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Introduction: Patients with multiple sclerosis (MS) have complex needs that range from organising one's everyday life to measures of disease-specific therapy monitoring to palliative care. Patients with MS are likely to depend on multiple healthcare providers and various authorities, which are often difficult to coordinate. Thus, they will probably benefit from comprehensive cross-sectoral coordination of services provided by care and case management (CCM). Though studies have shown that case management improves quality of life (QoL), functional status and reduces service use, such benefits have not yet been investigated in severely affected patients with MS. In this explorative phase ll clinical trial, we evaluated a CCM with long-term, cross-sectoral and outreaching services and, in addition, considered the unit of care (patients and caregivers)., Methods and Analysis: Eighty patients with MS and their caregivers will be randomly assigned to either the control (standard care) or the intervention group (standard care plus CCM (for 12 months)). Regular data assessments will be done at baseline and then at 3-month intervals. As primary outcome, we will evaluate patients' QoL. Secondary outcomes are patients' treatment-related risk perception, palliative care needs, anxiety/depression, use of healthcare services, caregivers' burden and QoL, meeting patients' and caregivers' needs, and evaluating the CCM intervention. We will also evaluate CCM through individual interviews and focus groups. The sample size calculation is based on a standardised effect of 0.5, and one baseline and four follow-up assessments (with correlation 0.5). Linear mixed models for repeated measures will be applied to analyse changes in quantitative outcomes over time. Multiple imputation approaches are taken to assess the robustness of the results. The explorative approach (phase ll clinical trial) with embedded qualitative research will allow for the development of a final design for a confirmative phase lll trial., Ethics and Dissemination: The trial will be conducted under the Declaration of Helsinki and has been approved by the Ethics Commission of Cologne University's Faculty of Medicine. Trial results will be published in an open-access scientific journal and presented at conferences., Trial Registration Number: German Register for Clinical Studies (DRKS) (DRKS00022771)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, Switzerland)., (© 2021. The Author(s).)

Background: Alemtuzumab is given as two annual courses. Patients with continued disease activity may receive as-needed additional courses., Objective: To evaluate efficacy and safety of additional alemtuzumab courses in the CARE-MS (Comparison of Alemtuzumab and Rebif ® Efficacy in Multiple Sclerosis) studies and their extensions., Methods: Subgroups were based on the number of additional alemtuzumab courses received. Exclusion criteria: other disease-modifying therapy (DMT); <12-month follow-up after last alemtuzumab course., Results: In the additional-courses groups, Courses 3 and 4 reduced annualized relapse rate (12 months before: 0.73 and 0.74, respectively; 12 months after: 0.07 and 0.08). For 36 months after Courses 3 and 4, 89% and 92% of patients were free of 6-month confirmed disability worsening, respectively, with 20% and 26% achieving 6-month confirmed disability improvement. Freedom from magnetic resonance imaging (MRI) disease activity increased after Courses 3 and 4 (12 months before: 43% and 53%, respectively; 12 months after: 73% and 74%). Safety was similar across groups; serious events occurred irrespective of the number of courses., Conclusion: Additional alemtuzumab courses significantly improved outcomes, without increased safety risks, in CARE-MS patients with continued disease activity after Course 2. How this compares to outcomes if treatment is switched to another DMT instead remains unknown.

Background: Accurate measurement of medication adherence using classical observational studies typically depends on patient self-reporting and is often costly and slow. In contrast, digital observational studies that collect data directly from the patient may pose minimal burden to patients while facilitating accurate, timely, and cost-efficient collection of real-world data. In Germany, ~80% of patients with multiple sclerosis (MS) treated with interferon beta 1b (Betaferon) use an electronic autoinjector (BETACONNECT), which automatically records every injection. Patients may also choose to use a medical app (myBETAapp) to document injection data and their well-being (using a "wellness tracker" feature)., Objective: The goal of this pilot study was to establish a digital study process that allows the collection of medication usage data and to assess medication usage among patients with MS treated with interferon beta-1b who use myBETAapp., Methods: The PROmyBETAapp digital observational study was a mixed prospective and retrospective, noninterventional, cohort study conducted among users of myBETAapp in Germany (as of December 2017: registered accounts N=1334; actively used accounts N=522). Between September and December 2017, users received two invitations on their app asking them to participate. Interested patients were provided detailed information and completed an electronic consent process. Data from consenting patients' devices were collected retrospectively starting from the first day of usage if historical data were available in the database and collected prospectively following consent attainment. In total, 6 months of data on medication usage behavior were collected along with 3 months of wellness tracker data. Descriptive statistics were used to analyze persistence, compliance, and adherence to therapy., Results: Of the 1334 registered accounts, 96 patients (7.2%) provided informed consent to participate in the study. Of these, one patient withdrew consent later. For another patient, injection data could not be recorded during the study period. Follow-up of the remaining 94 patients ended in May 2018. The mean age of participants was 46.6 years, and 50 (53%) were female. Over the 6-month study period, persistence with myBETAapp usage was 96% (90/94), mean compliance was 94% of injections completed, and adherence (persistence and ≥80% compliance) was 89% (84/94). There was no apparent difference between male and female participants and no trend across age groups. The wellness tracker was used by 21% of participants (20/94), with a mean of 3.1 entries per user., Conclusions: This study provides important information on medication usage among patients with MS treated with interferon beta-1b and on consenting behavior of patients in digital studies. In future studies, this approach may allow patients' feedback to be rapidly implemented in existing digital solutions., Trial Registration: ClinicalTrials.gov NCT03134573; https://clinicaltrials.gov/ct2/show/NCT03134573., (©Volker Limmroth, Klaus Hechenbichler, Christian Müller, Markus Schürks. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 29.07.2019.)

Adherence to long-term treatment in chronic diseases such as multiple sclerosis is challenging. Many disease-modifying drugs (DMDs) for MS need to be injected. Injection devices may improve satisfaction with the injection procedure and boost adherence. Meeting patients' needs in handling and design of autoinjectors and other supporting elements may be key to successful therapy. The BETACONNECT™ system is a platform-based approach in DMD therapy. It combines autoinjector technology with digital tools to support patient self-management and facilitate communication between patients and healthcare providers. Here, we describe the components of the BETACONNECT system and review data on patients' satisfaction with the BETACONNECT autoinjector and how it compares to other devices. Additionally, we present first data on patients' satisfaction with the myBETAapp™.

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.

Introduction: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system requiring long-term treatment, which is often hampered by non-adherence to self-applicable therapies, provoking continued disease activity and health care system burdens. This study assessed the influence of a personal digital assistant (PDA) with diary function (n = 339 patients) on persistence and adherence to an interferon beta treatment regimen in comparison to a paper patient diary (n = 330 patients)., Methods: Patients who recently started with subcutaneous injections of interferon beta-1b were recruited in this prospective, non-interventional, national cohort study for an observational period of 2 years after successful completion of the initial dose escalation., Results: Therapy persistence as assessed by the drop-out rate within 104 weeks was about 50% in both study cohorts. In male patients, the drop-out rate was 10% lower when using a PDA compared to the non-PDA group. Use of a PDA with an injection reminder function increased adherence to the injection schedule (every other day) by a mean of 24.5 injections over 24 months in comparison to use of a PDA without injection reminder function., Conclusion: Persistence in this study was in the published range of observational MS studies. Furthermore, in male patients continuation of therapy might be positively influenced by use of a PDA, and both female and male patients might benefit from an integrated reminder function. In conclusion, electronic diaries reminding patients of upcoming injections can promote an improved adherence to MS therapy., Trial Registration: ClinicalTrials.gov identifier: NCT00902135., Funding: Bayer Vital GmbH.

Genome-wide association studies (GWAS) successfully identified various chromosomal regions to be associated with multiple sclerosis (MS). The primary aim of this study was to replicate reported associations from GWAS using an exome array in a large German study. German MS cases (n = 4,476) and German controls (n = 5,714) were genotyped using the Illumina HumanExome v1-Chip. Genotype calling was performed with the Illumina Genome Studio(TM) Genotyping Module, followed by zCall. Single-nucleotide polymorphisms (SNPs) in seven regions outside the human leukocyte antigen (HLA) region showed genome-wide significant associations with MS (P values < 5 × 10(-8) ). These associations have been reported previously. In addition, SNPs in three previously reported regions outside the HLA region yielded P values < 10(-5) . The effect of nine SNPs in the HLA region remained (P < 10(-5) ) after adjustment for other significant SNPs in the HLA region. All of these findings have been reported before or are driven by known risk loci. In summary, findings from previous GWAS for MS could be successfully replicated. We conclude that the regions identified in previous GWAS are also associated in the German population. This reassures the need for detailed investigations of the functional mechanisms underlying the replicated associations., (© 2015 WILEY PERIODICALS, INC.)

Background: Disease modifying treatments (DMT) for MS such as interferon beta (IFNβ) have been shown to reduce the risk for disease progression. Therefore adherence to treatment is essential for treatment outcome.Here we want to evaluate if participation in a patient management program (PMP) improves adherence to DMT as well as health and cost outcomes associated with MS., Methods: In this open-label multicentre prospective observational study, German MS patients treated with once weekly intramuscular (IM) IFNβ-1a (Avonex), were offered participation in a PMP and followed for up to 12 months. The PMP included injection trainings, support and quarterly visits for up to 12 months after initiation of therapy. Utilisation of health care services was evaluated. The primary endpoint was to evaluate the direct and indirect cost associated with MS from payer, patient and societal perspective, in patients who participate in the PMP. Secondary endpoint was the clinical outcome in patients who participate in the PMP (differentiated in adherent versus non-adherent patients)., Results: In total 731 patients (mean age: 38.2, 73.7% female) were enrolled, 640 (88%) were observed for twelve months. After six months 34% of patients had participated in the PMP continuously and 21% temporarily; 39% had not participated. After twelve months, the proportions of participants were: 37% continuously and 19% temporarily; 40% had not participated. After 6 months, mean reduction in cost per patient in the participants group (€ 2151) was almost twice as high as the cost reduction amongst non-participants (€ 1131). After twelve months, the annual relapse rate was reduced by 58% compared to baseline in both the participant and non-participant groups., Conclusions: In a real-world-setting, participation in a patient management program was associated with improved medication adherence and lower total MS-related direct and indirect cost over time.

Background: Natalizumab for multiple sclerosis (MS) increases the risk of progressive multifocal leukoencephalopathy (PML)., Objective: We aimed to assess the effect of natalizumab on cellular composition and functional B cell parameters including patients with natalizumab-associated PML (n=37)., Methods: Cellular composition by flow cytometry, levels of immunoglobulin (Ig)G/IgM by immunonephelometry, and oligoclonal bands by isoelectric focusing were studied in blood and cerebrospinal fluid., Results: In MS patients treated with natalizumab without PML (n=59) the proportion of CD19+ B cells was higher in blood, but lower in cerebrospinal fluid compared with MS patients not treated with natalizumab (n=17). The CD4/CD8-ratio in cerebrospinal fluid was lower, and IgG and IgM levels as well as the IgG index dropped in longitudinal samples during natalizumab therapy. Oligoclonal bands persisted, but the total amount of the intrathecally produced IgG fraction, and the polyclonal intrathecal IgG reactivity to measles, rubella, and zoster declined. At the time of diagnosis of PML patients with natalizumab-associated PML had low total IgG levels in blood and cerebrospinal fluid., Conclusions: Natalizumab impacts B and T cell distribution and exerts an inhibitory effect on surrogates of B cell function in periphery and in cerebrospinal fluid, potentially contributing to the increased risk of developing PML., (© The Author(s), 2014.)

Introduction: IFNβ products and glatiramer acetate are established treatment first-line options in long-term disease-modifying therapy of multiple sclerosis (MS). These self-injectable medications are used once weekly to once daily. Injection-related issues are common patient-cited reasons for nonadherence. Autoinjectors have been shown to support long-term adherence to injectable medications. The ability to self-inject in MS patients has been associated with a reduced risk of missed injections and drug discontinuation, and a beneficial effect on patient independence., Areas Covered: The recently introduced easy-to-use prefilled once-weekly pen is a safe and effective device for intramuscular (IM) IFNβ-1a application and provides a convenient method for self-injection. We reviewed the available published evidence on the characteristics of this device. The once-weekly pen facilitates self-injection and was preferred over prefilled syringes by patients in a prospective open-label, multicenter Phase IIIb trial in MS patients who had been using IM IFNβ-1a in prefilled syringes., Expert Opinion: The simple and safe handling, shielded short needle, single-use disposable design and virtually painless injection by the device may contribute to adherence, quality of life and independence in patients using IM IFNβ-1a.

Background: Multiple sclerosis is a chronic, incurable, demyelinating disease that requires long-term treatment. Rates of non-adherence to prescribed therapy of up to 50% have been reported for chronic diseases. Strategies to improve treatment adherence are therefore of the utmost importance. This study will evaluate the effect of using electronic and paper diaries on treatment adherence to interferon beta-1b in patients with a first clinical isolated syndrome (CIS) or relapsing-remitting multiple sclerosis (RRMS). Here we report on the study design and results of baseline assessments., Methods: Patients were recruited into a prospective national multicenter cohort study for an observational period of 2 years. At the start of the study, patients opted to use a digital (DiD) or paper diary (PD) to document self-administered injections of interferon beta-1b. Adherence to treatment will be assessed on the dropout rate at the end of the observation period and on the regularity of injections every other day at 6-month intervals. Patient-related health outcomes will also be evaluated., Results: 700 patients with a mean age of 38.3 (SD 10.3) years and a mean duration of disease since diagnosis of 3.6 (SD 5.9) years were enrolled. 383 patients opted for the digital diary, 192 of which included an injection reminder. Significantly more male than female patients opted for the DiD. Only gender was identified as a factor influencing the decision for DiD or PD. Based on rating scales, a significantly higher proportion of women had depressive comorbidities at baseline., Conclusions: Demographic characteristics of the two cohorts were similar at baseline. More women chose a paper diary, and more had depression at baseline. These imbalances will be addressed in the analysis of the study as possible confounders influencing long-term treatment adherence in the digital and paper diary cohorts.

CD4+CD25+ regulatory T (T(reg)) cells play a major role in controlling autoimmunity by suppressing self-reactive T cells. Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system, where T cells are of major importance. T(reg) cell frequency and function are potential therapeutic targets of MS treatment. Mitoxantrone (MX) is a potent immunosuppressant for the treatment of active MS. We investigated the long-term effects of MX on the suppressive function of T(reg) after mitogen and myelin basic protein (MBP) stimulation in 20 MX-treated patients. MX therapy did not restore the reduced suppressive activity of a mixture of CD25(intermediate) or CD25(high) expressing T(reg) (healthy controls, MBP: 37.3%; MS patients, MBP: -1.9 vs. 6.6% suppression after MX treatment for 6 months, p > 0.2). The frequency of T(reg) cells was not affected by MX. A single infusion of MX (10 mg/m(2) body surface) induced a selective and persistent reduction of approximately 30% of absolute and relative counts of B lymphocytes (p < 0.05). MX therapy does not influence T(reg) cell frequency or function. MX seems to exhibit its efficacy in MS mainly by a suppression of humoral immunity., (2008 S. Karger AG, Basel.)

Background: The pathophysiology of multiple sclerosis (MS)-associated fatigue is poorly understood. Immunological mechanisms may play a role. Alterations in immunological profile indicate a chronic immune activation in MS patients with fatigue. T-regulatory (Treg) cells seem to play a key role in coordinating autoimmune mechanisms in MS. This is the first study investigating the relationship between Treg cell function and fatigue in MS patients., Methods: In this cross-sectional in vitro, ex vivo study, we isolated peripheral blood mononuclear cells (PBMCs) from 20 MS patients with fatigue, determined lymphocyte subsets by flow cytometry and suppressive function of Treg cells in PBMC cultures with antigen stimulation. Forkhead box protein 3 expression was evaluated by PCR. Results were compared with 20 MS patients without fatigue and with 19 healthy controls., Results: Leukocytes and lymphocyte subsets including Treg cell frequency did not differ in patients with and without fatigue. Co-culturing of Treg cells with CD4+CD25- cells did not lead to a significant suppression of myelin basic protein- and pokeweed mitogen-induced proliferation in MS patients in contrast to healthy controls. There were no statistical differences between MS patients with and without fatigue regarding this suppression activity., Conclusions: Fatigue seems not to be associated with impaired function of Treg cells in untreated MS patients.

Fatigue is one of the most frequent and most disabling symptoms in multiple sclerosis (MS). We investigated the possible association of the MS-related fatigue syndrome with the available disease-modifying therapies and the main disease characteristics in a cross-sectional study on 320 consecutive patients. The prevalence of severe fatigue (Fatigue Severity Scale score > or =5) was 50%. In a multivariate regression model controlling for age, disease subtype, duration and disability we did not find a significant association between the use of immunosuppressive or immunomodulatory drugs compared to no treatment (OR = 1.34, p = 0.38 for immunosuppressants; OR = 0.95, p = 0.85 for immune-modulating agents). Although all used disease-modifying agents successfully reduce disease activity and inflammation, they do not appear to exhibit a significant effect on MS-related fatigue., (Copyright 2007 S. Karger AG, Basel.)

Aims: It was investigated whether the cortical activity during tasks requiring focused or divided attention is reduced in multiple sclerosis patients with prominent deficits (MS(+D)) and increased in patients without impairment (MS(-D)) in these specific attention functions., Methods: Six MS(+D) patients with attention deficits, six unimpaired MS(-D) patients, and age-, gender-, and education-matched healthy control subjects were examined with functional magnetic resonance imaging (fMRI). The experimental paradigm consisted of visual tasks requiring focused or divided attention., Results: Performance accuracy and reaction times were impaired in MS(+D) patients. This subgroup showed reduced activation within superior and inferior frontal gyrus during focused attention. Under conditions of divided attention decreased activity was found within middle and inferior frontal gyrus, inferior parietal structures, and occipital areas. No compensatory activity was observed. MS(-D) patients did neither differ in behavioral data nor in cortical activity in attention related structures from control subjects., Conclusions: The study found evidence for the neural correlate of attentional deficits in MS patients. In patients with specific attention deficits, reduced cortical activity in prefrontal and parietal areas, which are associated with attention and executive control, reflects the patients' reduced performance on a behavioral level. Our findings also suggest impaired top-down attentional control on sensory structures in these patients. In patients without verifiable attention deficits a normal functioning of structures relevant for executive attention was observed. Compensatory activity in these structures as a marker of reorganization in less pronounced stages of the disease was not found.

Multiple sclerosis (MS) is an autoimmune disorder directed against self antigens of the central nervous system. CD4(+)CD25(+)FoxP3(+) regulatory T cell (T(reg)) mediated suppression is an essential mechanism of self-tolerance. We studied whether changes in the suppressive function of a mixture of CD25(high) and CD25(intemediate) expressing T(reg) cells in myelin basic protein (MBP)-induced proliferation occurred in untreated MS patients. Suppression of MBP-induced proliferation was observed in 13 out of 29 (45%) MS patients; this was significantly (p<0.05) less compared with 17 out of 19 (89%) healthy individuals. Relative T(reg) counts was significantly increased in MS patients (mean+/-S.D.; 20+/-8%) compared with healthy individuals (15+/-5%). These findings suggest that impaired T(reg) function may be involved in pathogenesis of MS.

Azathioprine (Aza) is a widely used immunosuppressive drug in multiple sclerosis (MS) treatment. Recently, the incidence of secondary myelodysplastic syndromes (sMDS) associated with a poor prognosis was found to be elevated in patients treated with Aza for non-malign disorders. Three hundred and seventeen MS patients were retrospectively analysed and complete blood counts were examined for those exposed to Aza. We identified one case of sMDS (cumulative dose 627 g) in a young patient and two further malignancies (cumulative doses 27 g and 54 g) in the Aza group (n = 81; 3.7%). In the non-Aza (n = 236) group, five malignancies (2.1%, P = 0.419) were identified. Including our patient, four cases of sMDS after long-term Aza therapy in MS have been reported so far. Cases suggest a time- and dose-dependent risk of sMDS in long-term therapy of MS with Aza. Long-term Aza therapy needs careful monitoring.

Many modulators of inflammation, including chemokines, neuropeptides, and neurotransmitters signal via G protein-coupled receptors (GPCR). GPCR kinases (GRK) can phosphorylate agonist-activated GPCR thereby promoting receptor desensitization. Here we describe that in leukocytes from patients with active relapsing-remitting multiple sclerosis (MS) or with secondary progressive MS, GRK2 levels are significantly reduced. Unexpectedly, cells from patients during remission express even lower levels of GRK2. The level of GRK2 in leukocytes of patients after stroke, a neurological disorder with paralysis but without an autoimmune component, was similar to GRK2 levels in cells from healthy individuals. In addition, we demonstrate that the course of recombinant myelin oligodendrocyte glycoprotein (1-125)-induced experimental autoimmune encephalomyelitis (EAE), an animal model for MS, is markedly different in GRK2(+/-) mice that express 50% of the GRK2 protein in comparison with wild-type mice. Onset of EAE was significantly advanced by 5 days in GRK2(+/-) mice. The earlier onset of EAE was associated with increased early infiltration of the CNS by T cells and macrophages. Although disease scores in the first phase of EAE were similar in both groups, GRK2(+/-) animals did not develop relapses, whereas wild-type animals did. The absence of relapses in GRK2(+/-) mice was associated with a marked reduction in inflammatory infiltrates in the CNS. Recombinant myelin oligodendrocyte glycoprotein-induced T cell proliferation and cytokine production were normal in GRK2(+/-) animals. We conclude that down-regulation of GRK2 expression may have important consequences for the onset and progression of MS.

Background: Alemtuzumab is given as two annual courses. Patients with continued disease activity may receive as-needed additional courses. Objective: To evaluate efficacy and safety of additional alemtuzumab courses in the CARE-MS (Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis) studies and their extensions. Methods: Subgroups were based on the number of additional alemtuzumab courses received. Exclusion criteria: other disease-modifying therapy (DMT); <12-month follow-up after last alemtuzumab course. Results: In the additional-courses groups, Courses 3 and 4 reduced annualized relapse rate (12 months before: 0.73 and 0.74, respectively; 12 months after: 0.07 and 0.08). For 36 months after Courses 3 and 4, 89% and 92% of patients were free of 6-month confirmed disability worsening, respectively, with 20% and 26% achieving 6-month confirmed disability improvement. Freedom from magnetic resonance imaging (MRI) disease activity increased after Courses 3 and 4 (12 months before: 43% and 53%, respectively; 12 months after: 73% and 74%). Safety was similar across groups; serious events occurred irrespective of the number of courses. Conclusion: Additional alemtuzumab courses significantly improved outcomes, without increased safety risks, in CARE-MS patients with continued disease activity after Course 2. How this compares to outcomes if treatment is switched to another DMT instead remains unknown. [ABSTRACT FROM AUTHOR]

Background: First dose observation for cardiac effects is required for fingolimod, but recommendations on the extent vary. This study aims to assess cardiac safety of fingolimod first dose. Individual bradyarrhythmic episodes were evaluated to assess the relevance of continuous electrocardiogram (ECG) monitoring.Methods: START is an ongoing open-label, multi-center study. At the time of analysis 3951 patients were enrolled. The primary endpoints are the incidence of bradycardia (heart rate < 45 bpm) and second-/third-degree AV blocks during treatment initiation. The relevance of Holter was assessed by matching ECG findings with the occurrence of clinical symptoms as well as by rigorous analysis of AV blocks with regard to the duration of pauses and the minimal heart rate recorded during AV block.Results: Thirty-one patients (0.8%) developed bradycardia (<45 bpm), 62 patients (1.6%) had second-degree Mobitz I and/or 2:1 AV blocks with a lowest reading (i.e. mean of ten consecutive beats) of 35 bpm and the longest pause lasting for 2.6 s. No Mobitz II or third-degree AV blocks were observed. Only one patient complained about mild chest discomfort and fatigue. After 1 week, there was no second-/third-degree AV block.Conclusions: Continuous Holter ECG monitoring in this large real-life cohort revealed that bradycardia and AV conduction abnormalities were rare, transient and benign. No further unexpected abnormalities were detected. The data presented here give an indication that continuous Holter ECG monitoring does not add clinically relevant value to patients' safety.Trial Registration: NCT01585298 ; registered April 23, 2012. [ABSTRACT FROM AUTHOR]

Background: Natalizumab provides rapid and high-efficacy control of multiple sclerosis disease activity with long-term stabilization. However, the benefits of the drug are countered by a risk of developing progressive multifocal leukoencephalopathy in patients infected with the John Cunningham Virus. Close monitoring is required in patients with increased progressive multifocal leukoencephalopathy risk receiving natalizumab in the long-term for an optimal benefit-risk evaluation. Standardized high-quality monitoring procedures may provide a superior basis for individual benefit and risk evaluation and thus improve treatment decisions. The non-interventional study TRUST was designed to capture natalizumab effectiveness under real-life conditions and to examine alternate approaches for clinical assessments, magnetic resonance imaging monitoring and use of biomarkers for progressive multifocal leukoencephalopathy risk stratification.Methods/design: TRUST is a non-interventional, multicenter, prospective cohort study conducted at approximately 200 German neurological centers. The study is intended to enroll 1260 relapsing-remitting multiple sclerosis patients with ongoing natalizumab therapy for at least 12 months. Patients will be followed for a period of 3 years, irrespective of treatment changes after study start. Data on clinical, subclinical and patient-centric outcomes will be documented in order to compare the effectiveness of continuous versus discontinued natalizumab treatment. Furthermore, the type and frequency of clinical, magnetic resonance imaging and biomarker assessments, reasons for continuation or discontinuation of therapy and the safety profile of natalizumab will be collected to explore the impact of a systematic patient management approach and its potential impact on patient outcome. Specifically, the role of biomarkers, the use of expert opinions, the impact of high-frequency magnetic resonance imaging assessment for early progressive multifocal leukoencephalopathy detection and the role of additional radiological and clinical expert advice will be explored.Discussion: TRUST was initiated in spring 2014 and enrollment is anticipated to be completed by mid 2016. Annual interim analyses will deliver continuous information and transparency with regard to the patient cohorts and the completeness and quality of data as well as closely monitor any safety signals in the natalizumab-treated cohort. The study's results may provide insights into opportunities to improve the benefit-risk assessment in clinical practice and support treatment decisions. [ABSTRACT FROM AUTHOR]

Background: Natalizumab for multiple sclerosis (MS) increases the risk of progressive multifocal leukoencephalopathy (PML). Objective: We aimed to assess the effect of natalizumab on cellular composition and functional B cell parameters including patients with natalizumab-associated PML (n=37). Methods: Cellular composition by flow cytometry, levels of immunoglobulin (Ig)G/IgM by immunonephelometry, and oligoclonal bands by isoelectric focusing were studied in blood and cerebrospinal fluid. Results: In MS patients treated with natalizumab without PML (n=59) the proportion of CD19+ B cells was higher in blood, but lower in cerebrospinal fluid compared with MS patients not treated with natalizumab (n=17). The CD4/CD8-ratio in cerebrospinal fluid was lower, and IgG and IgM levels as well as the IgG index dropped in longitudinal samples during natalizumab therapy. Oligoclonal bands persisted, but the total amount of the intrathecally produced IgG fraction, and the polyclonal intrathecal IgG reactivity to measles, rubella, and zoster declined. At the time of diagnosis of PML patients with natalizumabassociated PML had low total IgG levels in blood and cerebrospinal fluid. Conclusions: Natalizumab impacts B and T cell distribution and exerts an inhibitory effect on surrogates of B cell function in periphery and in cerebrospinal fluid, potentially contributing to the increased risk of developing PML. [ABSTRACT FROM AUTHOR]

No abstract available [ABSTRACT FROM AUTHOR]

Background: In a phase 2b study in patients with relapsing–remitting MS (RRMS), BG-12 240 mg three times daily significantly reduced the number of new gadolinium-enhanced (Gd+) lesions from weeks 12 to 24 (primary end point) by 69% compared with placebo.Objective: In this analysis, the effect of BG-12 240 mg three times daily on the number of Gd+ lesions from weeks 12 to 24 was evaluated in subgroups based on baseline disease characteristics and demographics.Methods: Two hundred and fifty-seven patients were randomized equally to receive BG-12 (120 mg once daily or three times daily or 240 mg three times daily) or placebo.Results: BG-12 240 mg three times daily significantly reduced the number of new Gd+ lesions compared with placebo in the following subgroups: Expanded Disability Status Scale (EDSS) score ≤ 2.5 (74%), EDSS score > 2.5 (63%), no Gd+ lesions (80%), ≥ 1 Gd+ lesion (55%), age < 40 years (49%), age ≥ 40 years (89%), female patients (81%), disease duration ≤ 6 years (81%) and disease duration > 6 years (54%) (all comparisons p < 0.05).Conclusion: BG-12 demonstrated efficacy in patients with RRMS by decreasing new Gd+ lesion development across a range of subgroups defined by baseline disease characteristics or demographics. [ABSTRACT FROM AUTHOR]

Interferon beta preparations are the most widely used initial therapies prescribed for patients with relapsing–remitting multiple sclerosis. Phase III studies have demonstrated comparable efficacy on clinical measures of disease activity, variable benefits on radiological measures, and good overall tolerability. Subsequent clinical studies have attempted to compare directly the three available interferon beta preparations, reporting both safety and efficacy data. We review the literature on studies evaluating interferon beta therapy for patients with relapsing–remitting multiple sclerosis, discuss reasons for discrepant findings, and assess the utility of interferon beta-based combination regimens as the focus of future studies in the increasingly complex multiple sclerosis therapy landscape. [ABSTRACT FROM PUBLISHER]

Background: Natalizumab is a humanized monoclonal antibody directed against very late activation antigen 4 (VLA-4) and has a potent effect on disease activity in multiple sclerosis. Blockade of VLA-4 with natalizumab may not only interfere with autoimmunological mechanisms but also with central nervous system immune surveillance. Methods: Longitudinal ex vivo and in vitro study to determine the effect of natalizumab on the frequency of distinct immune cells and on the frequency and suppressive function of natural CD4+CD25+ regulatory T cells (Tregs). Results: Natalizumab binding to VLA-4 was more marked for B cells than for T cells (49% reduction in VLA-4-expressing B cells compared to 24.5% reduction of T cells). There was an increase in circulating B cells over T cells (2.6 vs. 1.5 fold, p < 0.001). Natural killer cells increased 1.5-fold (p = 0.01). Natalizumab led to a relative decrease in CD4+CD25+ Tregs from 18.9 to 14.1% (p = 0.04). The impaired suppressive capacity of Tregs was not restored. Conclusion: Natalizumab reduces VLA-4 expression on all investigated immune cells, but changes were most marked for B cells. Further differential effects on immune cells may be relevant to opportunistic central nervous system infections during treatment with natalizumab. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Acute interferon-β (IFN-β) administration transiently activates the hypothalamic-pituitary-adrenal (HPA) axis, increases granulocytes, and reduces lymphocytes in peripheral blood. To test whether these effects are still present after long-term treatment, 13 patients with relapsing-remitting multiple sclerosis were analyzed at baseline, and 1, 2, 4, and 8 h after IFN-β1a injection at two occasions: at the initial administration and after 1 year of continuous treatment. Long-term treatment reduced the responsiveness of the HPA axis to the injection, and abolished the distributional changes in leukocyte numbers. One-year treatment with IFN-β1a did not induce mood alterations as assessed by the Profile of Mood States. These results suggest that long-term IFN-β therapy has a profound impact on leukocyte distribution and the neuroendocrine response to the drug. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Interferon-β-1b (IFN-β-1b) has been shown to reduce the relapse rate in patients with relapsing-remitting multiple sclerosis (MS) and disease progression in patients with secondary progressive MS. While acute administration of IFN-β-1b is known to cause flu-like symptoms, chronic medication has been suggested to cause mood alterations and anxiety attacks, and secondary to this neuropsychological deficits that may impair daily life. It is unknown, however, whether the latter symptoms are induced by acute IFN-β-1b administration. Therefore, we examined the impact of a single subcutaneous injection of IFN-β-1b in 8 healthy males. In a crossover design, each subject was injected subcutaneously with either 8 million IU IFN-β-1b or placebo (NaCl) at 8:00 h. Flu-like symptoms (body temperature, heart rate, blood pressure), mood status [‘profile of mood states’, Befindlichkeitsskala (BFS)] and neuropsychological performance (trail marking test, verbal memory test, d2 attention test) and were assessed at baseline, 4, 8 and 24 h after injection. IFN-β-1b increased body temperature, heart rate and fatigue. Nevertheless, acute IFN-β-1b injection did not impair any parameters of neuropsychological performance. Thus, although IFN-β-1b produces physiological symptoms indicative of sickness behavior, these data suggest that IFN-β-1b administration does not have an impact on the cognitive capacity following acute administration.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: In CARE-MS I and II (trial registration: NCT00530348, NCT00548405), alemtuzumab treatment (12 mg/day; baseline: 5 days; 12 months later: 3 days) improved clinical and magnetic resonance imaging (MRI) outcomes vs subcutaneous interferon beta-1a over 2 years in patients with relapsing-remitting multiple sclerosis (MS). In 2 consecutive extensions (NCT00930553, NCT02255656 [TOPAZ]), patients could receive additional alemtuzumab (12 mg/day; 3 days; ≥12 months apart). Objectives: Evaluate yearly efficacy and safety of alemtuzumab in pooled CARE-MS patients who did or did not receive additional alemtuzumab through year 9. Methods: Pooled CARE-MS patients were stratified by the total number of courses received (exactly 2 courses, exactly 3 courses, ≥4 courses). Inclusion criteria: additional alemtuzumab (ie, courses 3 or 4) received by month 97 to allow ≥12 months of follow-up; no other disease-modifying therapy through year 9. Data were censored at course 5 (if received) in the ≥4 courses group. Outcomes data were rebaselined after the last alemtuzumab course. Results: 742/811 (91%) alemtuzumab-treated patients entered the extension and could receive additional courses; courses 3 and 4 were given most frequently in years 3 (19%) and 4 (6%), respectively. Of 742 extension patients, 359 (48%), 148 (20%), and 121 (16%) were included in the 2-, 3-, and ≥4-courses groups, with 303, 76, and 15 remaining on study in year 4 after last course, respectively. Over 4 years after last course, annualized relapse rate was 0.07, 0.08, and 0.23 in the 2-, 3-, and ≥4-courses groups, respectively, and change in mean Expanded Disability Status Scale score at year 4 vs after last course was -0.06, +0.08, and +0.56, respectively. Over 4 years, 83%, 85%, and 94% were free of 6-month confirmed disability worsening, and 23%, 11%, and 15% had 6-month confirmed disability improvement in the 2-, 3-, and ≥4-courses groups, respectively. In year 4, 78%, 73%, and 69% were free of MRI disease activity. Serious adverse events were generally similar between cohorts during years 1-3 after last treatment (5.1%-11.4% per year), but low patient numbers in the ≥4-courses group confounded analysis of serious adverse events in year 4 after last course. Conclusions: Efficacy of additional alemtuzumab was maintained over 4 years after last course in CARE-MS patients, although the ≥4-courses group had higher disease activity and disability, as expected. Alemtuzumab safety was generally consistent between groups, except for the ≥4-courses cohort in year 4 after last course wherein interpretation was limited by low numbers of available patients. [ABSTRACT FROM AUTHOR]

Abstract: Multiple sclerosis (MS) is an autoimmune disorder directed against self antigens of the central nervous system. CD4+CD25+FoxP3+ regulatory T cell (Treg) mediated suppression is an essential mechanism of self-tolerance. We studied whether changes in the suppressive function of a mixture of CD25high and CD25intemediate expressing Treg cells in myelin basic protein (MBP)-induced proliferation occurred in untreated MS patients. Suppression of MBP-induced proliferation was observed in 13 out of 29 (45%) MS patients; this was significantly (p <0.05) less compared with 17 out of 19 (89%) healthy individuals. Relative Treg counts was significantly increased in MS patients (mean±S.D.; 20±8%) compared with healthy individuals (15±5%). These findings suggest that impaired Treg function may be involved in pathogenesis of MS. [Copyright &y& Elsevier]