Research

https://link.springer.com/article/10.1007/s00415-020-10074-4

https://www.ncbi.nlm.nih.gov/pubmed/32929591?dopt=Abstract

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Should I stop or should I go on? Disease modifying therapy after the first clinical episode of multiple sclerosis.

J Neurol. 2020 Sep 14;:

Authors: Monschein T, Salhofer-Polanyi S, Altmann P, Zrzavy T, Dal-Bianco A, Bsteh G, Rommer P, Berger T, Leutmezer F

Abstract

INTRODUCTION: Treatment with disease-modifying therapies (DMT) in patients with clinically isolated syndrome (CIS) represents standard care in multiple sclerosis (MS) patients nowadays. Since a proportion of patients may show no evidence of disease activity (NEDA) after some time of treatment, the question might arise about the risks of stopping DMT.

METHODS: We present a cohort of 49 patients who started DMT immediately after CIS and had no evidence of disease activity (NEDA-3) for at least five years before discontinuation of therapy. Thereafter, patients underwent clinical and MRI follow-up for at least five consecutive years.

RESULTS: Of 49 patients discontinuing DMT, 53% (n = 26) had NEDA for at least further five years, while 47% (n = 23) showed either a relapse/disease progression (18.4%, n = 9), MRI activity (14.3%, n = 7) or both (14.3%, n = 7). The main predictive factor for sustained NEDA was age at DMT termination. Patients aged > 45 years had a significantly lower risk of disease reactivation (13% vs. 54% in patients aged < 45 years, p < 0.001) after DMT discontinuation. DISCUSSION: In CIS patients with immediate DMT after their first clinical episode, older age at the time of DMT discontinuation is the main predictive factor for sustained NEDA status. PMID: 32929591 [PubMed - as supplied by publisher]

https://www.mdpi.com/2075-4418/10/9/685/htm

https://www.ncbi.nlm.nih.gov/pubmed/32932824?dopt=Abstract

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Serum Neurofilament Light Chain Levels are Associated with Lower Thalamic Perfusion in Multiple Sclerosis.

Diagnostics (Basel). 2020 Sep 11;10(9):

Authors: Jakimovski D, Bergsland N, Dwyer MG, Ramasamy DP, Ramanathan M, Weinstock-Guttman B, Zivadinov R

Abstract

Both perfusion-weighted imaging (PWI) measures and serum neurofilament light (sNfL) chain levels have been independently associated with disability in multiple sclerosis (MS) patients. This study aimed to determine whether these measures are correlated to each other or independently describe different MS processes. For this purpose, 3T MRI dynamic susceptibility contrast (DSC)-PWI and single-molecule assay (Simoa)-based sNfL methods were utilized when investigating 86 MS patients. The perfusion measures of mean transit time (MTT), cerebral blood volume (CBV), and cerebral blood flow (CBF) were derived for the normal-appearing whole brain (NAWB), the normal-appearing white matter (NAWM), the gray matter (GM), the deep GM (DGM), and the thalamus. The normalized CBV and CBF (nCBV and nCBV) were calculated by dividing by the corresponding NAWM measure. Age- and sex-adjusted linear regression models were used to determine associations between the DSC-PWI and sNfL results. False discovery rate (FDR)-adjusted p-values < 0.05 were considered statistically significant. A greater age and thalamic MTT were independently associated with higher sNfL levels (p < 0.001 and p = 0.011) and explained 36.9% of sNfL level variance. NAWM MTT association with sNfL levels did not survive the FDR correction. In similar models, a lower thalamic nCBF and nCBV were both associated with greater sNfL levels (p < 0.001 and p = 0.022), explaining 37.8% and 44.7% of the variance, respectively. In conclusion, higher sNfL levels were associated with lower thalamic perfusion. PMID: 32932824 [PubMed]

https://smw.ch/article/doi/smw.2020.20330

https://www.ncbi.nlm.nih.gov/pubmed/32920791?dopt=Abstract

When a T cell engages a B cell: novel insights in multiple sclerosis.

Swiss Med Wkly. 2020 Aug 24;150:w20330

Authors: Jelcic I, Sospedra M, Martin R

Abstract

Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) in which autoreactive T cells are considered to be the major effector cells in orchestrating and promoting CNS injuries. However, B cells emerged as additional important cellular player in multiple sclerosis immunopathogenesis since B cell depletion therapy has been found to be very effective in reducing new relapses. This short review summarises important new insights into the interaction between these two cell populations and outlines recent observations regarding how memory B cells activate brain-homing autoreactive T cells in multiple sclerosis.

PMID: 32920791 [PubMed – as supplied by publisher]

https://journals.sagepub.com/doi/abs/10.1177/1352458519886943?journalCode=msja

https://www.ncbi.nlm.nih.gov/pubmed/31682184?dopt=Abstract

The temporal and causal relationship between inflammation and neurodegeneration in multiple sclerosis.

Mult Scler. 2019 Nov 04;:1352458519886943

Authors: Milo R, Korczyn AD, Manouchehri N, Stüve O

Abstract

It is currently incompletely understood whether inflammation and neurodegeneration are causally related in multiple sclerosis (MS). The sequence of a potential causal relationship is also unknown. Inflammation is present in rather all clinical stages of MS. Its role in the pathogenesis of MS is supported by histopathological analyses, genetic data, and numerous animal models of MS. All approved disease-modifying therapies that reduce clinical relapses and diminish the accumulation of lesions on neuroimaging are anti-inflammatory. Axonal loss and accelerated brain volume loss can also be detected from clinical disease onset throughout all stages. The expression of neurofilament light chain in cerebrospinal fluid and serum, a scaffolding protein in axons and dendrites, is a biomarker of neuronal injury associated with clinical relapses and reflects neuronal loss during episodes of acute inflammation. The recent association of human endogenous retrovirus (HERV) and its envelope proteins with MS illustrates a pathogenic pathway that causally links central nervous system (CNS)-intrinsic proinflammatory effects and inhibition of myelin repair and neuroregeneration. A review of current data on the causal relationship between inflammation and neurodegeneration in MS identified numerous plausible pathomechanisms that link the two events. Observations from most experimental models appear to favor a pathogenesis in which inflammation precedes neurodegeneration.

PMID: 31682184 [PubMed – as supplied by publisher]

https://pubs.rsna.org/doi/10.1148/radiol.2019190306

Atrophied Brain T2 Lesion Volume at MRI Is Associated with Disability Progression and Conversion to Secondary Progressive Multiple Sclerosis

https://link.springer.com/article/10.1007%2Fs11011-019-00488-z

https://www.ncbi.nlm.nih.gov/pubmed/31529356?dopt=Abstract

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Nrf2 deficiency increases oligodendrocyte loss, demyelination, neuroinflammation and axonal damage in an MS animal model.

Metab Brain Dis. 2019 Sep 16;:

Authors: Nellessen A, Nyamoya S, Zendedel A, Slowik A, Wruck C, Beyer C, Fragoulis A, Clarner T

Abstract

Oxidative stress is a pathophysiological hallmark of many CNS diseases, among multiple sclerosis (MS). Accordingly, boosting the astrocytic transcription factor nuclear factor E2-related factor 2 (Nrf2) system in an MS mouse model efficiently ameliorates oligodendrocyte loss, neuroinflammation and axonal damage. Moreover, Dimethylfumarate, an efficient activator of Nrf2, has recently been approved as therapeutic option in MS treatment. Here, we use the cuprizone mouse model of MS to induce oxidative stress, selective oligodendrocyte loss, microglia and astrocyte activation as well as axonal damage in both wild type and Nrf2-deficient mice. We found increased oligodendrocyte apoptosis and loss, pronounced neuroinflammation and higher levels of axonal damage in cuprizone-fed Nrf2-deficient animals when compared to wild type controls. In addition, Nrf2-deficient animals showed a higher susceptibility towards cuprizone within the commissura anterior white matter tract, a structure that is relatively insensitive to cuprizone in wild type animals. Our data highlight the cuprizone model as a suitable tool to study the complex interplay of oxidative stress, neuroinflammation and axonal damage. Further studies will have to show whether distinct expression patterns of Nrf2 are involved in the variable susceptibility towards cuprizone in the mouse.

PMID: 31529356 [PubMed – as supplied by publisher]

https://www.mdpi.com/2305-6320/6/3/95

https://www.ncbi.nlm.nih.gov/pubmed/31547410?dopt=Abstract

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Dietary Supplements on Controlling Multiple Sclerosis Symptoms and Relapses: Current Clinical Evidence and Future Perspectives.

Medicines (Basel). 2019 Sep 12;6(3):

Authors: Tryfonos C, Mantzorou M, Fotiou D, Vrizas M, Vadikolias K, Pavlidou E, Giaginis C

Abstract

Background: Multiple sclerosis (MS) constitutes a chronic progressive demyelinating disease which negatively affects the central nervous system. MS symptoms detrimentally affect the quality of life, as well as the life expectancy of MS patients. In this aspect, the present study aims to critically summarize and evaluate the currently available clinical studies focusing on the potential beneficial effects of dietary supplements on controlling MS symptomatology and relapse. Methods: PubMed database was comprehensively searched, using relative keywords to identify clinical trials that investigated the beneficial effects of dietary supplementation against MS symptomatology and progression. 40 clinical trials were found, which were divided into categories. Results: Nutritional status of MS patients, as well as supplementation have been suggested as potential factors affecting progression. Several substantial studies have documented a systematically high prevalence of vitamin A, B12 and D3 deficiency amongst MS patients. At present, clinical data have suggested that most of the dietary supplements under study may exert antioxidant and anti-inflammatory properties, improving depression symptomatology and quality of life overall. However, malnutrition risk in MS patients has not been adequately explored in order for more precise conclusions to be drawn. The supplements that may have a positive effect on MS are vitamins, fatty acids, antioxidants, phytochemicals and melatonin. Conclusions: Several dietary supplements may decrease inflammation and fatigue, also increasing also autoimmunity tolerance in MS patients, and thus improving quality of life and life expectancy. Currently, there is no effective clinical indication for applying dietary supplementation as complementary treatment against MS symptomatology.

PMID: 31547410 [PubMed]

https://www.jni-journal.com/article/S0165-5728(19)30184-5/fulltext

https://www.ncbi.nlm.nih.gov/pubmed/31521828?dopt=Abstract

Impact of interferon β-1b, interferon β-1a and fingolimod therapies on serum interleukins-22, 32α and 34 concentrations in patients with relapsing-remitting multiple sclerosis.

J Neuroimmunol. 2019 Sep 06;337:577062

Authors: Abdel-Dayem MA, Shaker ME, Gameil NM

Abstract

Interleukins (ILs)-22, 32α and 34 were monitored in the sera of relapsing-remitting multiple sclerosis (RRMS) patients at different time intervals with or without interferon β-1b, interferon β-1a and fingolimod treatments. The results showed that sera of untreated RRMS patients were statistically higher in concentration of IL-22 (P < .001), but not IL-32α and IL-34, than those of healthy individuals. Interestingly, interferon β-1b, interferon β-1a and fingolimod treatments led to a significant decrease of serum concentrations of ILs-22 and 32α, but not 34, at 6 and 12 months of treatment, compared to their initial concentrations before initiating therapy. The correlation analysis revealed that the changes of serum IL-22 (r = 0.814) and, to a lesser extent, IL-32α (r = 0.381) concentrations were positively correlated with those of expanded disability status score. In conclusion, serum IL-22 concentration may be a potential marker for MS disease severity and efficacy of treatment. PMID: 31521828 [PubMed - as supplied by publisher]

https://www.ncbi.nlm.nih.gov/pubmed/31540711?dopt=Abstract

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Early effective treatment may protect from cognitive decline in paediatric multiple sclerosis.

Eur J Paediatr Neurol. 2019 Sep 05;:

Authors: Johnen A, Elpers C, Riepl E, Landmeyer NC, Krämer J, Polzer P, Lohmann H, Omran H, Wiendl H, Göbel K, Meuth SG

Abstract

BACKGROUND: Cognitive impairment (CI) is a critical feature for patients with childhood or juvenile multiple sclerosis (MS).

OBJECTIVE: To promote the understanding of CI and to address the impact of different pharmacological treatment strategies on cognitive performance in this patient group.

METHODS: A cohort of 19 patients with therapy-naïve or ß-Interferon-treated juvenile MS completed a comprehensive neuropsychological assessment at initial presentation (baseline) and on average 2.5 years later (follow-up). The assessments were complemented with a neuropaediatric examination and conventional cerebral magnetic resonance imaging (MRI).

RESULTS: 9 patients (47%) were impaired in at least one test at baseline (z-score <-1.645 compared with age-adjusted normative data), with the highest impairment frequency in the domains processing speed and attention & executive functions. At follow-up a higher impairment frequency was prominent in those patients whose therapy had not been escalated (N = 13, 69% impaired in at least one test), while cognition was preserved or ameliorated in patients whose treatment had been escalated to highly effective drugs (N = 6, 0% impaired) during the observational period. These group differences at follow-up were not attributable to differences regarding demographics, MRI metrics or cognitive performance at baseline. CONCLUSION: Our findings confirm that paediatric MS is associated with considerable CI already in early disease stages. Early administration of highly effective treatment may protect from cognitive decline or alleviate CI in juvenile MS, but larger controlled trials are warranted to confirm these preliminary results. PMID: 31540711 [PubMed - as supplied by publisher]

https://journals.sagepub.com/doi/10.1177/1545968319868713

https://www.ncbi.nlm.nih.gov/pubmed/31431121?dopt=Abstract

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Interleukin-6 Disrupts Synaptic Plasticity and Impairs Tissue Damage Compensation in Multiple Sclerosis.

Neurorehabil Neural Repair. 2019 10;33(10):825-835

Authors: Stampanoni Bassi M, Iezzi E, Mori F, Simonelli I, Gilio L, Buttari F, Sica F, De Paolis N, Mandolesi G, Musella A, De Vito F, Dolcetti E, Bruno A, Furlan R, Finardi A, Marfia GA, Centonze D, Rizzo FR

Abstract

Background: Synaptic plasticity helps in reducing the clinical expression of brain damage and represents a useful mechanism to compensate the negative impact of new brain lesions in multiple sclerosis (MS). Inflammation, altering synaptic plasticity, could negatively influence the disease course in relapsing-remitting MS (RR-MS). Objective: In the present study, we explored whether interleukin (IL)-6, a major proinflammatory cytokine involved in MS pathogenesis, alters synaptic plasticity and affects the ability to compensate for ongoing brain damage. Methods: The effect of IL-6 incubation on long-term potentiation (LTP) induction was explored in vitro, in mice hippocampal slices. We also explored the correlation between the cerebrospinal fluid (CSF) levels of this cytokine and the LTP-like effect induced by the paired associative stimulation (PAS) in a group of RR-MS patients. Finally, we examined the correlation between the CSF levels of IL-6 at the time of diagnosis and the prospective disease activity in a cohort of 150 RR-MS patients. Results: In vitro LTP induction was abolished by IL-6. Consistently, in patients with MS, a negative correlation emerged between IL-6 CSF concentrations and the effect of PAS. In MS patients, longer disease duration before diagnosis was associated with higher IL-6 CSF concentrations. In addition, elevated CSF levels of IL-6 were associated with greater clinical expression of new inflammatory brain lesions, unlike in patients with low or absent IL-6 concentrations, who had a better disease course. Conclusions: IL-6 interfering with synaptic plasticity mechanisms may impair the ability to compensate the clinical manifestation of new brain lesions in RR-MS patients.

PMID: 31431121 [PubMed – indexed for MEDLINE]

http://ijms.sums.ac.ir/article_44955.html

https://www.ncbi.nlm.nih.gov/pubmed/31439976?dopt=Abstract

Sema3A and miR-497-5p can be considered critical targets for further studies on future treatments of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis

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Negative Regulation of Semaphorin-3A Expression in Peripheral Blood Mononuclear Cells Using MicroRNA-497-5p.

Iran J Med Sci. 2019 Jul;44(4):325-333

Authors: Shapoori S, Ganjalikhani-Hakemi M, Rezaeepoor M, Alsahebfosoul F, Khosravi S, Etemadifar M, Mansourian M

Abstract

Background: Semaphorin-3A (Sema3A), as a secreted semaphorin, is an immune modulator molecule participating in the pathogenesis of autoimmune diseases. MicroRNAs (miRNAs) modulate the target-gene expression at the post-transcriptional level. It has been proposed that miRNAs may be crucial to the modulation of the function of semaphorins. Previous findings have proven that miR-497-5p is upregulated and Sema3A is downregulated in some autoimmune disorders. Thus, we aimed to examine the presence of any correlation between Sema3A and miR-497-5p in peripheral blood mononuclear cells (PBMCs).

Methods: PBMCs were cultured and transfected with miR-497-5p mimic using the X-tremeGENE™ reagent. The expression level of Sema3A was assessed after 48 hours in supernatants and cells via the enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction, respectively. Cell viability was evaluated using the methylthiazol tetrazolium assay. All the experiments were done in triplicate, and the statistical analyses were performed with SPSS, version 20. P values equal to or less than 0.05 were considered significant.

Results: We observed downregulation of the Sema3A gene (P=0.0001) and its secretion (P=0.032) in the PBMCs through miR-497-5p transfection. Moreover, transfection with miR-497-5p mimic and downregulation of Sema3A did not affect the viability of the PBMCs (P=0.061).

Conclusion: Based on the obtained results, we suggest that miR-497-5p has a high suppressive effect on Sema3A expression and both Sema3A and miR-497-5p can be considered critical targets for further studies on future therapeutic attempts for the treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.

PMID: 31439976 [PubMed]

https://www.msard-journal.com/article/S2211-0348(19)30276-7/fulltext

https://www.ncbi.nlm.nih.gov/pubmed/31279232?dopt=Abstract

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Plasma cell and B cell-targeted treatments for use in advanced multiple sclerosis.

Mult Scler Relat Disord. 2019 Jun 26;35:19-25

Authors: Baker D, Jacobs BM, Gnanapavan S, Schmierer K, Giovannoni G

Abstract

There is increasing evidence that agents that target peripheral B cells and in some instances plasma cells can exhibit marked effects on relapsing multiple sclerosis. In addition, B cells, including plasma cells, within the central nervous system compartment are likely to play an important role in disease progression in both relapsing and progressive MS. However, current B cell-targeting antibodies may not inhibit these, because of poor penetration into the central nervous system and often oligoclonal bands of immunoglobulin persist within the cerebrospinal fluid despite immunotherapy. Through targeting B cells and plasma cells in the CNS, it may be possible to obtain additional benefit above simple peripheral depletion of B cells. As such there are a number of inhibitors of B cell function and B cell depleting agents that have been developed for myeloma and B cell leukaemia and lymphoma, which could potentially be used off-label or as an experimental treatment for advanced (progressive) MS.

PMID: 31279232 [PubMed – as supplied by publisher]

https://www.ncbi.nlm.nih.gov/pubmed/31251938?dopt=Abstract

potential advantages and limitations of miRNAs as next generation targets in multiple sclerosis

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MicroRNAs change the games in central nervous system pharmacology.

Biochem Pharmacol. 2019 Jun 25;:

Authors: Davide M, Stefano R, Marta F, Davide L

Abstract

MicroRNAs (miRNAs) represent a class of important post-transcriptional regulators of gene expression, enabling cells to follow their intrinsic developmental program. By directly binding to their targets, miRNAs can both promote transcriptional patterns in crucial steps of cell growth, and act as powerful buffering system that titrate protein content in case of aberrant gene expression. The literature of the last decade showed that the presence of tissue-enriched miRNAs in body fluids could be reminiscent of disease state. This is particularly relevant in neurodegenerative disorders, in which peripheral biomarkers could be helpful means to detect disease onset. However, dysregulation of miRNAs is not merely a consequence of disease, but directly contributes to pathological outcomes. On this basis, increasing interest is growing in the development of pharmacological agents targeting specific miRNAs. Actually, this apparently futuristic approach is already part of the current therapies. In fact, several drugs approved for CNS disorders, such as L-Dopa or valproic acid, were also demonstrated to restore some miRNAs. Moreover, ongoing clinical trials demonstrated that miRNA-based drugs are effective against tumors, suggesting that miRNAs also represent a promising class of therapeutic molecules. However, several issues still need to be addressed, particularly in case of CNS diseases, in which stability and delivery are crucial aspects of the therapy. In this commentary, we highlighted potential advantages and limitations of miRNAs as next generation targets in CNS pharmacology, focusing on multiple sclerosis, a chronic demyelinating disease lacking specific therapeutic targets and bona-fide biomarkers.

PMID: 31251938 [PubMed – as supplied by publisher]

https://www.nejm.org/doi/10.1056/NEJMoa1901981

https://www.ncbi.nlm.nih.gov/pubmed/31075187?dopt=Abstract

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Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis.

N Engl J Med. 2019 06 20;380(25):2406-2417

Authors: Montalban X, Arnold DL, Weber MS, Staikov I, Piasecka-Stryczynska K, Willmer J, Martin EC, Dangond F, Syed S, Wolinsky JS, Evobrutinib Phase 2 Study Group

Abstract

BACKGROUND: Bruton’s tyrosine kinase (BTK) regulates the functions of B cells and myeloid cells that are implicated in the pathogenesis of multiple sclerosis. Evobrutinib is a selective oral BTK inhibitor that has been shown to inhibit B-cell activation both in vitro and in vivo.

METHODS: In this double-blind, randomized, phase 2 trial, we assigned patients with relapsing multiple sclerosis to one of five groups: placebo, evobrutinib (at a dose of 25 mg once daily, 75 mg once daily, or 75 mg twice daily), or open-label dimethyl fumarate (DMF) as a reference. The primary end point was the total (cumulative) number of gadolinium-enhancing lesions identified on T1-weighted magnetic resonance imaging at weeks 12, 16, 20, and 24. Key secondary end points included the annualized relapse rate and change from baseline in the score on the Expanded Disability Status Scale (EDSS).

RESULTS: A total of 267 patients were randomly assigned to a trial group. The mean (±SD) total number of gadolinium-enhancing lesions during weeks 12 through 24 was 3.85±5.44 in the placebo group, 4.06±8.02 in the evobrutinib 25-mg group, 1.69±4.69 in the evobrutinib 75-mg once-daily group, 1.15±3.70 in the evobrutinib 75-mg twice-daily group, and 4.78±22.05 in the DMF group. The baseline adjusted rate ratios for the total number of lesions over time as compared with placebo were 1.45 in the evobrutinib 25-mg group (P = 0.32), 0.30 in the evobrutinib 75-mg once-daily group (P = 0.005), and 0.44 in the evobrutinib 75-mg twice-daily group (P = 0.06). The unadjusted annualized relapse rate at week 24 was 0.37 in the placebo group, 0.57 in the evobrutinib 25-mg group, 0.13 in the evobrutinib 75-mg once-daily group, 0.08 in the evobrutinib 75-mg twice-daily group, and 0.20 in the DMF group. There was no significant effect of trial group on the change from baseline in the EDSS score. Elevations in liver aminotransferase values were observed with evobrutinib.

CONCLUSIONS: Patients with relapsing multiple sclerosis who received 75 mg of evobrutinib once daily had significantly fewer enhancing lesions during weeks 12 through 24 than those who received placebo. There was no significant difference with placebo for either the 25-mg once-daily or 75-mg twice-daily dose of evobrutinib, nor in the annualized relapse rate or disability progression at any dose. Longer and larger trials are required to determine the effect and risks of evobrutinib in patients with multiple sclerosis. (Funded by EMD Serono; ClinicalTrials.gov number, NCT02975349.).

PMID: 31075187 [PubMed – indexed for MEDLINE]

https://journals.sagepub.com/doi/abs/10.1177/1352458519849513?journalCode=msja

https://www.ncbi.nlm.nih.gov/pubmed/31144577?dopt=Abstract

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A proof-of-concept application of a novel scoring approach for personalized medicine in multiple sclerosis.

Mult Scler. 2019 May 30;:1352458519849513

Authors: Pellegrini F, Copetti M, Bovis F, Cheng D, Hyde R, de Moor C, Kieseier BC, Sormani MP

Abstract

BACKGROUND: Stratified medicine methodologies based on subgroup analyses are often insufficiently powered. More powerful personalized medicine approaches are based on continuous scores.

OBJECTIVE: We deployed a patient-specific continuous score predicting treatment response in patients with relapsing-remitting multiple sclerosis (RRMS).

METHODS: Data from two independent randomized controlled trials (RCTs) were used to build and validate an individual treatment response (ITR) score, regressing annualized relapse rates (ARRs) on a set of baseline predictors.

RESULTS: The ITR score for the combined treatment groups versus placebo detected differential clinical response in both RCTs. High responders in one RCT had a cross-validated ARR ratio of 0.29 (95% confidence interval (CI) = 0.13-0.55) versus 0.62 (95% CI = 0.47-0.83) for all other responders (heterogeneity p = 0.038) and were validated in the other RCT, with the corresponding ARR ratios of 0.31 (95% CI = 0.18-0.56) and 0.61 (95% CI = 0.47-0.79; heterogeneity p = 0.036). The strongest treatment effect modifiers were the Short Form-36 Physical Component Summary, age, Visual Function Test 2.5%, prior MS treatment and Expanded Disability Status Scale.

CONCLUSION: Our modelling strategy detects and validates an ITR score and opens up avenues for building treatment response calculators that are also applicable in routine clinical practice.

PMID: 31144577 [PubMed – as supplied by publisher]

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217208

https://www.ncbi.nlm.nih.gov/pubmed/31141529?dopt=Abstract

Plasma protein profiling reveals candidate biomarkers for multiple sclerosis treatment.

PLoS One. 2019;14(5):e0217208

Authors: Bedri SK, Nilsson OB, Fink K, Månberg A, Hamsten C, Ayoglu B, Manouchehrinia A, Nilsson P, Olsson T, Hillert J, Grönlund H, Glaser A

Abstract

Multiple sclerosis (MS) treatment options have improved significantly over the past decades, but the consequences of MS can still be devastating and the needs for monitoring treatment surveillance are considerable. In the current study we used affinity proteomics technology to identify potential biomarkers which could ultimately be used to as facilitate treatment decisions. We profiled the intra-individual changes in the levels of 59 target proteins using an antibody suspension bead array in serial plasma samples from 44 MS patients during treatment with natalizumab followed by fingolimod. Nine proteins showed decreasing plasma levels during natalizumab treatment, with PEBP1 and RTN3 displaying the most significant changes. Protein levels remained stable during fingolimod treatment for both proteins. The decreasing PEBP1 levels during natalizumab treatment could be validated using ELISA and replicated in an independent cohort. These results support the use of this technology as a high throughput method of identifying potentially useful biomarkers of MS treatment.

PMID: 31141529 [PubMed – in process]

https://www.tandfonline.com/doi/abs/10.1080/14656566.2019.1615880?journalCode=ieop20

https://www.ncbi.nlm.nih.gov/pubmed/31090469?dopt=Abstract

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Pharmacoeconomics of synthetic therapies for multiple sclerosis.

Expert Opin Pharmacother. 2019 Aug;20(11):1331-1340

Authors: D’Amico E, Chisari CG, Gitto L, Zanghì A, Toscano S, Patti F

Abstract

Introduction: Recently, the economic impact of multiple sclerosis (MS), which includes both direct and indirect costs, has been increasing. While direct costs comprise health-care costs, such as the cost of pharmaceuticals, additional treatments such as physiotherapy, and medical aids, indirect costs are triggered by the productivity loss of patients and caregivers. Although new drugs for MS have changed the therapeutic scenario, they have increased the direct costs of health-care services. Areas covered: This review describes the pharmacoeconomic aspects of synthetic therapies for MS. Additionally, it discusses the economic impact of the various classes of licensed disease-modifying treatments (DMTs) for relapsing forms of MS. Expert opinion: The emerging and more expensive DMTs for MS represent a considerable challenge for health-care systems and resource consumption. Future research should focus on the long-term efficacy of DMTs and the cost of treating MS in a real-life setting. Future biological and radiological biomarkers could help stratify patients at early stages of MS, helping physicians design a personalized therapeutic approach that could have a positive impact in economic terms.

PMID: 31090469 [PubMed – indexed for MEDLINE]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511768/

https://www.ncbi.nlm.nih.gov/pubmed/31105859?dopt=Abstract

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Therapeutic effect of transplanted umbilical cord mesenchymal stem cells in a cynomolgus monkey model of multiple sclerosis.

Am J Transl Res. 2019;11(4):2516-2531

Authors: Liu S, Wang J, Han R, Meng M, Wang W, Zhao Y, Yang F, Yang L, Gao H, Zhao Y, Yang L, Wang R, Tang W, Li Y, Duan S, Wang J, He Z, Li L, Hou Z

Abstract

Multiple sclerosis (MS) is a demyelinating disease affecting 2.5 million young people worldwide because of its immune-mediated pathological mechanisms. Recent studies have shown that stem cell transplantation is a new potential therapy for MS. There has been renewed interest in cell therapy to improve quality of life for MS patients. In this study, the experimental autoimmune encephalomyelitis (EAE) model, which is the most commonly model to mimic MS, was successfully established in cynomolgus monkeys. To evaluate the therapeutic effect of human umbilical cord mesenchymal stem cells (UCMSCs) on MS, we intravenously transplanted UCMSCs into cynomolgus monkeys with EAE. Our results showed that UCMSC transplantation significantly ameliorated the clinical symptoms of MS. Magnetic resonance imaging and clinical signs indicated that demyelination was obviously decreased after UCMSCs therapy. Moreover, the present study showed that the mechanisms, involved in the effects of UCMSCs on MS, included their immunomodulatory functions to regulate cytokine secretion and affect functional differentiation of the T cell lineage.

PMID: 31105859 [PubMed]

https://link.springer.com/article/10.1007%2Fs11899-019-00505-z

https://www.ncbi.nlm.nih.gov/pubmed/30828772?dopt=Abstract

[Read more…] about Autologous Haematopoietic Stem Cell Transplantation in Multiple Sclerosis: a Review of Current Literature and Future Directions for Transplant Haematologists and Oncologists

https://onlinelibrary.wiley.com/doi/abs/10.1002/jcp.28355

https://www.ncbi.nlm.nih.gov/pubmed/30815864?dopt=Abstract

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Integrative analysis of OIP5-AS1/HUR1 to discover new potential biomarkers and therapeutic targets in multiple sclerosis.

J Cell Physiol. 2019 Feb 27;:

Authors: Gharesouran J, Taheri M, Sayad A, Mazdeh M, Omrani MD

Abstract

Multiple sclerosis (MS) is a devastating autoimmune disease of the central nervous system associated with demyelination and axonal injury. This study was designed to find potential lncRNAs and their targets that are associated with the molecular basis of MS pathogenesis. In this study, peripheral blood samples were obtained from 50 relapsing-remitting MS (RR-MS) patients and 50 healthy controls. lncRNAs and their target were selected for validation using TaqMan Real-Time PCR. Interactions were studied based on approaches that used to investigation biological functions and signaling pathways affected by differentially expressed messenger RNAs (mRNAs). The results of this study indicate an increase in the expression of HUR1 (p = 0.0001), CPSF7 (p = 0.02), and reduction of CSTF2 expression (p = 0.04). Also, an increase in the expression of OIP5-AS1 (p = 0.01) was observed in men less than 30 years old. We performed a comparative analysis of the long noncoding RNAs (lncRNAs), and then we ranked them as candidate biomarkers according to a decreasing area under the receiver operating characteristic (ROC) curve (AUC) and plotted the results. Dysregulation of lncRNA expression has been linked to diseases. Further studies on the HUR1 gene can be used as diagnostic tools for the identification of high-risk individuals in families with a history of disease before, during, and even after treatment. Our data uncovered the expression profiles of lncRNAs and mRNAs in MS patients, which will help delineate the molecular mechanisms in MS pathogenesis. However, further studies need to determine the precise role of these genes in the pathological process in MS.

PMID: 30815864 [PubMed – as supplied by publisher]

https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/EP087480

https://www.ncbi.nlm.nih.gov/pubmed/30811744?dopt=Abstract

Therapeutic effect of oligomeric proanthocyanidin in cuprizone-induced demyelination.

Exp Physiol. 2019 Feb 27;:

Authors: Wang Q, Wang J, Yang Z, Sui R, Miao Q, Li Y, Yu J, Liu C, Zhang G, Xiao B, Ma C

Abstract

NEW FINDINGS: What is the central question of this study? Oligomeric proanthocyanidin (OPC) has the capacity to alleviate abnormalities in neurological functioning. However, whether OPC can reduce the progression of demyelination or promote remyelination in demyelinating diseases remains unknown. What is the main finding and its importance? OPC can improved cuprizone (CPZ)-induced demyelination by inhibiting immune cell infiltration, reversing over-activated microglia, decreasing the inflammatory cytokines secreted by inflammatory cells and decreasing the production of MOG35-55 specific antibody in the brain.

ABSTRACT: Demyelinating diseases of the central nervous system (CNS), including multiple sclerosis (MS), neuromyelitis optica, acute disseminated encephalomylitis, are characterized by recurrent primary demyelination/remyelination and progressive neurodegeneration. In the present study, we investigate the therapeutic effect of oligomeric proanthocyanidin (OPC), the most effective component of grape seed extract, in cuprizone (CPZ)-fed C57BL/6 mice, a classic demyelination/remyelination model. Our results show that OPC attenuated abnormal behavior, reduced demyelination, and increased expression of myelin basic protein (MBP) and expression of O4+ oligodendrocytes in the corpus callosum. OPC also reduced the numbers of B cells and T cells, activated microglia in the corpus callosum, and inhibited secretion of inflammatory factors. Further, concentrations of myelin oligodendrocyte glycoprotein-specific antibodies were significantly reduced in serum and brain homogenates after OPC treatment. Together, these results demonstrate a potent therapeutic effect for OPC in CPZ-mediated demyelination and clearly highlight multiple effects of this natural product in attenuating myelin-specific autoantibodies and the inflammatory microenvironment in the brain. This article is protected by copyright. All rights reserved.

PMID: 30811744 [PubMed – as supplied by publisher]

The last consider the hypothesis of molecular mimicry mechanism, which is potentially triggered by viral antigen inducing MS autoimmunity. The Human Endogenous Retroviruses W family (HERV-W) is the subject of studies within this field, based on the detection of HERV-W envelope gene proteins in MS patients’ samples.

https://www.sciencedirect.com/science/article/pii/S0968432818304396?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/30802755?dopt=Abstract

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Cross-reactivity between myelin oligodendrocyte glycoprotein and human endogenous retrovirus W protein: nanotechnological evidence for the potential trigger of multiple sclerosis.

Micron. 2019 Feb 18;120:66-73

Authors: de Luca V, Martins Higa A, Malta Romano C, Pimenta Mambrini G, Peroni LA, Trivinho-Strixino F, Lima Leite F

Abstract

Multiple sclerosis (MS) is an autoimmune and inflammatory demyelinating disease of the central nervous system. Experimental evidence supports the reactivity of autoantibodies against components of myelin sheath including the myelin oligodendrocyte glycoprotein (MOG). The MS etiology is still unknown, but some risk factors associated with immune dysregulation, genetic susceptibility, and environmental factors are under investigation. The last consider the hypothesis of molecular mimicry mechanism, which is potentially triggered by viral antigen inducing MS autoimmunity. The Human Endogenous Retroviruses W family (HERV-W) is the subject of studies within this field, based on the detection of HERV-W envelope gene proteins in MS patients’ samples. In the biomedical field of diagnosis and therapeutics, nanotechnology is of great use for the detailed study of molecular mechanisms involving specific interactions between biomolecules providing high specificity and sensitivity of response. In view of the significance of etiological aspects for the comprehension of MS mechanisms of action, we applied a nanotechnological approach designed for antibody detection. For this, we analyzed MOG peptide sequences similar to the HERV-W protein. These sequences were subjected to interaction with anti-HERV-W antibodies using atomic force spectroscopy (AFS) and silver nanoparticles (AgNPs) methods to survey the potential occurrence of molecular mimicry. Our results revealed the molecular recognition between the anti-HERV-W antibody and the HERV-W and MOG epitopes by AFS and AgNPs approaches. Specific non-linear shape of force curves and median adhesion force values within the expected range for an antigen-antibody interaction were obtained for HERV-W and MOG peptides, 163 pN and 178 pN, respectively, suggesting the occurrence of cross-reactivity in these systems.

PMID: 30802755 [PubMed – as supplied by publisher]

https://www.sciencedirect.com/science/article/abs/pii/S0024320518308610?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/30620895?dopt=Abstract

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The protective effects of β-caryophyllene on LPS-induced primary microglia M1/M2 imbalance: A mechanistic evaluation.

Life Sci. 2019 Feb 15;219:40-73

Authors: Askari VR, Shafiee-Nick R

Abstract

AIMS: Neuroinflammation is observed as a routine characterization of neurodegenerative disorders such as dementia, multiple sclerosis (MS) and Alzheimer’s diseases (AD). Scientific evidence propounds both of the neuromodulatory and immunomodulatory effects of CB2 in the immune system. β-Caryophyllene (BCP) is a dietary selective CB2 agonist, which deserves the anti-inflammatory and antioxidant effects at both low and high doses through activation of the CB2 receptor.

METHODS: In this study, we investigated the protective effects of a broad range concentration of BCP against LPS-induced primary microglia cells inflammation and M1/M2 imbalance and identifying the portion of the involvement of related signaling pathways on BCP effects using pharmacological antagonists of CB2, PPAR-γ, and sphingomyelinase (SMase).

KEY FINDINGS: The protective effects of BCP on LPS-induced microglia imbalance is provided by the M2 healing phenotype of microglia, releasing the anti-inflammatory (IL-10, Arg-1, and urea) and anti-oxidant (GSH) parameters and reducing the inflammatory (IL-1β, TNF-α, PGE2, iNOS and NO) and oxidative (ROS) biomarkers. Moreover, we showed that BCP exerts its effects through CB2 receptors which overproduction of ceramides by SMase at middle to higher concentrations of BCP reduce the protective activity of BCP and results in the activation of the PPAR-γ pathway.

SIGNIFICANCE: In conclusion, the low concentration of BCP has higher selective anti-inflammatory effects rather than high levels. On this occasion, BCP by modulating the microglia is able to have potential therapeutic effects in neuro-inflammation conditions and microglia cells such as MS and AD.

PMID: 30620895 [PubMed – indexed for MEDLINE]

https://www.frontiersin.org/articles/10.3389/fnhum.2019.00031/full

https://www.ncbi.nlm.nih.gov/pubmed/30809137?dopt=Abstract

[Read more…] about The Effects of Transcutaneous Spinal Direct Current Stimulation on Neuropathic Pain in Multiple Sclerosis: Clinical and Neurophysiological Assessment

https://www.sciencedirect.com/science/article/pii/S221315821930066X?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/30798167?dopt=Abstract

Frontal brain activity and cognitive processing speed in multiple sclerosis: An exploration of EEG neurofeedback training.

Neuroimage Clin. 2019 Feb 11;22:101716

Authors: Keune PM, Hansen S, Sauder T, Jaruszowic S, Kehm C, Keune J, Weber E, Schönenberg M, Oschmann P

Abstract

BACKGROUND: Cognitive deficits including impaired information processing speed as assessed by the Symbol Digit Modalities Test (SDMT) are common in multiple sclerosis (MS). Oscillatory markers of processing speed may be extracted from magnetoencephalographic (MEG) and electroencephalographic (EEG) resting-state recordings. In this context, an increased proportion of frontal slow-wave (theta, 4-8 Hz) to fast-wave (beta, 13-30 Hz) EEG activity was indicative of impaired SDMT performance. Such an increased theta/beta ratio may reflect oscillatory slowing associated with deficits in attention control. Therapeutic approaches that consider atypical oscillatory activity in MS remain sparse.

OBJECTIVES: In a cross-sectional design, we examined the relation between SDMT performance, the EEG theta/beta ratio and its components. We also explored longitudinally, whether EEG neurofeedback could be used to induce a putatively adaptive alteration in these EEG parameters, toward a pattern indicative of improved processing speed.

METHODS: N = 58 MS patients (RRMS/SPMS/PPMS N: 18/35/3, 2 cases excluded) participated in a neuropsychological examination and a resting-state EEG recording. Subsequently, N = 10 patients received neurofeedback training for two weeks in a hospitalized setting. The purpose was to reduce the frontal theta/beta ratio through operant conditioning.

RESULTS: In the cross-sectional examination, patients with slow SDMT speed displayed an increased theta/beta ratio, relative to those with normal speed. This involved increased frontal theta power, whereas beta power was equal across groups. The theta/beta ratio remained stable during neurofeedback across sessions of the two-week training period. In an exploratory secondary analysis, within sessions a reduction in the theta/beta ratio during active training blocks relative pre/post session resting-states was observed, driven by reduced theta power.

CONCLUSIONS: These findings provide support for utilizing frontal EEG theta activity as an inverse marker of processing speed in MS. Across sessions, there was no support for successful operant conditioning of the theta/beta ratio during the two-week training period. The observed state-specific shift within sessions, involving a transient reduction in theta activity, nevertheless may provide a rationale for a further investigation of neurofeedback as a treatment approach in MS.

PMID: 30798167 [PubMed – as supplied by publisher]

https://www.sciencedirect.com/science/article/abs/pii/S0008874918304258?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31130183?dopt=Abstract

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The role of B cells in multiple sclerosis: Current and future therapies.

Cell Immunol. 2019 May;339:10-23

Authors: Negron A, Robinson RR, Stüve O, Forsthuber TG

Abstract

While it was long held that T cells were the primary mediators of multiple sclerosis (MS) pathogenesis, the beneficial effects observed in response to treatment with Rituximab (RTX), a monoclonal antibody (mAb) targeting CD20, shed light on a key contributor to MS that had been previously underappreciated: B cells. This has been reaffirmed by results from clinical trials testing the efficacy of subsequently developed B cell-depleting mAbs targeting CD20 as well as studies revisiting the effects of previous disease-modifying therapies (DMTs) on B cell subsets thought to modulate disease severity. In this review, we summarize current knowledge regarding the complex roles of B cells in MS pathogenesis and current and potential future B cell-directed therapies.

PMID: 31130183 [PubMed – in process]