Long-term comparative analysis of no evidence of disease activity (NEDA-3) status between multiple sclerosis patients treated with natalizumab and fingolimod for up to 4 years

Comparative effectiveness of natalizumab and fingolimod over a follow-up longer than 2 years has been not addressed yet

Mitochondria, Oxidative Stress, cAMP Signalling and Apoptosis: A Crossroads in Lymphocytes of Multiple Sclerosis, a Possible Role of Nutraceutics

Multiple sclerosis (MS) is a complex inflammatory and neurodegenerative chronic disease that involves the immune and central nervous systems (CNS). The pathogenesis involves the loss of blood–brain barrier integrity, resulting in the invasion of lymphocytes into the CNS with consequent tissue damage. The MS etiology is probably a combination of immunological, genetic, and environmental factors. It has been proposed that T lymphocytes have a main role in the onset and propagation of MS, leading to the inflammation of white matter and myelin sheath destruction. Cyclic AMP (cAMP), mitochondrial dysfunction, and oxidative stress exert a role in the alteration of T lymphocytes homeostasis and are involved in the apoptosis resistance of immune cells with the consequent development of autoimmune diseases. The defective apoptosis of autoreactive lymphocytes in patients with MS, allows these cells to perpetuate, within the CNS, a continuous cycle of inflammation. In this review, we discuss the involvement in MS of cAMP pathway, mitochondria, reactive oxygen species (ROS), apoptosis, and their interaction in the alteration of T lymphocytes homeostasis. In addition, we discuss a series of nutraceutical compounds that could influence these aspect

The Value and Sustainability of Ocrelizumab in Relapsing Multiple Sclerosis: A Cost-Effectiveness and Budget Impact Analysis

INTRODUCTION: The availability of ocrelizumab for the relapsing forms of multiple sclerosis (MS) in the Italian markets raised some questions about its economic impact and value compared to the alternative treatment options available.AIM: To assess the cost-effectiveness and budget impact of ocrelizumab compared to the most used second line disease modifying therapies (DMTs) in Italy.METHODS: The study was divided in two phases: Phase 1 – based on the development of a decision analytical Markov model to assess the cost-effectiveness of ocrelizumab compared to natalizumab and fingolimod, and Phase 2 – based on the development of a budget impact model to assess the economic impact of ocrelizumab in Italy. Both models used the National Health System perspective; a lifetime horizon was applied in the cost-effectiveness analysis and a 3-year time horizon in the budget impact. The cost-effectiveness analysis results were reported as incremental cost-effectiveness ratio (ICER) expressed as € per Quality Adjusted Life Year (QALY) gained, the budget impact analysis results were reported as difference in the overall budget (€) between a scenario with and without ocrelizumab.RESULTS: The two analyses reported ocrelizumab as a cost-effective option compared to natalizumab and fingolimod with a positive impact on the overall NHS budget. In the base-case analysis, the ICER was € 2,023 for ocrelizumab compared to fingolimod; while ocrelizumab resulted cost-saving compared to natalizumab. The sensitivity analysis confirmed the base-case analysis results. Further, the use of ocrelizumab was associated to a budget decrease of € 21 million (-2.6%) in a 3-year time horizon.CONCLUSION: The results of our cost-effectiveness and budget impact models reported ocrelizumab as an effective and efficient treatment in patients with relapsing forms of MS who failed a first line DMTs from the Italian NHS perspective

The role of exercise parameters on small extracellular vesicles and microRNAs cargo in preventing neurodegenerative diseases

Physical activity (PA), which includes exercise, can reduce the risk of developing various non-communicable diseases, including neurodegenerative diseases (NDs), and mitigate their adverse effects. However, the mechanisms underlying this ability are not yet fully understood. Among several possible mechanisms proposed, such as the stimulation of brain-derived neurotrophic factor (BDNF), endothelial nitric oxide synthase (eNOS), insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and nerve growth factor (NGF), the possible involvement of particular vesicular structures enclosed in lipid membranes known as extracellular vesicles (EVs) has recently been investigated. These EVs would appear to exert a paracrine and systemic action through their ability to carry various molecules, particularly so-called microRNAs (miRNAs), performing a function as mediators of intercellular communication. Interestingly, EVs and miRNAs are differentially expressed following PA, but evidence on how different exercise parameters may differentially affect EVs and the miRNAs they carry is still scarce. In this review we summarized the current human findings on the effects of PA and different exercise parameters exerted on EVs and their cargo, focusing on miRNAs molecules, and discussing how this may represent one of the biological mechanisms through which exercise contributes to preventing and slowing NDs

Impact of Natalizumab on Cognitive Performances and Fatigue in Relapsing Multiple Sclerosis: A Prospective, Open-Label, Two Years Observational Study

Background and Objectives: Natalizumab reduces the relapse rate and magnetic resonance imaging activity in patients with Relapsing-Remitting Multiple Sclerosis (RRMS). So far the influence of natalizumab on cognitive functions and fatigue in MS remains uncertain. The aim of this prospective, open-label, observational study was to evaluate the possible effects of natalizumab on cognition and fatigue measures in RRMS patients treated for up to two years. Methods: Cognitive performances were examined by the Rao’s Brief Repeatable Battery (BRB), the Stroop test (ST) and the Cognitive Impairment Index (CII), every 12 months. Patients who failed in at least 3 tests of the BRB and the ST were classified as cognitively impaired (CI). Fatigue Severity Scale (FSS) was administered every 12 months to assess patient’s selfreported fatigue. One hundred and 53 patients completed 1 and 2 year-natalizumab treatment, respectively. Results: After 1 year of treatment the percentage of CI patients decreased from 29 % (29/100) at baseline to 19 % (19/100) (p = 0.031) and the mean baseline values of CII (13.5266.85) and FSS (4.0161.63) scores were significantly reduced (10.4867.12, p,0.0001 and 3.6161.56, p = 0.008). These significant effects were confirmed in the subgroup of patients treated up to two years. Conclusions: These results demonstrate that a short-term NTZ treatment may significantly improve cognitive performance

An Internet- and Kinect-Based Multiple Sclerosis Fitness Intervention Training With Pilates Exercises: Development and Usability Study

background: balance impairments are common in people with multiple sclerosis (MS), with reduced ability to maintain position and delayed responses to postural adjustments. Pilates is a popular alternative method for balance training that may reduce the rapid worsening of symptoms and the increased risk of secondary conditions (eg, depression) that are frequently associated with physical inactivity.objective: In this paper, we aimed to describe the design, development, and usability testing of MS Fitness Intervention Training (MS-FIT), a Kinect-based tool implementing Pilates exercises customized for MS. methods: MS-FIT has been developed using a user-centered design approach (design, prototype, user feedback, and analysis) to gain the target user's perspective. a team composed of 1 physical therapist, 2 game programmers, and 1 game designer developed the first version of MS-FIT that integrated the knowledge and experience of the team with MS literature findings related to pilates exercises and balance interventions based on exergames. MS-FIT, developed by using the Unity 3D (Unity Technologies) game engine software with kinect Sensor V2 for Windows, implements exercises for breathing, posture, and balance. Feedback from an Italian panel of experts in MS rehabilitation (neurologists, physiatrists, physical therapists, 1 statistician, and 1 bioengineer) and people with MS was collected to customize the tool for use in MS. The context of MS-FIT is traveling around the world to visit some of the most important cities to learn the aspects of their culture through pictures and stories. At each stay of the travel, the avatar of a Pilates teacher shows the user the exercises to be performed. Overall, 9 people with MS (n=4, 44% women; mean age 42.89, SD 11.97 years; mean disease duration 10.19, SD 9.18 years; Expanded Disability Status Scale score 3.17, SD 0.75) were involved in 3 outpatient user test sessions of 30 minutes; MS-FIT's usability was assessed through an ad hoc questionnaire (maximum value=5; higher the score, higher the usability) evaluating easiness to use, playability, enjoyment, satisfaction, and acceptance.Results: A user-centered design approach was used to develop an accessible and challenging tool for balance training. all people with MS (9/9, 100%) completed the user test sessions and answered the ad hoc questionnaire. the average score on each item ranged from 3.78 (SD 0.67) to 4.33 (SD 1.00), which indicated a high usability level. The feedback and suggestions provided by 64% (9/14) of people with MS and 36% (5/14) of therapists involved in the user test were implemented to refine the first prototype to release MS-FIT 2.0. Conclusions: The participants reported that MS-FIT was a usable tool. It is a promising system for enhancing the motivation and engagement of people with MS in performing exercise with the aim of improving their physical status

Pregnancy and fetal outcomes after Glatiramer Acetate exposure in patients with multiple sclerosis: a prospective observational multicentric study.

BACKGROUND: Only few studies have assessed safety of in utero exposure to glatiramer acetate (GA). Following a previous study assessing the safety of interferon beta (IFNB) pregnancy exposure in multiple sclerosis (MS), we aimed to assess pregnancy and fetal outcomes after in utero exposure to GA, using the same dataset, with a specific focus on the risk of spontaneous abortion. MATERIALS AND METHODS: We recruited MS patients, prospectively followed-up in 21 Italian MS Centres, for whom a pregnancy was recorded in the period 2002–2008. Patients were divided into 2 groups: drug-exposed pregnancies (EP: suspension of the drug less than 4 weeks from conception); non-exposed pregnancies (NEP: suspension of the drug at least 4 weeks from conception or never treated pregnancies). All the patients were administered a structured interview which gathered detailed information on pregnancy course and outcomes, as well as on possible confounders. Multivariate logistic and linear models were used for treatment comparisons. RESULTS: Data on 423 pregnancies were collected, 17 were classified as EP to GA, 88 as EP to IFNB, 318 as NEP. Pregnancies resulted in 16 live births in the GA EP, 75 live births in the IFNB EP, 295 live births in the NEP. GA exposure was not significantly associated with an increased risk of spontaneous abortion (OR = 0.44;95% CI 0.044-4.51;p = 0.49). Mean birth weight and length were not significantly different in pregnancies exposed to GA than in non exposed pregnancies (p = 0.751). The frequency of preterm delivery, observed in 4 subjects exposed to GA (25% of full term deliveries), was not significantly higher in pregnancies exposed to GA than in those non exposed (p > 0.735). These findings were confirmed in the multivariate analysis. There were neither major complications nor malformations after GA exposure. CONCLUSIONS: Data in our cohort show that mother’s GA exposure is not associated with a higher frequency of spontaneous abortion, neither other negative pregnancy and fetal outcomes. Our findings point to the safety of in utero GA exposure and can support neurologists in the therapeutic counselling of MS women planning a pregnancy

Epidural analgesia and cesarean delivery in multiple sclerosis post-partum relapses: the Italian cohort study

BACKGROUND: Few studies have systematically addressed the role of epidural analgesia and caesarean delivery in predicting the post-partum disease activity in women with Multiple Sclerosis (MS).The objective of this study was to assess the impact of epidural analgesia (EA) and caesarean delivery (CD) on the risk of post-partum relapses and disability in women with MS. METHODS: In the context of an Italian prospective study on the safety of immunomodulators in pregnancy, we included pregnancies occurred between 2002 and 2008 in women with MS regularly followed-up in 21 Italian MS centers. Data were gathered through a standardized, semi-structured interview, dealing with pregnancy outcomes, breastfeeding, type of delivery (vaginal or caesarean) and EA. The risk of post-partum relapses and disability progression (1 point on the Expanded Disability Status Sclae, EDSS, point, confirmed after six months) was assessed through a logistic multivariate regression analysis. RESULTS: We collected data on 423 pregnancies in 415 women. Among these, 349 pregnancies resulted in full term deliveries, with a post-partum follow-up of at least one year (mean follow-up period 5.5±3.1 years). One hundred and fifty-five patients (44.4%) underwent CD and 65 (18.5%) EA. In the multivariate analysis neither CD, nor EA were associated with a higher risk of post-partum relapses. Post-partum relapses were related to a higher EDSS score at conception (OR=1.42; 95% CI 1.11-1.82; p=0.005), a higher number of relapses in the year before pregnancy (OR=1.62; 95% CI 1.15-2.29; p=0.006) and during pregnancy (OR=3.07; 95% CI 1.40-6.72; p=0.005). Likewise, CD and EA were not associated with disability progression on the EDSS after delivery. The only significant predictor of disability progression was the occurrence of relapses in the year after delivery (disability progression in the year after delivery: OR= 4.00; 95% CI 2.0-8.2; p<0.001; disability progression over the whole follow-up period: OR= 2.0; 95% CI 1.2-3.3; p=0.005). CONCLUSIONS: Our findings, show no correlation between EA, CD and postpartum relapses and disability. Therefore these procedures can safely be applied in MS patients. On the other hand, post-partum relapses are significantly associated with increased disability, which calls for the need of preventive therapies after delivery

SARS-CoV-2 vaccination and multiple sclerosis: a large multicentric study on relapse risk after the third booster dose

Background: COVID-19 vaccines have been recommended to people with multiple sclerosis (pwMS) and, to ensure durable immunity, a third booster dose has been administered in several countries. Data about potential risks associated with the third booster dose in pwMS, such as vaccine-triggered disease exacerbations, are still scarce. Objective: To investigate whether the administration of a third booster dose of mRNA COVID-19 vaccines was associated with an increased risk of short-term disease reactivation in a large cohort of pwMS. Methods: We retrospectively selected 1265 pwMS who received a third booster dose of an mRNA COVID-19 vaccine. Demographic and clinical data were collected, including the presence, number and characteristics of relapses in the 60 days prior to and after the third booster dose. Results: In the selected cohort, the relapse rate in the two months after administration of the third booster dose of mRNA COVID-19 vaccines did not increase when compared with the prior two months. Indeed, the percentage of pwMS experiencing relapses in the 60 days following the administration of the third booster dose was 2.1%, similar to the percentage recorded in 60 days prior to vaccination, which was 1.9%. Conclusions: The third booster dose of mRNA COVID-19 vaccines appeared to be safe for pwMS