Relapse In Relapsing-remitting Multiple Sclerosis Research Articles

Cerebrospinal Fluid Chloride Is Associated with Disease Activity of Relapsing-Remitting Multiple Sclerosis: A Retrospective Cohort Study.

Blood-brain barrier dysfunction in active multiple sclerosis (MS) lesions leads to pathological changes in the cerebrospinal fluid (CSF). This study aimed to investigate the possible association between routine CSF findings, especially CSF chloride, at the time of the first lumbar puncture and the relapse risk and disability progression of relapsing-remitting MS (RRMS). This retrospective study included 77 patients with RRMS at the MS Center of our institution from January 2012 to December 2020. The Anderson and Gill (AG) model and Spearman correlation analysis were used to explore predictors of relapse and disability during follow-up. In the multivariate AG model, patients with elevated CSF chloride level (hazard ratio [HR], 1.1; 95% confidence interval [CI]: 1.06-1.22; p = 0.001) had a high risk of MS relapse. Using median values of CSF chloride (123.2 mmol/L) as a cut-off, patients with CSF chloride level ≥ 123.2 mmol/L had a 120% increased relapse risk compared with those with CSF chloride level < 123.2 mmol/L (HR = 2.20; 95% CI: 1.19-4.05; p = 0.012). Elevated CSF chloride levels might be a biologically unfavorable predictive factor for disease relapse in RRMS.

Misconceptions about multiple sclerosis and pregnancy in the Qassim region in 2021-2022: a cross-sectional study.

Multiple sclerosis (MS) is a disease with higher female prevalence, and the majority of patients are of childbearing age. Thus, pregnancy concerns are important for patients with MS and their families. Improving the understanding of the effects of pregnancy on the progress of MS could improve the knowledge about pregnancy-related issues in MS patients. The aim of this study is to evaluate the general knowledge of Saudi adults living in the Qassim region regarding pregnancy-related relapses in relapsing-remitting MS (RRMS) and to identify misconceptions regarding pregnancy, breastfeeding, and the use of oral hormonal contraceptives among female MS patients. A representative random cluster sample of 337 participants was used in this cross-sectional study. All participants were living in one of the following cities in the Qassim region: Buraydah, Unaizah, and Alrrass. Data collection was done between February 2022 and March 2022 using a self-administered questionnaire. The overall mean knowledge score was 7.42 (SD 4.21), with poor, moderate, and good knowledge representing 77.2%, 187%, and 4.2% of the sample, respectively. Higher knowledge scores were associated with age less than 40 years, being a student, knowing about MS, and knowing someone with MS. Other variables such as gender, educational level, and residence location did not show significant differences regarding the knowledge score. Our results demonstrate that knowledge and attitude are suboptimal among the Qassim population regarding the effects of MS on pregnant patients, pregnancy outcomes, breastfeeding, and usage of contraceptive methods, with 77.2% showing poor total knowledge scores.

Early non-disabling relapses are important predictors of disability accumulation in people with relapsing-remitting multiple sclerosis

Background: The prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear. Objective: To determine whether early non-disabling relapses predict disability accumulation in RRMS. Methods: We redefined mild relapses in MSBase as ‘non-disabling’, and moderate or severe relapses as ‘disabling’. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up. Results: People who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated (n = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00–1.68) or given platform DMTs (n = 1074 vs 7262; HR = 1.33, 95% CI = 1.15–1.54), but not if given high-efficacy DMTs (n = 572 vs 3534; HR = 0.90, 95% CI = 0.71–1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically. Conclusion: This study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions.

Development, validation and clinical usefulness of a prognostic model for relapse in relapsing-remitting multiple sclerosis

BackgroundPrognosis for the occurrence of relapses in individuals with relapsing-remitting multiple sclerosis (RRMS), the most common subtype of multiple sclerosis (MS), could support individualized decisions and disease management and could be helpful for efficiently selecting patients for future randomized clinical trials. There are only three previously published prognostic models on this, all of them with important methodological shortcomings.ObjectivesWe aim to present the development, internal validation, and evaluation of the potential clinical benefit of a prognostic model for relapses for individuals with RRMS using real-world data.MethodsWe followed seven steps to develop and validate the prognostic model: (1) selection of prognostic factors via a review of the literature, (2) development of a generalized linear mixed-effects model in a Bayesian framework, (3) examination of sample size efficiency, (4) shrinkage of the coefficients, (5) dealing with missing data using multiple imputations, (6) internal validation of the model. Finally, we evaluated the potential clinical benefit of the developed prognostic model using decision curve analysis. For the development and the validation of our prognostic model, we followed the TRIPOD statement.ResultsWe selected eight baseline prognostic factors: age, sex, prior MS treatment, months since last relapse, disease duration, number of prior relapses, expanded disability status scale (EDSS) score, and number of gadolinium-enhanced lesions. We also developed a web application that calculates an individual’s probability of relapsing within the next 2 years. The optimism-corrected c-statistic is 0.65 and the optimism-corrected calibration slope is 0.92. For threshold probabilities between 15 and 30%, the “treat based on the prognostic model” strategy leads to the highest net benefit and hence is considered the most clinically useful strategy.ConclusionsThe prognostic model we developed offers several advantages in comparison to previously published prognostic models on RRMS. Importantly, we assessed the potential clinical benefit to better quantify the clinical impact of the model. Our web application, once externally validated in the future, could be used by patients and doctors to calculate the individualized probability of relapsing within 2 years and to inform the management of their disease.

Multiple Sclerosis: circRNA Profile Defined Reveals Links to B-Cell Function.

Background and ObjectivesTo investigate the total circular RNA (circRNA) profile in patients with relapsing-remitting multiple sclerosis (RRMS) and healthy controls (HCs).MethodsHybridization microarray was used to define the circRNA profile in peripheral blood mononuclear cells (PBMCs) from 20 untreated patients with RRMS (10 in relapse and 10 in remission) and 10 HCs. We analyzed close to 14,000 individual circRNAs per sample. The discovery set data were validated using quantitative reverse transcription-PCR with an independent cohort of 47 patients with RRMS (19 in relapse and 28 in remission) and 27 HCs.ResultsMicroarray analysis revealed 914 transcripts to be differentially expressed between patients with RRMS in relapse and HCs (p < 0.05). We validated 3 circRNAs from 5 showing highest levels of differential expression in the RRMS relapse vs HC group: hsa_circRNA_101348, hsa_circRNA_102611, and hsa_circRNA_104361. Their expression was significantly increased during relapse in RRMS (p = 0.0002, FC = 2.9; p = 0.01, FC = 1.6; and p = 0.001, FC = 1.5, respectively) and in patients showing gadolinium enhancement on brain MRI (hsa_circRNA_101348, p = 0.0039, FC = 2.4; hsa_circRNA_104361, p = 0.029, FC = 1.7). Bioinformatic analysis revealed 15 microRNAs interacting with these circRNAs in a complementary manner and led to the discovery and validation of 3 protein-coding RNAs upregulated in patients with RRMS during relapse. Two of these, AK2 and IKZF3, have previously been implicated in B-cell function.DiscussioncircRNAs display a distinct profile in PBMCs from patients with RRMS, and our results may implicate circRNA in the known disturbed B-cell activity in RRMS and thus represent a novel biomarker for monitoring relapse activity.

Factors associated with relapses in relapsing-remitting multiple sclerosis: A systematic review and meta-analysis.

The relapse is character of relapsing-remitting multiple sclerosis. The therapeutic goal is to reduce the risk of relapse. Factors associated with relapses can help to manage and prevent relapses. In addition, patients and doctors all pay attention to it. However, there are differences between studies. Our aim is to summarize factors associated with relapses in relapsing-remitting multiple sclerosis (RRMS). PubMed, EMBASE, Web of science, Cochrane library, CNKI, Wanfang, SinoMed, and VIP were searched to identify risk factors about relapses in RRMS, which should be in cohort or case-control studies. This article was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The quality of studies was evaluated by the Newcastle-Ottawa Scale (NOS). Meta-analysis, subgroup and sensitivity analyses, and publication bias were all performed with Stata. This research has been registered on the international prospective register of systematic reviews (PROSPERO, CRD42019120502). 43 articles were included. Infection, postpartum period, risk gene, stress, and vitamin D were risk factors for relapses in RRMS. Pregnancy period was the protective factor. Among those, infection increased the risk of relapses in infection period (relative risk [RR], 2.07 [confidence interval (CI), 1.64 to 2.60]). Women in the postpartum period increased the risk of relapses compared with women before pregnancy (RR, 1.43 [CI, 1.19 to 1.72]), or women in pregnancy period (RR, 2.07 [CI, 1.49 to 2.88]). Women in the pregnancy period decreased the risk of relapses (RR, 0.56 [CI, 0.37 to 0.84]) compared with women before pregnancy. However, fewer studies, heterogeneity, and sample size were the limitations. It is reliable to adopt results about infection, pregnancy period, and postpartum period.

RORγT is overexpressed in iNKT and γδ T cells during relapse in relapsing-remitting multiple sclerosis

The aim of the current study is to evaluate IL-17 production and RORγT, and IL-23R expression by iNKT, Th17 and γδ T cells in the peripheral blood of relapsing-remitting multiple sclerosis patients. Samples of peripheral blood from 21 relapse patients and 12 remission patients, and 15 healthy volunteers were stained with monoclonal antibodies for flow cytometry analysis. No significant differences in iNKT, γδ T and Th17 percentages were noted. The significant overexpression of RORγT was observed in all three subpopulations – therefore, iNKT, γδ T and Th cells may be an important source of IL-17 shortly prior to the relapse.

Low levels of alpha-synuclein in peripheral tissues are related to clinical relapse in relapsing-remitting multiple sclerosis: a pilot cross-sectional study

The protein alpha-synuclein (α-Syn) has been linked to neuroinflammatory conditions. We investigated whether the presence of α-Syn in peripheral tissues is a surrogate of brain inflammatory status in a small group of relapsing-remitting multiple sclerosis (RRMS) patients in a pilot cross-sectional study. Skin biopsies and peripheral blood were sampled from 34 healthy controls and 23 MS patients for measurement of α-Syn levels. Within the RRMS group 15 patients were in remission, and 8 patients were in the relapsing phase. The protein α-Syn was evaluated by means of immunohistochemistry and flow cytometry in skin and nucleated blood cells, respectively. In the skin, α-Syn levels were lower in relapsing MS than in the other groups, both in positive area (p = .021) and staining intensity (p = .004). In blood, the percentage of α-Syn-positive lymphocytes and monocytes were not statistically different between study groups. Moreover, the use of systemic steroids did not affect α-Syn positivity in MS-relapse patients. Finally, epidermic Langerhans cells did not stain positively for α-Syn. Overall, the levels of α-Syn positivity were lower in inflammatory relapse of RRMS patients when measured in peripheral tissues. We discuss the role of α-Syn levels in inflammation according to the obtained results.

Low Levels of Alpha-Synuclein in Peripheral Tissues are Related to Clinical Relapse in Relapsing-Remitting Multiple Sclerosis (P1.392)

Low Levels of Alpha-Synuclein in Peripheral Tissues are Related to Clinical Relapse in Relapsing-Remitting Multiple Sclerosis (P1.392)

Glutathione-PEGylated liposomal methylprednisolone in comparison to free methylprednisolone: slow release characteristics and prolonged lymphocyte depression in a first-in-human study.

Intravenous high-dose free methylprednisolone (MP) hemisuccinate is the primary treatment for an acute relapse in relapsing-remitting multiple sclerosis. However, it is inconvenient and its side effects are undesirable. Both dose and dosing frequency can be reduced by incorporating free MP in glutathione-PEGylated liposomes, creating a slow-release formulation with reduced toxicity and prolonged peripheral efficacy. This first-in-human study was designed to assess the safety, pharmacokinetics and pharmacodynamics of glutathione-PEGylated liposomes containing MP (2B3-201). The first part was a double-blind, three-way cross over study in 18 healthy male subjects, receiving ascending doses of 2B3-201, active comparator (free MP) or placebo. Part 2 of the study was an open-label infusion of 2B3-201 (different doses), exploring pretreatment with antihistamines and different infusion schedules in another 18 healthy male subjects, and a cross-over study in six healthy female subjects. MP plasma concentrations, lymphocyte counts, adrenocorticotropic hormone, osteocalcin and fasting glucose were determined. Safety and tolerability profiles were assessed based on adverse events, safety measurements and central nervous system tests. The most frequent recorded AE related to 2B3-201 was an infusion related reaction (89%). 2B3-201 was shown to have a plasma half-life between 24 and 37h and caused a prolonged decrease in the lymphocyte count, adrenocorticotropic hormone and osteocalcin, and a rise in fasting glucose. 2B3-201 is considered safe, with no clinically relevant changes in central nervous system safety parameters and no serious adverse events. In addition, 2B3-201 shows a long plasma half-life and prolonged immunosuppressive effects.

Clinical Course and Treatment in MOG Antibody Seropositive Children: A Case Series

AbstractMyelin oligodendrocyte glycoprotein (MOG) antibodies have been associated with pediatric demyelinating diseases. The clinical course in a patient with MOG positivity is variable but not well-characterized. Here, we describe the clinical course and treatment in MOG antibody positive demyelinating diseases in our pediatric population. This case series is of 13 patients who tested MOG antibody positive: two relapsing remitting multiple sclerosis (RR-MS), seven acute demyelinating encephalomyelitis (ADEM) or ADEM-optic neuritis (ADEM-ON), two clinically isolated syndrome (CIS), and two neuromyelitis optica (NMO). These patients appear to have more relapses, requiring more medications including IV steroids and IVIG. These patients are also more likely to start on disease modifying therapy (DMT) earlier, and β-interferon appears to not prevent relapses. MOG antibody positivity could provide as a marker for predicting frequent relapses in RR-MS and NMO patients, allowing for therapeutic intervention with earlier DMT.

Global exosome transcriptome profiling reveals biomarkers for multiple sclerosis.

Accumulating evidence supports a role for exosomes in immune regulation. In this study, we investigated the total circulating exosome transcriptome in relapsing-remitting multiple sclerosis (RRMS) patients and healthy controls (HC). Next generation sequencing (NGS) was used to define the global RNA profile of serum exosomes in 19 RRMS patients (9 in relapse, 10 in remission) and 10 HC. We analyzed 5 million reads and >50,000 transcripts per sample, including a detailed analysis of microRNAs (miRNAs) differentially expressed in RRMS. The discovery set data were validated by quantification using digital quantitative polymerase chain reaction with an independent cohort of 63 RRMS patients (33 in relapse, 30 in remission) and 32 HC. Exosomal RNA NGS revealed that of 15 different classes of transcripts detected, 4 circulating exosomal sequences within the miRNA category were differentially expressed in RRMS patients versus HC: hsa-miR-122-5p, hsa-miR-196b-5p, hsa-miR-301a-3p, and hsa-miR-532-5p. Serum exosomal expression of these miRNAs was significantly decreased during relapse in RRMS. These miRNAs were also decreased in patients with a gadolinium enhancement on brain magnetic resonance imaging. In vitro secretion of these miRNAs by peripheral blood mononuclear cells was also significantly impaired in RRMS. These data show that circulating exosomes have a distinct RNA profile in RRMS. Because putative targets for these miRNAs include the signal transducer and activator of transcription 3 and the cell cycle regulator aryl hydrocarbon receptor, the data suggest a disturbed cell-to-cell communication in this disease. Thus, exosomal miRNAs might represent a useful biomarker to distinguish multiple sclerosis relapse. Ann Neurol 2017;81:703-717.

Association of seasonal serum 25-hydroxyvitamin D levels with disability and relapses in relapsing-remitting multiple sclerosis.

The aim of this study was to evaluate the association of serum 25-hydroxyvitamin D (25(OH)D) with disability and frequency of relapses in relapsing-remitting multiple sclerosis (MS) patients. The study included 184 patients with relapsing-remitting MS who were receiving immune-modulating drugs and no vitamin D supplementation. The concentration of 25(OH)D was measured in February and August 2014. The level of disability was assessed twice according to the Expanded Disability Status Scale (EDSS). The patients were divided into two groups: EDSS 0.0-2 and 2.5-4. The control group comprised 58 age- and sex-matched healthy subjects. The 25(OH)D levels were compared with the occurrence of relapses and the level of disability. Mean serum 25(OH)D concentrations were significantly lower in winter in both MS patients and controls. Winter level of 25(OH)D was significantly lower in severe MS cases (EDSS 2.5-4.0) than in mild cases (EDSS 0.0-2.0) (P=0.022), and in the controls (P=0.008), especially in females (r=0.38, P=0.0015). Logistic regression analysis showed the winter serum 25(OH)D was significantly associated with MS (odds ratio 0.925; 95% confidence interval, 0.822-0.970). Serum 25(OH)D levels were significantly lower in MS patients with relapses than in those without relapses both in winter, and in summer. Hypovitaminosis D was more prevalent during winter than summer, both in the sample group and the control, especially in female MS patients with higher levels of disability. Low vitamin D levels are associated with a more severe course of disease and an increased number of relapses.

Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis.

Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis.

Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis

Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis

Interferon–β Induces Hepatocyte Growth Factor in Monocytes of Multiple Sclerosis Patients

Interferon-β is a first-line therapy used to prevent relapses in relapsing-remitting multiple sclerosis. The clinical benefit of interferon-β in relapsing-remitting multiple sclerosis is attributed to its immunomodulatory effects on inflammatory mediators and T cell reactivity. Here, we evaluated the production of hepatocyte growth factor, a neuroprotective and neuroinflammation-suppressive mediator, by peripheral blood mononuclear cells collected from interferon-β−treated relapsing-remitting multiple sclerosis patients, relapsing remitting multiple sclerosis patients not treated with interferon-β, and healthy volunteers. Using intracellular flow cytometry analysis, increased production of hepatocyte growth factor was observed in circulating CD14+ monocytes from patients undergoing long-term treatment with interferon-β versus untreated patients. Complementary in vitro studies confirmed that treatment with interferon-β induced rapid and transient transcription of the hepatocyte growth factor gene in CD14+ monocytes and that intracellular and secreted monocytic hepatocyte growth factor protein levels were markedly stimulated by interferon-β treatment. Additional exploration revealed that “pro-inflammatory” (CD14+CD16+) monocytes produced similar levels of hepatocyte growth factor in response to interferon-β as “classical” (CD14+CD16−) monocytes, and that CD14+ monocytes but not CD4+ T cells express the hepatocyte growth factor receptor c-Met. Our findings suggest that interferon-β may mediate some of its therapeutic effects in relapsing-remitting multiple sclerosis through the induction of hepatocyte growth factor by blood monocytes by coupling immune regulation and neuroprotection.

Different Patterns in Monthly Distribution of Clinical Relapses in Relapsing-Remitting Multiple Sclerosis between UK and Greece (P01.141)

Different Patterns in Monthly Distribution of Clinical Relapses in Relapsing-Remitting Multiple Sclerosis between UK and Greece (P01.141)

Soluble HLA Class I and Class II Molecules in Relapsing-Remitting Multiple Sclerosis: Acute Response to Interferon-β1a Treatment and Their Use as Markers of Disease Activity

During relapses in relapsing-remitting multiple sclerosis (RRMS), serum soluble HLA class I surface antigen (sHLA-I) levels are reported to either decrease or remain unchanged, whereas serum sHLA-II levels increase. Interferon-beta1b therapy was recently reported to increase serum sHLA-I in RRMS. In the present prospective study, solid-phase enzyme-linked immunosorbent assay was used to measure sHLA-I and sHLA-II in the sera of 21 RRMS patients during a clinical exacerbation, and then six weeks after treatment with high-dose interferon-beta1a (IFN-beta1a). Pretreatment serum sHLA-I was significantly lower in patients than in normal controls (P < 0.0005). Pretreatment sHLA-II was also significantly lower than in normal controls (P = .003) unless enhancing MRI lesions (objectified relapse) were present; then sHLA-II levels were similar to normal controls (relative increase). Six weeks after initiation of IFN-beta1a treatment, a significant increase in serum sHLA-I was observed in all 21 RRMS patients (P < .0005). Conversely, serum sHLA-II decreased significantly after treatment in the entire patient group (P < .0005). The acute effect of IFN-beta1a on serum sHLA-I and sHLA-II was observed to be the opposite of that occurring during RRMS relapses. Monitoring of both sHLA-I and sHLA-II appears necessary if these molecules are to be developed as RRMS activity markers.