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In two parallel randomized trials in patients with MS, ublituximab resulted in lower relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not affect disability.

Multiple sclerosis is a chronic disease of the CNS that leads to substantial disability in most patients. The early phase is characterised by relapses and the later phase by progressive disability. Results from immunological, genetic, and histopathological studies and treatment trials have shown that the immune system plays a key part in the disease course. Findings from animal models and immunological studies of patients with multiple sclerosis suggest a change in the involvement of the immune system during disease initiation and progression. These findings suggest that a peripheral immune response targeting the CNS drives the disease process during the early phase, whereas immune reactions within the CNS dominate the progressive phase. These concepts for the differential involvement of immune responses in the early and progressive phase of this disease have important implications for future research in the pathogenesis and treatment of multiple sclerosis.

Daclizumab, a humanised monoclonal antibody, reduced multiple sclerosis disease activity in previous non-randomised studies. We aimed to assess whether daclizumab reduces disease activity in patients with active relapsing multiple sclerosis who are receiving interferon beta treatment. We did a phase 2, randomised, double-blind, placebo-controlled study at 51 centres in the USA, Canada, Germany, Italy, and Spain. Patients with active relapsing multiple sclerosis who were taking interferon beta were randomly assigned to receive add-on subcutaneous daclizumab 2 mg/kg every 2 weeks (interferon beta and high-dose daclizumab group), daclizumab 1 mg/kg every 4 weeks (interferon beta and low-dose daclizumab group), or interferon beta and placebo for 24 weeks. The randomisation scheme was generated by Facet Biotech. All patients and assessors were masked to treatment with the exception of Facet Biotech bioanalysts who prepared data for the data safety monitoring board or generated pharmacokinetic or pharmacodynamic data, a drug accountability auditor, and the site pharmacist. The primary endpoint was total number of new or enlarged gadolinium contrast-enhancing lesions measured on brain MRI scans every 4 weeks between weeks 8 and 24. Effects of daclizumab on prespecified subsets of lymphocytes and quantitative T-cell proliferative response were assessed in an exploratory pharmacodynamic substudy. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00109161. From May, 2005, to March, 2006, 288 patients were assessed for eligibility, and 230 were randomly assigned to receive interferon beta and high-dose daclizumab (n=75), interferon beta and low-dose daclizumab (n=78), or interferon beta and placebo (n=77). The adjusted mean number of new or enlarged gadolinium contrast-enhancing lesions was 4·75 in the interferon beta and placebo group compared with 1·32 in the interferon beta and high-dose daclizumab group (difference 72%, 95% CI 34% to 88%; p=0·004) and 3·58 in the interferon beta and low-dose daclizumab group (25%, −76% to 68%; p=0·51). In the pharmacodynamic substudy, daclizumab was not associated with significant changes in absolute numbers of T cells, B cells, or natural killer cells, or T-cell proliferative response compared with interferon beta alone. The number of CD56 bright natural killer cells was seven to eight times higher in both daclizumab groups than in the interferon beta and placebo group (interferon beta and low-dose daclizumab group p=0·002; interferon beta and high-dose daclizumab group p<0·0001). Common adverse events were equally distributed across groups. Add-on daclizumab treatment reduced the number of new or enlarged gadolinium contrast-enhancing lesions compared with interferon beta alone and might reduce multiple sclerosis disease activity to a greater extent than interferon beta alone. Facet Biotech and Biogen Idec.

Background: In this study, we aimed to evaluate the association of lamina cribrosa thickness (LCT) and lamina cribrosa depth (LCD), as determined by spectral domain optical coherence tomography (SD-OCT), with visual evoked potentials (VEPs) in patients with multiple sclerosis (MS). Materials and Methods: Patients enrolled in this prospective, cross-sectional study were divided into three groups. Group 1 consisted of 25 relapsing-remitting MS patients with VEP pathology in one or both eyes. In patients with VEP pathology in both eyes, one eye was chosen randomly. Group 2 comprised 25 relapsing-remitting MS patients with no VEP pathology or optic neuritis history. A randomly selected single eye of each patient was evaluated. Group 3 consisted of 25 age- and sex-matched healthy volunteers; a randomly selected single eye of these participants was examined. LCT, LCD, and retinal nerve fiber layer (RNFL) thickness measurements were determined in four quadrants (superior, inferior, nasal, and temporal) by SD-OCT. Results: The three groups were similar in terms of age and sex. The mean LCT was lower in Group 1 than in Group 2, but the difference was not statistically significant (268.80 ± 36.69 μm [min-max = 222-394 μm] versus 285.80 ± 12.00 μm [min-max = 249-338 μm]; P = 0.148). The mean LCT was significantly lower in Group 1 than in Group 3 (268.80 ± 36.69 μm [min-max = 222-394 μm] versus 294.80 ± 12.00 μm [min-max = 232-351 μm]; P = 0.012). There was a weak positive correlation between LCT and RNFL-inferior, RNFL-nasal, and RNFL-temporal. Conclusion: We found that the lamina cribrosa was thinner in MS patients with VEP pathology. To the best of our knowledge, this is a novel finding. Our results imply that LCT could be used as an indicator of optic neuritis in MS patients.

ObjectivesTo evaluate the combined contribution of brain and cervical cord damage in predicting 5-year clinical worsening in a multicentre cohort of definite multiple sclerosis (MS) patients.MethodsBaseline 3.0T brain and cervical cord T2-weighted and three-dimensional T1-weighted MRI was acquired in 367 patients with MS (326 relapse-onset and 41 progressive-onset) and 179 healthy controls. Expanded Disability Status Scale (EDSS) score was obtained at baseline and after a median follow-up of 5.1 years (IQR=4.8–5.2). At follow-up, patients were classified as clinically stable/worsened according to EDSS changes. Generalised linear mixed models identified predictors of clinical worsening, evolution to secondary progressive (SP) MS and reaching EDSS=3.0, 4.0 and 6.0 milestones at 5 years.ResultsAt follow-up, 120/367 (33%) patients with MS worsened clinically; 36/256 (14%) patients with relapsing–remitting evolved to SPMS. Baseline predictors of EDSS worsening were progressive-onset versus relapse-onset MS (standardised beta (β)=0.97), higher EDSS (β=0.41), higher cord lesion number (β=0.41), lower normalised cortical volume (β=−0.15) and lower cord area (β=−0.28) (C-index=0.81). Older age (β=0.86), higher EDSS (β=1.40) and cord lesion number (β=0.87) independently predicted SPMS conversion (C-index=0.91). Predictors of reaching EDSS=3.0 after 5 years were higher baseline EDSS (β=1.49), cord lesion number (β=1.02) and lower normalised cortical volume (β=−0.56) (C-index=0.88). Baseline age (β=0.30), higher EDSS (β=2.03), higher cord lesion number (β=0.66) and lower cord area (β=−0.41) predicted EDSS=4.0 (C-index=0.92). Finally, higher baseline EDSS (β=1.87) and cord lesion number (β=0.54) predicted EDSS=6.0 (C-index=0.91).ConclusionsSpinal cord damage and, to a lesser extent, cortical volume loss helped predicting worse 5-year clinical outcomes in MS.

BackgroundMultiple sclerosis (MS) progression independent of relapses is driven by brain innate immune cell activation. The aim of this study was to evaluate the association between chitinase-3-like protein 1 (CHI3L1), expressed in brain by astrocytes and microglia, measured from blood and smouldering inflammation measured using 18 kDa translocator protein (TSPO) positron emission tomography (PET) in patients with MS.MethodsThe study cohort included 55 patients with MS (25 progressive MS (PMS) and 30 relapsing remitting MS (RRMS)) and 17 healthy controls (HC). CHI3L1 was measured with commercial ELISA from plasma samples. A subcohort (44 MS and 9 HC) underwent TSPO-PET to assess [11C]PK11195 distribution volume ratio (DVR) and MRI concurrent to blood sampling. These imaging outcomes were used in respective correlation and linear regression analyses.ResultsCHI3L1 concentration in plasma was higher in PMS (23.5 ng/mL) compared with HC (16.8 ng/mL, p=0.0055) and RRMS (19.3 ng/mL, p=0.049). CHI3L1 associated with brain [11C]PK11195 DVR in all MS (standardised estimate 0.89, 95% CI 0.23 to 1.55, p=0.010) and in PMS (Spearman correlation ρ=0.58, 95% CI 0.058 to 0.86, p=0.032). Additionally, CHI3L1 was associated with smaller brain volume in both MS (−0.75, −1.38 to –0.11, p=0.023) and PMS (ρ=−0.56, –0.83 to –0.095, p=0.021). Furthermore, CHI3L1 was associated with Expanded Disability Status Scale (0.70, 0.12 to 1.28, p=0.019) and age (0.93, 0.37 to 1.48, p=0.002) among all patients with MS.ConclusionsAssociation of CHI3L1 with glial activation and brain volume loss identifies plasma CHI3L1 as a promising biomarker for smouldering inflammation and MS progression-related pathology.

Multiple Sclerosis (MS) is a chronic autoimmune disease of the central nervous system, progressing from Relapsing–Remitting MS (RRMS) to Secondary Progressive MS (SPMS) in many cases. The transition involves complex biological changes. Our study aims to identify potential biomarkers for distinguishing SPMS by analyzing gene expression differences between normal-appearing and lesioned parietal grey matter, which may also contribute to understand the pathogenesis of SPMS. We utilized public datasets from the Gene Expression Omnibus (GEO), applying bioinformatics and machine learning techniques including Weighted Gene Co-expression Network Analysis (WGCNA), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO) enrichment analysis, protein–protein interaction (PPI) networks, the Least Absolute Shrinkage and Selection Operator (LASSO), and Random Forest (RF) for predictive model construction. Our study also included analyses of immune cell infiltration. The study identified 359 DEGs, with 105 up-regulated and 254 down-regulated. WGCNA identified 264 common genes, which were subjected to KEGG and GO enrichment analyses, highlighting their role in immune response and viral infection pathways. Four genes (BCL3, GBP1, IFI16, and CCR1) were identified as key biomarkers for SPMS, supported by LASSO regression and RF analyses. These genes were further validated through receiver operating characteristic (ROC) curves, demonstrating significant predictive potential for SPMS. Our study provides a novel set of biomarkers for SPMS from lesioned grey matter of SPMS cases, offering potential for diagnosis and targeted therapeutic strategies. The identified biomarkers link closely with SPMS pathology, especially regarding immune system modulation.

Cortical pathology contributes to chronic cognitive impairment of patients suffering from the neuroinflammatory disease multiple sclerosis (MS). How such gray matter inflammation affects neuronal structure and function is not well understood. In the present study, we use functional and structural in vivo imaging in a mouse model of cortical MS to demonstrate that bouts of cortical inflammation disrupt cortical circuit activity coincident with a widespread, but transient, loss of dendritic spines. Spines destined for removal show local calcium accumulations and are subsequently removed by invading macrophages or activated microglia. Targeting phagocyte activation with a new antagonist of the colony-stimulating factor 1 receptor prevents cortical synapse loss. Overall, our study identifies synapse loss as a key pathological feature of inflammatory gray matter lesions that is amenable to immunomodulatory therapy. Synapse loss is prominent in the cortex in multiple sclerosis (MS). In a cortical MS model, Jafari et al. show that phagocytes remove synapses by engulfment, which is triggered by local calcium accumulations and prevented by blocking colony-stimulating factor 1 signaling.

Background: It is unclear if all patients with relapsing–remitting multiple sclerosis (RRMS) ultimately develop progressive MS. Onset of progressive disease course seems to be age- rather than disease duration-dependent. Some forms of progressive MS (e.g. primary progressive MS (PPMS)) are uncommon in population-based studies. Ascertainment of patients with PPMS from clinic-based populations can facilitate a powerful comparison of age at progression onset between secondary progressive MS (SPMS) and PPMS but may introduce unclear biases. Objective: Our aim is to confirm that onset of progressive disease course is more relevant to the patient’s age than the presence or duration of a pre-progression relapsing disease course in MS. Methods: We studied a population-based MS cohort (n=210, RRMS n=109, progressive MS n=101) and a clinic-based progressive MS cohort (n=754). Progressive course was classified as primary (PPMS; n=322), single attack (SAPMS; n=112) and secondary progressive (SPMS; n=421). We studied demographics (chi2 or t-test), age-of-progression-onset (t-test) and time to Expanded Disability Status Scale of 6 (EDSS6) (Kaplan–Meier analyses). Results: Sex ratio (p=0.58), age at progression onset (p=0.37) and time to EDSS6 (p=0.16) did not differ between the cohorts. Progression had developed before age 75 in 99% of patients with known progressive disease course; 38% with RRMS did not develop progression by age 75. Age at progression onset did not differ between SPMS (44.9±9.6), SAPMS (45.5±9.6) and PPMS (45.7±10.8). In either cohort, only 2% of patients had reached EDSS6 before onset of progression. Conclusions: Patients with RRMS do not inevitably develop a progressive disease course. Onset of progression is more dependent on age than the presence or duration of a pre-progression symptomatic disease course. Moderate disability is sustained predominantly after the onset of a progressive disease course in MS.

Background: Post-mortem analyses of multiple sclerosis (MS) eyes demonstrate prominent retinal neuronal ganglion cell layer (GCL) loss, in addition to related axonal retinal nerve fiber layer (RNFL) loss. Despite this, clinical correlations of retinal neuronal layers remain largely unexplored in MS. Objectives: To determine if MS patients exhibit in vivo retinal neuronal GCL loss, deeper retinal neuronal loss, and investigate correlations between retinal layer thicknesses, MS clinical subtype and validated clinical measures. Methods: Cirrus HD-optical coherence tomography (OCT), utilizing automated intra-retinal layer segmentation, was performed in 132 MS patients and 78 healthy controls. MS classification, Expanded Disability Status Scale (EDSS) and visual function were recorded in study subjects. Results: GCL+inner plexiform layer (GCIP) was thinner in relapsing–remitting MS (RRMS; n = 96, 71.6 µm), secondary progressive MS (SPMS; n = 20, 66.4 µm) and primary progressive MS (PPMS; n = 16, 74.1 µm) than in healthy controls (81.8 µm; p < 0.001 for all). GCIP thickness was most decreased in SPMS, and although GCIP thickness correlated significantly with disease duration, after adjusting for this, GCIP thickness remained significantly lower in SPMS than RRMS. GCIP thickness correlated significantly, and better than RNFL thickness, with EDSS, high-contrast, 2.5% low-contrast and 1.25% low-contrast letter acuity in MS. 13.6% of patients also demonstrated inner or outer nuclear layer thinning. Conclusions: OCT segmentation demonstrates in vivo GCIP thinning in all MS subtypes. GCIP thickness demonstrates better structure-function correlations (with vision and disability) in MS than RNFL thickness. In addition to commonly observed RNFL/GCIP thinning, retinal inner and outer nuclear layer thinning occur in MS.