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Friedreich's Ataxia (FA) is an inherited neurodegenerative disorder resulting from decreased expression of the mitochondrial protein frataxin, for which there is no approved therapy. High throughput screening of clinically used drugs identified Dimethyl fumarate (DMF) as protective in FA patient cells. Here we demonstrate that DMF significantly increases frataxin gene (FXN) expression in FA cell model, FA mouse model and in DMF treated humans. DMF also rescues mitochondrial biogenesis deficiency in FA-patient derived cell model. We further examined the mechanism of DMF's frataxin induction in FA patient cells. It has been shown that transcription-inhibitory R-loops form at GAA expansion mutations, thus decreasing FXN expression. In FA patient cells, we demonstrate that DMF significantly increases transcription initiation. As a potential consequence, we observe significant reduction in both R-loop formation and transcriptional pausing thereby significantly increasing FXN expression. Lastly, DMF dosed Multiple Sclerosis (MS) patients showed significant increase in FXN expression by ~85%. Since inherited deficiency in FXN is the primary cause of FA, and DMF is demonstrated to increase FXN expression in humans, DMF could be considered for Friedreich's therapy.

Clinical and MRI outcomes from ASCLEPIOS and ALITHIOS were analysed in patients receiving Ofatumumab (OMB) during the core and extension (OMB-OMB) and patients who switched from Teriflunomide (TER) to OMB in the extension (TER-OMB). Of the 1882 patients randomized, 946/936 received OMB/TER and 690/677 continued/were switched to OMB in the extension.Switching from TER to OMB in the extension significantly reduced the ARR by 68.3–76.6%; continuing OMB in the extension further reduced ARR by 39.9–65.1%. Within the prior DMT subgroups, the lowest mean ARR was achieved in patients in the OMB-OMB group with ≤1 DMT (0.046–0.049). Switching to/continuing OMB was associated with a consistent numerical reduction in the risk of 3/6mCDW with the greatest benefit observed in patients on continuous OMB with ≤1 DMT or ≤40 years old. The almost complete suppression of T1 Gd+ activity seen in those randomised to OMB in the core was mirrored in the TER-OMB groups in the extension (90.00–100% across all prior DMT and age subgroups) and sustained in the OMB-OMB group. New/enlarging T2 lesions showed a similar, though delayed, suppression in the TER-OMB group.Switching from TER to OMB in ALITHIOS reduced clinical and MRI disease activity across all prior DMT and age subgroups.

Background Regular and consistent disease assessment could provide a clearer picture of burden in generalised myasthenia gravis (gMG) and improve patient care; however, the use of assessment tools in practice lacks standardisation. This modified Delphi approach was taken to review current evidence on assessment tool use in gMG and develop expert‐derived consensus recommendations for good practice. Methods A European expert panel of 15 experienced gMG neurologists contributed to development of this consensus, four of whom formed a lead Sub‐committee. The PICO (Population, Intervention, Control, Outcomes) framework was used to define six clinical questions on gMG assessment tools, a systematic literature review was conducted, and evidence‐based statements were developed. According to a modified Delphi voting process, consensus was reached when ≥70% of the experts rated agreement with a statement as ≥8 on a scale of 1–10. Results Eighteen expert‐ and evidence‐based consensus statements based on six themes were developed. Key recommendations include: consistent use of the Myasthenia Gravis Activities of Daily Living score (MG‐ADL) across clinical settings, followed by a simple question (e.g., Patient Acceptable Symptom State [PASS]) or scale to determine patient satisfaction in clinical practice; use of a Quantitative Myasthenia Gravis [QMG] or quality of life [QoL] assessment when the MG‐ADL indicates disease worsening; and consideration of symptom state to determine the timing and frequency of recommended assessments. Expert panel consensus was reached on all 18 statements after two voting rounds. Conclusions This process provided evidence‐ and expert consensus‐based recommendations for the use of objective and subjective assessment tools across gMG research and care to improve management and outcomes for patients.

Twenty years on from its initial approval as the first monoclonal antibody for the treatment of multiple sclerosis (MS), natalizumab remains a valuable high-efficacy treatment option for people with relapsing-remitting MS, with robust real-world evidence supporting its long-term efficacy and well-characterized safety profile, provided that the risk of progressive multifocal leukoencephalopathy (PML) is monitored and mitigated. This review explores the long-term clinical impact of natalizumab. It draws on two decades of experience to guide treatment strategies with natalizumab, including its use early in the disease course, switching to natalizumab, its use during vaccination, and PML risk management and exit strategies. Guidance on the use of natalizumab in pregnant and breastfeeding women with MS, children with MS, and people with comorbidities is discussed, along with reflections on what has been learned from 20 years with natalizumab, and what the future holds for this impactful treatment in MS and beyond. Graphical abstract

Introduction Eculizumab, a complement active antibody, and efgartigimod, an Fc fragment that blocks neonatal Fc receptor, are both approved to treat generalized myasthenia gravis (gMG) patients. The objective of this study is to describe the clinical response to both treatments in a real-life setting. Methods We collected baseline and follow-up clinical data using the Myasthenia Gravis-Activities of Daily Living (MG-ADL), and Quantitative Myasthenia Gravis (QMG). We included 63 patients, 32 treated with eculizumab and 31 with efgartigimod. Of the efgartigimod-treated patients, 22 were anti-acetylcholine receptor antibody-positive (AChR-Ab +) and 9 were AChR-Ab- (3 MuSK-Ab + and 6 seronegative). Results Both treatments showed similar efficacy relative to the MG-ADL scale reduction ( p  = 0.237). Efgartigimod had a similar effect on both AChR-Ab + and AChR-Ab- ( p  = 0.280). Eculizumab was superior to efgartigimod relative to the QMG score reduction for the entire dataset ( p  = 0.003) and was more likely to achieve a clinical response at the QMG compared to efgartigimod (OR 1.373; p  = 0.016). Steroid-sparing effect was higher for eculizumab than efgartigimod ( – 16.7 vs  – 5.2 mg of the baseline daily dose at follow-up; p  = 0.001). Mean speed of prednisone reduction was  – 13.1 mg of the daily dose for each month of follow-up for eculizumab-treated patients and  – 3.2 for efgartigimod ( p  = 0.001). We found three serious events, all not related to treatment in the investigator’s opinion. One eculizumab-treated patient experienced a severe pneumonia and died despite treatment. Conclusions Our study provides evidence that eculizumab and efgartigimod can be used in clinical practice to reduce disability in gMG patients. Eculizumab-treated patients had a higher QMG response and steroid sparing effect. Efgartigimod may offer a more flexible schedule due to its cyclical use, no need for vaccination, and efficacy in AChR-Ab- patients.

Background and purpose Generalized myasthenia gravis (gMG) continues to present significant challenges for clinical management due to an unpredictable disease course, frequent disease fluctuations, and varying response to therapy. The recent availability of new pharmacologic therapies presents a valuable opportunity to reevaluate how this disease is classified, assessed, and managed and identify new ways to improve the clinical care of patients with gMG. Methods Narrative review was made of publications identified via searches of PubMed and selected congresses (January 2000–September 2022). Results New consensus definitions are required to ensure consistency, to better characterize patients, and to identify patients who will benefit from specific drugs and earlier use of these agents. There is a need for more frequent, standardized patient assessment to identify the cause of motor function deficits, provide a clearer picture of the disease burden and its impact on daily living and quality of life (QoL), and better support treatment decision‐making. Novel approaches that target different components of the immune system will play a role in more precise treatment of patients with gMG, alongside the development of new algorithms to guide individualized patient management. Conclusions gMG has a physical, mental, and social impact, resulting in a considerable burden of disease and substantially decreased QoL, despite standard treatments. The availability of novel, targeted treatments that influence key pathological mediators of gMG, together with new biomarkers, offers the potential to optimize patient management and ultimately enables a greater number of patients to achieve minimal manifestation status and a reduced burden of disease.

Early intervention with high-efficacy disease-modifying therapy (HE DMT) may be the best strategy to delay irreversible neurological damage and progression of multiple sclerosis (MS). In European healthcare systems, however, patient access to HE DMTs in MS is often restricted to later stages of the disease due to restrictions in reimbursement despite broader regulatory labels. Although not every patient should be treated with HE DMTs at the initial stages of the disease, early and unrestricted access to HE DMTs with a positive benefit–risk profile and a reasonable value proposition will provide the freedom of choice for an appropriate treatment based on a shared decision between expert physicians and patients. This will further optimize outcomes and facilitate efficient resource allocation and sustainability in healthcare systems and society.

Myasthenia gravis (MG) is a rare, autoimmune, neurological disorder. Most MG patients have autoantibodies against acetylcholine receptors (AChRs). Some have autoantibodies against muscle-specific tyrosine kinase (MuSK) or lipoprotein-receptor-related protein 4 (LRP4), and some are seronegative. Standard of care, which includes anti-cholinesterase drugs, thymectomy, corticosteroids (CS), and off-label use of non-steroidal immunosuppressive drugs (NSISTs), is bounded by potential side effects and limited efficacy in refractory generalized MG (gMG) patients. This highlights the need for new therapeutic approaches for MG. Eculizumab, a monoclonal antibody that inhibits the complement system, has been recently approved in Italy for refractory gMG. A panel of 11 experts met to discuss unmet therapeutic needs in the acute and chronic phases of the disease, as well as the standard of care for refractory patients. Survival was emphasized as an acute phase outcome. In the chronic phase, persistent remission and early recognition of exacerbations to prevent myasthenic crisis and respiratory failure were considered crucial. Refractory patients require treatments with fast onset of action, improved tolerability, and the ability to slow disease progression and increase life expectancy. The Panel agreed that eculizumab would presumably meet the therapeutic needs of many refractory gMG patients. The panel concluded that the unmet needs of current standard of care treatments for gMG are significant. Evaluating new therapeutic options accurately is essential to find the best balance between efficacy and tolerability for each patient. Collecting real-world data on novel molecules in routine clinical practice is necessary to address unmet needs.

Historically, Friedreich’s Ataxia (FRDA) has been linked to a relatively preserved cerebellar cortex. Recent advances in neuroimaging have revealed altered cerebello-cerebral functional connectivity (FC), but the extent of intra-cerebellar FC changes and their impact on cognition remains unclear. This study investigates intra-cerebellar FC alterations and their cognitive implications in FRDA. In this cross-sectional, single-center study, resting-state functional MRI data from 17 patients with FRDA (average age 27.7 ± 13.6 years; F/M = 6/11) and 20 healthy controls (HC) (average age 29.4 ± 9.7 years; F/M = 9/11), all of whom underwent neuropsychological testing, were analyzed. From functional connectivity matrices, graph measures were computed at both the network and node levels using two complementary parcellations. FRDA patients exhibited decreased global efficiency ( p  = 0.04), nodal degree ( p  = 0.001) and betweenness centrality ( p  = 0.04) in the vermal portion of lobule VIII, along with reduced global efficiency in cerebellar regions belonging to the Control-A network ( p  = 0.02), one of the three subdivisions of the Frontoparietal network. Verbal memory deficits correlated with global efficiency in both the vermal portion of lobule VIII ( r  = 0.53, p  = 0.02) and the cerebellar regions of the Control-A network ( r  = 0.49, p  = 0.05). Graph analysis revealed regional intra-cerebellar FC changes in FRDA, marked by reduced functional centrality in cerebellar regions of the vermis and responsible for executive functions. These changes correlated with cognitive alterations, highlighting the role of the cerebellar cortex in the cognitive impairment observed in FRDA.

ObjectivesMyasthenia gravis (MG) is a rare, chronic, autoimmune neuromuscular disease which can affect functional and mental aspects of health and health-related quality of life (HRQoL). This study aims to obtain detailed knowledge of the impact of MG on HRQoL in a broad population from the perspective of the patient.DesignProspective, observational, digital, longitudinal real-world study.SettingAdult patients with MG from seven countries (USA, Japan, Germany, UK, Italy, Spain and Canada) downloaded a mobile application onto their phones and entered data about themselves and their MG.Outcome measuresData was collected using the following general and disease-specific patient-reported outcome measurements: EuroQol 5 Domains Health-Related Quality of Life Questionnaire (EQ-5D-5L), Myasthenia Gravis Activities of Daily Living (MG-ADL), Myasthenia Gravis Quality of Life 15-item revised scale (MG-QoL-15r), Hospital Anxiety and Depression Scale (HADS) and Health Utilities Index III (HUI3). Patients were categorised by their self-assessed Myasthenia Gravis Foundation of America (MGFA) class (I–V).ResultsBaseline results of 841 participants (mean age 47 years, 70% women) are reported . The distribution across the MGFA classes was: 13.9%, 31.0%, 38.1%, 15.5% and 1.6% for classes I–V. The MGFA class was a strong predictor of all aspects of HRQoL, measured with disease-specific and with generic instruments. The domains in which patients with MG most frequently mentioned problems were usual activities, anxiety and depression, tiredness, breathing and vision. The mean total MG-ADL Score was positively associated with increasing MGFA classes: 2.7, 4.4, 6.3 and 8.4 for MGFA classes I–IV. Mean baseline EQ-5D-5L utility was also associated with MGFA classes and was 0.817, 0.766, 0.648 and 0.530 for MGFA class I–IV.ConclusionsMG has a large impact on key aspects of health and HRQoL. The impact of this disease increases substantially with increasing disease severity.