Relapsing-remitting Multiple Sclerosis Patients Research Articles

CSF levels of Chitinase3like1 correlate with early response to cladribine in multiple sclerosis.

Cladribine has been introduced as a high-efficacy drug for treating relapsing-remitting multiple sclerosis (RRMS). Initial cohort studies showed early disease activity in the first year after drug initiation. Biomarkers that can predict early disease activity are needed. To estimate cerebrospinal fluid (CSF) markers of clinical and radiological responses after initiation of cladribine. Forty-two RRMS patients (30F/12M) treated with cladribine were included in a longitudinal prospective study. All patients underwent a CSF examination at treatment initiation, clinical follow-up including Expanded Disability Status Scale (EDSS) assessment, and a 3T MRI scan after 6,12 and 24 months, including the evaluation of white matter (WM) and cortical lesions (CLs). CSF levels of 67 inflammatory markers were assessed with immune-assay multiplex techniques. The 'no evidence of disease activity' (NEDA-3) status was assessed after two years and defined by no relapses, no disability worsening measured by EDSS and no MRI activity, including CLs. Three patients were lost at follow-up. At the end of follow-up, 19 (48%) patients remained free from disease activity. IFNgamma, Chitinase3like1, IL32, Osteopontin, IL12(p40), IL34, IL28A, sTNFR2, IL20 and CCL2 showed the best association with disease activity. When added in a multivariate regression model including age, sex, and baseline EDSS, Chitinase 3 like1 (p = 0.049) significantly increased in those patients with disease activity. Finally, ROC analysis with Chitinase3like1 added to a model with EDSS, sex, age previous relapses, WM lesion number, CLs, number of Gad enhancing lesions and spinal cord lesions provided an AUC of 0.76 (95%CI 0.60-0.91). CSF Chitinase 3 like1 might provide prognostic information for predicting disease activity in the first years after initiation of cladribine. The drug's effect on chronic macrophage and microglia activation deserves further evaluation.

Longitudinal enlargement of choroid plexus is associated with chronic lesion expansion and neurodegeneration in RRMS patients

Background and Objective: We explored dynamic changes in the choroid plexus (CP) in patients with relapsing-remitting multiple sclerosis (RRMS) and assessed its relationship with chronic lesion expansion and atrophy in various brain compartments. Methods: Fifty-seven RRMS patients were annually assessed for a minimum of 48 months with 3D FLAIR, pre- and post-contrast 3D T1 and diffusion-weighted magnetic resonance imaging (MRI). The CP was manually segmented at baseline and last follow-up. Results: The volume of CP significantly increased by 1.4% annually. However, the extent of CP enlargement varied considerably among individuals (ranging from −3.6 to 150.8 mm3 or −0.2% to 6.3%). The magnitude of CP enlargement significantly correlated with central (r = 0.70, p < 0.001) and total brain atrophy (r = −0.57, p < 0.001), white (r = −0.61, p < 0.001) and deep grey matter atrophy (r = −0.60, p < 0.001). Progressive CP enlargement was significantly associated with the volume and extent of chronic lesion expansion (r = 0.60, p < 0.001), but not with the number or volume of new lesions. Conclusion: This study provides evidence of progressive CP enlargement in patients with RRMS. Our findings also demonstrate that enlargement of the CP volume is linked to the expansion of chronic lesions and neurodegeneration of periventricular white and grey matter in RRMS patients.

Predictive factors and treatment challenges in malignant progression of relapsing-remitting multiple sclerosis

ObjectiveOur objective was to uncover the predictive factors that can help anticipate the malignant progression of individuals with Relapsing-Remitting Multiple Sclerosis (RRMS). Additionally, we sought to analyze and compare the response to treatment between patients with benign and malignant forms of RRMS. MethodsThis cohort study included RRMS patients categorized as benign (≥10 years since disease onset, Expanded Disability Status Scale (EDSS) ≤ 1) or malignant (≤5 years since disease onset, EDSS ≥6). Patients’ data, including demographics, medical history, treatment, and MRI (Magnetic Resonance Imaging) scans, were collected and statistically analyzed. ResultsAmong the 254 patients diagnosed with RRMS, 174 were found to have benign RRMS, while the remaining 80 were diagnosed with malignant RRMS. Notably, patients with malignant RRMS exhibited a significantly higher mean age of onset (32.00 ± 7.96 vs. 25.70 ± 17.19; P < 0.001) and a greater prevalence of males (40% vs. 18.4%; P = 0.014). Additionally, within the initial five years of diagnosis, patients with malignant RRMS experienced a higher number of relapses (median: 4 vs. 2; P < 0.001) and hospitalizations (median: 2 vs. 1; P = 0.006) compared to those with benign RRMS. Clinical presentations of malignant RRMS were predominantly characterized by multifocal attacks, whereas unifocal attacks were more prevalent in patients with benign RRMS. MRI scans revealed that malignant RRMS patients displayed a higher burden of plaques in the infratentorial and cord regions, as well as a greater number of black hole lesions. Conversely, benign RRMS patients exhibited a higher number of Gadolinium-enhanced lesions. Utilizing Disease-Modifying Therapies (DMTs) with an escalating approach has shown effectiveness in managing benign RRMS. However, it has proven insufficient in addressing malignant RRMS, resulting in frequent transitions to higher-line DMTs. As a result, it places a considerable burden on patients with malignant RRMS, consuming valuable time and resources, and ultimately yielding subpar outcomes. ConclusionOur study identifies prognostic factors for malignant progression in RRMS, including older age of onset, male gender, increased relapses and hospitalizations, multifocal attacks, higher plaque load, and black hole lesions. The current escalation strategy for DMTs is insufficient for managing malignant RRMS, requiring alternative approaches for improved outcomes. In other words, MS is a spectrum rather than a single disease, and some patients progress to a malignant phenotype of MS that is not effectively treated by the current approach.

Folate receptor alpha autoantibodies in the serum of patients with relapsing–remitting multiple sclerosis (RRMS)

Multiple sclerosis (MS) is a potentially progressive, autoimmune neurologic disorder of the central nervous system (CNS), resulting from an autoimmune attack on central nervous system white matter. Folate deficiencies are linked to DNA instability and breakdown of phospholipid membranes and thus might affect myelin integrity. Folic acid exerts its effects through its receptors (FRs). Folate receptor alpha autoantibodies (FRAA) can block folate transport to the brain. Due to important role of folate in the pathogenesis of MS, in this project we aimed to study FRAA serum levels in patients with relapsing remitting multiple sclerosis (RRMS). Fifty-four patients with RRMS and 58 healthy individuals were enrolled in this study. Serum samples were collected from all participants and folate receptor alpha autoantibody (FRAA) serum concentration was measured by Enzyme-linked immunosorbent assay (ELISA). The results showed that FRAA serum levels in patients with RRMS is 67.20±19.79ng/ml as compared to controls which was 37.32±13.26ng/ml. Significant increase in folate receptor autoantibody serum concentration was seen in patients with RRMS when compared to control group (P=0.007). The results showed that a high concentration of folate receptor autoantibody is associated with RRMS. We have also found that 85.18% (46/54) of patients with RRMS were positive for serum FRAA, whereas the prevalence in controls was only 46.55% (27/58). It is concluded that serum FRAA are more prevalent in RRMS patients than controls. The findings also suggest that FRAA might be involved in the pathophysiology of RRMS.

Diagnosis of multiple sclerosis using optical coherence tomography supported by explainable artificial intelligence.

Study of retinal structure based on optical coherence tomography (OCT) data can facilitate early diagnosis of relapsing-remitting multiple sclerosis (RRMS). Although artificial intelligence can provide highly reliable diagnoses, the results obtained must be explainable. The study included 79 recently diagnosed RRMS patients and 69 age matched healthy control subjects. Thickness (Avg) and inter-eye difference (Diff) features are obtained in 4 retinal layers using the posterior pole protocol. Each layer is divided into six analysis zones. The Support Vector Machine plus Recursive Feature Elimination with Leave-One-Out Cross Validation (SVM-RFE-LOOCV) approach is used to find the subset of features that reduces dimensionality and optimises the performance of the classifier. SVM-RFE-LOOCV was used to identify OCT features with greatest capacity for early diagnosis, determining the area of the papillomacular bundle to be the most influential. A correlation was observed between loss of layer thickness and increase in functional disability. There was also greater functional deterioration in patients with greater asymmetry between left and right eyes. The classifier based on the top-ranked features obtained sensitivity = 0.86 and specificity = 0.90. There was consistency between the features identified as relevant by the SVM-RFE-LOOCV approach and the retinotopic distribution of the retinal nerve fibres and the optic nerve head. This simple method contributes to implementation of an assisted diagnosis system and its accuracy exceeds that achieved with magnetic resonance imaging of the central nervous system, the current gold standard. This paper provides novel insights into RRMS affectation of the neuroretina.

The 7-year follow-up of the Hungarian BICAMS validation cohort implies that cognitive performance may improve in multiple sclerosis patients.

Cognitive impairment (CI) is a frequent symptom of multiple sclerosis (MS) and has a great impact on the patients' quality of life, so screening is essential. The brief international cognitive assessment for multiple sclerosis (BICAMS) was developed for this purpose. However, longitudinal data is lacking with the use of the battery. This study is to assess the performance of patients after 5 and 7 years of the original BICAMS validation study and to identify any influencing factors. BICAMS was used to measure cognitive function of 52 relapsing-remitting MS patients (RRMS) from the original validation study after 5 years (n = 43) and again, after 7 years (n = 42). Patients filled out the fatigue impact scale (FIS) and multiple sclerosis quality of life-54 (MSQoL-54) questionnaire, and we evaluated expanded disability status scale (EDSS). There was an improvement in the BVMT-R and the CVLT-II assessments at both the 5-year (p<0.001 and p=0.025) and the 7-year retest (p<0.001 and p=0.002). The prevalence of CI significantly decreased at the 5-year mark (p=0.021) but remained stable after that. There was no deterioration in MSQoL scores during the study. The basic cognitive performance is the most important influencing factor, but the duration of the disease, the EDSS score, and the escalation of the therapy also affect the cognitive scores. This is the longest longitudinal study utilizing the BICAMS battery, reinforcing its feasibility as a clinical screening tool. It seems that cognitive performance may improve in the long term and early initiation of effective therapy may influence this outcome.

Regional GABA levels modulate abnormal resting-state network functional connectivity and cognitive impairment in multiple sclerosis.

More evidence shows that changes in functional connectivity with regard to brain networks and neurometabolite levels correlated to cognitive impairment in multiple sclerosis. However, the neurological basis underlying the relationship among neurometabolite levels, functional connectivity, and cognitive impairment remains unclear. For this purpose, we used a combination of magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging to study gamma-aminobutyric acid and glutamate concentrations in the posterior cingulate cortex, medial prefrontal cortex and left hippocampus, and inter-network functional connectivity in 29 relapsing-remitting multiple sclerosis patients and 34 matched healthy controls. Neuropsychological tests were used to evaluate the cognitive function. We found that relapsing-remitting multiple sclerosis patients demonstrated significantly reduced gamma-aminobutyric acid and glutamate concentrations and aberrant functional connectivity involving cognitive-related networks compared to healthy controls, and both alterations were associated with specific cognition decline. Moreover, mediation analyses indicated that decremented hippocampus gamma-aminobutyric acid levels in relapsing-remitting multiple sclerosis patients mediated the association between inter-network functional connectivity in various components of default mode network and verbal memory deficits. In summary, our findings shed new lights on the essential function of GABAergic system abnormalities in regulating network dysconnectivity and functional connectivity in relapsing-remitting multiple sclerosis patients, suggesting potential novel approach to treatment.

Effect of high frequency repetitive transcranial magnetic stimulation (rTMS) on the balance and the white matter integrity in patients with relapsing-remitting multiple sclerosis: A long-term follow-up study

ObjectivesRepetitive Transcranial Magnetic Stimulation (rTMS) is considered as a safe and non-invasive developing technique used as a therapeutic method for patients with Relapsing-Remitting Multiple Sclerosis (RRMS) who suffer from disturbances in gait and balance. The aim of our study is to evaluate the long-term effect of high frequency rTMS as a therapeutic option for truncal ataxia in RRMS patients and to assess its impact on the integrity of the white matter (WMI), measured in the form of anisotropy metrics using diffusion tensor imaging (DTI). MethodsThe study was conducted in two phases: phase I; a randomized, single-blind, sham-controlled phase and phase II was a 12 months longitudinal open-label prospective phase. Phase I of the trial involved the randomization of 43 patients with RRMS and truncal ataxia to either real (n = 20) or sham (n = 19) rTMS (2 participants from each treatment group were excluded from the study; one developed a relapse before treatment, 2 declined to participate, and one did not show up). Phase II involved providing 12 actual treatments cycles to all patients; each cycle length is 4 weeks, repeated four times on a trimonthly basis, forming a total of 48 sessions. DTI was used for assessment of the WMI. All patients performed DTI 3 times: Imaging sessions were conducted at the screening visit, at the end of phase I, and after the last session in phase II for the first, second and third sessions respectively. A figure-of-8-shape coil, employing rTMS protocol and located over the cerebellum, was used. rTMS protocol is formed of 20 trains formed of 50 stimuli with 20 s apart (5 Hz of 80 % of resting Motor Threshold “MT”). The Berg Balance Scale (BBS), Time up and go (TUG) test, and 10-m walk test (10MWT) were first evaluated at the start of each cycle and just after the final rTMS session. ResultsThe genuine rTMS group's 10MWT, TUG, and BBS showed substantial improvement (p < 0.01), which is continued to be improved throughout the study Timeline, with a significant difference observed following the final rTMS session (P< 0.001). A longitudinal increase in FA was observed in both the Cerebello-Thalamo-Cortical (CTC) and Cortico-Ponto-Cerebellar (CPC) bilateral, as indicated by means of Fractional Anisotropy (FA) measures (p < 0.05). ConclusionIn ataxic RRMS patients, high frequency rTMS over the cerebellum has a long-term beneficial impact on both balance and WMI.

Response to Fingolimod in Multiple Sclerosis Patients Is Associated with a Differential Transcriptomic Regulation.

Fingolimod is an immunomodulatory sphingosine-1-phosphate (S1P) analogue approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). The identification of biomarkers of clinical responses to fingolimod is a major necessity in MS to identify optimal responders and avoid the risk of disease progression in non-responders. With this aim, we used RNA sequencing to study the transcriptomic changes induced by fingolimod in peripheral blood mononuclear cells of MS-treated patients and their association with clinical response. Samples were obtained from 10 RRMS patients (five responders and five non-responders) at baseline and at 12 months of fingolimod therapy. Fingolimod exerted a vast impact at the transcriptional level, identifying 7155 differentially expressed genes (DEGs) compared to baseline that affected the regulation of numerous signaling pathways. These DEGs were predominantly immune related, including genes associated with S1P metabolism, cytokines, lymphocyte trafficking, master transcription factors of lymphocyte functions and the NF-kB pathway. Responder and non-responder patients exhibited a differential transcriptomic regulation during treatment, with responders presenting a higher number of DEGs (6405) compared to non-responders (2653). The S1P, NF-kB and TCR signaling pathways were differentially modulated in responder and non-responder patients. These transcriptomic differences offer the potential of being exploited as biomarkers of a clinical response to fingolimod.

The relation between BTK expression and iron accumulation of myeloid cells in multiple sclerosis.

Activation of Bruton's tyrosine kinase (BTK) has been shown to play a crucial role in the proinflammatory response of B cells and myeloid cells upon engagement with B cell, Fc, Toll-like receptor, and distinct chemokine receptors. Previous reports suggest BTK actively contributes to the pathogenesis of multiple sclerosis (MS). The BTK inhibitor Evobrutinib has been shown to reduce the numbers of gadolinium-enhancing lesions and relapses in relapsing-remitting MS patients. In vitro, BTK inhibition resulted in reduced phagocytic activity and modulated BTK-dependent inflammatory signaling of microglia and macrophages. Here, we investigated the protein expression of BTK and CD68 as well as iron accumulation in postmortem control (n = 10) and MS (n = 23) brain tissue, focusing on microglia and macrophages. MS cases encompassed active, chronic active, and inactive lesions. BTK+ and iron+ cells positively correlated across all regions of interests and, along with CD68, revealed highest numbers in the center of active and at the rim of chronic active lesions. We then studied the effect of BTK inhibition in the human immortalized microglia-like HMC3 cell line in vitro. In particular, we loaded HMC3 cells with iron-dextran and subsequently administered the BTK inhibitor Evobrutinib. Iron treatment alone induced a proinflammatory phenotype and increased the expression of iron importers as well as the intracellular iron storage protein ferritin light chain (FTL). BTK inhibition of iron-laden cells dampened the expression of microglia-related inflammatory genes as well as iron-importers, whereas the iron-exporter ferroportin was upregulated. Our data suggest that BTK inhibition not only dampens the proinflammatory response but also reduces iron import and storage in activated microglia and macrophages with possible implications on microglial iron accumulation in chronic active lesions in MS.

Choroid plexus volume as a marker of retinal atrophy in relapsing remitting multiple sclerosis

ObjectiveTo evaluate choroid plexus (CP) volume as a biomarker for predicting clinical disability and retinal layer atrophy in relapsing remitting multiple sclerosis (RRMS). MethodsNinety-five RRMS patients and 26 healthy controls (HCs) underwent 3 T whole brain MRI, expanded disability status scale (EDSS) and optical coherence tomography (OCT). Fully automated intra-retinal segmentation was performed to obtain the volumes of the retinal nerve fiber layer (RNFL), combined ganglion cell layer -inner plexiform layer (GCIPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), retinal pigment epithelium (RPE), total macular volume (TMV) and papillomacular bundle (PMB). Automated segmentation of the CP within the lateral ventricles was performed and the choroid plexus volume (CPV) was normalized by total intracranial volume (TIV). Linear regression analysis and generalized estimating equation (GEE) models were applied to evaluate relationships between nCPV and EDSS, T2 lesion volume, disease duration, and retinal layer volumes, followed by Bonferroni correction analysis for multiple comparisons. ResultsRRMS patients had larger tChPV compared to HCs (p < 0.001). After Bonferroni correction, there was a significant positive correlation between tChPV and EDSS (r2 = 0.25, p = 0.0002), disease duration (r2 = 0.30, p = 0.01), and T2 lesion volume (r2 = 0.39, p = 0.0000). A robust negative correlation was found between tChPV and RNFL (p < 0.001), GCIPL (p = 0.003), TMV (p = 0.0185), PMB (p < 0.0001), G (p = 0.04), T(p = 0.0001). ConclusionsOur findings support the association of tChPV with disability and altered retinal integrity in RRMS.

Differentiating multiple sclerosis from cerebral small vessel disease using diffusion tensor imaging and magnetic resonance spectroscopy on normally appearing thalami

BackgroundDiffusion tensor imaging (DTI) and magnetic resonance spectroscopy (1H-MRS) can detect the microstructural changes in normal-appearing conventional MRI. So, they may differentiate between multiple sclerosis (MS) cases and cerebral small vessel disease (CSVD). This work aimed to investigate if MRS and DTI are helpful in differentiating between MS and CSVD cases. MethodsThe study was conducted on 90 subjects divided into three groups: 30 relapsing–remitting MS patients, 30 patients with MRI showing CSVD, and 30 healthy controls. Diffusion tensor imaging measuring thalamic FA, ADC values, and 1H-MRS were conducted on patients and controls. ResultsThalamic FA values were significantly higher in the RRMS group than in the control and CSVD groups (P < 0.001, for each) but significantly lower in the CSVD group than the control group (P < 0.001). Moreover, thalamic ADC values were significantly higher in the CSVD group than in the control and MS groups (P < 0.001, for each). Also, thalamic NAA values were significantly lower in RRMS and CSVD groups than in controls (P < 0.001 for each). Still, they were significantly lower in the RRMS group than the CSVD group only on the left side (P = 0.004). The thalamic NAA/Cr values were significantly lower in RRMS (P < 0.001 for both sides) and CVSD than in controls (P = 0.044 and 0.036, for RT and LT sides, respectively). ConclusionsThalamic DTI and 1H-MRS can help detect the microstructural changes in normal-appearing thalami in RRMS and CSVD patients. Moreover, they can help differentiate MS from CSVD patients.

The significance of miRNA-191-5P and miRNA-24-3P as novel biomarkers for multiple sclerosis: a case–control study

BackgroundMultiple sclerosis (MS) is a long-term disease that can lead to disability. microRNAs (miRNA) can provide noninvasive markers allowing more frequent and easy testing in MS. Treatment methods based on manipulating miRNA activity can be innovative. The purpose of this work is to measure the serum expression of miRNA-191-5P and miRNA-24-3P in MS patients. The investigation was carried out on 80 patients with MS (68 patients with Relapsing–remitting multiple sclerosis (RRMS), 12 patients with Progressive MS) and 40 healthy controls. The serum expression of miRNA-191-5P and miRNA-24-3P was measured using real-time quantitative PCR. The expression of the studied miRNAs was relatively calculated using the Eq. 2−ΔΔCt.ResultsSerum levels of miRNA-191 and miRNA-24 showed no difference between MS patients and healthy controls, and neither between RRMS and progressive MS groups. A negative correlation was detected between miRNA-191 and disease duration. Also, a positive correlation was detected between miRNA-191 and miRNA-24 expression. RRMS patients were significantly different from progressive MS patients regarding disease duration (p value 0.001) as well as expanded disability status scale score (p value < 0.001).ConclusionThe study uniquely analyzed the correlation between the miRNA-191 and miRNA-24, being expressed in all MS patients, and being positively correlated means they are influenced by the same factors and they can be therapeutically targeted in the same way, so further studies are required. The impact of disease duration on miRNA-191 expression encourages regular monitoring of miRNA-191.

Predictors of progression of multiple sclerosis in a sample of Egyptian patients

BackgroundMultiple sclerosis (MS) is a multifactorial neurodegenerative autoimmune disease with a varied clinical course and presentation, which is more frequent than ever in the Middle East. The aim of this work is to investigate potential predictors of MS progression in order to help in early diagnose and predict progressive course of the disease.ResultsThis is a retrospective case–control study conducted on a group of multiple sclerosis (MS) patients who developed secondary progression of the disease course (SPMS). The cases were matched with control MS patients who did not develop any disease progression (relapsing remitting MS (RRMS)). The matching was done for sex, and age with a ratio 1:1, total of 150 patients were included as cases and were matched with 150 control patients. Significant associations between MS progression and smoking, vitamin D deficiency, disease duration, delay in MS diagnosis, unemployment, site and number of lesions, and number of black holes were reported. About half of SPMS patients (53.3%) had 3 or more spinal lesions compared to only 1.4% of RRMS patients (p < 0.001). Moreover, about 76% of RRMS patients had no black holes in their radiological finding, while it was found that 35.3% of the SPMS patients had more than 5 black holes, compared to 8% of RRMS patients. Additionally, juxta-cortical site lesions were more frequent in SPMS than that in RRMS in a percentage 72.7 and 46%, respectively. Also, infra-tentorial lesions were found to be more frequent in SPMS group rather than RRMS group 92% and 78.7%, respectively.On the other hand, a lower SDMT scale was associated with a shorter time to SPMS diagnosis in the multivariate Cox regression analysis adjusted to baseline factors and 25-FWT (HR: 0.928, 95% CI: 0.906–0.95).ConclusionsMS secondary progression can be predicted among MS patients in routine practice comprising exposure history, clinical assessment, laboratory findings, and radiological examinations.

Real-world evidence and patient preference for subcutaneous versus intravenous natalizumab in the treatment of relapsing-remitting multiple sclerosis - initial results from the observational SISTER study.

The consideration of patient preference for a certain drug route of administration (RoA) plays an important role in promoting patient adherence in chronic diseases. Natalizumab is an established treatment for relapsing-remitting multiple sclerosis (RRMS) and can be administered as intravenous (IV) infusion or subcutaneous (SC) injection developed to enable a shorter and easier administration versus IV RoA. Primary objective is to compare patients' preference for RoA and satisfaction with SC versus IV natalizumab at baseline and subsequent visits up to 12 months. Secondary objectives include drug utilization, clinical outcomes, safety, and treatment satisfaction in a usual care setting. SISTER (Subcutaneous: Non-Interventional Study for Tysabri Patient Preference - Experience from Real World) is an ongoing, prospective, observational study where natalizumab is utilized according to local label. RRMS patients are included in three natalizumab cohorts: Patients switching from current IV to SC administration (switcher) and patients newly starting natalizumab on either SC or IV route (starter SC/IV). This interim analysis includes 262 patients (184 switchers, 39 SC starters, and 39 IV starters), median observation period was 9 months. 80.8% IV starters and 93.9% SC starters reported at baseline that they prefer the assigned RoA. Although initial satisfaction with chosen RoA was maintained over time from baseline through Month 12 in all three cohorts, the wish for change of the current RoA after 6 and 12 months was more frequently expressed among IV starters than in either SC cohort. Consistently, six patients (23.1%) starting with IV changed their RoA from IV to SC route.Mean global treatment satisfaction according to TSQM-II score at baseline remained high in the switcher group and increased through Month 12 in both IV and SC starter cohorts. Based on current data, there is a trend toward patients' preference for the natalizumab SC route over the IV route, which provides valuable insights into patients' preference for natalizumab RoA in routine care and complements available data from clinical studies with real-world data on SC natalizumab. This observational (non-interventional) study was registered in the local German PEI register for non-interventional studies (NIS-No. 611) and in the international CTgov register (NCT05304520).

Multiple sclerosis disease activity, a multi-biomarker score of disease activity and response to treatment in multiple sclerosis.

Regular assessment of disease activity in relapsing-remitting multiple sclerosis (RRMS) is required to optimize clinical outcomes. Biomarkers can be a valuable tool for measuring disease activity in multiple sclerosis (MS) if they reflect the pathological processes underlying MS pathogenicity. In this pilot study, we combined multiple biomarkers previously analyzed in RRMS patients into an MS disease activity (MSDA) score to evaluate their ability to predict relapses and treatment response to glatiramer acetate (GA). Response Gene to Complement 32 (RGC-32), FasL, IL-21, SIRT1, phosphorylated SIRT1 (p-SIRT1), and JNK1 p54 levels were used to generate cut-off values for each biomarker. Any value below the cutoff for RGC-32, FasL SIRT1, or p-SIRT1 or above the cutoff for IL-21 or JNK1 p54 was given a +1 value, indicating relapse or lack of response to GA. Any value above the cutoff value for RGC-32, FasL, SIRT1, p-SIRT1 or below that for IL-21 or JNK1 p54 was given a -1 value, indicating clinical stability or response to GA. An MSDA score above +1 indicated a relapse or lack of response to treatment. An MSDA score below -1 indicated clinical stability or response to treatment. Our results showed that the MSDA scores generated using either four or six biomarkers had a higher sensitivity and specificity and significantly correlated with the expanded disability status scale. Although these results suggest that the MSDA test can be useful for monitoring therapeutic response to biologic agents and assessing clinically challenging situations, the present findings need to be confirmed in larger studies.

Lower leukocytes pretreatment as a possible risk factor for therapy-induced leukopenia in interferon-beta-treated patients with multiple sclerosis.

Interferon-beta (IFN-β) still plays a fundamental role in immunomodulation of people with multiple sclerosis (MS) with low disease activity and in clinically isolated syndrome (CIS). In 2014, pegylated (PEG) interferon was licensed by the European Medicines Agency (EMA) for relapsing-remitting MS (RRMS), enabling a lower dosing frequency. Our retrospective study compares laboratory findings and adverse events between subcutaneous (sc.) PEG-IFN-β-1a and IFN-β-1a in RRMS and CIS patients. Patients with CIS or RRMS fulfilling the revised McDonald criteria from 2017 visiting the neurology department of the University Medical Center of the Johannes Gutenberg University Mainz from 2010 to 2019 and treated with sc. PEG-IFN-β-1a or sc. IFN-β-1a (n = 202) were screened for eligibility. Patients who underwent regular laboratory controls in-house were included in our analysis (n = 128). We evaluate disease progression through clinical examination, relapse history, and magnetic resonance imaging (MRI) disease activity (gadolinium-enhancing or new T2 lesions). Relevant laboratory findings such as leukopenia (leukocyte count < 3.5/nl) and neutropenia (neutrophil count <43% of lymphocytes or <1500/µl) were assessed. Telephone interviews evaluated the side effects of the respective medication. A subgroup of patients was analyzed regarding neutrophil quantities and qualities. Patients treated with sc. PEG-IFN-β-1a had significantly lower leukocyte counts (p = 0.046) and higher incidences of leukopenia (p = 0.006) and neutropenia (p = 0.03) compared to sc. IFN-β-1a. Clinical and MRI disease activity showed no significant differences, but people treated with sc. PEG-IFN-β-1a reported more common adverse events such as joint/muscle pain, injection-site reaction, and infections. No serious adverse events were reported. Treatment with sc. PEG-IFN-β-1a compared to unpegylated sc. IFN-β resulted in a significantly greater reduction in leukocyte and neutrophil levels with a higher incidence of side effects. We suggest mandatory monitoring of differential blood counts before and during treatment.

Eomesodermin-expressing CD4+ Th cells and association with pregnancy in multiple sclerosis.

Pregnancy in patients with multiple sclerosis (MS) is accompanied by a decline of relapse activity with increased risk of relapses 3 months post-partum, for unknown reasons. Eomesodermin+ T-helper cells (Eomes+ Th cells) are known to mediate neuroinflammation and disease progression in MS and are induced by prolactin-secreting cells. Here, investigated immune cell alterations and the pathophysiological role of Eomes+ Th cells for disease activity during pregnancy and post-partum in MS. We enrolled n = 81 pregnant patients with relapsing-remitting MS (RRMS), n = 27 post-partum RRMS and n = 26 female RRMS control patients under the umbrella of the German Multiple Sclerosis and Pregnancy Registry. Clinical data were collected and immune cell alterations were analysed using flow cytometry. While CD3+CD4+ Th cells were unaffected, CD3+CD8+ cytotoxic T-cells were elevated post-partum (p = 0.02) with reduced B-cell frequencies (p = 0.01) compared to non-pregnant RRMS patients. NK cells were elevated during first trimester (p = 0.02) compared to the third trimester. Frequencies of Eomes+ Th and Eomes+ Tc cells did not differ. There was no correlation of prolactin release and expression of Eomes+ Th cells. However, Eomes+ Th cells correlated with lower frequencies of regulatory T-cells during second (r = -0.42; p < 0.05) and third trimester (r = -0.37; p < 0.05). Moreover, Eomes+ Th cells correlated with frequencies of B-cells during third trimester (r = 0.54; p = 0.02). Frequencies of Eomes+ Th cells were not associated with the number of relapses before pregnancy, during pregnancy or post-partum. However, Eomes+ Th cells strongly correlated with disability post-partum as assessed using the EDSS (r = 0.52; p = 0.009). Pregnancy in MS is associated with robust immunological alterations. Eomes+ Th cells are capable of inducing immune cell alterations during the course of pregnancy, most evident during the second and third trimester as shown with a correlation of reduced Treg cells and a significant increase of B-cells. Importantly, Eomes+ Th cells correlate with disability post-partum. In summary, during late pregnancy in MS an inflammatory, cytotoxic and dysregulated immunological environment is primed gaining function post-delivery. This may be responsible for post-partum disability accumulation.

TAURUS-MS II: real-world use of teriflunomide in Germany and changes in treatment patterns over time.

Teriflunomide is a once-daily oral disease-modifying therapy (DMT) for the treatment of relapsing-remitting multiple sclerosis (RRMS). Only limited information is available about its real-world use and changes over time. To collect real-world data on teriflunomide use in clinical routine (and comparison to the previously conducted study TAURUS-MS). National, open, non-interventional, prospective, multicenter study. TAURUS-MS II was conducted at 220 German sites between July 2017 and March 2022, including RRMS patients treated with teriflunomide. Data on patient demographics, MS history, previous treatment, therapy satisfaction, and safety were collected. In total, 752 patients were included (65% female) with a mean age (±standard deviation) of 43 ± 11 years. Sixty-six percent had DMT before, and 46% had discontinued their last pretreatment ≤6 months prior to study entry. Among the latter, previous DMTs were interferon (21%), glatiramer acetate (11%), and dimethyl fumarate (9%), and reasons for discontinuation were adverse events (AEs; 55%) and insufficient efficacy (16%). Over 24 months, the mean treatment Satisfaction Questionnaire for Medication scores improved by 6 ± 29 points on effectiveness, 8 ± 20 on convenience, and 12 ± 25 on global satisfaction. The mean number of MS relapses decreased from 0.81 ± 0.81 in the 24 months prior to 0.27 ± 0.57 within 24 months after study entry. Non-serious AEs occurred in 423 patients (56%) and serious AEs in 49 patients (7%). Most reported AEs were alanine aminotransferase increase (11%), hypertension (8%), and alopecia (7%). Compared to TAURUS-MS, patients in TAURUS-MS II were younger, had a higher employment rate, and a higher share of treatment-naïve patients. Mean number of relapses was significantly reduced. Patient satisfaction was significantly improved compared to previous DMT. Tolerability was comparable to previous trials. Bundesinstitut für Arzneimittel und Medizinprodukte public database for non-interventional studies, number 7138.

Contemporary Patterns of High-Efficacy Disease Modifying Therapy Use in Korean Patients with Relapsing-Remitting Multiple Sclerosis

Background: Despite the compelling evidence indicating that early initiation of high-efficacy disease modifying therapies (DMTs) is more effective in controlling disease activity and preventing long-term disability in relapsing-remitting multiple sclerosis (RRMS), there is a scarcity of data regarding the implementation of such treatments in Korea. This study aimed to investigate the actual proportion of patients requiring high-efficacy DMT when disease activity is closely monitored.Methods: We conducted a retrospective analysis of medical records of 104 patients with RRMS who developed their disease after 2015 at the National Cancer Center in Korea. The status of no evidence of disease activity-3 (NEDA-3) was defined as no relapse, disability progression, or active lesions in annual magnetic resonance imaging evaluations.Results: Among 104 RRMS patients, 95 started with moderate-efficacy DMT, and nine with high-efficacy DMT. Of patients, 51% showed disease activity despite moderate-efficacy DMT, and prompting 41% to escalate high-efficacy DMT with a median time to switch of 20 months. Following the switch to a high-efficacy DMT, NEDA-3 was maintained in 82% of patients for a median of 27 months (interquartile range: 22, 45). Among the nine patients initially on high-efficacy DMT, no patient exhibited any signs of disease activity after median 34 months of treatment. The majority of patients experienced no significant side effects of high-efficacy DMT.Conclusion: The study showed a significant number of patients requiring escalation to high-efficacy DMT within a few years of treatment initiation with moderate-efficacy DMT, emphasizing the importance of early intervention strategies in managing the patients.