Cohort Of Multiple Sclerosis Patients Research Articles

Prevalence of insulin resistance and dyslipidemia in multiple sclerosis and its correlation with disease activity

Insulin resistance (IR) and dyslipidemia have been described as comorbidity in multiple sclerosis (MS) contributing to disease progression and disability. To study the prevalence of IR and dyslipidemia in a North Indian cohort of MS patients and its correlation with disease activity.

Racial and ethnic disparities in treatment response and tolerability in multiple sclerosis: A comparative study

BackgroundInter-individual response and tolerability profiles associated with available disease-modifying treatments (DMTs) are an important aspect of the therapeutic decision-making process in multiple sclerosis (MS). In the absence of racially diverse clinical studies, the possible effect of race and ethnicity on treatment outcome remains uncertain. This study aims to compare disease outcome among Hispanic, Black, and White patients with MS, and assess the impact of race/ethnicity on long-term outcome. MethodsA retrospective review of electronic medical records was performed on a multiethnic cohort of MS patients treated in a large academic center. Sociodemographic characteristics, treatment regimens, and disability outcomes were compared between the three groups. ResultsA total of 300 age- and gender-matched MS patients (100 Hispanic, 100 Black, and 100 White) were included in the study. When assessing the overall survival of MS patients without ambulatory disability 5 years from diagnosis, Hispanics and Blacks attained lower survival times compared to Whites (survival time ratio [STR] 0.17, p = 0.004; and 0.14, p = 0.002, respectively). Black patients had the highest rate of disease progression and treatment-limiting adverse events despite similar sociodemographic profiles and DMT exposure relative to Hispanics and Whites. ConclusionRacial/ethnic disparities in treatment outcome create an unmet need to identify tailored, multifaceted approaches to therapy selection in MS.

PD36-01 CORRELATION BETWEEN WHITE MATTER INTEGRITY AND LOWER URINARY TRACT SYMPTOMS (LUTS) IN FEMALE MULTIPLE SCLEROSIS PATIENTS

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Neurogenic Voiding Dysfunction (PD36)1 Sep 2021PD36-01 CORRELATION BETWEEN WHITE MATTER INTEGRITY AND LOWER URINARY TRACT SYMPTOMS (LUTS) IN FEMALE MULTIPLE SCLEROSIS PATIENTS Darshil Choksi, Khue Tran, Bradley Schott, Christof Karmonik, Timonthy Boone, and Rose Khavari Darshil ChoksiDarshil Choksi More articles by this author , Khue TranKhue Tran More articles by this author , Bradley SchottBradley Schott More articles by this author , Christof KarmonikChristof Karmonik More articles by this author , Timonthy BooneTimonthy Boone More articles by this author , and Rose KhavariRose Khavari More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002040.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Multiple Sclerosis (MS) is a demyelinating disease of the central nervous system and around 90% of MS patients experience LUTS. The degree of demyelination and signal disruption can be quantified by measuring the functional anisotropy (FA) and mean diffusivity (MD) of white matter tracts (WMTs) via diffusion tensor imaging (DTI). In this study, we analyzed the correlation between clinical variables evaluating LUTS (including urodynamics parameters and validated questionnaires) with both FA and MD values in a cohort of female MS patients. METHODS: Twenty-eight MS women with LUTS were enrolled in this prospective study. Urodynamics and validated questionnaires including the Urinary Distress Inventory (UDI-6) and Incontinence Impact Questionnaire (IIQ-7) were collected. DTI images were acquired (32 directions, one B0 image) for each subject using the standard MRI pulse sequence available on the Philips 3 Tesla Ingenia scanner. The AFNI software package was used to automatically align clinical DTI images onto the ICMB DTI81 atlas to extract the FA and MD values of 50 tracts for each subject. Pearson’s correlation was performed between FA and MD values versus each clinical variable for all 50 tracts. Any WMTs with a p-value less than 0.05 on the Pearson’s correlation with FA or MD in at least one of the clinical variables was considered a statistically significant correlation. A positive correlation coefficient (R) for MD and negative correlation for FA were noted as signs of WMT demyelination contributing directly to clinical symptoms whereas a negative correlation for MD and positive correlation for FA were noted to indicate compensatory strengthening of the WMT in an effort to maintain continence in the presence of MS. Only WMTs with |R| >0.3 were reported. RESULTS: Five WMTs (ML-L, CP-R, SS-R, UNC-L, and SFO-R) showed statistically significant demyelination in correlation to symptoms, whereas three WMTs (IFO-R, PCR-R, and CGH-L) displayed statistically significant compensatory strengthening (Table 1). CONCLUSIONS: The ability to correlate changes in WMT signaling to clinical symptoms strengthens our understanding of the demyelination that leads to LUTS in female MS patients and can enable the development of targeted therapies for patients early in the disease course. Source of Funding: Dr. Khavari reports that she is partially supported by K23DK118209, National Institute of Health, NIDDK (RK). Also supported by Houston Methodist Clinician Scientist Award (RK) © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e595-e595 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Darshil Choksi More articles by this author Khue Tran More articles by this author Bradley Schott More articles by this author Christof Karmonik More articles by this author Timonthy Boone More articles by this author Rose Khavari More articles by this author Expand All Advertisement Loading ...

Lesion features on magnetic resonance imaging discriminate multiple sclerosis patients.

Magnetic resonance imaging (MRI) provides insight into various pathological processes in multiple sclerosis (MS) and may provide insight into patterns of damage among patients. We sought to determine if MRI features have clinical discriminative power among a cohort of MS patients. Ninety-six relapsing remitting and seven progressive MS patients underwent myelin water fraction (MWF) imaging and conventional MRI for cortical thickness and thalamic volume. Patients were clustered based on lesion level MRI features using an agglomerative hierarchical clustering algorithm based on principal component analysis (PCA). One hundred and three patients with 1689 MS lesions were analyzed. PCA on MRI features demonstrated that lesion MWF and volume distributions (characterized by 25th, 50th, and 75th percentiles) accounted for 87% of the total variability based on four principal components. The best hierarchical cluster confirmed two distinct patient clusters. The clustering features in order of importance were lesion median MWF, MWF 25th, MWF 75th, volume 75th percentiles, median individual lesion volume, total lesion volume, cortical thickness, and thalamic volume (all p values <0.01368). The clusters were associated with patient Expanded Disability Status Scale (EDSS) (n=103, p=0.0338) at baseline and at 5years (n=72, p=0.0337). These results demonstrate that individual MRI features can identify two patient clusters driven by lesion-based values, and our unique approach is an analysis blinded to clinical variables. The two distinct clusters exhibit MWF differences, most likely representing individual remyelination capabilities among different patient groups. These findings support the concept of patient-specific pathophysiological processes and may guide future therapeutic approaches.

Association of clinical epidemiological factors to polypharmacy among patients with multiple sclerosis: real-life data

Introduction: Treatment for multiple sclerosis should focus on relapse prevention and treatment, as well as symptom and disease progression control, which require the use of multiple medications. Objective: To evaluate the association of polypharmacy and related clinical, epidemiological factors in multiple sclerosis patient cohorts. Methods: It was conducted a prospective study of multiple sclerosis patients that held a prescription of disease-modifying drugs between January and December 2017. The medications were analyzed and classified as either long-term or as-needed medications for therapeutic objective and prescription status purposes. Results: During 2017, 124 patients were attended, 106 were eligible for the study, and 81 agreed to participate. The average age was 40.95±11.69 years. The disease duration varied between 6 months and 30 years, with a median of 7 years. More than half of the multiple sclerosis patients suffered from comorbidities (54.32%), and 76.54% were categorized as polypharmacy. The comparison of polypharmacy between the groups yielded significant differences for comorbidities and employment status and regarding age between patients with polypharmacy and patients without polypharmacy of long-term medications. Conclusion: The age of the patient and the presence of comorbidities are important factors related to polypharmacy.

Biomarkers of systemic inflammation, soluble IL-2Rα and the multiple sclerosis-associated IL2RA SNP rs2104286 in healthy subjects and multiple sclerosis patients

Soluble interleukin-2 (IL-2) receptor α (sIL-2Rα) antagonizes IL-2 signaling and is involved in the pathogenesis of several immune-mediated diseases including multiple sclerosis (MS). The level of sIL-2Rα is affected by the MS-associated single nucleotide polymorphism (SNP) rs2104286.By use of ELISA and electrochemiluminescence, we investigated if 26 biomarkers of systemic inflammation were associated with sIL-2Rα and rs2104286 in cohorts of healthy subjects and MS patients in serum and heparin plasma.We found that sIL-2Rα significantly correlated with the level of tumor necrosis factor-α (TNFα) (r = 0.391, p = 0.002) in healthy subjects and the association was validated in a separate cohort. Additional, in healthy subjects we confirmed a previous report indicating that C-reactive protein (CRP) correlates with sIL-2Rα (r = 0.278, p = 0.034). None of the biomarkers of systemic inflammation were significantly associated with sIL-2Rα in MS patients. Furthermore, the MS-associated SNP rs2104286 was not significantly associated with any of the biomarkers of systemic inflammation in neither healthy subjects nor MS patients.We conclude that sIL-2Rα is associated with TNFα and CRP in healthy subjects. However, further research is required to confirm the use of sIL-2Rα as biomarker of systemic inflammation as well as to assess the mechanism underlying the observed correlation between levels of sIL-2Rα and TNFα.

Sex-specific signatures of intrinsic hippocampal networks and regional integrity underlying cognitive status in multiple sclerosis.

The hippocampus is an anatomically compartmentalized structure embedded in highly wired networks that are essential for cognitive functions. The hippocampal vulnerability has been postulated in acute and chronic neuroinflammation in multiple sclerosis, while the patterns of occurring inflammation, neurodegeneration or compensation have not yet been described. Besides focal damage to hippocampal tissue, network disruption is an important contributor to cognitive decline in multiple sclerosis patients. We postulate sex-specific trajectories in hippocampal network reorganization and regional integrity and address their relationship to markers of neuroinflammation, cognitive/memory performance and clinical severity. In a large cohort of multiple sclerosis patients (n = 476; 337 females, age 35 ± 10 years, disease duration 16 ± 14 months) and healthy subjects (n = 110, 54 females; age 34 ± 15 years), we utilized MRI at baseline and at 2-year follow-up to quantify regional hippocampal volumetry and reconstruct single-subject hippocampal networks. Through graph analytical tools we assessed the clustered topology of the hippocampal networks. Mixed-effects analyses served to model sex-based differences in hippocampal network and subfield integrity between multiple sclerosis patients and healthy subjects at both time points and longitudinally. Afterwards, hippocampal network and subfield integrity were related to clinical and radiological variables in dependency of sex attribution. We found a more clustered network architecture in both female and male patients compared to their healthy counterparts. At both time points, female patients displayed a more clustered network topology in comparison to male patients. Over time, multiple sclerosis patients developed an even more clustered network architecture, though with a greater magnitude in females. We detected reduced regional volumes in most of the addressed hippocampal subfields in both female and male patients compared to healthy subjects. Compared to male patients, females displayed lower volumes of para- and presubiculum but higher volumes of the molecular layer. Longitudinally, volumetric alterations were more pronounced in female patients, which showed a more extensive regional tissue loss. Despite a comparable cognitive/memory performance between female and male patients over the follow-up period, we identified a strong interrelation between hippocampal network properties and cognitive/memory performance only in female patients. Our findings evidence a more clustered hippocampal network topology in female patients with a more extensive subfield volume loss over time. A stronger relation between cognitive/memory performance and the network topology in female patients suggests greater entrainment of the brain’s reserve. These results may serve to adapt sex-targeted neuropsychological interventions.

Natural history of relapsing remitting multiple sclerosis in a long-lasting cohort from a tertiary MS centre in Portugal

BackgroundSeveral disease-modifying therapies (DMTs) have emerged in the last two decades for the treatment of multiple sclerosis (MS). The increasing use of these therapies has enhanced the need to study its impact on long-term disease progression and on the natural history of MS. This study aimed to characterize a Portuguese MS patient cohort in what concerns the natural history of disease by exploring differences throughout 3 decades. MethodsLongitudinal, retrospective, non-interventional study. Patients aged ≥ 18 years old, with confirmed diagnosis of relapsing-remitting MS (RRMS), were included. Biodemographic and clinical characteristics (MS diagnosis, patient follow-up, relapses, treatment, and exams) were assessed and compared according to the first appointment date throughout 10-year spans (1987-1996; 1997-2006; 2007-2016). Results548 patients were included in this analysis. Significant differences were observed between decades for evoked potential (EP) and cerebrospinal fluid (CSF) exams conducted at diagnosis, the first with less expression on the last decade; the median number of relapses per year (higher in the subgroup 07–16); EDSS at baseline and at last appointment (both higher in the subgroup 87–96); and the percentage of patients achieving EDSS 3.0 and EDSS 6.0 (increased in the subgroup 87–96). Additionally, time from diagnosis to first treatment was significantly lower in patients from the most recent decade, and a greater percentage of such patients, compared to the other two subgroups, was, at last appointment, under a second line DMT. ConclusionIn general, our study reflects findings from longitudinal studies on MS progression already published in the literature. In recent years, the growing number of more effective DMTs, along with earlier disease detection, and improvements in access to healthcare appear to have had a positive impact on patients’ access to treatment and, consequently, disease progression. Additional studies, with increased follow up time, are needed to further investigate the effect of treatment improvement in the natural history of MS.

The timed 25-foot walk in a large cohort of multiple sclerosis patients

Background: The timed 25-foot walk (T25FW) is a key clinical outcome measure in multiple sclerosis patient management and clinical research. Objectives: To evaluate T25FW performance and factors associated with its change in the Multiple Sclerosis Outcome Assessments Consortium (MSOAC) Placebo Database (n = 2465). Methods: We created confirmed disability progression (CDP) variables for T25FW and Expanded Disability Status Scale (EDSS) outcomes. We used intraclass correlation coefficients (ICCs) and Bland Altman plots to evaluate reliability. We evaluated T25FW changes and predictive validity using a mixed-effects model, survival analysis, and nested case–control analysis. Results: The mean baseline score for the T25FW in this study population was 9.2 seconds, median = 6.1 (standard deviation = 11.0, interquartile range (IQR) = 4.8, 9.0). The T25FW measure demonstrated excellent test–retest reliability (ICC = 0.98). Walk times increased with age, disability, disease type, and disease duration; relapses were not associated with an increase. Patients with T25FW progression had a faster time to EDSS-CDP compared to those without (hazards ratio (HR): 2.6; confidence interval (CI): 2.2, 3.1). Changes in the T25FW were more likely to precede changes in EDSS. Conclusion: This research confirms the association of the T25FW with disability and provides some evidence of predictive validity. Our findings support the continued use of the T25FW in clinical practice and clinical trials.

Response to hepatitis B vaccine in patients with multiple sclerosis: preliminary data

Background Studies in different autoimmune pathologies report a lower response rate (immunogenicity) to vaccinations than in the general population. Our objective is to analyze the immunogenicity of the vaccine against hepatitis B virus (HBV) in patients with multiple sclerosis (MS). Methods In a single prospective cohort of MS patients with negative HBV serology, hepatitis B (rDNA) B vaccine was administered at 0, 1 and 6 months. Immunogenicity was analyzed by the determination of antibodies to surface antigens of HBV. We considered a patient as a responder if antibodies level was higher than 10 IU/L. Posterior analysis of immunogenicity was conducted by demographic variables (e.g. MS phenotype, EDSS) and use of disease-modifying drugs (DMTs). Results Vaccination study of 251 patients: 160 of them were sero-negative (63.7%). Patients vaccinated: 99. Overall response: 74.1%. No significant relationship by sex (female 77.6% responders, male 68.8%) and MS phenotype (relapsing forms 74.3% responders, secondary progressive 50%). Variables associated with significantly lower immunogenicity were: age (>55 years), EDSS score (median: non-responders=3.0, responders=1.0), number of relapses and treatment with fingolimod (28.6% responders, n=7). Anti-CD20 therapies showed lower vaccine response (50%), but were not very represented in our sample (n=2). Immunogenicity with other DMTs: interferon/glatiramer 69.6% (n=23), teriflunomide 71.4% (n=14), dimethylfumarate 92.3% (n=13), natalizumab 100% (n=7). Conclusion The overall immunogenicity of our sample is lower than that reported in the general population (74 vs >86%), as in other autoimmune diseases. Preliminary data show a lower immunogenicity with older age, higher EDSS score, number of relapses and fingolimod use.

Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres

Background: Oral cladribine has been approved for the treatment of relapsing multiple sclerosis (MS) yet real-world evidence regarding its effectiveness and safety remains scarce. Objective: To evaluate efficacy and safety outcomes of MS patients following induction of cladribine. Methods: We evaluated our prospective cohort of cladribine-treated MS patients from two tertiary centres in Germany. Relapses, disability worsening and occurrence of new or enlarging T2-hyperintense magnetic resonance imaging (MRI) lesions were assessed as well as lymphocyte counts and herpes virus infections. Results: Among 270 patients treated with cladribine, we observed a profound reduction of both relapses and new or enlarging MRI lesions. Treatment appeared more efficacious, especially in patients without previous therapy or following platform substances. Patients switching from natalizumab were prone to re-emerging disease activity. Among patients following dimethyl fumarate pre-treatment, severe lymphopenia was common and associated with increased rates of herpes virus manifestations. Conclusion: Overall, we observed an efficacy and safety profile of cladribine consistent with data from the phase 3 clinical trial. However, patients switching from natalizumab experienced suboptimal disease control beyond rebound activity following cessation of natalizumab. Furthermore, dimethyl fumarate pre-treatment was associated with a profound risk of developing severe lymphopenia and subsequent herpes virus infections.

Serum Vitamin D Level among Multiple Sclerosis Patients in the Tropics: Experience from a Private Clinic in Addis Ababa, Ethiopia.

Multiple sclerosis (MS) is an immune mediated disabling neurological disorder. Very little is known about MS in Ethiopia. The objective of this study was to determine the prevalence of hypovitaminosis D and associated factors in cohort of MS patients in Ethiopia. A cross-sectional observational study was conducted among 25 multiple sclerosis patients at Yehuleshet Specialty Clinic, Addis Ababa, Ethiopia. The prevalence of vitamin D deficiency was 96% (n=24). The average serum vitamin D was 14.8 (±10.4) ng/mL. The mean age was 35.8 (±10) years. Females accounted for 80% (n=20). Relapsing and remitting MS was the commonest variant. Motor, sensory, and mixed symptoms accounted for 40% (n=10), 20% (n=5), and 24% (n=6), respectively. Cold or hot weather and stress were reported as worsening factors in 24% (n=6). Relapse rate was 44% (n=11). Fatigue and seizure disorder were reported by 80% (n=20) and 16% (n=4) respectively. Steroid is the commonest prescribed medication for the patients. A negative correlation was found between serum vitamin D and age (r = -0.062, p = 0.7). Similarly, a negative association was observed between vitamin D and duration of illness (r = -0.311, p = 0.1). Fatigue was reported by those with moderate hypovitaminosis compared to those having severe hypovitaminosis (p=0.002). Seizure was reported more by those with vitamin D below 10ng/mL compared to those having above 10 ng/mL (p=0.004). Our study demonstrates a high prevalence of hypovitaminosis D in Ethiopian MS patients. Hypovitaminosis D was associated with increment in age and duration of illness.

Depression and anxiety in multiple sclerosis patients: The role of genetic variability of interleukin 1β

BackgroundMood disorders, as depression and anxiety, are frequent in Multiple Sclerosis (MS) patients. High pro-inflammatory cytokine levels (e.g. IL-1β) have been reported in depressed individuals. ObjectiveWe aimed to investigate the role of the rs16944 (IL-1β-511 C>T) polymorphism in the development of anxiety and depression symptoms in a Portuguese cohort of MS patients. Methods393 MS patients answered the Hospital Anxiety and Depression Scale (HADS) at T1. This questionnaire was reapplied to a subgroup of 175 MS patients approximately three years later (T2). HADS cut-off scores for anxiety and depression were respectively ≥11 and ≥8. ResultsAt T1, anxiety was found in 106 MS patients (27.0%) and 11 controls (16.7%); whereas depression was identified in 116 (29.5%) MS patients and 9 controls (13.6%). Persistent anxiety and depression were respectively recorded in 12% and 20% of MS patients. The rs16944TT genotype was found to be a susceptibility factor for the occurrence of depression at T1 (OR = 3.16, p=0.002) and the development of persistent depression (OR = 5.63, p=0.003) in MS. ConclusionStudy results support the hypothesis that inflammation is a significant factor in psychopathology development.

COVID-19 vaccination in patients with multiple sclerosis: What we have learnt by February 2021

Background: Since vaccination against coronavirus disease 2019 (COVID-19) became available, risks related to vaccinating patients with multiple sclerosis (MS) need to be carefully assessed. Objective: Characterize safety and occurrence of immediate relapses following COVID-19 vaccination in a large cohort of MS patients. Methods: We assessed the safety of BNT162b2 COVID-19 vaccination in adult MS patients. Results: Between 20 December 2020 and 25 January 2021, 555 MS patients received the first dose of BNT162b2 vaccine and 435 received the second dose. There were three cases of COVID-19 infection encountered after the first dose. Safety profile of COVID-19 vaccine was characterized by pain at the injection site, fatigue, and headache. No increased risk of relapse activity was noted over a median follow-up of 20 and 38 days after first and second vaccine doses, respectively. The rate of patients with acute relapse was 2.1% and 1.6% following the first and second doses, respectively, similar to the rate in non-vaccinating patients during the corresponding period. Mild increase in the rate of adverse events was noted in younger patients (18–55 years), among patients with lower disability (Expanded Disability Status Scale (EDSS) ⩽3.0), and in patients treated with immunomodulatory drugs. Conclusion: COVID-19 BNT162b2 vaccine proved safe for MS patients. No increased risk of relapse activity was noted.

Cancer risk for multiple sclerosis patients treated with azathioprine and disease-modifying therapies: an Italian observational study.

The risk of malignancy associated with sequential disease-modifying therapies (DMTs) for patients with multiple sclerosis (MS) is uncertain. The aim of this study was to analyze the risk of cancer in patients with MS treated with azathioprine (AZA) and the influence of sequential DMTs on the risk. We retrospectively enrolled a cohort of AZA-treated MS patients followed in two Italian centers from 1987 to 2019. The ratio between observed and expected cancers in the Italian general population was calculated as standardized incidence ratio (SIR). Associations between AZA and DMTs and cancer were estimated by Cox proportional hazards model. We identified 500 AZA-treated MS patients, followed for a median time of 9.7 (0.1-45.7) years: 61.8% of them were treated with DMTs. We found 22 cases of cancer (4.4%). The SIR was 1.14 (95% CI 0.98-1.29), not significantly increased in comparison with the general population. However, the risk was significantly higher in the quintiles of age 32-45, SIR 1.21 (95% CI 1.21-1.42), and 46-51, SIR 1.11 (95% CI 1.11-1.32) than in older cases. Age at AZA treatment onset was the only covariate significantly related to cancer incidence (HR = 1.049, 95% CI 1.007-1.093). The exposure to other DMTs did not modify the risk. The risk of malignancy in MS patients after AZA was similar to that of the general population and did not change with other DMTs sequential treatments. The increased risk in the younger ages should be considered in treatment assessment.

Microbial Dysbiosis and Lack of SCFAs Production on the Gut of Patients With Multiple Sclerosis in a Spanish Cohort

Multiple Sclerosis (MS) is a heterogeneous disease on its clinic and evolution, on which the myelin sheath of the axons is attacked by the own immune system. The origin of MS is still unknown; however, genetic, epigenetic and environmental factors seem to be implicated in its development. In the last years, much effort has been made to describe the gut microbiota dysbiosis of MS patients. Nevertheless, differences in geographical location, diets and lifestyles have made this goal difficult to achieve; therefore, the role of the bacterial dysbiosis in the MS is unclear. The microbiota produces thousands of biologically active substances among which are notable the Short Chain Fatty Acids (SCFAs) excretion. These metabolites are the main mediators of the interaction with the immune and neuroendocrine systems; in consequence, their analysis in the MS could be of great interest. The aim of this study is to determine the microbial dysbiosis and its SCFAs production in a Spanish cohort of MS patients. The gut microbiota of the Spanish cohort of MS patients is characterized by an increment in members of the phylum Proteobacteria, especially marked on those patients that are not receiving any disease modifying treatment. Regarding SCFAs production, a lack in total SCFAs excretion and an altered profile of SCFAs in MS patients, (characterized by a decrease of butyric acid production) could be observed. This alteration is more evident when patients with an Expanded Disability Status Scale (EDSS) score higher than 1 were considered, also presenting a significative reduction of caproic acid and an increase of acetic acid excretion. The abundance of Proteobacteria and acetate and the low excretion of total SCFAs, especially butyrate, are common characteristics of MS patients and, besides, both are associated with a worse prognosis of the disease. Funding Statement: This work was supported by the Spanish Network of Multiple Sclerosis (REEM) under the grant (BIOD19- 021). Declaration of Interests: The authors report no conflict of interest. Ethics Approval Statement: The local ethical committee approved this trial with the reference 09/157.

Plasma neurofilament light chain levels are predictors of disease activity in multiple sclerosis as measured by four-domain NEDA status, including brain volume loss

Background: The research is focused on sensitive biomarkers in multiple sclerosis (MS). Objective: The aim of the study was to assess the relationship between plasma neurofilament light chain (pNfL) and disease activity as defined by the concept NEDA (no evident disease activity), including brain volumetry, in a cohort of MS patients treated with disease-modifying treatment (DMT). Methods: Levels of pNfL (Single Molecule Array (SIMOA) technology) were examined in 95 RRMS (relapsing-remitting multiple sclerosis) patients and analyzed in relationship to NEDA-3 status and NEDA-BVL (brain volume loss; NEDA-3 extended by brain volumetry) during the last 12 months. The statistical model was developed using logistic regression analysis, including the independent variables: demographic, clinical, and magnetic resonance imaging (MRI) data. Dependent variables were NEDA-3 and NEDA-BVL status. Results: The mean age of the study participants (n = 95, 62% females) was 37.85 years (standard deviation (SD) = 9.62) and the median disability score was 3.5 (2.5–4.1). Receiver operating characteristics (ROC) analysis showed that pNfL predicts NEDA-3 (the sensitivity and specificity of the model were 92% and 78%, respectively, p < 0.001) and NEDA-BVL status (the sensitivity and specificity were 80% and 65%, respectively, p < 0.001). Conclusion: The results show that pNfL levels are a useful biomarker of disease activity determined by NEDA-BVL status, including brain MRI-volumetry in patients with RRMS.

Validation of Computer-Adaptive Contrast Sensitivity as a Tool to Assess Visual Impairment in Multiple Sclerosis Patients.

BackgroundImpairment of visual function is one of the major symptoms of people with multiple sclerosis (pwMS). A multitude of disease effects including inflammation and neurodegeneration lead to structural impairment in the visual system. However, the gold standard of disability quantification, the expanded disability status scale (EDSS), relies on visual assessment charts. A more comprehensive assessment of visual function is the full contrast sensitivity function (CSF), but most tools are time consuming and not feasible in clinical routine. The quantitative CSF (qCSF) test is a computerized test to assess the full CSF. We have already shown a better correlation with visual quality of life (QoL) than for classical high and low contrast charts in multiple sclerosis (MS).ObjectiveTo study the precision, test duration, and repeatability of the qCSF in pwMS. In order to evaluate the discrimination ability, we compared the data of pwMS to healthy controls.MethodsWe recruited two independent cohorts of MS patients. Within the precision cohort (n = 54), we analyzed the benefit of running 50 instead of 25 qCSF trials. The repeatability cohort (n = 44) was assessed by high contrast vision charts and qCSF assessments twice and we computed repeatability metrics. For the discrimination ability we used the data from all pwMS without any previous optic neuritis and compared the area under the log CSF (AULCSF) to an age-matched healthy control data set.ResultsWe identified 25 trials of the qCSF algorithm as a sufficient amount for a precise estimate of the CSF. The median test duration for one eye was 185 s (range 129–373 s). The AULCSF had better test–retest repeatability (Mean Average Precision, MAP) than visual acuity measured by standard high contrast visual acuity charts or CSF acuity measured with the qCSF (0.18 vs. 0.11 and 0.17, respectively). Even better repeatability (MAP = 0.19) was demonstrated by a CSF-derived feature that was inspired by low-contrast acuity charts, i.e., the highest spatial frequency at 25% contrast. When compared to healthy controls, the MS patients showed reduced CSF (average AULCSF 1.21 vs. 1.42, p < 0.01).ConclusionHigh precision, usability, repeatability, and discrimination support the qCSF as a tool to assess contrast vision in pwMS.

The Choroid Plexus Is Permissive for a Preactivated Antigen-Experienced Memory B-Cell Subset in Multiple Sclerosis.

The role of B cells in multiple sclerosis (MS) is increasingly recognized. B cells undergo compartmentalized redistribution in blood and cerebrospinal fluid (CSF) during active MS, whereby memory B cells accumulate in the CSF. While B-cell trafficking across the blood–brain barrier has been intensely investigated, cellular diapedesis through the blood–CSF barrier (BCSFB) is incompletely understood. To investigate how B cells interact with the choroid plexus to transmigrate into the CSF we isolated circulating B cells from healthy donors (HC) and MS patients, utilized an inverted cell culture filter system of human choroid plexus papilloma (HIBCPP) cells to determine transmigration rates of B-cell subsets, immunofluorescence, and electron microscopy to analyze migration routes, and qRT-PCR to determine cytokines/chemokines mediating B-cell diapedesis. We also screened the transcriptome of intrathecal B cells from MS patients. We found, that spontaneous transmigration of HC- and MS-derived B cells was scant, yet increased significantly in response to B-cell specific chemokines CXCL-12/CXCL-13, was further boosted upon pre-activation and occurred via paracellular and transcellular pathways. Migrating cells exhibited upregulation of several genes involved in B-cell activation/migration and enhanced expression of chemokine receptors CXCR4/CXCR5, and were predominantly of isotype class switched memory phenotype. This antigen-experienced migratory subset displayed more pronounced chemotactic activities in MS than in HC and was retrieved in intrathecal B cells from patients with active MS. Trafficking of class-switched memory B cells was downscaled in a small cohort of natalizumab-exposed MS patients and the proportions of these phenotypes were reduced in peripheral blood yet were enriched intrathecally in patients who experienced recurrence of disease activity after withdrawal of natalizumab. Our findings highlight the relevance of the BCSFB as important gate for the entry of potentially harmful activated B cells into the CSF.

Cancer diagnosis in a Spanish cohort of multiple sclerosis patients under dimethylfumarate treatment

BackgroundPotential increase of cancer incidence is one of the main safety concerns of the disease-modifying therapies employed in Multiple Sclerosis (MS). ObjectiveDetailed description of patients who developed cancer among a prospective cohort of Spanish MS patients on dimethyl fumarate (DMF) treatment. MethodsWe describe patients who developed cancer among a cohort of 886 MS patients on DMF treatment (2681 patient-years), with a median time of exposure of 39.5 months (IQR 23-51.5), who participated in a multicentre and prospective real-world study conducted in 16 Spanish National Health System hospitals from February 2014 to May 2019. Local researchers were periodically contacted by the investigation team to monitor safety issues. Cancer histories were collected from the medical records and the information was updated at July 30th 2020. ResultsEight Caucasian women developed cancer, which accounts for 0.9% and an accumulated malignancy rate of 298.39 cases per 100,000 patient-years of DMF exposure. At the time of cancer diagnosis, age was between 33 to 67 years and median time on DMF treatment 16.5 months (range 1-53). Two patients had familiar history of cancer. No specific cancer lines were found (breast cancer in 2 cases, thyroid in 3, urothelial carcinoma, cervix and a progression to leiomyosarcoma from a mitotically active leiomyoma). DMF was withdrawn during cancer treatment in 6 patients and reintroduced later. All cancers except one are in complete remission. The patient with leiomyosarcoma died by cancer progression. ConclusionA relationship between cancers and DMF is unlikely because the malignancy rate was similar to that of the age-and sex-matched general population, and because of the absence of specific tumour cell lines. Nevertheless, as with other immunosuppressive DMTs, clinicians treating MS should be aware of any potential cancer symptom and demand proper testing.