Multiple Sclerosis, Relapsing-Remitting
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Publication
Journal: Frontiers in Immunology
February/23/2022
Abstract
Background: Emerging evidence of antibody-independent functions, as well as the clinical efficacy of anti-CD20 depleting therapies, helped to reassess the contribution of B cells during multiple sclerosis (MS) pathogenesis.
Objective: To investigate whether CD19+ B cells may share expression of the serine-protease granzyme-B (GzmB), resembling classical cytotoxic CD8+ T lymphocytes, in the peripheral blood from relapsing-remitting MS (RRMS) patients.
Methods: In this study, 104 RRMS patients during different treatments and 58 healthy donors were included. CD8, CD19, Runx3, and GzmB expression was assessed by flow cytometry analyses.
Results: RRMS patients during fingolimod (FTY) and natalizumab (NTZ) treatment showed increased percentage of circulating CD8+GzmB+ T lymphocytes when compared to healthy volunteers. An increase in circulating CD19+GzmB+ B cells was observed in RRMS patients during FTY and NTZ therapies when compared to glatiramer (GA), untreated RRMS patients, and healthy donors but not when compared to interferon-β (IFN). Moreover, regarding Runx3, the transcriptional factor classically associated with cytotoxicity in CD8+ T lymphocytes, the expression of GzmB was significantly higher in CD19+Runx3+-expressing B cells when compared to CD19+Runx3- counterparts in RRMS patients.
Conclusions: CD19+ B cells may exhibit cytotoxic behavior resembling CD8+ T lymphocytes in MS patients during different treatments. In the future, monitoring "cytotoxic" subsets might become an accessible marker for investigating MS pathophysiology and even for the development of new therapeutic interventions.
Keywords: MS treatment; cytotoxicity; granzyme B; neurodegeneration; neuroinflammation.
Publication
Journal: BMC Neurology
February/22/2022
Abstract
Background: Some current evidence is pointing towards an association between COVID-19 and worsening of multiple sclerosis (MS), stressing the importance of preventing COVID-19 among people with MS (pwMS). However, population-based evidence regarding the long-term post-COVID-19 course of relapsing-remitting multiple sclerosis (RRMS) was limited when this study was initiated.
Objective: To detect possible changes in MS clinical disease activity after COVID-19.
Methods: We conducted an observational study from July 2020 until July 2021 in the Isfahan MS clinic, comparing the trends of probable disability progression (PDP) - defined as a three-month sustained increase in expanded disability status scale (EDSS) score - and relapses before and after probable/definitive COVID-19 diagnosis in a cohort of people with RRMS (pwRRMS).
Results: Ninety pwRRMS were identified with definitive COVID-19, 53 of which were included in the final analysis. The PDP rate was significantly (0.06 vs 0.19, P = 0.04), and the relapse rate was insignificantly (0.21 vs 0.30, P = 0.30) lower post-COVID-19, compared to the pre-COVID-19 period. The results were maintained after offsetting by follow-up period in the matched binary logistic model. Survival analysis did not indicate significant difference in PDP-free (Hazard Ratio [HR] [95% CI]: 0.46 [0.12, 1.73], P = 0.25) and relapse-free (HR [95% CI]: 0.69 [0.31, 1.53], P = 0.36) survivals between the pre- and post-COVID-19 periods. Sensitivity analysis resulted similar measurements, although statistical significance was not achieved.
Conclusion: While subject to replication in future research settings, our results did not confirm any increase in the long-term clinical disease activity measures after COVID-19 contraction among pwRRMS.
Keywords: COVID-19; Demyelinating diseases; Disease progression; Multiple sclerosis; Neuroinflammation.
Publication
Journal: Nature Reviews Neurology
February/21/2022
Abstract
Despite the development of highly effective treatments for relapsing-remitting multiple sclerosis (MS), limited progress has been made in addressing primary progressive or secondary progressive MS, both of which lead to loss of oligodendrocytes and neurons and axons, and to irreversible accumulation of disability. Neuroinflammation is central to all forms of MS. The current effective therapies for relapsing-remitting MS target the peripheral immune system; these treatments, however, have repeatedly failed in progressive MS. Greater understanding of inflammation driven by CNS-resident cells - including astrocytes and microglia - is, therefore, required to identify novel potential therapeutic opportunities. Advances in imaging, biomarker analysis and genomics suggest that microglia and astrocytes have central roles in the progressive disease process. In this Review, we provide an overview of the involvement of astrocytes and microglia at major sites of pathology in progressive MS. We discuss current and future therapeutic approaches to directly target glial cells, either to inhibit pathogenic functions or to restore homeostatic functions lost during the course of the disease. We also discuss how bidirectional communication between astrocytes and microglia needs to be considered, as therapeutic targeting of one is likely to alter the functions of the other.
Publication
Journal: Asia Pacific Allergy
February/20/2022
Abstract
Background Multiple sclerosis is a chronic, demyelinating disorder occurring primarily as two main forms of relapsing-remitting multiple sclerosis (RRMS) found predominantly in women, and primary progressive multiple sclerosis (PPMS) occurring predominantly in men. In this retrospective single-center study, we aimed to explore the effects of anti-cluster of differentiation (CD)20 treatment for both relapsing-remitting and primary progressive forms of multiple sclerosis (MS) in a population-based cohort treated at the university hospital. Methodology The diagnostic factors being assessed were forms of multiple sclerosis (MS), age at first relapse, whereas therapeutic factors were age at first disease-modifying therapy (DMT), age at starting anti-CD20, reason to switch to anti-CD20 and the duration of anti-CD20 treatment. Primary outcomes measured were number of relapses and progression in disability as measured by the Expanded Disability Status Scale, while secondary outcomes measures being assessed number of cerebral lesions on MRI and level of IgG at the beginning and end of the 12-month treatment. Results Treatment with anti-CD20 demonstrated a reduction in number of relapses 12 months after treatment, no change in the progression of disability in RRMS type, but an increase in PPMS type. No change was observed in cerebral MRI lesions at the end of treatment after 12 months. A statistically significant reduction in serum IgG value was observed after 12 months from the start of treatment, where only one out of 26 (3.8%) patients developed hypogammaglobulinemia with IgG less than 6 g/L but none developed hypogammaglobulinemia of less than 5 g/L. Conclusion Anti-CD20 antibodies as disease-modifying therapy can profoundly impact the course and progression of MS in both its forms if utilized at an earlier stage in patients and therefore greatly improve the quality of life in patients living with multiple sclerosis.
Keywords: anti cd-20; disease-modifying therapy; multiple sclerosis; multiple sclerosis phenotypes; quality of life.
Publication
Journal: Frontiers in Immunology
February/20/2022
Abstract
Background: B cells can contribute to immune-mediated disorders. Targeting CD20 has proved to be efficacious in several B cell-mediated immunopathologies, as illustrated by the use of rituximab, the first anti-CD20 monoclonal antibody (mAb). Following rituximab, second- and third-generation anti-CD20 mAbs have been developed and tried in immune-mediated diseases, including obinutuzumab, ocrelizumab, ofatumumab, ublituximab, and veltuzumab. However, their safety and efficacy has not been systematically reviewed.
Objective: To evaluate safety and efficacy of obinutuzumab, ocrelizumab, ofatumumab, ublituximab, and veltuzumab for the treatment of immune-mediated disorders compared to placebo, conventional treatment or other biologics.
Methods: The PRISMA checklist guided the reporting of the data. We searched the PubMed database between 4 October 2016 and 22 July 2021 concentrating on immune-mediated disorders.
Results: The literature search identified 2220 articles. After screening titles and abstracts against the inclusion and exclusion criteria and assessing full texts, 27 articles were finally included in a narrative synthesis.
Conclusions: Obinutuzumab has shown promising results in a case series of patients with phospholipase A2 receptor-associated membranous nephropathy and mixed results in systemic lupus erythematosus. Ocrelizumab has been approved for the use in patients with relapsing-remitting multiple sclerosis and primary progressive multiple sclerosis. Ocrelizumab was also tested in patients with rheumatoid arthritis, demonstrating promising results, and in systemic lupus erythematosus, revealing mixed results; however, in these conditions, its use was associated with increased risk of serious infections. Ofatumumab received approval for treating patients with relapsing-remitting multiple sclerosis. Moreover, ofatumumab showed promising results in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis, rheumatoid arthritis, and systemic lupus erythematosus, as well as mixed results in phospholipase A2 receptor-associated membranous nephropathy. Ublituximab was assessed in relapsing-remitting multiple sclerosis and neuromyelitis optica spectrum disorder, with promising results, however, the included number of patients was too small to conclude. Veltuzumab was tested in patients with immune thrombocytopenia resulting in improved platelet counts.
Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD4201913421.
Keywords: immune-mediated diseases; multiple sclerosis; obinutuzumab; ocrelizumab; ofatumumab; systemic lupus erythematosus; ublituximab; veltzumab.
Publication
Journal: Biomedicine and Pharmacotherapy
February/19/2022
Abstract
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS). Dysregulated immune responses have been implicated in MS development. Growing evidence has indicated that inhibitory immune checkpoint molecules can substantially regulate immune responses and maintain immune tolerance. V-domain Ig suppressor of T cell activation (VISTA) is a novel inhibitory immune checkpoint molecule that can suppress immune responses; however, its expression pattern in the peripheral blood mononuclear cells (PBMCs) of relapsing-remitting multiple sclerosis (RRMS) has not thoroughly been studied. Herein, we evaluated Vsir expression in PBMCs of RRMS patients and characterized the expression pattern of the Vsir in the PBMCs of MS patients. Besides, we investigated the effect of fingolimod, IFNβ-1α, glatiramer acetate (GA), and dimethyl fumarate (DMF) on Vsir expression in PBMCs of RRMS patients. Our results have shown that Vsir expression is significantly downregulated in the PBMCs of patients with RRMS. Besides, the single-cell RNA sequencing results have demonstrated that Vsir expression is downregulated in classical monocyte, intermediate monocytes, non-classical monocytes, myeloid DCs (mDC), Plasmacytoid dendritic cells (pDCs), and naive B-cells of PBMCs of MS patients compared to the control. In addition, DMF, IFNβ-1α, and GA have significantly upregulated Vsir expression in the PBMCs of RRMS patients. Collectively, the current study has shed light on Vsir expression in the PBMCs of MS patients; however, further studies are needed to elucidate the significance of VISTA in the mentioned immune cells.
Keywords: Immune checkpoint; Multiple sclerosis; Single-cell transcriptomics; VISTA; Vsir.
Publication
Journal: Revue Neurologique
February/18/2022
Abstract
Background: Six monthly courses of mitoxantrone were approved in France in 2003 for patients with highly active multiple sclerosis (MS).
Objective: To report the 10-year clinical follow-up and safety of mitoxantrone as an induction drug followed by maintenance therapy in patients with early highly active relapsing-remitting MS (RRMS) and an Expanded Disability Status Scale (EDSS) score<4, 12months prior to mitoxantrone initiation.
Methods: In total, 100 consecutive patients with highly active RRMS from the Rennes EDMUS database received monthly mitoxantrone 20mg combined with methylprednisolone 1g for 3 (n=75) or 6months (n=25) followed by first-line disease-modifying drug (DMD). The 10-year clinical impact was studied through clinical activity, DMD exposure, and adverse events.
Results: Twenty-four percent were relapse-free over 10years and the mean annual number of relapses was 0.2 at 10years. The mean EDSS score remained significantly improved for up to 10years, changing from 3.5 at mitoxantrone initiation to 2.7 at 10years. The probability of disability worsening and improvement from mitoxantrone initiation to 10years were respectively 27% and 58%, and 13% converted to secondary progressive MS. Patients only remained untreated or treated with a first-line maintenance DMD for 6.5years in average. In our cohort, mitoxantrone was generally safe. No leukemia was observed and six patients developed neoplasms, including 4 solid cancers.
Conclusion: Monthly mitoxantrone for 3 or 6months, followed by maintenance first-line treatment, may be an attractive therapeutic option for patients with early highly active RRMS, particularly in low-income countries.
Keywords: Disease-modifying therapies; Mitoxantrone; Multiple sclerosis.
Publication
Journal: Restorative Neurology and Neuroscience
February/17/2022
Abstract
Background: Multiple sclerosis (MS) is associated with progressive brain atrophy, which in turn correlates with disability, depression, and cognitive impairment. Relapsing-remitting multiple sclerosis (RRMS) is a type of MS in which relapses of the disease are followed by remission periods. This is the most common type of the disease. There is a significant need for easy and low-cost methods to these cerebral changes. Changes in retinal layer thickness may reflect alterations in brain white and gray matter volumes. Therefore, this paper aims to determine whether retinal layer thickness, measured using optical coherence tomography (OCT), correlates with volumetric brain assessments obtained by magnetic resonance imaging (MRI).
Methods: This retrospective cohort study recruited 53 patients with relapsing-remitting MS who underwent MRI and OCT examinations for evaluation of brain compartment volumes and thickness of retinal layers, respectively. OCT parameters, including central retinal thickness; retinal nerve fiber layer thickness (RNFL, peripapillary thickness); ganglion cell complex thickness (GCC, macular thickness); and Expanded Disability Status Scale (EDSS) results were compared with MRI parameters (cerebral cortex; cerebral cortex and basal ganglia combined; brain hemispheres without the ventricular system; and white matter plaques). We also checked whether there is a correlation between the number of RRMS and OCT parameters.
Objective: Our primary objective was to identify whether these patients had retinal thickness changes, and our secondary objective was to check if those changes correlated with the MRI brain anatomical changes.
Results: RNFL and GCC thicknesses were strongly (p-value < 0.05) associated with (i) cerebral cortex volume, (ii) combination of brain cortex and basal ganglia volumes, and (iii) the hemispheres but without the ventricular system. White matter plaques (combined) showed only weak or no correlation with RNFL and GCC. There was no correlation between central retinal thickness and brain compartment volumes, and there were weak or no correlations between the summary EDSS scores and OCT results.
Conclusions: Retinal layer thickness measured by OCT correlates with select volumetric brain assessments on MRI. During the course of RRMS, the anatomo-pathological structure of the retina might serve as a surrogate marker of brain atrophy and clinical progression within selected domains.
Keywords: Multiple sclerosis; brain atrophy; cognitive impairment; optic neuritis; optical coherence tomography.
Publication
Journal: Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova
February/16/2022
Abstract
Objective: To evaluate the efficacy and safety of samPEG-IFN-β1a 180 μg and 240 μg administered once every 2 weeks for the treatment of relapsing remitting multiple sclerosis (RRMS) compared to placebo and low dose interferon beta-1a (LIB) 30 μg administered once weekly. The primary endpoint after 52 weeks of therapy was the time to first relapse, the hypotheses of non-inferiority and superiority to LIB were tested.
Material and methods: This international, multicenter, double blind, comparative, placebo-controlled clinical study enrolled 399 patients with the diagnosis of RRMS, randomized in 4 groups: samPEG-IFN-β1a180 μg (n=114), samPEG-IFN-β1a 240 μg (n=114), LIB (n=114) and placebo (n=57). Placebo group patients participated in the study for 20 weeks. After 52 weeks of therapy and 4 weeks of follow-up, LIB group patients completed their participation in the study, patients from PEG-IFN-β1a groups continued to receive therapy until week 100 inclusive. The article presents the results of an analysis conducted after the end of 52 weeks of a double-blind, comparative, randomized, placebo-controlled clinical trial.
Results: Final analysis of the efficacy and safety was performed after 52 weeks of study. Main statistical hypothesis testing proved that both doses of samPEG-IFN-β1a were equally effective when compared to LIB by the primary endpoint - «Time to first relapse». Due to detection of statistically significant differences in the primary endpoint between the study drug and the reference drug, indicating a greater efficacy of the study drug, an additional testing was carried out and the hypothesis of superiority of samPEG-IFN-β1a at a dose of 240 μg over the reference LIB was proved. Evaluation of the dynamics of certain key parameters of magnetic resonance imaging (MRI) of the brain and clinical outcomes demonstrated a positive effect of samPEG-IFN-β1a therapy in the form of decreased activity of the demyelinating process in the brain and reduce the number of relapses. The proportion of patients without new T2 lesions after 52 weeks was 87.6% and 90.4% in 180 μg and 240 μg samPEG-IFN-β1a groups, versus 72.6% in the LIB group (p=0.0199 and p=0.0033). No progression of multiple sclerosis was shown based on EDSS scale evaluation. During the study, the most common adverse reactions were flu-like symptoms and injection site reactions.
Conclusion: The new drug samPEG-IFN-β1a is an effective and safe agent for relapsing remitting multiple sclerosis treatment, while having an advantage over other low-dose interferons in the form of reduced frequency of intramuscular injections.
Цель исследования: Изучение эффективности и безопасности применения препарата сампэгинтерферона β-1a (самПЭГ-ИФН-β1a) в дозах 180 и 240 мкг (1 раз в 2 нед) для лечения ремиттирующего рассеянного склероза (РРС) в сравнении с плацебо и препаратом низкодозного интерферона β (НИБ) 30 мкг (1 раз в неделю). Первичной конечной точкой после 52 нед терапии являлся показатель «Время до первого обострения», для которого были оценены гипотезы неменьшей эффективности и превосходства по отношению к НИБ.
Материал и методы: В международном многоцентровом слепом сравнительном плацебо-контролируемом исследовании (КИ) приняли участие 399 пациентов с РРС, которые были рандомизированы в четыре группы: самПЭГ-ИФН-β1a 180 мкг (n=114), самПЭГ-ИФН-β1a 240 мкг (n=114), НИБ (n=114) и плацебо (n=57). Пациенты группы плацебо принимали участие в исследовании на протяжении 20 нед. После 52 нед терапии и 4 нед наблюдения пациенты группы НИБ завершили участие в исследовании, пациенты групп самПЭГ-ИФН-β1a продолжили получать лечение до недели 100 включительно. В статье приводятся результаты анализа, проведенного после окончания 52 нед двойного слепого сравнительного рандомизированного плацебо-контролируемого периода исследования.
Результаты: Через 52 нед терапии был выполнен итоговый анализ показателей эффективности и безопасности. При проверке основной статистической гипотезы исследования доказана неменьшая эффективность обеих доз самПЭГ-ИФН-β1a по отношению к препарату сравнения НИБ по первичной конечной точке — «Время до первого обострения». В связи с обнаружением статистически значимых различий по первичной конечной точке между исследуемым препаратом и препаратом сравнения, свидетельствующих о большей эффективности исследуемого препарата, была проведена дополнительная оценка и доказана гипотеза превосходства самПЭГ-ИФН-β1a в дозе 240 мкг над препаратом сравнения НИБ. Оценка динамики ключевых параметров МРТ головного мозга и клинических показателей продемонстрировала положительный эффект от применяемой терапии самПЭГ-ИФН-β1a в виде снижения активности демиелинизирующего процесса в головном мозге и уменьшения количества обострений. Доля пациентов без новых очагов при МРТ в T2-режиме после 52 нед составила 87,6 и 90,4% в группах препарата самПЭГ-ИФН-β1a 180 и 240 мкг против 72,6% в группе НИБ (p=0,0199 и p=0,0033). Было показано отсутствие прогрессирования течения РС при оценке по шкале EDSS. В ходе исследования наиболее частыми нежелательными реакциями были гриппоподобный синдром и реакции в месте введения.
Заключение: Препарат самПЭГ-ИФН-β1a является эффективным и безопасным средством для лечения РРС, обладая преимуществом перед другими низкодозными препаратами интерферона в виде снижения частоты внутримышечных инъекций.
Keywords: DMT; RRMS; multiple sclerosis; pegylated interferon beta-1a; samPEG-IFN-β1a.
Publication
Journal: Journal of Rehabilitation Medicine
February/16/2022
Abstract
Long-term physiotherapy is of considerable benefit to patients with motor dysfunction or gait impairment in patients with multiple sclerosis (MS). The aim of this study was to determine the effectiveness of 12-week intensive circuit class therapy (ICT) for patients with MS, with a wider focus on fatigue and gait ability. Methods: A total of 46 relapsing-remitting MS patients were divided randomly: Twenty-three of them (mean Expanded Disability Status Scale (EDSS) 2.33±0.74) took part in an intensive 12-week course of ICT and 23 (mean EDSS 2.04±0.63) served as a control group. The EDSS, Timed Up and Go (TUG) test and Four-Stage Balance Test (FSBT) made up the physical testing part, supplemented by questionnaires such as the Modified Fatigue Impact Scale (MFIS), 12-Item Multiple Sclerosis Walking Scale (MSWS-12), Beck Depression Inventory (BDI) and 36-Item Short Form Survey (SF-36). Results: Significant improvements were found among ICT-exercising patients in FSBT (p<0.05), TUG test (p<0.01), MFIS (p<0.01), BDI (p<0.05), MSWS-12 (p<0.05) and the three subscales of SF-36 after 12 weeks of ICT, while there were no significant changes in the control group. ICT-exercising patients exhibited significant improvements in FSBT (p=0.005), TUG test (p=0.005), MFIS (p=0.001), BDI (p=0.002), MSWS-12 (p=0.001) and the three subscales of SF-36 after 12 weeks of ICT compared to control group. Conclusion: Intensive circuit class therapy is an effective therapeutic approach for improving gait and balance problems in patients with MS. It has also proved to alleviate fatigue and symptoms of depression.
Publication
Journal: Therapeutic Advances in Neurological Disorders
February/16/2022
Abstract
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Publication
Journal: International Journal of Molecular Sciences
February/14/2022
Abstract
Teriflunomide (TFN) limits relapses in relapsing-remitting multiple sclerosis (RRMS) by reducing lymphocytic proliferation through the inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) and the subsequent modulation of de novo pyrimidine synthesis. Alterations of mitochondrial function as a consequence of oxidative stress have been reported during neuroinflammation. Previously, we showed that TFN prevents alterations of mitochondrial motility caused by oxidative stress in peripheral axons. Here, we aimed to validate TFN effects on mitochondria and neuronal activity in hippocampal brain slices, in which cellular distribution and synaptic circuits are largely preserved. TFN effects on metabolism and neuronal activity were investigated by assessing oxygen partial pressure and local field potential in acute slices. Additionally, we imaged mitochondria in brain slices from the transgenic Thy1-CFP/COX8A)S2Lich/J (mitoCFP) mice using two-photon microscopy. Although TFN could not prevent oxidative stress-related depletion of ATP, it preserved oxygen consumption and neuronal activity in CNS tissue during oxidative stress. Furthermore, TFN prevented mitochondrial shortening and fragmentation of puncta-shaped and network mitochondria during oxidative stress. Regarding motility, TFN accentuated the decrease in mitochondrial displacement and increase in speed observed during oxidative stress. Importantly, these effects were not associated with neuronal viability and did not lead to axonal damage. In conclusion, during conditions of oxidative stress, TFN preserves the functionality of neurons and prevents morphological and motility alterations of mitochondria.
Keywords: acute hippocampal slices; dihydroorotate dehydrogenase (DHODH); mitochondria; mitochondrial morphology; mitochondrial motility; multiple sclerosis; neurodegeneration; oxidative stress; teriflunomide (TFN); two-photon microscopy.
Publication
Journal: International Journal of Molecular Sciences
February/14/2022
Abstract
Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS). Its first clinical presentation (clinically isolated syndrome, CIS) is often followed by the development of relapsing-remitting MS (RRMS). The periphery-to-CNS transmission of inflammatory molecules is a major pathophysiological pathway in MS. This could include signalling via extracellular vesicle (EV) microRNAs (miRNAs). In this study, we investigated the serum EV miRNome in CIS and RRMS patients and matched controls, with the aims to identify MS stage-specific differentially expressed miRNAs and investigate their biomarker potential and pathophysiological relevance. miRNA sequencing was conducted on serum EVs from CIS-remission, RRMS-relapse, and viral inflammatory CNS disorder patients, as well as from healthy and hospitalized controls. Differential expression analysis was conducted, followed by predictive power and target-pathway analysis. A moderate number of dysregulated serum EV miRNAs were identified in CIS-remission and RRMS-relapse patients, especially relative to healthy controls. Some of these miRNAs were also differentially expressed between the two MS stages and had biomarker potential for patient-control and CIS-RRMS separations. For the mRNA targets of the RRMS-relapse-specific EV miRNAs, biological processes inherent to MS pathophysiology were identified using in silico analysis. Study findings demonstrate that specific serum EV miRNAs have MS stage-specific biomarker potential and contribute to the identification of potential targets for novel, efficacious therapies.
Keywords: biomarker; clinically isolated syndrome; extracellular vesicles; inflammation; microRNA; pathophysiology; relapsing–remitting multiple sclerosis.
Publication
Journal: Multiple Sclerosis and Related Disorders
February/14/2022
Abstract
Background: A diagnosis of multiple sclerosis (MS) can be categorized based on its disease course into the following phenotypes: relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS). With one exception, studies of MS by phenotype either provide only prevalence data or if describing drug utilization, the emphasis is on patients with RRMS; while drug utilization by phenotype tends to be examined over the course of a year. No recent studies have comprehensively evaluated MS phenotypes by prevalence, drug utilization, and comorbidities over time from a population-based perspective, which is essential for understanding the disease burden and identifying unmet needs in MS. Germany is one of the few countries where specific MS phenotypes are commonly recorded in routine clinical practice. The purpose of this study was to compare MS phenotypes with respect to changes in their population-based prevalence rates and the types of MS treatments prescribed over time, as well as the frequency of clinical conditions associated with MS based on data from a German health insurance database.
Methods: This retrospective, observational, cohort study used data from a German health insurance database for the period 2010 to 2017. Patients aged 18+ years with a specified phenotype of MS based on ICD-10 diagnosis coding were included in the analysis.
Results: In 2010, RRMS was reported in 73%, PPMS in 8%, and SPMS in 19% of patients with MS with a known phenotype. The mean ages of patients were 41.4, 53.6, and 52.8 years, respectively, and all phenotypes were associated with a female predominance (69%, 63% and 63%, respectively). The prevalence rate of each phenotype markedly increased during the study period (RRMS +113%, PPMS +40%, SPMS +54%; in 2017 the rates were 183, 14, and 34 per 100,000, respectively). The mean age of patients reporting each phenotype also increased (p<0.01), while the female:male proportion remained stable in RRMS and SPMS, the proportion of females significantly declined over time in the PPMS group. The overall percentage of patients prescribed a disease-modifying drug increased across the phenotypes from 51% to 57%. Prescription of interferon-based therapies declined in each phenotype, with the greatest declines observed in RRMS and PPMS. The PPMS and SPMS groups had significantly more prescriptions for symptom management than the RRMS group. Depression was the most prevalent clinical condition associated with each phenotype. There was a significant difference in the percentage of patients with depression across the phenotypes (p = 0.03), with the highest among SPMS (44%) compared with RRMS (35%) or PPMS (37%). Significant differences (p<0.05) across the phenotypes were also observed for the composite prevalence of cardiovascular conditions (highest in PPMS) and cognitive dysfunction (highest in SPMS).
Conclusion: The increasing numbers of patients across each MS phenotype, aging population in patients with MS regardless of phenotype, gender differences and variations across the types of treatments prescribed, and clinical conditions associated with each MS phenotype present new insight into the disease burden and treatment strategies of MS. These should be considered when developing healthcare strategies and optimizing care for patients with MS.
Keywords: Drug utilization; Epidemiology; Multiple sclerosis; Primary progressive multiple sclerosis; Relapsing-remitting multiple sclerosis; Secondary progressive multiple sclerosis.
Publication
Journal: Multiple Sclerosis and Related Disorders
February/14/2022
Abstract
Background: Early intervention with well-tolerated disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) is recommended in order to delay disease progression, reduce neurologic damage, preserve brain volume, and optimize long-term patient outcomes. Lack of conversion of new/newly enlarging T2 (NET2) or gadolinium-enhancing (Gd+) lesions to chronic hypointensities (black hole conversion) and achievement of no evidence of disease activity (NEDA) early in the course of treatment are considered potential indicators of treatment effect and predictors of longer-term clinical outcomes.
Methods: Patients with RRMS who were treated with peginterferon beta-1a in the 2-year ADVANCE phase 3 clinical trial (NCT0090639) and its 2-year open-label extension study, ATTAIN (NCT01332019), were grouped as newly diagnosed (diagnosed ≤1 year prior to enrollment and DMT naive) or non-newly diagnosed. For analyses of the impact of early treatment and disease activity control, the newly diagnosed and non-newly diagnosed subgroups were further divided based on whether they initiated peginterferon beta-1a every 2 weeks (Q2W) starting in study year 1 (continuously treated) or peginterferon beta-1a Q2W or every 4 weeks in study year 2 (delayed treatment). Patient subgroups were evaluated for conversion of NET2 or Gd+ lesions to persistent black holes (PBHs), brain atrophy (percentage change in whole brain volume [WBV]), achievement of NEDA composite outcomes, and the association of these disease activity measures with longer-term clinical outcomes (annualized relapse rate [ARR] and confirmed disability worsening [CDW]).
Results: At 2 years, significantly fewer PBHs developed from NET2 lesions or Gd+ lesions in newly diagnosed and non-newly diagnosed patients continuously treated with peginterferon beta-1a than in the corresponding delayed-treatment groups (all p<0.0001). Percentage decrease in WBV from 6 months (rebaselined) to 2 years was significantly lower for newly diagnosed and non-newly diagnosed patients who received continuous peginterferon beta-1a treatment than for patients who received delayed treatment (both p ≤ 0.0442). In study year 1, a higher proportion of newly diagnosed and non-newly diagnosed patients treated with peginterferon beta-1a than those treated with placebo achieved NEDA (newly diagnosed: 28.3% vs 13.5% [p = 0.0010]; non-newly diagnosed: 40.8% vs 15.8% [p<0.0001]). NEDA rates remained stable over study years 2-4 for the newly diagnosed (range: 50.0%-53.9%) and non-newly diagnosed (range: 54.4%-57.0%) subgroups. Patients without PBH conversion had significantly lower ARR at 2 years (newly diagnosed: p = 0.0109; non-newly diagnosed: p = 0.0044) and a lower proportion of patients with 12-week CDW at 2 years (newly diagnosed: p = 0.2787; non-newly diagnosed: p = 0.0045) than the corresponding patient subgroups with PBH conversion. Patients who achieved NEDA in ADVANCE (study years 1-2) had a significantly lower ARR in ATTAIN (study years 3-4) than patients who did not achieve NEDA (newly diagnosed, p = 0.0003; non-newly diagnosed, p = 0.0001). Over 4 years, safety outcomes did not differ for the newly diagnosed and non-newly diagnosed patient subgroups.
Conclusions: These results indicate that newly diagnosed and non-newly diagnosed patients treated continuously with peginterferon beta-1a Q2W experienced better disease control over time than those who received delayed treatment. Patients with NEDA or evidence of less radiological disease activity in the first 2 years of treatment had better longer-term clinical outcomes than those with evidence of greater disease activity.
Keywords: Brain atrophy; Early treatment; No evidence of disease activity; Peginterferon beta-1a; Persistent T1 hypointensities.
Publication
Journal: European Journal of Neurology
February/14/2022
Abstract
Background: The Bacillus Calmette-Guerin (BCG) vaccine could reduce the incidence of multiple sclerosis (MS) through immunomodulation. Previous studies, presenting some limitations, reported no association. We re-examined this association in a large cohort focusing on relapsing-remitting MS (RRMS).
Methods: The cohort included 400,563 individuals, and was linked with the Quebec provincial BCG vaccination registry and administrative health data. Individuals were followed-up from 1983 to 2014 and then within period 1 (1983-1996) and period 2 (1997-2014), for the occurrence of MS. Incident MS cases were defined as those with ≥3 hospital or physician claims for MS. Subjects with ≥1 drug reimbursement for MS disease-modifying therapies were classified as RRMS. Cox proportional hazards regression was used to estimate hazard ratios (HR) over the follow-ups, adjusting for potential confounders. Possible effect modification due to sex was assessed.
Results: A total of 178,335 (46%) individuals were BCG vaccinated. There were 274 (0.06%) incident MS cases identified in 1983-1996, and 1,433 (0.4%) in 1997-2014. No association was found with RRMS, either in period 1 (adjusted HRs= 0.96, 95% confidence interval: 0.63-1.45; 96 cases) or in period 2 (HRadj= 1.02, 0.85-1.23; 480 cases). The remaining MS cases, for whom the phenotype was unknown, were positively associated with BCG over the entire follow-up (HRadj= 1.25, 1.10-1.41; 1,131 cases) and in period 2 (HRadj=1.33, 1.17-1.52; 953 cases). No interaction with sex was found.
Conclusion: Findings suggest that BCG vaccination does not decrease the risk of RRMS, and that future studies should consider phenotypes of MS.
Keywords: Adult; Bacillus Calmette-Guerin vaccination; Population-based cohort study; Risk factor; relapsing-remitting multiple sclerosis.
Publication
Journal: Multiple Sclerosis and Related Disorders
February/14/2022
Abstract
Background: Multiple Sclerosis is the most common chronic demyelinating disease of the central nervous system, representing the main cause of non-traumatic disabling disorders in young adults. The etiology of Multiple Sclerosis is not fully appreciated, although strong evidence points to genetic and environmental factors. The role of the gut microbiome in Multiple Sclerosis pathogenesis is a rapidly emerging area of study in that field.
Aim: The aim of the present study is to identify the gut microbiome that are likely related to Multiple Sclerosis as well as their possible role in the susceptibility and the course of the disease.
Methods: Thirty Egyptian patients with relapsing remitting multiple sclerosis, who presented to the Multiple Sclerosis Clinic of Alexandria University Hospital were enrolled in the study. These were diagnosed according to the McDonald 2017 criteria. A cross matching control group of 20 healthy subjects of similar age and sex was included. Stool specimens were taken from each for detection of gut microbiome profile by quantitative SYBR Green Real Time PCR assay.
Results: The present study demonstrate that RRMS patients have a distinct gut microbiome compared to healthy controls, with certain gut microbes showing decreased or increased abundance in Multiple Sclerosis patients compared to controls. Multiple Sclerosis patients have significantly higher B. fragilis than the normal control. Although the level of Prevotella, and Lactobacilli appear much less in MS patients than the control, the difference was not statistically significant. The same for C. perfringes which was higher in Multiple Sclerosis patients.
Conclusion: The overall results of the study agree with previous studies reporting that patients with Multiple Sclerosis in Egypt exhibit microbial gut dysbiosis. However, the results of individual bacteria may differ, according to the age, treatment, level of physcial exercise and type of therapy at the time of enrollment.
Keywords: 16S rRNA; Dysbiosis; Gut microbiome; Multiple sclerosis; Real time PCR.
Publication
Journal: Multiple Sclerosis and Related Disorders
February/11/2022
Abstract
Background: Alemtuzumab is an anti-CD52 antibody approved for the treatment of relapsing remitting multiple sclerosis (RRMS). The summary of product characteristics (SmPC) provides recommendations on the administration of alemtuzumab to prevent or reduce the risk of serious side effects associated with alemtuzumab infusion, including myocardial ischemia, hemorrhagic stroke, arterial dissection, and pulmonary alveolar hemorrhage. However, real-world implementation of alemtuzumab infusion management recommendations has not been previously assessed.
Methods: Here we provide a large-scale multi-center (in- and outpatient) observational study on alemtuzumab infusion management in daily clinical care in Germany (ALEMLL08025; INFUSE-MS; NIS-no. 364). Parameters of infusion management - including infusion administration, clinical and laboratory monitoring - were assessed, compared between study centers and the occurrence of infusion-associated reactions (IARs) was documented. Moreover, the TSQM and MSIS-29 questionnaires were used to quantify patient satisfaction and health-related quality of life.
Results: 140 RRMS patients were enrolled in this study. Alemtuzumab infusion regimes (treatment course 1 and 2) were comparable between infusion sites and in accordance with recommendations by the SmPC. Standardization of infusion management was associated with a satisfactory safety profile. IARs were usually mild, headache (13.6%), rash (10.7%), and pyrexia (6.4%) being the most common ones. TSQM and MSIS-29 scores denoted high patient satisfaction and health-related quality of life among RRMS patients treated with alemtuzumab.
Conclusion: In conclusion, our results indicate that infusion management of alemtuzumab is highly standardized and in line with the SmPC. Alemtuzumab treatment and implementation of infusion management recommendations are associated with a satisfactory safety profile regarding the occurrence of IARs, a high patient satisfaction and health-related quality of life as important indicators for the quality of MS care.
Keywords: Multiple sclerosis; alemtuzumab; infusion management; infusion-associated reactions.
Publication
Journal: Immunity
February/11/2022
Abstract
Type I interferons (IFNs) are pleiotropic cytokines with potent antiviral properties that also promote protective T cell and humoral immunity. Paradoxically, type I IFNs, including the widely expressed IFNβ, also have immunosuppressive properties, including promoting persistent viral infections and treating T-cell-driven, remitting-relapsing multiple sclerosis. Although associative evidence suggests that IFNβ mediates these immunosuppressive effects by impacting regulatory T (Treg) cells, mechanistic links remain elusive. Here, we found that IFNβ enhanced graft survival in a Treg-cell-dependent murine transplant model. Genetic conditional deletion models revealed that the extended allograft survival was Treg cell-mediated and required IFNβ signaling on T cells. Using an in silico computational model and analysis of human immune cells, we found that IFNβ directly promoted Treg cell induction via STAT1- and P300-dependent Foxp3 acetylation. These findings identify a mechanistic connection between the immunosuppressive effects of IFNβ and Treg cells, with therapeutic implications for transplantation, autoimmunity, and malignancy.
Keywords: CTLA-4 Ig; Foxp3; acetylation; interferon-beta; regulatory T cells; transplant.
Publication
Journal: Neurology and Therapy
February/10/2022
Abstract
Introduction: It is important to confirm the effectiveness and tolerability of disease-modifying treatments for relapsing-remitting multiple sclerosis (RRMS) in real-world treatment settings. This prospective observational cohort study (VIRGILE) was performed at the request of the French health authorities. The primary objective was to evaluate the effectiveness of fingolimod 0.5 mg in reducing the annualised relapse rate (ARR) in patients with RRMS.
Methods: Participating neurologists enrolled all adult patients with RRMS starting fingolimod treatment between 2014 and 2016, who were followed for 3 years. Follow-up consultations took place at the investigator's discretion. The primary outcome measure was the change in ARR at month 24 after fingolimod initiation. Relapses and adverse events were documented at each consultation; disability assessment (EDSS) and magnetic resonance imagery were performed at the investigator's discretion.
Results: Of 1055 eligible patients, 633 patients were assessable at month 36; 405 (64.0%) were treated continuously with fingolimod for 3 years. The ARR decreased from 0.92 ± 0.92 at inclusion to 0.31 ± 0.51 at month 24, a significant reduction of 0.58 [95% CI - 0.51 to - 0.65] relapses/year (p < 0.001). Since starting fingolimod, 461 patients (60.9%) remained relapse-free at month 24 and 366 patients (55.5%) at month 36. In multivariate analysis, no previous disease-modifying treatment, number of relapses in the previous year and lower EDSS score at inclusion were associated with a greater on-treatment reduction in ARR. The mean EDSS score remained stable over the course of the study. Sixty-one out of 289 (21.1%) patients presented new radiological signs of disease activity. Treatment-related serious adverse events were lymphopenia (N = 21), bradycardia (N = 19), elevated transaminases (N = 9) and macular oedema (N = 9).
Conclusions: The effectiveness and tolerability of fingolimod in everyday clinical practice are consistent with findings of previous phase III studies. Our study highlights the utility of fingolimod for the long-term management of patients with multiple sclerosis.
Keywords: Disability; Disease-modifying treatment; Effectiveness; Quality of life; Radiological markers; Relapsing–remitting multiple sclerosis; Tolerability.
Publication
Journal: Journal of Neuroinflammation
February/10/2022
Abstract
There are over 15 disease-modifying drugs that have been approved over the last 20 years for the treatment of relapsing-remitting multiple sclerosis (MS), but there are limited treatment options available for progressive MS. The development of new drugs for the treatment of progressive MS remains challenging as the pathophysiology of progressive MS is poorly understood.The progressive phase of MS is dominated by neurodegeneration and a heightened innate immune response with trapped immune cells behind a closed blood-brain barrier in the central nervous system. Here we review microglia and border-associated macrophages, which include perivascular, meningeal, and choroid plexus macrophages, during the progressive phase of MS. These cells are vital and are largely the basis to define lesion types in MS. We will review the evidence that reactive microglia and macrophages upregulate pro-inflammatory genes and downregulate homeostatic genes, that may promote neurodegeneration in progressive MS. We will also review the factors that regulate microglia and macrophage function during progressive MS, as well as potential toxic functions of these cells. Disease-modifying drugs that solely target microglia and macrophage in progressive MS are lacking. The recent treatment successes for progressive MS include include B-cell depletion therapies and sphingosine-1-phosphate receptor modulators. We will describe several therapies being evaluated as a potential treatment option for progressive MS, such as immunomodulatory therapies that can target myeloid cells or as a potential neuroprotective agent.
Keywords: Macrophages; Microglia; Multiple sclerosis; Neurodegeneration; Primary progressive; Secondary progressive; Therapeutics.
Publication
Journal: European Journal of Neurology
February/10/2022
Abstract
Background: Effectiveness of autologous haematopoietic stem-cell transplantation (AHSCT) in relapsing-remitting multiple sclerosis (MS) is well known, but in secondary-progressive (SP-) MS it is still controversial. Therefore, AHSCT activity was evaluated in SP-MS using low-dose immunosuppression with cyclophosphamide (Cy) as a comparative treatment.
Methods: Retrospective monocentric 1:2 matched study in SP-MS patients treated with BEAM-AHSCT (cases) or IV pulses of Cy (controls) at a single Academic centre in Florence. Controls were selected according to baseline characteristics adopting cardinality matching after trimming on the estimated propensity-score. Kaplan-Meier and Cox analyses were used to estimate survival free from relapses (R-FS), disability progression (P-FS) and NEDA-2.
Results: 93 SP-MS were included: 31 AHSCT, 62 Cy. Mean follow-up: 99 months in the AHSCT and 91 months in the Cy groups. R-FS was higher in AHSCT compared to Cy patients: at year 5, 100% vs 52% respectively (p<0.0001). P-FS did not differ between the groups (at year 5: 70% in AHSCT and 81% in Cy, p=0.572), nor did NEDA-2 (p=0.379). A sensitivity analysis including the 31 "best-matched" controls only confirmed these results. Three neoplasms (2 Cy, 1 AHSCT) and two fatalities (2 Cy) occurred.
Conclusion: This study provides Class III evidence, in SP-MS, on the superior effectiveness of AHSCT compared to Cy on relapse activity, without differences on disability accrual. Despite the suppression of relapses was observed in the AHSCT group only, AHSCT did not show advantages over Cy on disability, suggesting that in SP-MS disability progression becomes more based on non-inflammatory neurodegeneration than on inflammation.
Keywords: autologous hematopoietic stem cell transplantation; case-control study; disability progression; multiple sclerosis; progressive multiple sclerosis.
Publication
Journal: Multiple Sclerosis
February/10/2022
Abstract
Introduction: The Multiple Sclerosis Prediction Score (MSPS, www.msprediction.com) estimates, for any month during the course of relapsing-remitting multiple sclerosis (MS), the individual risk of transition to secondary progression (SP) during the following year.
Objective: Internal verification of the MSPS algorithm in a derivation cohort, the Gothenburg Incidence Cohort (GIC, n = 144) and external verification in the Uppsala MS cohort (UMS, n = 145).
Methods: Starting from their second relapse, patients were included and followed for 25 years. A matrix of MSPS values was created. From this matrix, a goodness-of-fit test and suitable diagnostic plots were derived to compare MSPS-calculated and observed outcomes (i.e. transition to SP).
Results: The median time to SP was slightly longer in the UMS than in the GIC, 15 vs. 11.5 years (p = 0.19). The MSPS was calibrated with multiplicative factors: 0.599 for the UMS and 0.829 for the GIC; the calibrated MSPS provided a good fit between expected and observed outcomes (chi-square p = 0.61 for the UMS), which indicated the model was not rejected.
Conclusion: The results suggest that the MSPS has clinically relevant generalizability in new cohorts, provided that the MSPS was calibrated to the actual overall SP incidence in the cohort.
Keywords: Epidemiology; multiple sclerosis; outcome measurement; progressive; relapsing/remitting.
Publication
Journal: BioImpacts
February/9/2022
Abstract
Multiple sclerosis is an inflammatory disease of the spinal cord and brain. Receptor for advanced glycation end products and Apolipoprotein A1 (Apo-AI) have been recommended to have a pathogenic role in the neuroinflammatory disorder as multiple sclerosis. The purpose of this research was to measure the plasma levels of S100A12 and Apo-A1 in the first-degree family of relapsing-remitting multiple sclerosis (RRMS) patients. Plasma levels of S100A12 & Apo-A1 were evaluated via enzyme-linked immunosorbent assay in the thirty-five new cases of untreated patients with deterministic RRMS according to the McDonald criteria, twenty-four healthy controls, and twenty-six first-degree members of untreated RRMS patients (called them as high-risk group). The main findings of this study were as follows: the plasma level of S100A12 was significantly lower in the new cases of untreated RRMS (P ≤ 0.05; 0.045) and high-risk (P ≤ 0.05; 0.001) groups. Although the plasma protein level of Apo-A1 was reduced significantly in the high-risk group (P < 0.05, P = 0.003) as compared to the healthy control group, there was no significant difference in the untreated RRMS patients (P = 0.379). The plasma level of vitamin D3 in both RRMS patients and high-risk groups displayed significance reduction, although, there was no significant association between vitamin D and S100A12 & Apo-A1 levels. Given the role of S100A12 and Apo-A1 in the inflammatory process performed in the first-degree family members of the RRMS patients, which revealed a significant decrease in this group, we concluded that they can be considered as one of the contributing factors in the pathogenesis of MS, though more research is needed before assuming them as predictive biomarkers.
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