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Melinda Magyari,1,3 Nils Koch-Henriksen,1,2 Per Soelberg Sørensen3 1Danish Multiple Sclerosis Registry, Department of Neurology, Rigshospitalet, Copenhagen, 2Department of Clinical Epidemiology, Clinical Institute, University of Aarhus, Aarhus, 3Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Aim of the database: The Danish Multiple Sclerosis Treatment Register (DMSTR) serves as a clinical quality register, enabling the health authorities to monitor the quality of the disease-modifying treatment, and it is an important data source for epidemiological research. Study population: The DMSTR includes all patients with multiple sclerosis who had been treated with disease-modifying drugs since 1996. At present, more than 8,400 patients have been registered in this database. Data are continuously entered online into a central database from all sites in Denmark at start and at regular visits. Main variables: Include age, sex, onset year and year of the diagnosis, basic clinical information, and information about treatment, side effects, and relapses. Descriptive data: Notification is done at treatment start, and thereafter at every scheduled clinical visit 3 months after treatment start, and thereafter every 6 months. The longitudinally collected information about the disease activity and side effects made it possible to investigate the clinical efficacy and adverse events of different disease-modifying therapies. Conclusion: The database contributed to a certain harmonization of treatment procedures in Denmark and will continue to be a major factor in terms of quality in clinical praxis, research and monitoring of adverse events, and plays an important role in research. Keywords: multiple sclerosis, epidemiology, immunomodulatory treatment, neutralizing antibodies, observational studies, registry research, disease modifying therapy

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a

The article presents a study of the potential of early binding antibody (BAb) titers or different interferon-beta (IFN-b) biomarkers to predict neutralizing antibodies (NAb). The study included patients with multiple sclerosis (MS) or clinically isolated syndrome (CIS) that receive de novo IFN-b treatment. Results showed that BAb titers reliably predict Nabs, with CXCL-10 as a potential sensitive biomarker for IFN-b response and abrogation by anti-IFN-b antibodies.

The article presents a study which investigates the activation of CD4+ T cells, monocytes and dendritic cells (DC) in multiple sclerosis (MS) patients treated with glatiramer acetate (GA). The cross-sectional study used flow cytometry to assess the activation of CD4+ T cells, monocytes and DC of 39 untreated and 29 GA-treated MS patients in relation to disease activity. Results showed that prominent changes in circulating antigen-presenting cells and CD4+ T cells in MS patients treated with GA.

Background: Glatiramer acetate (GA) treatment suppresses disease activity in multiple sclerosis (MS). The immunological response to treatment may differ in patients who are stable on GA therapy and patients with breakthrough disease activity, but the results of previous studies are inconsistent.Objectives: We studied the immunological response to GA and its relationship with disease activity.Methods: Anti-GA antibodies in plasma and the expression of genes encoding cytokines and T-cell-polarizing transcription factors in blood cells were analysed by flow cytometric bead array and polymerase chain reaction (PCR) analysis in 39 untreated and 29 GA-treated relapsing–remitting MS patients. Definition of breakthrough disease was based on the occurrence of relapses, disability progression, or gadolinium (Gd)-enhanced MRI.Results: The expression of T helper type 1 (Th1) and Th17 cytokines and transcription factors was reduced during long-term treatment, but there was no relationship between the expression of cytokines and transcription factors and anti-GA antibodies. High expression of mRNA encoding GATA3 and lymphotoxin-β (LT-β) was associated with low disease activity in Gd-enhanced MRI studies. None of the variables studied were associated with clinical disease activity. GA treatment resulted in the development of IgG and IgG4 anti-GA antibodies during the first months of treatment, persisting during long-term treatment.Conclusions: The observed relationship between the expression of mRNA encoding GATA3 and LT-β expression and MRI disease activity deserves further analysis in future studies. The development of anti-GA antibodies was observed in all patients treated with GA, but this was not related with measures of cellular immunity, clinical or MRI disease activity. [ABSTRACT FROM AUTHOR]

Background: Monthly application of high-dose intravenous immunoglobulin (IVIG) to patients with secondary progressive multiple sclerosis (MS) showed no clinical benefit in the European Study on Immunoglobulin in MS (ESIMS). Magnetic resonance imaging (MRI) results may provide insights into the morphologic consequences of such treatment. Methods: A total of 318 patients (mean age 44±7 years) were enrolled in 31 European and Canadian centres and treated monthly with 1 g/kg body weight of IVIG or equivalent amounts of albumin 0.1% for 27 months. MRI was performed at baseline and after 12 and 24 months and comprised of conventional dualecho T2-weighted and T1-weighted scans before and after application of 0.1 mmol/kg Gd-DTPA. Results: Similar to clinical variables, MRI measures at baseline were well comparable between treatment groups except for a somewhat lower mean number of contrast-enhancing lesions and number of active scans in IVIG-treated patients. Over the trial period there was almost no change of the T2-lesion load and the 'black hole' volume in both treatment groups and the cumulative number of contrast-enhancing lesions were similar. There was only a trend for fewer new or enlarged T2-lesions in IVIG patients, which disappeared after correction for the imbalance in the number of contrast-enhancing lesions at baseline. Brain volume in terms of a partial cerebral fraction decreased significantly less with IVIG than placebo treatment (final visit: -0.62 9±0.88% versus -0.88 9±0.91%; P =0.009). This difference remained statistically significant with correction for active lesions at baseline (P =0.02) and was seen primarily in male patients and those with an Expanded Disability Status Scale score ≥6 and no relapses in the two years before the study. Conclusion: The absence of significant differences in conventional MRI measures between both treatment groups parallels the negative clinical results of ESIMS. The causes for and possible long-term clinical effects of a lower rate of brain volume loss in IVIG patients should be explored further. [ABSTRACT FROM AUTHOR]

BACKGROUND: RNF (Rebif New Formulation, Merck Serono International S.A., Geneva, Switzerland), a formulation of interferon-beta1a (IFN-beta1a) without human- or animal-derived components, is currently under investigation. It was developed with the aim of maximizing the treatment benefit for patients with multiple sclerosis (MS) by improving injection tolerability and reducing the development of neutralizing antibodies (NAbs). OBJECTIVE: This paper reports the results of planned 24- and 48-week interim analyses comparing immunogenicity and tolerability data from an ongoing study of RNF with historical-control data for the currently approved formulation of IFN-beta1a from the EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy) study. METHODS: Patients in the 96-week, multicenter, singlearm, Phase IIIb RNF study received 44 microg/0.5 mL SC tiw; patients in the EVIDENCE study received an identical regimen of the currently approved formulation of IFN-beta1a. Criteria for inclusion in the RNF study were age between 18 and 60 years, an Expanded Disability Status Scale (EDSS) score <6.0, and a diagnosis of relapsing MS (McDonald criteria). Criteria for inclusion in the EVIDENCE study were age between 18 and 55 years, an EDSS score of 0 to 5.5, and a diagnosis of clinically definite relapsing-remitting MS (Poser criteria). Patients in both studies were treatment naive. Both studies used the same cytopathic-effect assay for NAbs to assess immunogenicity; patients who had NAb titers >or=20 neutralizing units (NU)/mL were considered NAb+. The primary end point was to compare the proportions of NAb+ patients in the RNF study and the historical data. Comparisons were descriptive and used exact 95% CIs. Safety analyses included 8 prespecified adverse events (AEs) of interest. RESULTS: Baseline demographic characteristics were well balanced between the RNF (N = 260) and EVIDENCE (N = 339) studies, except that patients in the RNF study were slightly younger (median age, 34.0 vs 39.0 years, respectively), and a few had secondary progressive MS (n = 6) or progressive relapsing MS (n = 1). At week 48, 87.3% of patients in the RNF study remained on treatment. The incidence of the prespecified AEs of interest in the RNF and EVIDENCE studies was as follows: flu-like symptoms (70.8% and 48.1%, respectively), injection-site reactions (29.6% and 83.8%), hepatic disorders (13.1% and 16.8%), cytopenia (9.6% and 11.8%), depression and suicidal ideation (5.8% and 19.8%), skin rashes (5.4% and 12.1%), hypersensitivity reactions (5.4% and 3.2%), and thyroid disorders (2.3% and 5.0%). Overall, the majority (96.9%) of AEs in the RNF study were mild (69.5%) or moderate (27.5%) in severity. The proportions of patients in the RNF and EVIDENCE studies with NAbs at both 24 and 48 weeks were 2.5% (95% CI, 0.9-5.5) and 14.3% (95% CI, 10.7-18.6), respectively; the proportions with NAbs at week 48 only were 13.9% (95% CI, 9.9-18.7) and 24.4% (95% CI, 19.9-29.4). The proportions of NAb+ patients with high NAb titers (>1000 NU/mL) at week 48 were 11.1% in the RNF study and 19.5% in the EVIDENCE study. CONCLUSIONS: The results of these interim analyses suggest that RNF had an improved overall tolerability and safety profile and a lower immunogenic potential compared with the approved IFN-beta1a formulation assessed in the EVIDENCE study. Two-year results from the RNF study are anticipated before the end of 2007. [ABSTRACT FROM AUTHOR]

Background: Interferon beta reduces activity in multiple sclerosis as measured clinically and by magnetic resonance imaging (MRI). We assessed the effect of interferon beta-1a on the occurrence of relapses in patients after first presentation with neurological events, who are at high risk of conversion to clinically definite multiple sclerosis.Methods: Eligible patients had had a first episode of neurological dysfunction suggesting multiple sclerosis within the previous 3 months and had strongly suggestive brain MRI findings. Patients were randomly assigned interferon beta-1a 22 microg or placebo subcutaneously once weekly for 2 years. Neurological and clinical assessments were done every 6 months and brain MRI every 12 months. Analyses excluded one patient assigned placebo who received no study injections.Findings: 241 (78%) of 308 randomised patients received study treatment for 2 years; 278 (90%) remained in the study until termination. 57 (85%) of 67 who stopped therapy did so after conversion to clinically definite multiple sclerosis. Fewer patients developed clinically definite multiple sclerosis in the interferon group than in the placebo group (52/154 [34%] vs 69/154 [45%]; p=0.047). The time at which 30% of patients had converted to clinically definite multiple sclerosis was 569 days in the interferon group and 252 in the placebo group (p=0.034). The annual relapse rates were 0.33 and 0.43 (p=0.045). The number of new T2-weighted MRI lesions and the increase in lesion burden were significantly lower with active treatment.Interpretation: Interferon beta-1a treatment at an early stage of multiple sclerosis had significant positive effects on clinical and MRI outcomes. [ABSTRACT FROM AUTHOR]

This paper retraces the early history of the European Journal of Neurology (EJN), as it is about to enter its 30th year. It describes how our discipline organized itself during the latter part of the 20th century in Europe. In some ways, the creation and the evolution of the journal parallel the process of unification of Europe in its current form in the late 1980s and early 1990s. It started as a new journal with no impact factor and no indexation. It grew progressively thanks to the support of the European Federation of Neurological Societies (EFNS) and from the European scientific community The progressive merging of EFNS with the European Society of Neurology and the creation of the European Academy of Neurology were essential for reaching the current prominence of EJN within neurological publishing and for making it the widely heard official voice of European neurology., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

It remains elusive whether lesions and inflammation in the sub/juxtacortical white matter reflect cortical and/or meningeal pathologies. Elucidating this could have implications for MRI monitoring as sub/juxtacortical lesions are detectable by routine MRI, while cortical lesions and meningeal inflammation are not. By large-area microscopy, we quantified total and mixed active plaque loads along with densities and sizes of perivascular mononuclear infiltrates (infiltrates) in the sub/juxtacortical white matter ≤2 mm from the cortex, intra-cortically and in the meninges. Data were related to ante-mortem clinical parameters in a false discovery rate-corrected analysis. We compared 12 patients with primary progressive multiple sclerosis (PPMS) and 15 with secondary progressive MS to 22 controls. Fifteen patients and 11 controls contributed with hemispheric sections. Sections were stained with haematoxylin-eosin, for myelin and for microglia/macrophages. B cells and T cells were confirmed in a subset. Immunoglobulin G depositions in selected cortical plaques resembled depositions described before in "slowly expanding" plaques in the white matter. We quantified plaque activity by measuring microglia-dominated and macrophage-dominated areas. Sub/juxtacortical plaques (load and activity) reflected plaque activity in the cerebral cortex. Plaque activity and infiltrates were more pronounced in the sub/juxtacortical white matter than in the cerebral cortex while conversely, the total plaque load was highest in the cortex. Infiltrates correlated trans-cortically and sub/juxtacortical plaque activity reflected cortical and meningeal infiltrates. Sub/juxtacortical infiltrate sizes correlated with shorter survival after progression onset. Two patients with PPMS and putatively fatal brain stem lesions argue against incidental findings. Trans-cortical inflammatory flares and plaque activity may be pathogenic in progressive MS. We suggest emphasis on sub/juxtacortical MRI lesions as plausible surrogates for cortical and meningeal pathologies and, when present, as indicators for cognitive testing., (© 2024 The Author(s). Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Torben Fog was committed to multiple sclerosis (MS) research for more than four decades, starting before the defence of his thesis in 1948 and lasting until his death in 1987. His research was multi-facetted, making him one of the great pioneers in the study of essential parts of the pathology, immunology and treatment of MS. He has contributed with meticulous studies of the MS plaques, documenting the perivenous distribution of plaques in the spinal cord. He constructed a scoring system for the disability in MS and used a computer programme to calculate a total neurological deficit. Together with his co-workers, Fog in 1972 was the first to report the association between MS and the human leukocyte antigen system. Fog can be considered as the father of immunomodulatory therapy in MS, treating MS patients with the first transfer factor, and as early as 1980, he was the first to treat MS with intramuscular natural interferon., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: P. S. Sørensen has received personal compensation for consultations, serving on scientific advisory boards, steering committees, independent data-monitoring committees or have received honoraria as speaker from Merck, Novartis and TEVA. S. Bramow has received personal compensations from Biogen Denmark, Merck Denmark and Novartis Denmark for educational activities and received congress travel support from Novartis Denmark. M. Magyari has served in the scientific advisory board for Sanofi, Novartis and Merck and has received honoraria for lecturing from Biogen, Merck, Novartis, Roche, Genzyme and Bristol Myers Squibb. L. Werdelin has nothing to declare. N. Koch-Henriksen has nothing to declare. P. Vermersch has received honoraria and congress travel support from Biogen, Sanofi Genzyme, Novartis, Teva, Merck, Roche, Imcyse, AB Science, Janssen and BMS-Celgene and research supports from Novartis, Sanofi Genzyme and Merck. F. Sellebjerg has served on scientific advisory boards, served as a consultant, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Lundbeck, Merck, Novartis, Roche and Sanofi Genzyme. His laboratory has received research support from Biogen, Merck, Novartis, Roche and Sanofi Genzyme.

Background: Estimating the effect of disease-modifying treatment of MS in observational studies is impaired by bias from unmeasured confounders, in particular indication bias., Objective: To show how instrumental variables (IVs) reduce bias., Methods: All patients with relapsing onset of MS 1996-2010, identified by the nationwide Danish Multiple Sclerosis Registry, were followed from onset. Exposure was treatment index throughout the first 12 years from onset, defined as a cumulative function of months without and with medium- or high-efficacy treatment, and outcomes were hazard ratios (HRs) per unit treatment index for sustained Expanded Disability Scale Score (EDSS) 4 and 6 adjusted for age at onset and sex, without and with an IV. We used the onset cohort (1996-2000; 2001-2005; 2006-2010) as an IV because treatment index increased across the cohorts., Results: We included 6014 patients. With conventional Cox regression, HRs for EDSS 4 and 6 were 1.15 [95% CI: 1.13-1.18] and 1.17 [1.13-1.20] per unit treatment index. Only with IVs, we confirmed a beneficial effect of treatment with HRs of 0.86 [0.81-0.91] and 0.82 [0.74-0.90]., Conclusion: The use of IVs eliminates indication bias and confirms that treatment is effective in delaying disability. IVs could, under some circumstances, be an alternative to marginal structural models., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: N.K.-H. did not declare any competing interests. L.C.T did not declare any competing interests. M.M. has served in scientific advisory board for Sanofi, Novartis, and Merck and has received honoraria for lecturing from Biogen, Merck, Novartis, Roche, Genzyme, and Bristol Myers Squibb. P.S.S. has received personal compensation for serving on advisory boards for Biogen, Merck, Novartis, and Teva; was on steering committees or independent data monitoring boards in trials sponsored by Merck and Novartis; and has received speaker honoraria from Biogen, Merck, Teva, BMS/Celgene, and Novartis. No other disclosures were reported.

Background: Autologous hematopoietic stem cell treatment (AHSCT) is considered an effective treatment option for patients with aggressive relapsing-remitting multiple sclerosis (RRMS). Still there are few randomized and controlled studies of AHSCT to shed light on the safety and efficacy of the treatment, and therefore experiences from single centers are important., Aim: To describe the Danish experience with AHSCT regarding patient characteristics, safety, and efficacy., Method: Nationwide retrospective single center study of patients with multiple sclerosis (MS) treated with AHSCT., Results: A total of 32 patients were treated with AHSCT from May 2011 to May 2021. Seven were treated with carmustine, etoposide, cytarabine arabinoside, and melphalan (BEAM) as well as antithymocyte globulin (ATG). Twenty-five patients were treated with cyclophosphamide (CY) and ATG. In the whole cohort, relapse-free survival (RFS) was 77% (95% CI: 64-94%), worsening-free survival (WFS) was 79% (95% CI: 66-96%), MRI event-free survival (MFS) was 93% (95% CI: 85-100%), and no evidence of disease (NEDA-3) was 69% (95% CI: 54-89%) at the end of year two post-AHSCT. We had no treatment related mortality and only few severe adverse events (AEs)., Conclusion: AHSCT of patients with aggressive RRMS was an effective and relatively safe treatment with few serious AEs and no mortality in Danish patients., Competing Interests: Declaration of Competing Interest F. Jespersen has nothing to disclose. S. L. Petersen has served on scientific advisory boards for Janssen-Cilag and Novartis. P. Andersen has nothing to disclose. F. Sellebjerg has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, H. Lundbeck A/S, Merck, Novartis, Roche and Sanofi Genzyme. His-laboratory has received research support from Biogen, Merck, Novartis, Roche and Sanofi Genzyme. M. Magyari has served in scientific advisory board for Sanofi, Novartis, Merck, and has received honoraria for lecturing from Biogen, Merck, Novartis, Roche, Genzyme, Bristol Myers Squibb. P. S. Sørensen has received personal compensation for serving on scientific advisory boards, steering committees, independent data monitoring committees or have received speaker honoraria for Biogen, Merck, Novartis, TEVA and Celgene/BMS. M. Blinkenberg reports personal fees from Biogen, Sanofi Genzyme, Biogen, Merck, Novartis, Bristol-Myers Squibb, Roche and non-financial support from Biogen, Roche and Sanofi Genzyme., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The aim of this study was to investigate the feasibility of automatically assessing the 2-Minute Walk Distance (2MWD) for monitoring people with multiple sclerosis (pwMS). For 154 pwMS, MS-related clinical outcomes as well as the 2MWDs as evaluated by clinicians and derived from accelerometer data were collected from a total of 323 periodic clinical visits. Accelerometer data from a wearable device during 100 home-based 2MWD assessments were also acquired. The error in estimating the 2MWD was validated for walk tests performed at hospital, and then the correlation (r) between clinical outcomes and home-based 2MWD assessments was evaluated. Robust performance in estimating the 2MWD from the wearable device was obtained, yielding an error of less than 10% in about two-thirds of clinical visits. Correlation analysis showed that there is a strong association between the actual and the estimated 2MWD obtained either at hospital (r = 0.71) or at home (r = 0.58). Furthermore, the estimated 2MWD exhibits moderate-to-strong correlation with various MS-related clinical outcomes, including disability and fatigue severity scores. Automatic assessment of the 2MWD in pwMS is feasible with the usage of a consumer-friendly wearable device in clinical and non-clinical settings. Wearable devices can also enhance the assessment of MS-related clinical outcomes.

Background: Natalizumab is a widely used high-efficacy treatment in multiple sclerosis (MS). Real-world evidence regarding long-term effectiveness and safety is warranted. We performed a nationwide study evaluating prescription patterns, effectiveness, and adverse events., Methods: A nationwide cohort study using the Danish MS Registry. Patients initiating natalizumab between June 2006 and April 2020 were included. Patient characteristics, annualized relapse rates (ARRs), confirmed Expanded Disability Status Scale (EDSS) score worsening, MRI activity (new/enlarging T2- or gadolinium-enhancing lesions), and reported adverse events were evaluated. Further, prescription patterns and outcomes across different time periods ("epochs") were analysed., Results: In total, 2424 patients were enrolled, with a median follow-up time of 2.7 years (interquartile range (IQR) 1.2-5.1). In recent epochs, patients were younger, had lower EDSS scores, had fewer pre-treatment relapses and were more often treatment naïve. At 13 years of follow-up, 36% had a confirmed EDSS worsening. On-treatment ARR was 0.30, corresponding to a 72% reduction from pre-initiation. MRI activity was rare, 6.8% had activity within 2-14 months from treatment start, 3.4% within 14-26 months, and 2.7% within 26-38 months. Approximately 14% of patients reported adverse events, with cephalalgia constituting the majority. During the study, 62.3% discontinued treatment. Of these, the main cause (41%) was due to JCV antibodies, while discontinuations due to disease activity (9%) or adverse events (9%) were less frequent., Conclusion: Natalizumab is increasingly used earlier in the disease course. Most patients treated with natalizumab are clinically stable with few adverse events. JCV antibodies constitute the main cause for discontinuation., Competing Interests: Declaration of Competing Interest MD Buron has received speaker honoraria from Novartis. F Sellebjerg has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, H. Lundbeck A/S, Merck, Novartis, Roche and Sanofi Genzyme. His laboratory has received research support from , Merck, Novartis, Roche and Sanofi Genzyme. M Magyari has served in scientific advisory board for Sanofi, Novartis, Merck, and has received honoraria for lecturing from Biogen, Merck, Novartis, Roche, Genzyme, Bristol Myers Squibb. J Romme Christensen has received speaker honoraria from Biogen. PV. Rasmussen has received speaker honoraria from TEVA, Biogen, Roche and Novartis, support for congress participation from Merck, Roche, Sanofi and TEVA, fees for serving on advisory boards from Merck, Roche, Novartis, Biogen, and Sanofi. PS. Sorensen has received personal compensation for serving on advisory boards for Biogen, Merck, Novartis, Teva; on steering committees or independent data monitoring boards in trials sponsored by Merck, and Novartis; and has received speaker honoraria from Biogen, Merck, Teva, BMS/Celgene, and Novartis. H Joensen, M Kant, D Bech and L Pontieri report no disclosures, (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to evaluate the association between changes in the autonomic control of cardiorespiratory system induced by walk tests and outcome measures in people with Multiple Sclerosis (pwMS). Methods: Electrocardiogram (ECG) recordings of 148 people with Relapsing-Remitting MS (RRMS) and 58 with Secondary Progressive MS (SPMS) were acquired using a wearable device before, during, and after walk test performance from a total of 386 periodical clinical visits. A subset of 90 participants repeated a walk test at home. Various MS-related symptoms, including fatigue, disability, and walking capacity were evaluated at each clinical visit, while heart rate variability (HRV) and ECG-derived respiration (EDR) were analyzed to assess autonomic nervous system (ANS) function. Statistical tests were conducted to assess differences in ANS control between pwMS grouped based on the phenotype or the severity of MS-related symptoms. Furthermore, correlation coefficients ( r ) were calculated to assess the association between the most significant ANS parameters and MS-outcome measures. Results: People with SPMS, compared to RRMS, reached higher mean heart rate (HRM) values during walk test, and larger sympathovagal balance after test performance. Furthermore, pwMS who were able to adjust their HRM and ventilatory values, such as respiratory rate and standard deviation of the ECG-derived respiration, were associated with better clinical outcomes. Correlation analyses showed weak associations between ANS parameters and clinical outcomes when the Multiple Sclerosis phenotype is not taken into account. Blunted autonomic response, in particular HRM reactivity, was related with worse walking capacity, yielding r = 0.36 r = 0.29 (RRMS) and r > 0.5 (SPMS). A positive strong correlation r > 0.7 r > 0.65 between cardiorespiratory parameters derived at hospital and at home was also found. Conclusion: Autonomic function, as measured by HRV, differs according to MS phenotype. Autonomic response to walk tests may be useful for assessing clinical outcomes, mainly in the progressive stage of MS. Participants with larger changes in HRM are able to walk longer distance, while reduced ventilatory function during and after walk test performance is associated with higher fatigue and disability severity scores. Monitoring of disorder severity could also be feasible using ECG-derived cardiac and respiratory parameters recorded with a wearable device at home., Competing Interests: MB has received speaker honoraria from Novartis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kontaxis, Laporta, Garcia, Guerrero, Zabalza, Matteo, Lucia, Simblett, Weyer, Hotopf, Narayan, Rashid, Folarin, Dobson, Buron, Leocani, Cummins, Vairavan, Costa, Magyari, Sørensen, Nos, Bailón, Comi and the RADAR-CNS Consortium.)

What Is This Summary About?: People with multiple sclerosis (shortened to MS) who are taking cladribine tablets may have concerns about whether they can be vaccinated against COVID-19. This summary details the findings from a previously published article, in which an international committee of 10 MS experts developed recommendations to answer some important questions about COVID-19 vaccines in people with MS (including relapsing-remitting or active secondary progressive disease) taking cladribine tablets., What Were the Results?: The committee identified 13 recommendations, which were all agreed upon by at least three-quarters (75%) of the 38 voting MS experts. Generally, they recommended that people with MS taking cladribine tablets should be vaccinated for COVID-19 as soon as possible, because the vaccine is thought to be both safe and effective, and vaccine responses were not likely to be affected by cladribine tablets., What Do the Results Mean?: Overall, people with MS taking cladribine tablets should receive the COVID-19 vaccine to protect themselves, unless advised differently by their healthcare provider.

Background: Multiple sclerosis is a chronic immune-mediated disease of the brain and spinal cord resulting in physical and cognitive impairment in young adults. It is hypothesized that a disrupted bacterial and viral gut microbiota is a part of the pathogenesis mediating disease impact through an altered gut microbiota-brain axis. The aim of this study is to explore the characteristics of gut microbiota in multiple sclerosis and to associate it with disease variables, as the etiology of the disease remains only partially known., Methods: Here, in a case-control setting involving 148 Danish cases with multiple sclerosis and 148 matched healthy control subjects, we performed shotgun sequencing of fecal microbial DNA and associated bacterial and viral microbiota findings with plasma cytokines, blood cell gene expression profiles, and disease activity., Results: We found 61 bacterial species that were differentially abundant when comparing all multiple sclerosis cases with healthy controls, among which 31 species were enriched in cases. A cluster of inflammation markers composed of blood leukocytes, CRP, and blood cell gene expression of IL17A and IL6 was positively associated with a cluster of multiple sclerosis-related species. Bacterial species that were more abundant in cases with disease-active treatment-naïve multiple sclerosis were positively linked to a group of plasma cytokines including IL-22, IL-17A, IFN-β, IL-33, and TNF-α. The bacterial species richness of treatment-naïve multiple sclerosis cases was associated with number of relapses over a follow-up period of 2 years. However, in non-disease-active cases, we identified two bacterial species, Faecalibacterium prausnitzii and Gordonibacter urolithinfaciens, whose absolute abundance was enriched. These bacteria are known to produce anti-inflammatory metabolites including butyrate and urolithin. In addition, cases with multiple sclerosis had a higher viral species diversity and a higher abundance of Caudovirales bacteriophages., Conclusions: Considerable aberrations are present in the gut microbiota of patients with multiple sclerosis that are directly associated with blood biomarkers of inflammation, and in treatment-naïve cases bacterial richness is positively associated with disease activity. Yet, the finding of two symbiotic bacterial species in non-disease-active cases that produce favorable immune-modulating compounds provides a rationale for testing these bacteria as adjunct therapeutics in future clinical trials., (© 2022. The Author(s).)

Background: Over the decades, several natural history studies on patients with primary (PPMS) or secondary progressive multiple sclerosis (SPMS) were reported from international registries. In PPMS, a consistent heterogeneity on long-term disability trajectories was demonstrated. The aim of this study was to identify subgroups of patients with SPMS with similar longitudinal trajectories of disability over time., Methods: All patients with MS collected within Big MS registries who received an SPMS diagnosis from physicians (cohort 1) or satisfied the Lorscheider criteria (cohort 2) were considered. Longitudinal Expanded Disability Status Scale (EDSS) scores were modelled by a latent class growth analysis (LCGA), using a non-linear function of time from the first EDSS visit in the range 3-4., Results: A total of 3613 patients with SPMS were included in the cohort 1. LCGA detected three different subgroups of patients with a mild (n=1297; 35.9%), a moderate (n=1936; 53.6%) and a severe (n=380; 10.5%) disability trajectory. Median time to EDSS 6 was 12.1, 5.0 and 1.7 years, for the three groups, respectively; the probability to reach EDSS 6 at 8 years was 14.4%, 78.4% and 98.3%, respectively. Similar results were found among 7613 patients satisfying the Lorscheider criteria., Conclusions: Contrary to previous interpretations, patients with SPMS progress at greatly different rates. Our identification of distinct trajectories can guide better patient selection in future phase 3 SPMS clinical trials. Additionally, distinct trajectories could reflect heterogeneous pathological mechanisms of progression., Competing Interests: Competing interests: AS received research support from MSBase. JL received research support from Innosuisse—Swiss Innovation Agency, Biogen and Novartis; he served on advisory boards for Biogen, Novartis, Roche and Teva. SV received consulting and lecture fees, travel grants and research support from Biogen, Celgene, Genentech, Genzyme, Medday Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Aventis and Teva Pharma. MT has served on scientific advisory boards for Biogen, Novartis, Roche and Genzyme; has received speaker honoraria and travel support from Biogen Idec, Sanofi-Aventis, Merck Serono, Teva, Genzyme and Novartis; and has received research grants for her institution from Biogen Idec, Merck Serono and Novartis. JH has received honoraria for serving on advisory boards for Biogen, Sanofi-Genzyme and Novartis; and speaker’s fees from Biogen, Novartis, Merck Serono, Bayer-Schering, Teva and Sanofi-Genzyme. He has served as PI for projects or received unrestricted research support from Biogen Idec, Merck Serono, TEVA, Sanofi-Genzyme and Bayer-Schering; his MS research is funded by the Swedish Research Council and the Swedish Brain Foundation. RH is an employee of Biogen and holds a stock. FP is an employee of Biogen. MM has served on scientific advisory board for Biogen Idec and Teva; and has received honoraria for lecturing from Biogen Idec, Merck Serono, Sanofi-Aventis and Teva. NK-H has received honoraria for lecturing and participating in advisory councils, travel expenses for attending congresses and meetings, and financial support for monitoring the Danish Multiple Sclerosis Treatment Register from Bayer-Schering, Merck Serono, Biogen Idec, Teva, Sanofi-Aventis and Novartis. PSS has served on scientific advisory boards for Merck Serono, Teva, Novartis, Sanofi-Aventis and Biogen Idec; has received research support from Biogen Idec, Novartis and Sanofi-Aventis; and received speaker honoraria from Merck Serono, Novartis, Teva, Sanofi-Aventis, Biogen Idec and Genzyme. TS received compensation for serving on scientific advisory boards, honoraria for consultancy and funding for travel from Biogen; and speaker honoraria from Novartis. AvdW reported receiving grants from National Health and Medical Research Council (NHMRC), Novartis, Roche and MS Research Australia; and personal fees from Biogen, Merck, Novartis and Roche. DH received compensation for travel, speaker honoraria and consultant fees from Biogen, Novartis, Merck Healthcare (Darmstadt, Germany), Bayer, Sanofi, Roche and Teva, as well as support for research activities from Biogen. She was also supported by the Charles University: Cooperation Program in neuroscience. EH received honoraria/research support from Biogen, Merck Serono, Novars, Roche and Teva; has been a member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novars and Sanofi Genzyme. MG received consulting fees from Teva Canada Innovation, Biogen, Novartis and Genzyme Sanofi; and lecture payments from Teva Canada Innovation, Novartis and EMD. He has also received a research grant from Canadian Institutes of Health Research. SE received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche and Teva. FG received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, Mitsubishi and ONO Pharmaceuticals. OG has nothing to disclose. MT received travel grants from Novartis, Bayer-Schering, Merck and Teva; and has participated in clinical trials by Sanofi Aventis, Roche and Novartis. SO has nothing to disclose. OS has received honoraria and consulting fees from Bayer Schering, Novartis, Merck, Biogen and Genzyme companies. VVP received travel grants from Merck Healthcare (Darmstadt, Germany), Biogen, Sanofi, Bristol Meyer Squibb, Almirall and Roche. His institution has received research grants and consultancy fees from Roche, Biogen, Sanofi, Merck Healthcare (Darmstadt, Germany), Bristol Meyer Squibb, Janssen, Almirall and Novartis Pharma. MJS received consulting fees, speaker honoraria, and/or travel expenses for scientific meetings from Alexion, Bayer Healthcare, Biogen, Bristol Myers Squibb, Celgene, Janssen, Merck-Serono, Novartis, Roche, Sanofi and Teva. JP accepted travel compensation from Novartis, Biogen, Genzyme and Teva; and speaking honoraria from Biogen, Novartis, Genzyme and Teva. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme. PAM received speakers fees and travel grants from Novartis, Biogen, T’évalua and Sanofi. RG has nothing to disclose. SM has received a MENACTRIMS clinical fellowship grant (2020). TC-T received speaking/consulting fees and/or travel funding from Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. CZ has nothing to disclose. KdG has nothing to disclose. JLS-M accepted travel compensation from Novartis, Merck and Biogen; speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva; and has participated in clinical trials by Biogen, Merck and Roche. BY and SK have nothing to disclose. MPS has received consulting fees from Biogen, Merck, Teva, Genzyme, Roche, Novartis, GeNeuro and MedDay. TK reported receiving grants from MS Research Australia and grants, personal fees and non-financial support from Biogen; personal fees and non-financial support from Sanofi Genzyme and Merck; personal fees from Roche, Novartis, WebMD Global, Teva and BioCSL; and grants from NHMRC, MS Research Australia, ARSEP-OFSEP, UK MS Society and Medical Research Future Fund. HB’s institution (Monash University) received compensation for consulting, talks, and advisory/steering board activities from Alfred Health, Biogen, Merck, Novartis, Roche and UCB pharma; research support from Biogen, Merck, Roche, MS Australia, National Health and Medical Research (Australia) and the Medical Research Future Fund (Australia), the Pennycook Foundation, Novartis and Roche. He has received personal compensation for steering group activities from Oxford Health Policy Forum., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Changes in lifestyle, finances and work status during COVID-19 lockdowns may have led to biopsychosocial changes in people with pre-existing vulnerabilities such as Major Depressive Disorders (MDDs) and Multiple Sclerosis (MS)., Methods: Data were collected as a part of the RADAR-CNS (Remote Assessment of Disease and Relapse-Central Nervous System) program. We analyzed the following data from long-term participants in a decentralized multinational study: symptoms of depression, heart rate (HR) during the day and night; social activity; sedentary state, steps and physical activity of varying intensity. Linear mixed-effects regression analyses with repeated measures were fitted to assess the changes among three time periods (pre, during and post-lockdown) across the groups, adjusting for depression severity before the pandemic and gender., Results: Participants with MDDs (N = 255) and MS (N = 214) were included in the analyses. Overall, depressive symptoms remained stable across the three periods in both groups. A lower mean HR and HR variation were observed between pre and during lockdown during the day for MDDs and during the night for MS. HR variation during rest periods also decreased between pre- and post-lockdown in both clinical conditions. We observed a reduction in physical activity for MDDs and MS upon the introduction of lockdowns. The group with MDDs exhibited a net increase in social interaction via social network apps over the three periods., Conclusions: Behavioral responses to the lockdown measured by social activity, physical activity and HR may reflect changes in stress in people with MDDs and MS. Remote technology monitoring might promptly activate an early warning of physical and social alterations in these stressful situations. Future studies must explore how stress does or does not impact depression severity.

Background and Objectives: Multiple sclerosis (MS) is a progressive inflammatory and neurodegenerative disease of the central nervous system affecting over 2.5 million people globally. In-clinic six-minute walk test (6MWT) is a widely used objective measure to evaluate the progression of MS. Yet, it has limitations such as the need for a clinical visit and a proper walkway. The widespread use of wearable devices capable of depicting patients' activity profiles has the potential to assess the level of MS-induced disability in free-living conditions., Methods: In this work, we extracted 96 features in different temporal granularities (from minute-level to day-level) from wearable data and explored their utility in estimating 6MWT scores in a European (Italy, Spain, and Denmark) MS cohort of 337 participants over an average of 10 months' duration. We combined these features with participants' demographics using three regression models including elastic net, gradient boosted trees and random forest. In addition, we quantified the individual feature's contribution using feature importance in these regression models, linear mixed-effects models, generalized estimating equations, and correlation-based feature selection (CFS)., Results: The results showed promising estimation performance with R 2 of 0.30, which was derived using random forest after CFS. This model was able to distinguish the participants with low disability from those with high disability. Furthermore, we observed that the minute-level (≤ 8 minutes) step count, particularly those capturing the upper end of the step count distribution, had a stronger association with 6MWT. The use of a walking aid was indicative of ambulatory function measured through 6MWT., Conclusions: This study demonstrates the utility of wearables devices in assessing ambulatory impairments in people with MS in free-living conditions and provides a basis for future investigation into the clinical relevance., Competing Interests: Declaration of Competing Interest SV and VAN are employees of Janssen Research and Development LLC. MM has served in scientific advisory board for Sanofi, Novartis, Merck, and has received honoraria for lecturing from Biogen, Merck, Novartis, Roche, Genzyme, Bristol Myers Squibb., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Constipation is a prevalent gastrointestinal complication in diabetes. The pathophysiology may include neural dysfunction and impaired gastrocolic reflex; however, investigation of the latter has been limited in diabetes. Using the wireless motility capsule, we investigated whether the gastrocolic reflex was impaired in adults with type 1 diabetes compared to healthy., Methods: One hundred and four adults with type 1 diabetes underwent investigation with the wireless motility capsule and recorded sleep cycle, eating habits, and bowel movements in a diary. Colonic motility index, contraction amplitudes, time-to-peak, peak motility, and colonic transit time were investigated directly in response to a meal. Diagnosis of peripheral (nerve conduction) and autonomic (orthostatic hypotension) polyneuropathy was verified., Results: In comparison with health, people with diabetes had at the time of ingestion decreased motility index and contraction amplitudes (p < 0.001), prolonged time-to-peak (p = 0.01), and borderline decreased peak motility (p = 0.06), which taken together indicate impaired coordination of the gastrocolic reflex. These features were most prominent in those with concomitant peripheral or autonomic neuropathy. Additionally, they were associated with prolonged colonic transit time (p > 0.01)., Conclusions: In type 1 diabetes, the gastrocolic reflex was delayed and diminished and further associated with the presence of neuropathy and constipation. These results suggest that impaired reflex is part of the underlying pathogenesis in the development of constipation., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study proposes a contrastive convolutional auto-encoder (contrastive CAE), a combined architecture of an auto-encoder and contrastive loss, to identify individuals with suspected COVID-19 infection using heart-rate data from participants with multiple sclerosis (MS) in the ongoing RADAR-CNS mHealth research project. Heart-rate data was remotely collected using a Fitbit wristband. COVID-19 infection was either confirmed through a positive swab test, or inferred through a self-reported set of recognised symptoms of the virus. The contrastive CAE outperforms a conventional convolutional neural network (CNN), a long short-term memory (LSTM) model, and a convolutional auto-encoder without contrastive loss (CAE). On a test set of 19 participants with MS with reported symptoms of COVID-19, each one paired with a participant with MS with no COVID-19 symptoms, the contrastive CAE achieves an unweighted average recall of 95.3 % , a sensitivity of 100 % and a specificity of 90.6 % , an area under the receiver operating characteristic curve (AUC-ROC) of 0.944, indicating a maximum successful detection of symptoms in the given heart rate measurement period, whilst at the same time keeping a low false alarm rate., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Elsevier Ltd. All rights reserved.)

Background: Gaps in current evidence and guidance leave clinicians with unanswered questions on the use of cladribine tablets for the treatment of multiple sclerosis (MS) in the era of the COVID-19 pandemic, in particular relating to COVID-19 vaccination., Objective: We describe a consensus-based program led by international MS experts with the aim of supplementing current guidelines and treatment labels by providing timely recommendations relating to COVID-19 vaccination and the use of cladribine tablets in clinical practice., Methods: A steering committee (SC) of 10 international MS experts identified 7 clinical questions to answer concerning the use of cladribine tablets and COVID-19 vaccination, which addressed issues relating to patient selection, timing and efficacy, and safety. Clinical recommendations to address each question were drafted using available evidence combined with expert opinion from the SC. An extended faculty of 28 MS experts, representing 19 countries, in addition to the 10 SC members, voted on the recommendations. Consensus on recommendations was achieved when ⩾75% of respondents expressed an agreement score of 7-9, on a 9-point scale., Results: Consensus was achieved on all 13 recommendations. Clinical recommendations are provided on whether all patients with MS receiving cladribine tablets should be vaccinated against COVID-19, and whether they should be prioritized; the timing of vaccination around dosing of cladribine tablets (i.e. before and after a treatment course); and the safety of COVID-19 vaccination for these patients., Conclusion: These expert recommendations provide timely guidance on COVID-19 vaccination in patients receiving cladribine tablets, which is relevant to everyday clinical practice., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: P.R. has received honoraria for lectures/steering committee meetings from Merck KGaA (Darmstadt, Germany), Biogen Idec, Bayer Schering Pharma, Boehringer-Ingelheim, Sanofi-Aventis, Genzyme, Novartis, Teva Pharmaceutical Industries, and Serono Symposia International Foundation. D.C. is an advisory board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva; and has received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck KGaA (Darmstadt, Germany), Mitsubishi, Novartis, Roche, Sanofi-Genzyme, and Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. G.G. has received speaker honoraria and consulting fees from AbbVie, Actelion, Atara Bio, Almirall, Bayer Schering Pharma, Biogen Idec, FivePrime, GlaxoSmithKline, GW Pharmaceuticals, Merck & Co., Merck KGaA (Darmstadt, Germany), Pfizer Inc, Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd, Sanofi-Genzyme, UCB, Vertex Pharmaceuticals, Ironwood, and Novartis; and has received research support unrelated to this study from Biogen Idec, Merck & Co., Novartis, and Ironwood. L.H.H. has received speaking and consulting fees from Biogen, Genzyme, Genentech, Novartis, Bristol Myers Squibb, and EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany). CO-G has received speaker and consulting fees from Biogen, Celgene, Merck KGaA (Darmstadt, Germany), Novartis, Roche, Sanofi-Genzyme, and Teva. D.S. has received grants and/or personal fees from Teva, Merck KGaA (Darmstadt, Germany), Novartis, Roche, Genzyme, Sanofi-Genzyme, Biogen Inc., and Bayer HealthCare. P.S.S. has served on advisory boards for Biogen, Merck Healthcare KGaA (Darmstadt, Germany), Novartis, Teva, MedDay Pharmaceuticals, and GSK; on steering committees or independent data monitoring boards in trials sponsored by Merck KGaA (Darmstadt, Germany), Teva, GSK, and Novartis; and has received speaker honoraria from Biogen Idec, Merck KGaA (Darmstadt, Germany), Teva, Sanofi-Aventis, Genzyme, Celgene, and Novartis. His department has received research support from Biogen, Merck KGaA (Darmstadt, Germany), Teva, Novartis, Roche, and Genzyme. P.V. has received honoraria or consulting fees from Biogen, Sanofi-Genzyme, Servier, Novartis, Merck KGaA (Darmstadt, Germany), Celgene, Roche, MedDay, and Almirall; and research support from Biogen, Sanofi-Genzyme, Bayer, and Merck KGaA (Darmstadt, Germany). H.W. is a member of scientific advisory boards/steering committees for Bayer Healthcare, Biogen Idec, Sanofi-Genzyme, Merck KGaA (Darmstadt, Germany), Novartis, Roche, and Teva. He received speaker honoraria and travel support from Bayer Vital GmbH, Bayer Schering AG, Biogen, CSL Behring, EMD Serono, Fresenius Medical Care, Genzyme, Merck KGaA (Darmstadt, Germany), Omniamed, Novartis, Sanofi-Aventis, and Teva. He received compensation as a consultant from Biogen Idec, Merck KGaA (Darmstadt, Germany), Novartis, Omniamed, Roche, and Sanofi-Genzyme. He has received research supports from Bayer Healthcare, Bayer Vital, Biogen Idec, Merck KGaA (Darmstadt, Germany), Novartis, Sanofi-Genzyme, Sanofi US, and Teva as well as German Ministry for Education and Research (BMBF), German Research Foundation (DFG), Else Kröner Fresenius Foundation, Fresenius Foundation, Hertie Foundation, Merck KGaA (Darmstadt, Germany), Novartis, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (ISKF) Muenster, and RE Children’s Foundation. H.S. is an employee of Ares Trading SA, Eysins, Switzerland (an affiliate of Merck KGaA Darmstadt, Germany). B.Y. has received honoraria for lectures and advisory boards from Bayer, Biogen, Genpharm, Genzyme, Merck KGaA (Darmstadt, Germany), and Novartis; and has received research grants from Bayer, Biogen, Merck KGaA (Darmstadt, Germany), Novartis, and Pfizer., (© The Author(s), 2021.)

Background: The relative cardiovascular safety of gonadotropin-releasing hormone (GnRH) antagonists compared with GnRH agonists in men with prostate cancer and known atherosclerotic cardiovascular disease remains controversial., Methods: In this international, multicenter, prospective, randomized, open-label trial, men with prostate cancer and concomitant atherosclerotic cardiovascular disease were randomly assigned 1:1 to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide for 12 months. The primary outcome was the time to first adjudicated major adverse cardiovascular event (composite of death, myocardial infarction, or stroke) through 12 months., Results: Because of slower-than-projected enrollment and fewer-than-projected primary outcome events, enrollment was stopped before the 900 planned participants were accrued. From May 3, 2016, to April 16, 2020, a total of 545 patients from 113 sites across 12 countries were randomly selected. Baseline characteristics were balanced between study groups. The median age was 73 years, 49.8% had localized prostate cancer; 26.3% had locally advanced disease, and 20.4% had metastatic disease. A major adverse cardiovascular event occurred in 15 (5.5%) patients assigned to degarelix and 11 (4.1%) patients assigned to leuprolide (hazard ratio, 1.28 [95% CI, 0.59-2.79]; P =0.53)., Conclusions: PRONOUNCE (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease) is the first, international, randomized clinical trial to prospectively compare the cardiovascular safety of a GnRH antagonist and a GnRH agonist in patients with prostate cancer. The study was terminated prematurely because of the smaller than planned number of participants and events, and no difference in major adverse cardiovascular events at 1 year between patients assigned to degarelix or leuprolide was observed. The relative cardiovascular safety of GnRH antagonists and agonists remains unresolved. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02663908.