclerosis. Frexalimab is a second-generation anti-CD40L monoclonal antibody being evaluated for the treatment of multiple sclerosis. METHODS: In this phase 2, double-blind, randomized trial, we assigned, in a 4:4:1:1 ratio, participants with relapsing multiple sclerosis to receive 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose), or the matching placebos for each active treatment. The primary end point was the number of new gadolinium-enhancing T1-weighted lesions seen on magnetic resonance imaging at week 12 relative to week 8. Secondary end points included the number of new or enlarging T2-weighted lesions at week 12 relative to week 8, the total number of gadolinium-enhancing T1-weighted lesions at week 12, and safety. After 12 weeks, all the participants could receive open-label frexalimab. RESULTS: Of 166 participants screened, 129 were assigned to a trial group; 125 participants (97%) completed the 12-week double-blind period. The mean age of the participants was 36.6 years, 66% were women, and 30% had gadolinium-enhancing lesions at baseline. At week 12, the adjusted mean number of new gadolinium-enhancing T1-weighted lesions was 0.2 (95% confidence interval [CI], 0.1 to 0.4) in the group that received 1200 mg of frexalimab intravenously and 0.3 (95% CI, 0.1 to 0.6) in the group that received 300 mg of frexalimab subcutaneously, as compared with 1.4 (95% CI, 0.6 to 3.0) in the pooled placebo group. The rate ratios as compared with placebo were 0.11 (95% CI, 0.03 to 0.38) in the 1200-mg group and 0.21 (95% CI, 0.08 to 0.56) in the 300-mg group. Results for the secondary imaging end points were generally in the same direction as those for the primary analysis. The most common adverse events were coronavirus disease 2019 and headaches. CONCLUSIONS: In a phase 2 trial involving participants with multiple sclerosis, inhibition of CD40L with frexalimab had an effect that generally favored a greater reduction in the number of new gadolinium-enhancing T1-weighted lesions at week 12 as compared with placebo. Larger and longer trials are needed to determine the long-term efficacy and safety of frexalimab in persons with multiple sclerosis. (Funded by Sanofi; ClinicalTrials.gov number, NCT04879628.).

Ublituximab versus Teriflunomide in Relapsing Multiple Sclerosis.

BACKGROUND: The monoclonal antibody ublituximab enhances antibody-dependent cellular cytolysis and produces B-cell depletion. Ublituximab is being evaluated for the treatment of relapsing multiple sclerosis. METHODS: In two identical, phase 3, double-blind, double-dummy trials (ULTIMATE I and II), participants with relapsing multiple sclerosis were randomly assigned in a 1:1 ratio to receive intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72) and oral placebo or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary end point was the annualized relapse rate. Secondary end points included the number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI) by 96 weeks and worsening of disability. RESULTS: A total of 549 participants were enrolled in the ULTIMATE I trial, and 545 were enrolled in the ULTIMATE II trial; the median follow-up was 95 weeks. In the ULTIMATE I trial, the annualized relapse rate was 0.08 with ublituximab and 0.19 with teriflunomide (rate ratio, 0.41; 95% confidence interval [CI], 0.27 to 0.62; P<0.001); in the ULTIMATE II trial, the annualized relapse rate was 0.09 and 0.18, respectively (rate ratio, 0.51; 95% CI, 0.33 to 0.78; P = 0.002). The mean number of gadolinium-enhancing lesions was 0.02 in the ublituximab group and 0.49 in the teriflunomide group (rate ratio, 0.03; 95% CI, 0.02 to 0.06; P<0.001) in the ULTIMATE I trial and 0.01 and 0.25, respectively (rate ratio, 0.04; 95% CI, 0.02 to 0.06; P<0.001), in the ULTIMATE II trial. In the pooled analysis of the two trials, 5.2% of the participants in the ublituximab group and 5.9% in the teriflunomide group had worsening of disability at 12 weeks (hazard ratio, 0.84; 95% CI, 0.50 to 1.41; P = 0.51). Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group. Serious infections occurred in 5.0% in the ublituximab group and in 2.9% in the teriflunomide group. CONCLUSIONS: Among participants with relapsing multiple sclerosis, ublituximab resulted in lower annualized relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not result in a significantly lower risk of worsening of disability. Ublituximab was associated with infusion-related reactions. (Funded by TG Therapeutics; ULTIMATE I and II ClinicalTrials.gov numbers, NCT03277261 and NCT03277248.).

Real-World Healthcare Cost Savings and Reduced Relapse Rate with Off-Label Rituximab versus Disease-Modifying Treatments Approved for Relapsing-Remitting Multiple Sclerosis: A Nationwide Cost-Effectiveness Study.

OBJECTIVE: Although off-label use of rituximab is a common alternative to disease-modifying therapies (DMTs) approved for multiple sclerosis (MS) in several countries, the impact of this on treatment cost-effectiveness is not well known. METHODS: We evaluated the relative cost-effectiveness of rituximab and MS-approved DMTs in a register-based cohort study of Swedish residents with relapsing-remitting MS, aged 18-65 years, starting treatment with rituximab, natalizumab, fingolimod, or dimethyl fumarate between January 2010 and July 2016, and followed through July 2021 (n = 5,924). By linking the population-based Swedish MS register to several Swedish health care and demographic registers, we estimated health care costs in relation to number of relapses, over 5 years from treatment start. Differences between treatments were estimated in inverse probability of treatment-weighted regression models, adjusting for a broad range of potential confounders covering demographics, medical history, and MS-related clinical characteristics. RESULTS: Off-label rituximab was associated with both lower total health care costs (mean cost savings ranged $35,000-$66,000 vs. each approved DMT), and fewer relapses (mean number of prevented relapses ranged 0.12-0.22), per started therapy over 5 years. Results were robust to variations in discounting and pricing of health care visits, with the main driver of cost-savings being the price of the index drug itself. INTERPRETATION: The cost-effectiveness of rituximab dominated the MS-approved alternatives. Off-label, low-dose rituximab should be considered for persons with MS and could reduce barriers to treatment, especially in resource-limited settings. ANN NEUROL 2024;95:1099-1111.

Blood-based untargeted metabolomics in relapsing-remitting multiple sclerosis revealed the testable therapeutic target.

Metabolic aberrations impact the pathogenesis of multiple sclerosis (MS) and possibly can provide clues for new treatment strategies. Using untargeted metabolomics, we measured serum metabolites from 35 patients with relapsing-remitting multiple sclerosis (RRMS) and 14 healthy age-matched controls. Of 632 known metabolites detected, 60 were significantly altered in RRMS. Bioinformatics analysis identified an altered metabotype in patients with RRMS, represented by four changed metabolic pathways of glycerophospholipid, citrate cycle, sphingolipid, and pyruvate metabolism. Interestingly, the common upstream metabolic pathway feeding these four pathways is the glycolysis pathway. Real-time bioenergetic analysis of the patient-derived peripheral blood mononuclear cells showed enhanced glycolysis, supporting the altered metabolic state of immune cells. Experimental autoimmune encephalomyelitis mice treated with the glycolytic inhibitor 2-deoxy-D-glucose ameliorated the disease progression and inhibited the disease pathology significantly by promoting the antiinflammatory phenotype of monocytes/macrophage in the central nervous system. Our study provided a proof of principle for how a blood-based metabolomic approach using patient samples could lead to the identification of a therapeutic target for developing potential therapy.

Cytoprotective E-WE thrombin reduces disease severity in a murine model of relapsing-remitting multiple sclerosis.

The blood-brain barrier is composed of microvascular endothelial cells, immune cells, and astrocytes that work in concert with the coagulation cascade to control inflammation and immune cell infiltration into the central nervous system. Endothelial cell dysfunction leading to increased permeability and compromised barrier function are hallmarks of neuroinflammatory and autoimmune disorders, including multiple sclerosis (MS). Therapeutic strategies that improve or protect endothelial barrier function may be beneficial in the treatment or prevention of neuroinflammatory diseases. We therefore tested the hypothesis that biasing thrombin toward anticoagulant and cytoprotective activities would provide equivalent or even additive benefit compared with standard-of-care therapeutic strategies, including corticosteroids. In a mouse model of relapsing-remitting MS, treatment with the thrombin mutant, E-WE thrombin, an engineered thrombin mutant with cytoprotective activities that is biased toward anticoagulant and cytoprotective activity, reduced neuroinflammation and extracellular fibrin formation in SJL mice inoculated with proteolipid protein (PLP) peptide. When administered at the onset of detectable disease, E-WE thrombin significantly improved the disease severity of the initial attack as well as the relapse and delayed the onset of relapse to a similar extent as observed with methylprednisolone. Both methylprednisolone and E-WE thrombin reduced demyelination and immune cell recruitment. These results provide rationale for considering engineered forms of thrombin biased toward anticoagulant and cytoprotective activity as a therapeutic strategy and perhaps an effective alternative to high-dose methylprednisolone for the management of acute relapsing MS attacks.NEW & NOTEWORTHY There are limited treatment options for mitigating acute relapsing attacks for patients with multiple sclerosis. We tested the hypothesis that harnessing the cytoprotective activity of the blood coagulation enzyme, thrombin, would provide benefit and protection against relapsing disease in a mouse model of MS. Our results provide rationale for considering engineered forms of thrombin biased toward cytoprotective activity as a therapeutic strategy and perhaps an alternative to steroids for the management of relapsing MS attacks.

Development of an LC-MS/MS Method to Measure Sphingolipids in CSF from Patients with Multiple Sclerosis.

Multiple sclerosis is an inflammatory and degenerative disease characterized by different clinical courses including relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS). A hallmark of patients with multiple sclerosis (pwMS) includes a putative autoimmune response, which results in demyelination and neuroaxonal damage in the central nervous system. Sphingolipids in cerebrospinal fluid (CSF) have been proposed as potential biomarkers reflective of disease activity in pwMS. Hence, sensitive methods to accurately quantify sphingolipids in CSF are needed. In this study, we report the development of a sensitive high-throughput multiplexed liquid chromatography coupled to a tandem mass spectrometry method to perform quantitation on 14 species of sphingolipids in human CSF. We applied this method to measure CSF sphingolipids in healthy controls (n = 10), PPMS (n = 27), and RMS (n = 17) patients before and after ocrelizumab treatment. The median CSF levels of the 14 sphingolipids measured herein was higher in PPMS (17.2 ng/mL) and RMS (17.6 ng/mL) when compared with the healthy controls (13.8 ng/mL). Levels of sphingolipids were decreased by 8.6% at week 52 after treatment with ocrelizumab in RMS patients but not in PPMS patients. Specifically, C16 glucosylceramide (-26%; P = 0.004) and C18 ceramides (-13%; P = 0.042) decreased from baseline in RMS patients. Additionally, in PPMS patients C16 glucosylceramide levels correlated with CSF neurofilament heavy levels at baseline (Rho =0.532; P = 0.004) and after treatment (Rho =0.424; P = 0.028). Collectively, these results indicate that CSF sphingolipid levels are altered in pwMS and treatment with ocrelizumab results in significant shifts in the sphingolipid profile that may reflect a reduction in disease activity supporting further investigation into sphingolipids as tools to monitor disease state. SIGNIFICANCE STATEMENT: This study describes the development of a new method to measure 14 sphingolipid species in CSF. These results demonstrate that sphingolipids levels are elevated in CSF from pwMS compared to healthy controls. Distinct sphingolipid signatures were observed between patients with different clinical disease courses, and these lipid signatures changed after treatment with ocrelizumab, especially in RMS patients. This method enables further investigation into the role of sphingolipids as candidate biomarkers in pwMS and other central nervous system disorders.

Deciphering the shift from benign to active relapsing-remitting multiple sclerosis: Insights into T regulatory cell dysfunction and apoptosis regulation.

BACKGROUND: Relapsing-remitting multiple sclerosis (RRMS), a common demyelinating disease among young adults, follows a benign course in 10-15% of cases, where patients experience minimal neurological disability for a decade following disease onset. However, there is potential for these benign cases to transition into a clinically active, relapsing state. OBJECTIVE: To elucidate the biological mechanisms underlying the transition from benign to active RRMS using gene expression analysis. METHODS: We employed complementary-DNA microarrays to examine peripheral-blood gene expression patterns in patients with benign MS, defined as having a disease duration exceeding 10 years and an Expanded Disability Status Scale (EDSS) score of ≤3.0. We compared the gene expression pattern between patients who switched to active disease (Switching BMS) with those who maintained a benign state (Permanent-BMS) during an additional 5-year follow-up. RESULTS: We identified two primary mechanisms linked to the transition from benign MS to clinically active disease. The first involves the suppression of regulatory T cell activity, and the second pertains to the dysfunction of nuclear receptor 4 A family-dependent apoptosis. These mechanisms collectively contribute to an augmented autoimmune response and increased disease activity. CONCLUSIONS: The intricate gene regulatory networks that operate in switching-BMS are related to suppression of immune tolerance and aberrant apoptosis. These findings may lead to new therapeutic targets to prevent the escalation to active disease.

Alterations in the innate and adaptive immune system in a real-world cohort of multiple sclerosis patients treated with ocrelizumab.

B cell depletion by the anti-CD20 antibody ocrelizumab is effective in relapsing-remitting (RR) and primary progressive (PP) multiple sclerosis (MS). We investigated immunological changes in peripheral blood of a real-world MS cohort after 6 and 12 months of ocrelizumab. All RRMS and most PPMS patients (15/20) showed treatment response. Ocrelizumab not only reduced CD20+ B cells, but also numbers of CD20+ T cells. Absolute numbers of monocytes, dendritic cells and CD8+ T cells were increased, while CD56hi natural killer cells were reduced after ocrelizumab. The residual B cell population shifted towards transitional and activated, IgA+ switched memory B cells, double negative B cells, and antibody-secreting cells. Delaying the treatment interval by 2-3 months increased mean B cell frequencies and enhanced naive B cell repopulation. Ocrelizumab reduced plasma levels of interleukin(IL)-12p70 and interferon(IFN)-α2. These findings will contribute to understanding ineffective treatment responses, dealing with life-threatening infections and further unravelling MS pathogenesis.

Patients with multiple sclerosis who develop immunogenicity to interferon-beta have distinct transcriptomic and proteomic signatures prior to treatment which are associated with disease severity.

Anti-drug antibodies (ADA) reduce the efficacy of immunotherapies in multiple sclerosis (MS) and are associated with increased disease progression risk. Blood biomarkers predicting immunogenicity to biopharmaceuticals represent an unmet clinical need. Patients with relapsing remitting (RR)MS were recruited before (baseline), three, and 12 (M12) months after commencing interferon-beta treatment. Neutralising ADA-status was determined at M12, and patients were stratified at baseline according to their M12 ADA-status (ADA-positive/ADA-negative). Patients stratified as ADA-positive were characterised by an early dampened response to interferon-beta (prior to serum ADA detection) and distinct proinflammatory transcriptomic/proteomic peripheral blood signatures enriched for 'immune response activation' including phosphoinositide 3-kinase-γ and NFκB-signalling pathways both at baseline and throughout the treatment course, compared to ADA-negative patients. These immunogenicity-associated proinflammatory signatures significantly overlapped with signatures of MS disease severity. Thus, whole blood molecular profiling is a promising tool for prediction of ADA-development in RRMS and could provide insight into mechanisms of immunogenicity.

Effects of anti-CD20 therapy on circulating and intrathecal follicular helper T cell subsets in multiple sclerosis.

Follicular helper T (Tfh) cells and their interplay with B cells likely contribute to the pathogenesis of relapsing-remitting multiple sclerosis (RRMS). Tfh cells are enriched in cerebrospinal fluid (CSF) in RRMS, but effects of anti-CD20 therapy are unknown. We investigated Tfh cells in controls, untreated and anti-CD20-treated patients with RRMS using flow cytometry. CSF Tfh cells were increased in untreated patients. Compared to paired blood samples, CD25- Tfh cells were enriched in CSF in RRMS, but not in controls. Contrast-enhancing brain MRI lesions and IgG index correlated with CSF CD25- Tfh cell frequency in untreated patients with RRMS. Anti-CD20 therapy reduced the numbers of circulating PD1+ Tfh cells and CD25- Tfh cells, and the frequency of CSF CD25- Tfh cells. The study suggests that CD25- Tfh cells are recruited to the CSF in RRMS, associated with focal inflammation, and are reduced by anti-CD20 therapy.

CLADIN- CLADribine and INnate immune response in multiple sclerosis - A phase IV prospective study.

Cladribine (Mavenclad®) is an oral treatment for relapsing remitting MS (RRMS), but its mechanism of action and its effects on innate immune responses in unknown. This study is a prospective Phase IV study of 41 patients with RRMS, and aims to investigate the mechanism of action of cladribine on peripheral monocytes, and its impact on the P2X7 receptor. There was a significant reduction in monocyte count in vivo at week 1 post cladribine administration, and the subset of cells being most impacted were the CD14lo CD16+ 'non-classical' monocytes. Of the 14 cytokines measured in serum, CCL2 levels increased at week 1. In vitro, cladrabine induced a reduction in P2X7R pore as well as channel activity. This study demonstrates a novel mechanism of action for cladribine. It calls for studying potential benefits of cladribine in progressive forms of MS and other neurodegenerative diseases where innate immune related inflammation is implicated in disease pathogenesis.

Dimethyl Fumarate Delays Multiple Sclerosis in Radiologically Isolated Syndrome.

OBJECTIVE: The radiologically isolated syndrome (RIS) represents the earliest detectable pre-clinical phase of multiple sclerosis (MS). This study evaluated the impact of therapeutic intervention in preventing first symptom manifestation at this stage in the disease spectrum. METHODS: We conducted a multi-center, randomized, double-blinded, placebo-controlled study involving people with RIS. Individuals without clinical symptoms typical of MS but with incidental brain MRI anomalies consistent with central nervous system (CNS) demyelination were included. Within 12 MS centers in the United States, participants were randomly assigned 1:1 to oral dimethyl fumarate (DMF) 240 mg twice daily or placebo. The primary endpoint was the time to onset of clinical symptoms attributable to a CNS demyelinating event within a follow-up period of 96 weeks. An intention-to-treat analysis was applied to all participating individuals in the primary and safety investigations. The study is registered at ClinicalTrials.gov, NCT02739542 (ARISE). RESULTS: Participants from 12 centers were recruited from March 9, 2016, to October 31, 2019, with 44 people randomized to dimethyl fumarate and 43 to placebo. Following DMF treatment, the risk of a first clinical demyelinating event during the 96-week study period was highly reduced in the unadjusted Cox proportional-hazards regression model (hazard ratio [HR] = 0.18, 95% confidence interval [CI] = 0.05-0.63, p = 0.007). More moderate adverse reactions were present in the DMF (34 [32%]) than placebo groups (19 [21%]) but severe events were similar (DMF, 3 [5%]; placebo, 4 [9%]). INTERPRETATION: This is the first randomized clinical trial demonstrating the benefit of a disease-modifying therapy in preventing a first acute clinical event in people with RIS. ANN NEUROL 2023;93:604-614.

Trajectories of cognitive processing speed and physical disability over 11 years following initiation of a first multiple sclerosis disease-modulating therapy.

BACKGROUND: We analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (NCT03193866), a Swedish nationwide observational study in relapsing-remitting multiple sclerosis (RRMS), to identify trajectories of processing speed and physical disability after disease-modulating therapy (DMT) start. METHODS: Using a group-modelling approach, we assessed trajectories of processing speed with oral Symbol Digit Modalities Test (SDMT) and physical disability with Expanded Disability Status Scale, from first DMT start among 1645 patients with RRMS followed during 2011-2022. We investigated predictors of trajectories using group membership as a multinomial outcome and calculated conditional probabilities linking membership across the trajectories. RESULTS: We identified 5 stable trajectories of processing speed: low SDMT scores (mean starting values=29.9; 5.4% of population), low/medium (44.3; 25.3%), medium (52.6; 37.9%), medium/high (63.1; 25.8%) and high (72.4; 5.6%). We identified 3 physical disability trajectories: no disability/stable (0.8; 26.8%), minimal disability/stable (1.6; 58.1%) and moderate disability (3.2; 15.1%), which increased to severe disability. Older patients starting interferons were more likely than younger patients starting rituximab to be on low processing speed trajectories. Older patients starting teriflunomide, with more than one comorbidity, and a history of pain treatment were more likely to belong to the moderate/severe physical disability trajectory, relative to the no disability one. There was a strong association between processing speed and physical disability trajectories. CONCLUSIONS: In this cohort of actively treated RRMS, patients' processing speed remained stable over the years following DMT start, whereas patients with moderate physical disability deteriorated in physical function. Nevertheless, there was a strong link between processing speed and disability after DMT start.

Emulating randomised clinical trials in relapsing-remitting multiple sclerosis with non-randomised real-world evidence: an application using data from the MSBase Registry.

BACKGROUND: To mimic as closely as possible a randomised controlled trial (RCT) and calibrate the real-world evidence (RWE) studies against a known treatment effect would be helpful to understand if RWE can support causal conclusions in selected circumstances. The aim was to emulate the TRANSFORMS trial comparing Fingolimod (FTY) versus intramuscular interferon ß-1a (IFN) using observational data. METHODS: We extracted from the MSBase registry all the patients with relapsing-remitting multiple sclerosis (RRMS) collected in the period 2011-2021 who received IFN or FTY (0.5 mg) and with the same inclusion and exclusion criteria of the TRANSFORMS RCT. The primary endpoint was the annualised relapse rate (ARR) over 12 months. Patients were 1:1 propensity-score (PS) matched. Relapse-rate ratio (RR) was calculated by mean of a negative binomial regression. RESULTS: A total of 4376 patients with RRMS (1140 in IFN and 3236 in FTY) were selected. After PS, 856 patients in each group were matched. The ARR was 0.45 in IFN and 0.25 in FTY with a significant difference between the two groups (RR: 0.55, 95% CI: 0.45 to 0.68; p<0.001). The result of the emulation was very similar and fell within the 95% CI of that observed in the RCT (RR: 0.49, 95% CI: 0.37 to 0.64; p<0.001) with a standardised difference of 0.66 (p=0.51). CONCLUSIONS: By applying the same inclusion and exclusion criteria used in the RCT and employing appropriate methodology, we successfully replicated the RCT results with only minor discrepancies. Also, even if the confounding bias cannot be fully eliminated, conducting a rigorous target trial emulation could still yield valuable insights for comparative effectiveness research.

Trajectories of self-reported fatigue following initiation of multiple sclerosis disease-modifying therapy.

BACKGROUND: We analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (NCT03193866), a Swedish nationwide observational study in relapsing-remitting multiple sclerosis (RRMS), to identify trajectories of fatigue and their association with physical disability following start of disease-modifying therapy (DMT). METHODS: Using a group-modelling approach, we assessed trajectories of fatigue with the Fatigue Scale for Motor and Cognitive Functions and physical disability with Expanded Disability Status Scale among 1587 and 1818 individuals who initiated a first DMT and had a first DMT switch, respectively, followed during 2011-2022. We investigated predictors of fatigue trajectories using group membership as a multinomial outcome and calculated conditional probabilities linking membership across the trajectories. RESULTS: We identified five trajectories of fatigue in participants who initiated their first DMT: no fatigue (mean starting values=23.7; 18.2% of population), low (35.5; 23.9%), mild (49.0; 21.6%), moderate (61.3; 20.1%) and severe (78.7; 16.1%). While no, low, mild and severe fatigue trajectories remained stable, the moderate trajectory increased to severe fatigue. Similarly, we identified six fatigue trajectories among participants who did a DMT switch, all indicating stable values over time. Women initiating a first DMT were more likely than men to display a severe fatigue trajectory, relative to the no fatigue one. There was a strong association between fatigue and physical disability trajectories. CONCLUSIONS: In this cohort of people with actively treated RRMS, self-reported fatigue remained stable or increased over the years following DMT start. There was a strong association between fatigue and disability after DMT start.

Prospective trial of natalizumab personalised extended interval dosing by therapeutic drug monitoring in relapsing-remitting multiple sclerosis (NEXT-MS).

BACKGROUND: Extended interval dosing (EID) of natalizumab is a promising strategy to optimise treatment in multiple sclerosis (MS). Personalised EID by therapeutic drug monitoring can enable further extension of treatment intervals. METHODS: The NEXT-MS trial is an investigator-initiated prospective phase IV non-randomised study. Adults with a diagnosis of relapsing-remitting MS who received ≥6 natalizumab infusions were included in three groups: personalised EID with a target drug trough concentration of 10 µg/mL (EID10), an exploratory group of personalised EID with a target of 5 µg/mL (EID5) and standard interval dosing (SID) of 4 weeks. The primary outcome is radiological disease activity (new/newly enlarged T2 lesions) comparing the EID10 group to a historical cohort of SID (HSID). RESULTS: Results of the first phase of the NEXT-MS trial are reported here (n=376) as the study will continue with an amended protocol. In the EID10 group (n=251), incidence rate of radiological activity was 10.0 per 1000 person-years, which was non-inferior to the HSID cohort (24.7 per 1000 person-years (n=87), incidence rate difference 14.7, 90% CI -4.5 to 34.0). Incidence rate of radiological activity was 10.0 per 1000 person-years in the EID5 group (n=65), and 47.0 per 1000 person-years in the SID group (n=60). Serum neurofilament light levels did not increase over time within the EID groups. There were no cases of progressive multifocal leukoencephalopathy. CONCLUSIONS: MS disease activity is adequately controlled with personalised natalizumab EID. Interval extension to a drug trough concentration of 5 µg/mL is likely a safe target to extend natalizumab treatment intervals >6 weeks. TRIAL REGISTRATION NUMBER: NCT04225312.

Early postpartum treatment strategies and early postpartum relapses in women with active multiple sclerosis.

BACKGROUND: Relapse risk after delivery is increased in women with active multiple sclerosis (MS), the best strategy to reduce it is unknown. We aimed to assess the association of four different postpartum strategies with relapses during the first 6 months post partum. METHODS: This cohort study includes data prospectively collected through structured telephone interviews from the German Multiple Sclerosis and Pregnancy Registry. Pregnancies with active MS (fingolimod or natalizumab treatment OR relapse within 1 year before pregnancy) and postpartum follow-up of ≥6 months were included. We compared four strategies: (1) intention to breastfeed exclusively without disease-modifying therapy (DMT) (exclusive breast feeding ≥2 months or switching to non-exclusive/weaning within 2 weeks after a relapse during the first 2 months), (2) early treatment with natalizumab/fingolimod and (3) other DMT initiated within 6 weeks post partum before a relapse. If women did not or only partially breastfed, or started DMT≤6 weeks after delivery after a relapse or later, we assumed (4) no-DMT-no-exclusive- breastfeeding-strategy. Main outcome was time to postpartum MS relapses. RESULTS: In 867 women with 911 pregnancies, most (n=416) intended to breastfeed exclusively or had no-DMT-no-exclusive-breastfeeding-strategy (n=290); fewer started fingolimod (n=38), natalizumab (n=74) or another DMT (n=93) early. Recurrent time-to-event analysis showed a statistically significant reduction in relapse hazard only with the natalizumab/fingolimod-strategy as of months 3-4 post partum compared with intention-to-breastfeed-exclusively-strategy. The very early relapse risk was highest in no-DMT-no-exclusive-breastfeeding-strategy. CONCLUSION: In active MS, an early postpartum treatment strategy should be determined well before delivery. Natalizumab/fingolimod-strategy reduced postpartum relapse hazard from month 3, but none diminished the early postpartum relapse hazard.

Haematopoietic stem cell transplantation for treatment of relapsing-remitting multiple sclerosis in Sweden: an observational cohort study.

BACKGROUND: A growing evidence base supports the use of autologous haematopoietic stem cell transplantation (aHSCT) for treatment of relapsing-remitting multiple sclerosis (RRMS), but it has not yet been integrated into most national clinical guidelines. The objective of this study was to assess efficacy and safety when aHSCT is implemented in routine healthcare. METHODS: We assessed 231 patients and the final analysis included 174 RRMS patients who were treated with aHSCT in Sweden before 1 January 2020. Efficacy was evaluated by performing a retrospective analysis of prospectively collected data from the Swedish MS registry. Procedure-related safety was assessed by analysing data from electronic patient records covering a period of 100 days following aHSCT. RESULTS: With a median follow-up time of 5.5 (IQR: 3.4-7.5) years, the Kaplan-Meier estimate for no evidence of disease activity was 73% (95% CI 66% to 81%) at 5 years and 65% (95% CI 57% to 75%) at 10 years. Out of the 149 patients with baseline disability, 80 (54%) improved, 55 (37%) were stable and 14 (9%) deteriorated. The mean number of adverse events per patient was 1.7 (±SD: 1.5) for grade 3 events and 0.06 (±SD: 0.3) for grade 4 events. Febrile neutropenia was the most common adverse event, affecting 68% of patients. There was no treatment-related mortality. CONCLUSIONS: Treatment with aHSCT for RRMS is associated with freedom from disease activity in a majority of patients, with acceptable adverse events. This procedure should be considered a standard of care for patients with highly active RRMS.

Assessing treatment response to oral drugs for multiple sclerosis in real-world setting: a MAGNIMS Study.

BACKGROUND: The assessment of treatment response is a crucial step for patients with relapsing-remitting multiple sclerosis on disease-modifying therapies (DMTs). We explored whether a scoring system developed within the MAGNIMS (MRI in Multiple Sclerosis) network to evaluate treatment response to injectable drugs can be adopted also to oral DMTs. METHODS: A multicentre dataset of 1200 patients who started three oral DMTs (fingolimod, teriflunomide and dimethyl fumarate) was collected within the MAGNIMS network. Disease activity after the first year was classified by the 'MAGNIMS' score based on the combination of relapses (0-≥2) and/or new T2 lesions (<3 or ≥3) on brain MRI. We explored the association of this score with the following 3-year outcomes: (1) confirmed disability worsening (CDW); (2) treatment failure (TFL); (3) relapse count between years 1 and 3. The additional value of contrast-enhancing lesions (CELs) and lesion location was explored. RESULTS: At 3 years, 160 patients experienced CDW: 12% of them scored '0' (reference), 18% scored '1' (HR=1.82, 95% CI 1.20 to 2.76, p=0.005) and 37% scored '2' (HR=2.74, 95% CI 1.41 to 5.36, p=0.003) at 1 year. The analysis of other outcomes provided similar findings. Considering the location of new T2 lesions (supratentorial vs infratentorial/spinal cord) and the presence of CELs improved the prediction of CDW and TFL, respectively, in patients with minimal MRI activity alone (one or two new T2 lesions). CONCLUSIONS: Early relapses and substantial MRI activity in the first year of treatment are associated with worse short-term outcomes in patients treated with some of the oral DMTs.