Siponimod Chips Away at Progressive MS.

Progressive multiple sclerosis (PMS) causes slow accumulation of neurologic disability and has been refractory to treatment with the immunomodulatory medications that effectively control relapsing MS. Siponimod modestly slowed the rate of disability progression among PMS patients who had inflammatory disease activity, evidenced by new or gadolinium-enhancing MRI lesions. To view this Bench to Bedside, open or download the PDF.

A Noncanonical CD56dimCD16dim/- NK Cell Subset Indicative of Prior Cytotoxic Activity Is Elevated in Patients with Autoantibody-Mediated Neurologic Diseases.

Neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein Ab disease, and autoimmune myasthenia gravis (MG) are autoantibody-mediated neurologic conditions where autoantibodies can induce Ab-dependent cellular cytotoxicity (ADCC), a NK cell-mediated effector function. However, whether ADCC is a pathogenic mechanism in patients with these conditions has not been confirmed. We sought to characterize circulatory NK cells using functional assays, phenotyping, and transcriptomics to elucidate their role in pathology. NK cells from NMOSD patients and MG patients with elevated disease burden exhibited reduced ADCC and CD56dimCD16hi NK cells, along with an elevated frequency of CD56dimCD16dim/- NK cells. We determined that ADCC induces a similar phenotypic shift in vitro. Bulk RNA sequencing distinguished the CD56dimCD16dim/- population from the canonical CD56dimCD16hi cytotoxic and CD56hiCD16- immunomodulatory subsets, as well as CD56hiCD16+ NK cells. Multiparameter immunophenotyping of NK cell markers, functional proteins, and receptors similarly showed that the CD56dimCD16dim/- subset exhibits a unique profile while still maintaining expression of characteristic NK markers CD56, CD94, and NKp44. Notably, expression of perforin and granzyme is reduced in comparison with CD56dimCD16hi NK cells. Moreover, they exhibit elevated trogocytosis capability, HLA-DR expression, and many chemokine receptors, including CCR7. In contrast with NMOSD and MG, myelin oligodendrocyte glycoprotein Ab disease NK cells did not exhibit functional, phenotypic, or transcriptomic perturbations. In summary, CD56dimCD16dim/- NK cells are a distinct peripheral blood immune cell population in humans elevated upon prior cytotoxic activity by the CD56dimCD16hi NK cell subset. The elevation of this subset in NMOSD and MG patients suggests prior ADCC activity.

Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity.

A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20dimCD8+ T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20dimCD8+ T cells had a greater contribution to treatment-associated changes in the CD8+ T cell pool than was the case for CD4+ T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20dimCD8+ T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19+CD24highCD38high with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20dimCD8+ T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8+ T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development.

Shifting our attention earlier in the multiple sclerosis disease course.

PURPOSE OF REVIEW: Revisions of multiple sclerosis (MS) diagnostic criteria enable clinicians to diagnose patients earlier in the biologic disease course. Prompt initiation of therapy correlates with improved clinical outcomes. This has led to increased attention on the earliest stages of MS, including the MS prodrome and radiologically isolated syndrome (RIS). Here, we review current understanding and approach to patients with preclinical MS. RECENT FINDINGS: MS disease biology often begins well before the onset of typical MS symptoms, and we are increasingly able to recognize preclinical and prodromal stages of MS. RIS represents the best characterized aspect of preclinical MS, and its diagnostic criteria were recently revised to better capture patients at highest risk of conversion to clinical MS. The first two randomized control trials evaluating disease modifying therapy use in RIS also found that treatment could delay or prevent onset of clinical disease. SUMMARY: Despite progress in our understanding of the earliest stages of the MS disease course, additional research is needed to systematically identify patients with preclinical MS as well as capture those at risk for developing clinical disease. Recent data suggests that preventive immunomodulatory therapies may be beneficial for high-risk patients with RIS; though management remains controversial.

Choroid plexus volume differentiates MS from its mimics.

This study aimed to determine whether choroid plexus volume (CPV) could differentiate multiple sclerosis (MS) from its mimics. A secondary analysis of two previously enrolled studies, 50 participants with MS and 64 with alternative diagnoses were included. CPV was automatically segmented from 3T magnetic resonance imaging (MRI), followed by manual review to remove misclassified tissue. Mean normalized choroid plexus volume (nCPV) to intracranial volume demonstrated relatively high specificity for MS participants in each cohort (0.80 and 0.76) with an area under the receiver-operator characteristic curve of 0.71 (95% confidence interval (CI) = 0.55-0.87) and 0.65 (95% CI = 0.52-0.77). In this preliminary study, nCPV differentiated MS from its mimics.

A multicenter pilot study evaluating simplified central vein assessment for the diagnosis of multiple sclerosis.

BACKGROUND: The central vein sign (CVS) is a proposed magnetic resonance imaging (MRI) biomarker for multiple sclerosis (MS); the optimal method for abbreviated CVS scoring is not yet established. OBJECTIVE: The aim of this study was to evaluate the performance of a simplified approach to CVS assessment in a multicenter study of patients being evaluated for suspected MS. METHODS: Adults referred for possible MS to 10 sites were recruited. A post-Gd 3D T2*-weighted MRI sequence (FLAIR*) was obtained in each subject. Trained raters at each site identified up to six CVS-positive lesions per FLAIR* scan. Diagnostic performance of CVS was evaluated for a diagnosis of MS which had been confirmed using the 2017 McDonald criteria at thresholds including three positive lesions (Select-3*) and six positive lesions (Select-6*). Inter-rater reliability assessments were performed. RESULTS: Overall, 78 participants were analyzed; 37 (47%) were diagnosed with MS, and 41 (53%) were not. The mean age of participants was 45 (range: 19-64) years, and most were female (n = 55, 71%). The area under the receiver operating characteristic curve (AUROC) for the simplified counting method was 0.83 (95% CI: 0.73-0.93). Select-3* and Select-6* had sensitivity of 81% and 65% and specificity of 68% and 98%, respectively. Inter-rater agreement was 78% for Select-3* and 83% for Select-6*. CONCLUSION: A simplified method for CVS assessment in patients referred for suspected MS demonstrated good diagnostic performance and inter-rater agreement.

Diagnostic performance of central vein sign versus oligoclonal bands for multiple sclerosis.

BACKGROUND: Cerebrospinal fluid (CSF) oligoclonal bands (OCB) are a diagnostic biomarker in multiple sclerosis (MS). The central vein sign (CVS) is an imaging biomarker for MS that may improve diagnostic accuracy. OBJECTIVES: The objective of the study is to examine the diagnostic performance of simplified CVS methods in comparison to OCB in participants with clinical or radiological suspicion for MS. METHODS: Participants from the CentrAl Vein Sign in MS (CAVS-MS) pilot study with CSF testing were included. Select-3 and Select-6 (counting up to three or six CVS+ lesions per scan) were rated on post-gadolinium FLAIR* images. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value for Select-3, Select-6, OCB, and combinations thereof were calculated for MS diagnosis at baseline and at 12 months. RESULTS: Of 53 participants, 25 were OCB+. At baseline, sensitivity for MS diagnosis was 0.75 for OCB, 0.83 for Select-3, and 0.71 for Select-6. Specificity for MS diagnosis was 0.76 for OCB, 0.48 for Select-3, and 0.86 for Select-6. At 12 months, PPV for MS diagnosis was 0.95 for Select-6 and 1.00 for Select-6 with OCB+ status. DISCUSSION: Results suggest similar diagnostic performance of simplified CVS methods and OCB. Ongoing studies will refine whether CVS could be used in replacement or in conjunction with OCB.

Effect of GBCA Use on Detection and Diagnostic Performance of the Central Vein Sign: Evaluation Using a 3-T FLAIR* Sequence in Patients With Suspected Multiple Sclerosis.

BACKGROUND. The central vein sign (CVS) is a proposed MRI biomarker of multiple sclerosis (MS). The impact of gadolinium-based contrast agent (GBCA) administration on CVS evaluation remains poorly investigated. OBJECTIVE. The purpose of this study was to assess the effect of GBCA use on CVS detection and on the diagnostic performance of the CVS for MS using a 3-T FLAIR* sequence. METHODS. This study was a secondary analysis of data from the pilot study for the prospective multicenter Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS), which recruited adults with suspected MS from April 2018 to February 2020. Participants underwent 3-T brain MRI including FLAIR and precontrast and post-contrast echo-planar imaging T2*-weighted acquisitions. Postprocessing was used to generate combined FLAIR and T2*-weighted images (hereafter, FLAIR*). MS diagnoses were established using the 2017 McDonald criteria. Thirty participants (23 women, seven men; mean age, 45 years) were randomly selected from the CAVS-MS pilot study cohort. White matter lesions (WMLs) were marked using FLAIR* images. A single observer, blinded to clinical data and GBCA use, reviewed marked WMLs on FLAIR* images for the presence of the CVS. RESULTS. Thirteen of 30 participants had MS. Across participants, on precontrast FLAIR* imaging, 218 CVS-positive and 517 CVS-negative WMLs were identified; on post-contrast FLAIR* imaging, 269 CVS-positive and 459 CVS-negative WMLs were identified. The fraction of WMLs that were CVS-positive on precontrast and postcontrast images was 48% and 58% in participants with MS and 7% and 10% in participants without MS, respectively. The median patient-level CVS-positivity rate on precontrast and postcontrast images was 43% and 67% for participants with MS and 4% and 8% for participants without MS, respectively. In a binomial model adjusting for MS diagnoses, GBCA use was associated with an increased likelihood of at least one CVS-positive WML (odds ratio, 1.6; p < .001). At a 40% CVS-positivity threshold, the sensitivity of the CVS for MS increased from 62% on precontrast images to 92% on postcontrast images (p = .046). Specificity was not significantly different between precontrast (88%) and postcontrast (82%) images (p = .32). CONCLUSION. GBCA use increased CVS detection on FLAIR* images, thereby increasing the sensitivity of the CVS for MS diagnoses. CLINICAL IMPACT. The postcontrast FLAIR* sequence should be considered for CVS evaluation in future investigational trials and clinical practice.

Dimethyl fumarate treatment shifts the immune environment toward an anti-inflammatory cell profile while maintaining protective humoral immunity.

BACKGROUND: Delayed-release dimethyl fumarate (DMF) demonstrates sustained efficacy and safety for relapsing forms of MS. Absolute lymphocyte count (ALC) is reduced initially, then stabilizes on treatment. OBJECTIVE: PROCLAIM, a 96-week, prospective, open-label, phase 3b study, assessed lymphocyte subsets and immunoglobulin (Ig) levels during 48 and 96 weeks (W) of DMF treatment. METHODS: Patients received 240 mg DMF BID. Endpoints: lymphocyte subset count changes (primary); Ig isotypes and ALC changes (secondary); adverse events and relationship between ALC changes and ARR/EDSS (exploratory); and neurofilament assessment (ad hoc). RESULTS: Of 218 patients enrolled, 158 (72%) completed the study. Median ALC decreased 39% from baseline to W96 (BL-W96), stabilizing above the lower limit of normal (baseline: 1.82 × 109/L; W48: 1.06 × 109/L; W96: 1.05 × 109/L). CD4 + and CD8 + T cells correlated highly with ALC from BL-W96 (p < 0.001). Relative to total T cells, naive CD4 + and CD8 + T cells increased, whereas CD4 + and CD8 + central and effector memory T cells decreased. Total IgA, IgG, IgM, and IgG1-4 subclass levels remained stable. Adverse event rates were similar across ALC subgroups. ARR, EDSS, and neurofilament were not correlated with ALCs. CONCLUSION: Lymphocyte decreases with DMF were maintained over treatment, yet immunoglobulins remained stable. No increase in infection incidence was observed in patients with or without lymphopenia. SUPPORT: Biogen.

Streamlined EDSS for use in multiple sclerosis clinical practice: Development and cross-sectional comparison to EDSS.

BACKGROUND: The Expanded Disability Status Scale (EDSS) is the standard measure of disability in multiple sclerosis clinical trials. The EDSS has limited application in the clinical setting due to required completion time and scoring complexity. Systematically recording an objective, simplified, less time-intensive, and neurologist-derived disability score would be beneficial for patient care. OBJECTIVE: To develop and validate a streamlined version of the Expanded Disability Status Scale (sEDSS) for clinical monitoring. METHODS: The EDSS was modified by eliminating maneuvers with no impact on function, consolidating redundancies, and simplifying scoring. This sEDSS was refined and preliminarily validated using a pilot cohort of 102 patients. Subsequently, the sEDSS was retrospectively validated using 968 patients from the CombiRx trial. We evaluated correlation and agreement between each functional system as well as the overall sEDSS and EDSS. RESULTS: The sEDSS correlated strongly with the EDSS, both overall (Spearman's rho = 0.93) and for each functional system (Spearman's rho 0.65-0.97). Correlation was slightly lower for functional systems where scoring was modified for consolidation and simplification. CONCLUSION: The sEDSS had strong agreement and correlation with the existing EDSS and can provide a useful measure of disability in clinical practice.

Dimethyl fumarate induces changes in B- and T-lymphocyte function independent of the effects on absolute lymphocyte count.

BACKGROUND: Dimethyl fumarate (DMF) is used to treat relapsing multiple sclerosis and causes lymphopenia in a subpopulation of treated individuals. Much remains to be learned about how the drug affects B- and T-lymphocytes. OBJECTIVES: To characterize changes in B- and T-cell phenotype and function induced by DMF and to investigate whether low absolute lymphocyte count (ALC) is associated with unique functional changes. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from DMF-treated patients, untreated patients, and healthy controls. A subset of DMF-treated patients was lymphopenic (ALC < 800). Multiparametric flow cytometry was used to evaluate cellular phenotypes. Functional response to non-specific and viral peptide stimulation was assessed. RESULTS: DMF reduced circulating memory B-cells regardless of ALC. Follicular T-helper cells (CD4+ CXCR5+) and mucosal invariant T-cells (CD8+ CD161+) were also reduced. DMF reduced T-cell production of pro-inflammatory cytokines in response to polyclonal (PMA/ionomycin) and viral peptide stimulation, regardless of ALC. No differences in activation-induced cell death or circulating progenitors were observed between lymphopenic and non-lymphopenic DMF-treated patients. CONCLUSION: These data implicate DMF-induced changes in lymphocytes as an important component of the drug's efficacy and expand our understanding of the functional significance of DMF-induced lymphopenia.

Meta-analysis identifies common gut microbiota associated with multiple sclerosis.

BACKGROUND: Previous studies have identified a diverse group of microbial taxa that differ between patients with multiple sclerosis (MS) and the healthy population. However, interpreting findings on MS-associated microbiota is challenging, as there is no true consensus. It is unclear whether there is gut microbiota commonly altered in MS across studies. METHODS: To answer this, we performed a meta-analysis based on the 16S rRNA gene sequencing data from seven geographically and technically diverse studies comprising a total of 524 adult subjects (257 MS and 267 healthy controls). Analysis was conducted for each individual study after reprocessing the data and also by combining all data together. The blocked Wilcoxon rank-sum test and linear mixed-effects regression were used to identify differences in microbial composition and diversity between MS and healthy controls. Network analysis was conducted to identify bacterial correlations. A leave-one-out sensitivity analysis was performed to ensure the robustness of the findings. RESULTS: The microbiome community structure was significantly different between studies. Re-analysis of data from individual studies revealed a lower relative abundance of Prevotella in MS across studies, compared to controls. Meta-analysis found that although alpha and beta diversity did not differ between MS and controls, a higher abundance of Actinomyces and a lower abundance of Faecalibacterium were reproducibly associated with MS. Additionally, network analysis revealed that the recognized negative Bacteroides-Prevotella correlation in controls was disrupted in patients with MS. CONCLUSIONS: Our meta-analysis identified common gut microbiota associated with MS across geographically and technically diverse studies.

Gut Microbiome Wellness Index 2 enhances health status prediction from gut microbiome taxonomic profiles.

Recent advancements in translational gut microbiome research have revealed its crucial role in shaping predictive healthcare applications. Herein, we introduce the Gut Microbiome Wellness Index 2 (GMWI2), an enhanced version of our original GMWI prototype, designed as a standardized disease-agnostic health status indicator based on gut microbiome taxonomic profiles. Our analysis involves pooling existing 8069 stool shotgun metagenomes from 54 published studies across a global demographic landscape (spanning 26 countries and six continents) to identify gut taxonomic signals linked to disease presence or absence. GMWI2 achieves a cross-validation balanced accuracy of 80% in distinguishing healthy (no disease) from non-healthy (diseased) individuals and surpasses 90% accuracy for samples with higher confidence (i.e., outside the "reject option"). This performance exceeds that of the original GMWI model and traditional species-level α-diversity indices, indicating a more robust gut microbiome signature for differentiating between healthy and non-healthy phenotypes across multiple diseases. When assessed through inter-study validation and external validation cohorts, GMWI2 maintains an average accuracy of nearly 75%. Furthermore, by reevaluating previously published datasets, GMWI2 offers new insights into the effects of diet, antibiotic exposure, and fecal microbiota transplantation on gut health. Available as an open-source command-line tool, GMWI2 represents a timely, pivotal resource for evaluating health using an individual's unique gut microbial composition.

Systems Analysis of Immune Changes after B-cell Depletion in Autoimmune Multiple Sclerosis.

Multiple sclerosis (MS) is a complex genetically mediated autoimmune disease of the central nervous system where anti-CD20-mediated B cell depletion is remarkably effective in the treatment of early disease. While previous studies investigated the effect of B cell depletion on select immune cell subsets using flow cytometry-based methods, the therapeutic impact on patient immune landscape is unknown. In this study, we explored how a therapy-driven " in vivo perturbation " modulates the diverse immune landscape by measuring transcriptomic granularity with single-cell RNA sequencing (scRNAseq). We demonstrate that B cell depletion leads to cell type-specific changes in the abundance and function of CSF macrophages and peripheral blood monocytes. Specifically, a CSF-specific macrophage population with an anti-inflammatory transcriptomic signature and peripheral CD16 + monocytes increased in frequency post-B cell depletion. In addition, we observed increases in TNFα messenger RNA and protein in monocytes post-B cell depletion, consistent with the finding that anti-TNFα treatment exacerbates autoimmune activity in MS. In parallel, B cell depletion also induced changes in peripheral CD4 + T cell populations, including increases in the frequency of TIGIT + regulatory T cells and marked decreases in the frequency of myelin peptide loaded-tetramer binding CD4 + T cells. Collectively, this study provides an exhaustive transcriptomic map of immunological changes, revealing different mechanisms of action contributing to the high efficacy in B cell depletion treatment of MS.

Multicenter automated central vein sign detection performs as well as manual assessment for the diagnosis of multiple sclerosis.

BACKGROUND AND PURPOSE: The central vein sign (CVS) is a proposed diagnostic imaging biomarker for multiple sclerosis (MS). The proportion of white matter lesions exhibiting the CVS (CVS+) is higher in patients with MS compared to its radiological mimics. Evaluation for CVS+ lesions in prior studies have been performed by manual rating, an approach that is time-consuming and has variable inter-rater reliability. Accurate automated methods would facilitate efficient assessment for CVS. The objective of this study was to compare the performance of an automated CVS detection method with manual rating for the diagnosis of MS. MATERIALS AND METHODS: 3T MRI was acquired in 86 participants undergoing evaluation for MS in a 9-site multicenter study. Participants presented with either typical or atypical clinical syndromes for MS. An automated CVS detection method was employed and compared to manual rating, including total CVS+ proportion and a simplified counting method in which experts visually identified up to 6 CVS+ lesions using FLAIR* contrast (a voxel-wise product of T2 FLAIR and post-contrast T2*-EPI images). RESULTS: Automated CVS processing was completed in 79 of 86 participants (91%), of whom 28 (35%) fulfilled the 2017 McDonald criteria at the time of imaging. The area under the receiver-operator characteristic curve (AUC) for discrimination between participants with and without MS for the automated CVS approach was 0.78 (95% confidence interval: [0.67,0.88]). This was not significantly different from simplified manual counting methods (select6*) (0.80 [0.69,0.91]) or manual assessment of total CVS+ proportion (0.89 [0.82,0.96]). In a sensitivity analysis excluding 11 participants whose MRI exhibited motion artifact, the AUC for the automated method was 0.81 [0.70,0.91], which was not statistically different from that for select6* (0.79 [0.68,0.92]) or manual assessment of total CVS+ proportion (0.89 [0.81,0.97]). CONCLUSIONS: Automated CVS assessment was comparable to manual CVS scoring for differentiating patients with MS from those with other diagnoses. Large, prospective, multicenter studies utilizing automated methods and enrolling the breadth of disorders referred for suspicion of MS are needed to determine optimal approaches for clinical implementation of an automated CVS detection method. ABBREVIATIONS: CVS= central vein sign; CVS+ = white matter lesions exhibiting the CVS; MRI = magnetic resonance imaging; MS = multiple sclerosis; T2 FLAIR = T2 fluid-attenuated inversion recovery; T2*-EPI = T2*-weighted 3D echo planar imaging; FLAIR* = a voxel-wise product of T2 FLAIR and post-contrast T2*-EPI images; select6* = simplified counting method in which experts visually identified up to 6 CVS+ lesions on FLAIR* imaging.

Emerging Cerebrospinal Fluid Biomarkers of Disease Activity and Progression in Multiple Sclerosis.

Importance: Biomarkers distinguishing nonrelapsing progressive disease biology from relapsing biology in multiple sclerosis (MS) are lacking. Cerebrospinal fluid (CSF) is an accessible fluid that most closely reflects central nervous system biology. Objective: To identify CSF biological measures associated with progressive MS pathobiology. Design, Setting, and Participants: This cohort study assessed data from 2 prospective MS cohorts: a test cohort provided serial CSF, clinical, and imaging assessments in a multicenter study of patients with relapsing MS (RMS) or primary progressive MS (PPMS) who were initiating anti-CD20 treatment (recruitment: 2016-2018; analysis: 2020-2023). A single-site confirmation cohort was used to assess CSF at baseline and long-term (>10 year) clinical follow-up (analysis: 2022-2023). Exposures: Test-cohort participants initiated standard-of-care ocrelizumab treatment. Confirmation-cohort participants were untreated or received standard-of-care disease-modifying MS therapies. Main Outcomes and Measures: Twenty-five CSF markers, including neurofilament light chain, neurofilament heavy chain, and glial fibrillary acid protein (GFAP); 24-week confirmed disability progression (CDP24); and brain magnetic resonance imaging measures reflecting focal injury, tissue loss, and progressive biology (slowly expanding lesions [SELs]). Results: The test cohort (n = 131) included 100 patients with RMS (mean [SD] age, 36.6 [10.4] years; 68 [68%] female and 32 [32%] male; Expanded Disability Status Scale [EDSS] score, 0-5.5), and 31 patients with PPMS (mean [SD] age, 44.9 [7.4] years; 15 [48%] female and 16 [52%] male; EDSS score, 3.0-6.5). The confirmation cohort (n = 68) included 41 patients with RMS and 27 with PPMS enrolled at diagnosis (age, 40 years [range, 20-61 years]; 47 [69%] female and 21 [31%] male). In the test cohort, GFAP was correlated with SEL count (r = 0.33), greater proportion of T2 lesion volume from SELs (r = 0.24), and lower T1-weighted intensity within SELs (r = -0.33) but not with acute inflammatory measures. Neurofilament heavy chain was correlated with SEL count (r = 0.25) and lower T1-weighted intensity within SELs (r = -0.28). Immune markers correlated with measures of acute inflammation and, unlike GFAP, were impacted by anti-CD20. In the confirmation cohort, higher baseline CSF GFAP levels were associated with long-term CDP24 (hazard ratio, 2.1; 95% CI, 1.3-3.4; P = .002). Conclusions and Relevance: In this study, activated glial markers (in particular GFAP) and neurofilament heavy chain were associated specifically with nonrelapsing progressive disease outcomes (independent of acute inflammatory activity). Elevated CSF GFAP was associated with long-term MS disease progression.

Can the immune system be harnessed to repair the CNS?

Experimental and clinical data have demonstrated that activating the immune system in the CNS can be destructive. However, other studies have shown that enhancing an immune response can be therapeutic, and several clinical trials have been initiated with the aim of boosting immune responses in the CNS of individuals with spinal cord injury, multiple sclerosis and Alzheimer's disease. Here, we evaluate the controversies in the field and discuss the remaining scientific challenges that are associated with enhancing immune function in the CNS to treat neurological diseases.

Monoclonal antibodies as disease modifying therapy in multiple sclerosis.

Multiple sclerosis (MS), a demyelinating disease of the central nervous system, was untreatable until the mid-1990s when beta-interferons and glatiramer acetate were introduced. These agents, while effective, were relatively nonspecific in action. Over the last 10 years, research has focused toward developing more targeted therapies for the disease. Monoclonal antibodies (mAbs) have been central to these efforts and many of the mAbs studied in MS have been singularly effective. We review here the 6 monoclonal antibodies that have been approved for MS or are in late-stage clinical trials, focusing on the drugs' efficacy and safety. Additionally, we review several monoclonal antibodies that were studied in MS but were found to be ineffective or even deleterious in this patient population.