Multiple Sclerosis Disease Process Research Articles

Induction of IL-2 by interleukin-12 p40 homodimer and IL-12, but not IL-23, in microglia and macrophages: Implications for multiple sclerosis

The level of IL-2 increases markedly in serum and central nervous system (CNS) of patients with multiple sclerosis (MS) and animals with experimental allergic encephalomyelitis (EAE). However, mechanisms by which IL-2 is induced under autoimmune demyelinating conditions are poorly understood. The present study underlines the importance of IL-12p40 homodimer (p402), the so-called biologically inactive molecule, in inducing the expression of IL-2 in mouse BV-2 microglial cells, primary mouse and human microglia, mouse peritoneal macrophages, RAW264.7 macrophages, and T cells. Interestingly, we found that p402 and IL-12p70 (IL-12), but not IL-23, dose-dependently induced the production of IL-2 and the expression of IL-2 mRNA in microglial cells. Similarly, p402 also induced the activation of IL-2 promoter in microglial cells and RAW264.7 cells. Among various stimuli tested, p402 was the most potent stimulus followed by IFN-γ, bacterial lipopolysaccharide, HIV-1 gp120, and IL-12 in inducing the activation of IL-2 promoter in microglial cells. Moreover, p402, but not IL-23, increased NFATc2 mRNA expression and the transcriptional activity of NFAT. Furthermore, induction of IL-2 mRNA expression by over-expression of p40, but not by p19, cDNA indicated that p40, but not p19, is responsible for the induction of IL-2 mRNA in microglia. Finally, by using primary microglia from IL to 12 receptor β1 deficient (IL-12Rβ1-/-) and IL-12 receptor β2 deficient (IL-12Rβ2-/-) mice, we demonstrate that p402 induces the expression of IL-2 via IL-12Rβ1, but not IL-12Rβ2. In experimental autoimmune encephalomyelitis, an animal model of MS, neutralization of p402 by mAb a3-1d led to decrease in clinical symptoms and reduction in IL-2 in T cells and microglia. These results delineate a new biological function of p402, which is missing in the so-called autoimmune cytokine IL-23, and raise the possibility of controlling increased IL-2 and the disease process of MS via neutralization of p402.

Improvement in the multiple sclerosis functional composite score by multi-function swing suspension training program

BackgroundPhysical activity has been considered as a promising approach to slow down the disease process in Multiple Sclerosis (MS) patients. The functional impairments of MS have been studied in detail, while evidence of the efficacy of exercise training interventions on the Multiple Sclerosis functional composite (MSFC) score in these patients is limited. The aim of this study was to investigate the improvement in MSFC score by multi-function swing suspension training program (MFSST) in the women with MS. MethodsThe patients were divided into two groups as the intervention and control groups. A total of 47 MS patients completed the MSFC components at baseline and after the intervention: the timed 25-foot walk (T25FW); the 9-hole peg test (9HPT); and paced auditory serial addition test (PASAT). Z scores were created for each test based on control means. ResultsThe MSFC score, 9HPT, T25FW, and PASAT showed a significant increment in comparison with the baseline levels in the four, six, and eight weeks following the first exercise session (all p<0.05). These differences in the control group were not significant. The improvement in the MSFC score and the component Z-scores in the intervention groups was found from the fourth week onwards. ConclusionsThe study findings highlight that the progression of MS disability can be partially compensated by physical exercise. Overall, these results indicate that MFSST can be used as an effective treatment method in patients suffering from MS. Longer (years) exercise studies with larger samples of MS patients, with different MS subtypes, and of different sex, are needed to evaluate the effect of other types of exercise interventions on the MSFC score in MS patients with different disabilities.

Pathways to cures for multiple sclerosis: A research roadmap

Background: Multiple Sclerosis (MS) is a growing global health challenge affecting nearly 3 million people. Progress has been made in the understanding and treatment of MS over the last several decades, but cures remain elusive. The National MS Society is focused on achieving cures for MS. Objectives: Cures for MS will be hastened by having a roadmap that describes knowledge gaps, milestones, and research priorities. In this report, we share the Pathways to Cures Research Roadmap and recommendations for strategies to accelerate the development of MS cures. Methods: The Roadmap was developed through engagement of scientific thought leaders and people affected by MS from North America and the United Kingdom. It also included the perspectives of over 300 people living with MS and was endorsed by many leading MS organizations. Results: The Roadmap consist of three distinct but overlapping cure pathways: (1) stopping the MS disease process, (2) restoring lost function by reversing damage and symptoms, and (3) ending MS through prevention. Better alignment and focus of global resources on high priority research questions are also recommended. Conclusions: We hope the Roadmap will inspire greater collaboration and alignment of global resources that accelerate scientific breakthroughs leading to cures for MS.

Chapter 9 - Multiple Sclerosis and related disorders

Multiple Sclerosis (MS) is a common neuroinflammatory disorder which is associated with disabling clinical consequences. The MS disease process may involve neural centers implicated in the control of breathing, leading to ventilatory disturbances during both wakefulness and sleep. In this chapter, a brief overview of MS disease mechanisms and clinical sequelae including sleep disorders is provided. The chapter then focuses on obstructive sleep apnea-hypopnea (OSAH) which is the most prevalent respiratory control abnormality encountered in ambulatory MS patients. The diagnosis, prevalence, and clinical consequences as well as data on effects of OSAH treatment in MS patients are discussed, including the impact on the disabling symptom of fatigue and other clinical sequelae. We also review pathophysiologic mechanisms contributing to OSAH in MS, and in turn mechanisms by which OSAH may impact on the MS disease process, resulting in a bidirectional relationship between these two conditions. We then discuss central sleep apnea, other respiratory control disturbances, and the pathogenesis and management of respiratory muscle weakness and chronic hypoventilation in MS. We also provide a brief overview of Neuromyelitis Optica Spectrum Disorders and review current data on respiratory control disturbances and sleep-disordered breathing in that condition.

Microbiome signature in multiple sclerosis in North India

Background: Gut microbiome dysbiosis has been associated with many disorders including Multiple Sclerosis (MS) through bi-directional gut-brain axis. In western studies, characterization of gut microbiota in MS is well established but the differential effect of Indian diet in disease process of MS is yet to be explored. This ongoing study aims to study the gut microbiome in North Indian MS patients. Objective: To characterize the gut microbiota in North Indian MS patients and correlate it with disease activity.

Disease biomarkers in multiple sclerosis: current serum neurofilament light chain perspectives.

The continuous neuroinflammatory and neurodegenerative pathology in multiple sclerosis (MS) results in irreversible accumulation of physical and cognitive disability. Reliable early detection of MS disease processes can aid in the diagnosis, monitoring and treatment management of MS patients. Recent assay technological advancements now allow reliable quantification of serum-based neurofilament light chain (sNfL) levels, which provide temporal information regarding the degree of neuroaxonal damage. The relationship and predictive value of sNfL with clinical and cognitive outcomes, other paraclinical measures and treatment response is reviewed. sNfL measurement is an emerging, noninvasive and disease-responsive MS biomarker that is currently utilized in research and clinical trial settings. Understanding sNfL confounders and further assay standardization will allow clinical implementation of this biomarker.

Impact of aerobic exercise on clinical and magnetic resonance imaging biomarkers in persons with multiple sclerosis: An exploratory randomized controlled trial.

BackgroundThere is insufficient knowledge about how aerobic exercise impacts the disease process of multiple sclerosis, which is characterized by accumulation of white matter lesions and accelerated brain atrophy.ObjectiveTo examine the effect of aerobic exercise on neuroinflammation and neurodegeneration by magnetic resonance imaging and clinical measures of disease activity and progression in persons with multiple sclerosis.Patients and methodsAn exploratory 12-week randomized control trial including an intervention group (n = 14, 12 weeks of aerobic exercise twice weekly) and a control group (n = 14, continuation of usual lifestyle). Primary outcomes were magnetic resonance imaging measures (lesion load, brain structure volume change), while secondary outcomes included disability measures, blood cytokine levels, cognitive tests and patient-reported outcomes.ResultsThe effects of aerobic exercise on whole brain and grey matter atrophy were minor. Surprisingly, the observed effect on volume (atrophy) in selected brain substructures was heterogeneous. Putaminal and posterior cingulate volumes decreased, parahippocampal gyrus volume increased, thalamus and amygdala volume remained the same, and active lesion load and count decreased. However, apart from weak improvements in walking speed and brain-derived neurotrophic factor levels, there was no effect of aerobic exercise on other clinical, cognitive or patient-reported outcomes.ConclusionThese results suggest that aerobic exercise in persons with multiple sclerosis has a positive effect on the volume of some of the substructures of the brain, possibly indicating a slowing of the neurodegenerative process in these regions, but a negative impact on the volume of some other substructures, with unclear implications. Further research is needed to determine whether the slight decrease in active lesion volume and count implies an anti- inflammatory effect of aerobic exercise, and the exact significance of the heterogeneous results of volumetric assessments.LAY ABSTRACTThe aim of this study was to evaluate the effects of aerobic exercise (physical exercise in the form of aerobics) on people with multiple sclerosis who were being treated with fingolimod. Two groups of patients with multiple sclerosis were studied: an intervention group (n = 14) who undertook 12 weeks of exercise training, and a control group (n = 14) who continued with their usual lifestyle. Magnetic resonance imaging, bloodwork analysis and some other clinical assessments were performed before and after the 12-week period, and the patients completed several questionnaires about their wellbeing and accompanying symptoms of multiple sclerosis. The results suggest that aerobic exercise (combined with appropriate pharmacological treatment) can positively affect some of the brain regions in people with MS by reducing the rate of their degeneration and might decrease the inflammatory activity. However, longer and larger studies should be performed to evaluate whether such rehabilitation is effective and could, in the long-term, possibly slow down the rate of disability accrual.

PND1 IMPACT of EARLY Disease Modifying Therapy (DMT) Treatment Initiation and Use of High-Efficacy (HET) on Clinical and Health Outcomes in Patients with Multiple Sclerosis (MS)

To explore the impact of early DMT treatment initiation and use of HET on clinical and health outcomes in patients with MS. A targeted literature review was conducted using Embase (including Medline) to identify studies published from January 2006-March 2020. Search terms included clinical-outcomes: annualized relapse rate (ARR), disability progression, magnetic resonance imaging (MRI) outcomes; and health-related outcomes: quality of life (QoL), work-productivity, therapy persistence, and healthcare resource utilization (HCRU). Among the screened studies, 69 were included in this review (50 observational studies, 18 clinical trials, and 1 systematic review; 35 US/Canadian, 20 global, 12 European, and 2 Australian studies). ARR and disease progression were the most common outcomes in the included studies. Inhibition of MS disability, slower disease progression, lower ARR, improved persistence/adherence, cost-savings, and decrease in HCRU were achieved if a DMT was initiated early following diagnosis. Definition of HET varied across studies; while most studies identified infused DMTs as HET, some studies also included fingolimod as HET. Use of HET was associated with improvements in QoL, work productivity, therapy persistence, and reduction in hospitalizations. Of 4 studies which evaluated early initiation of HET (E-HET), all favored the induction vs escalation approach. Overall, several studies found that E-HET in the MS disease process produced greater efficacy in reducing relapse rate, MRI-activity, brain atrophy, and long-term disease progression. However, no studies were identified that addressed the effect of E-HET on health-related outcomes. Emerging evidence suggests that initiating E-HET in MS leads to better clinical outcomes while HET use is associated with improved health-related outcomes. However, a need exists to better understand the humanistic and economic benefits of initiating E-HET in the MS disease course and in standardizing the definition of HET to better inform treatment decision-making for patients and providers.

Editors' note: Optical coherence tomography for diagnosing optic neuritis: Are we there yet?

In the editorial “Optical coherence tomography for diagnosing optic neuritis: Are we there yet?,” Drs. Saidha and Naismith discussed the potential application of optical coherence tomography (OCT) in providing objective support for previous optic neuritis (ON) and in highlighting the research article by Drs. Xu et al. entitled “Optical coherence tomography is highly sensitive in detecting prior optic neuritis.” In a reader response, Dr. Avasarala highlights several potential issues hindering the use of OCT in this context, including the cost of OCT hardware, continually changing algorithms for retinal segmentation, and the paucity of data on OCT's performance relative to pattern shift visual evoked responses (VEPs), a relatively older test. He also notes that an earlier publication by Naismith et al. found that OCT was less sensitive than VEP in detecting subclinical previous ON. Replying to these comments, Drs. Saidha and Naismith note that this previous study used older third-generation time domain OCT and that current fourth-generation spectral domain OCT has a much higher resolution. They cite the excellent reliability and reproducibility of key OCT measures and note that they provide useful information about the global multiple sclerosis disease process. They also argue that OCT and VEP are better viewed as complementary measures of structure and function, respectively. This is especially true because VEP has its limitations too, including distinguishing inner retinal processes from optic nerve ones. Drs. Saidha and Naismith also speculate that the use of OCT in diagnosing acute ON may also become more apparent, given the frequent thickening of the retinal nerve fiber layer during acute ON. As OCT technology continues to evolve, its clinical applications are likely to be further clarified and expanded in the coming years. In the editorial “Optical coherence tomography for diagnosing optic neuritis: Are we there yet?,” Drs. Saidha and Naismith discussed the potential application of optical coherence tomography (OCT) in providing objective support for previous optic neuritis (ON) and in highlighting the research article by Drs. Xu et al. entitled “Optical coherence tomography is highly sensitive in detecting prior optic neuritis.” In a reader response, Dr. Avasarala highlights several potential issues hindering the use of OCT in this context, including the cost of OCT hardware, continually changing algorithms for retinal segmentation, and the paucity of data on OCT's performance relative to pattern shift visual evoked responses (VEPs), a relatively older test. He also notes that an earlier publication by Naismith et al. found that OCT was less sensitive than VEP in detecting subclinical previous ON. Replying to these comments, Drs. Saidha and Naismith note that this previous study used older third-generation time domain OCT and that current fourth-generation spectral domain OCT has a much higher resolution. They cite the excellent reliability and reproducibility of key OCT measures and note that they provide useful information about the global multiple sclerosis disease process. They also argue that OCT and VEP are better viewed as complementary measures of structure and function, respectively. This is especially true because VEP has its limitations too, including distinguishing inner retinal processes from optic nerve ones. Drs. Saidha and Naismith also speculate that the use of OCT in diagnosing acute ON may also become more apparent, given the frequent thickening of the retinal nerve fiber layer during acute ON. As OCT technology continues to evolve, its clinical applications are likely to be further clarified and expanded in the coming years.

Macular Ganglion Cell and Inner Plexiform Layer Thickness Is More Strongly Associated With Visual Function in Multiple Sclerosis Than Bruch Membrane Opening-Minimum Rim Width or Peripapillary Retinal Nerve Fiber Layer Thicknesses.

Optical coherence tomography (OCT) measurements of ganglion cell + inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thicknesses are associated with visual function (VF) and disability in multiple sclerosis (MS). However, the value of measuring Bruch membrane opening-minimum rim width (BMO-MRW) thickness in MS remains unclear. Sixty-eight patients with MS and 22 healthy controls (HCs) underwent spectral domain OCT, 100%-contrast visual acuity (VA), 2.5%- and 1.25%-contrast letter acuity (LA), and Expanded Disability Status Scale (EDSS) testing. Mixed-effects linear regression models, accounting for within-subject, intereye correlations, were used to assess relationships. The MS cohort exhibited significantly lower BMO-MRW (P = 0.01), pRNFL at 3.7-, 4.1-, and 4.7-mm diameters surrounding the optic disc (P < 0.001 for all), and GCIPL (P < 0.001) thicknesses than HCs. BMO-MRW thickness was associated with 100%-VA (P < 0.001, R = 0.08), 2.5%-LA (P < 0.001; R = 0.13), and 1.25%-LA (P = 0.002; R = 0.11). All measured pRNFL thicknesses were associated with high- and low-contrast VF (all: P < 0.001). GCIPL thickness was more strongly associated with 100%-VA (P < 0.001; R = 0.23), 2.5%-LA (P < 0.001; R = 0.27), and 1.25%-LA (P < 0.001; R = 0.21) than the other OCT measures assessed. All OCT measures were significantly, but weakly, associated with EDSS scores. BMO-MRW and pRNFL thicknesses are reduced and associated with VF and disability in MS, but GCIPL thickness is a stronger marker of visual impairment. Our findings corroborate the utility of OCT in providing valuable information regarding the MS disease process.

Astrocytes in the Pathogenesis of Multiple Sclerosis: An In Situ MicroRNA Study

Astrocytes are increasingly recognized as active contributors to the disease process in multiple sclerosis (MS), rather than being merely reactive. We investigated the expression of a selected microRNA (miRNA) panel that could contribute both to the injury and to the recovery phases of the disease. Individual astrocytes were laser microdissected from brain sections. We then compared the miRNAs' expressions in MS and control brain samples at different lesional stages in white versus grey matter regions. In active MS lesions, we found upregulation of ischemia-related miRNAs in white but not grey matter, often with reversion to the normal state in inactive lesions. In contrast to our previous findings on MS macrophages, expression of 2 classical inflammatory-related miRNAs, miRNA-155 and miRNA-146a, was reduced in astrocytes from active and chronic active MS lesions in white and grey matter, suggesting a lesser direct pathogenetic role for these miRNAs in astrocytes. miRNAs within the categories regulating aquaporin4 (-100, -145, -320) and glutamate transport/apoptosis/neuroprotection (-124a, -181a, and -29a) showed some contrasting responses. The regional and lesion-stage differences of expression of these miRNAs indicate the remarkable ability of astrocytes to show a wide range of selective responses in the face of differing insults and phases of resolution.

IL-22 Binding Protein Promotes the Disease Process in Multiple Sclerosis

Genome-wide association studies have mapped the specific sequence variants that predispose for multiple sclerosis (MS). The pathogenic mechanisms that underlie these associations could be leveraged to develop safer and more effective MS treatments but are still poorly understood. In this article, we study the genetic risk variant rs17066096 and the candidate gene that encodes IL-22 binding protein (IL-22BP), an antagonist molecule of the cytokine IL-22. We show that monocytes from carriers of the risk genotype of rs17066096 express more IL-22BP in vitro and cerebrospinal fluid levels of IL-22BP correlate with MS lesion load on magnetic resonance imaging. We confirm the pathogenicity of IL-22BP in both rat and mouse models of MS and go on to suggest a pathogenic mechanism involving lack of IL-22-mediated inhibition of T cell-derived IFN-γ expression. Our results demonstrate a pathogenic role of IL-22BP in three species with a potential mechanism of action involving T cell polarization, suggesting a therapeutic potential of IL-22 in the context of MS.

Cerebrospinal fluid biomarkers link toxic astrogliosis and microglial activation to multiple sclerosis severity

BackgroundOnce multiple sclerosis (MS) reaches the progressive stage, immunomodulatory treatments have limited efficacy. This suggests that processes other than activation of innate immunity may at least partially underlie disability progression during late stages of MS. Pathology identified these alternative processes as aberrant activation of astrocytes and microglia, and subsequent degeneration of oligodendrocytes and neurons. However, we mostly lack biomarkers that could measure central nervous system (CNS) cell-specific intrathecal processes in living subjects. This prevents differentiating pathogenic processes from an epiphenomenon. Therefore, we sought to develop biomarkers of CNS cell-specific processes and link them to disability progression in MS. MethodsIn a blinded manner, we measured over 1000 proteins in the cerebrospinal fluid (CSF) of 431 patients with neuroimmunological diseases and healthy volunteers using modified DNA-aptamers (SOMAscan®). We defined CNS cell type-enriched clusters using variable cluster analysis, combined with in vitro modeling. Differences between diagnostic categories were identified in the training cohort (n = 217) and their correlation to disability measures were assessed; results were validated in an independent validation cohort (n = 214). ResultsAstrocyte cluster 8 (MMP7, SERPINA3, GZMA and CLIC1) and microglial cluster 2 (DSG2 and TNFRSF25) were reproducibly elevated in MS and had a significant and reproducible correlation with MS severity suggesting their pathogenic role. In vitro studies demonstrated that proteins of astrocyte cluster 8 are noticeably released upon stimulation with proinflammatory stimuli and overlap with the phenotype of recently described neuro-toxic (A1) astrocytes. ConclusionMicroglial activation and toxic astrogliosis are associated with MS disease process and may partake in CNS tissue destruction. This hypothesis should be tested in new clinical trials.

Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis

Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS of unknown cause that remains incurable. Inflammasome-associated caspases mediate the maturation and release of the proinflammatory cytokines IL-1β and IL-18 and activate the pore-forming protein gasdermin D (GSDMD). Inflammatory programmed cell death, pyroptosis, was recently shown to be mediated by GSDMD. Here, we report molecular evidence for GSDMD-mediated inflammasome activation and pyroptosis in both myeloid cells (macrophages/microglia) and, unexpectedly, in myelin-forming oligodendrocytes (ODCs) in the CNS of patients with MS and in the MS animal model, experimental autoimmune encephalomyelitis (EAE). We observed inflammasome activation and pyroptosis in human microglia and ODCs in vitro after exposure to inflammatory stimuli and demonstrate caspase-1 inhibition by the small-molecule inhibitor VX-765 in both cell types. GSDMD inhibition by siRNA transduction suppressed pyroptosis in human microglia. VX-765 treatment of EAE animals reduced the expression of inflammasome- and pyroptosis-associated proteins in the CNS, prevented axonal injury, and improved neurobehavioral performance. Thus, GSDMD-mediated pyroptosis in select glia cells is a previously unrecognized mechanism of inflammatory demyelination and represents a unique therapeutic opportunity for mitigating the disease process in MS and other CNS inflammatory diseases.

Can Optical Coherence Tomography Be Used to Guide Treatment Decisions in Adult or Pediatric Multiple Sclerosis?

With the recognition that neurodegeneration represents the principal substrate of disability in multiple sclerosis (MS), there has been increased strives towards identifying biomarkers for accurately quantifying and tracking neurodegeneration during the disease course. The retina provides an opportune "window" into the central nervous system (CNS) in MS, with retinal changes in MS reflecting not only local, but also global aspects of neurodegeneration and inflammation operative in the disease. Optical coherence tomography (OCT) is a rapid, inexpensive, reproducible, high-resolution imaging technique allowing accurate quantification of discrete retinal layers. OCT determined thinning of inner retinal layers such as the retinal nerve fiber layer (RNFL) and in particular the composite of the ganglion cell and inner plexiform (GCIP) layers, predominantly related to optic neuropathy, have been shown to not only correlate with high and low contrast visual function in MS, but also global MS disability scores, as well as whole brain and particularly gray matter volumes. Rates of GCIP thinning have been shown to be accelerated among MS patients exhibiting inflammatory activity outside of the visual pathways, as well as disability progression during follow-up. Moreover, baseline RNFL thickness in MS has been shown to have utility for predicting future disability accumulation. On the other hand, thickening of the inner nuclear layer (INL) in MS, the pathophysiologic basis of which remains to be elucidated, has been found to predict the development of clinical and radiological inflammatory activity, as well as subsequent disability progression in MS. Given the potential for OCT to provide insight into neurodegeneration and inflammation occurring in MS, this review focuses on the potential utility of OCT within the clinical setting to influence treatment decisions for MS patients. The evolution of spectral domain-OCT technology, with improved resolution and reproducibility allowing intra-retinal layer segmentation, has facilitated the determination that the OCT derived measure GCIP thickness is a highly accurate measure for quantifying and tracking neurodegeneration, and conversely neuroprotection, in MS. The strong relationships between rates of GCIP and brain atrophy across MS subtypes over time underpin the insight derived regarding the global MS disease process from OCT and highlight OCT as an excellent complementary tool to magnetic resonance imaging (MRI) for tracking MS patients. More recently, longitudinal studies are emerging which support the utility of OCT for monitoring the differential effects of disease-modifying therapies (DMTs) in MS. Although further work is required, there is mounting evidence supporting the utility of OCT in the clinical setting to monitor disease course in individual patients with MS and to aid in the prediction of disease course. As pharmacological treatment options in MS expand to also include potentially neuroprotective and/or remyelinating or neurorestorative drugs, OCT as a biomarker of neurodegeneration and neuroprotection (and neuroinflammation to a lesser degree) may become an invaluable tool in both the research and clinical settings.

Meta-analysis of the Age-Dependent Efficacy of Multiple Sclerosis Treatments.

To perform a meta-analysis of randomized, blinded, multiple sclerosis (MS) clinical trials, to test the hypothesis that efficacy of immunomodulatory disease-modifying therapies (DMTs) on MS disability progression is strongly dependent on age. We performed a literature search with pre-defined criteria and extracted relevant features from 38 clinical trials that assessed efficacy of DMTs on disability progression. We fit a linear regression, weighted for trial sample size, and duration, to examine the hypothesis that age has a defining effect on the therapeutic efficacy of immunomodulatory DMTs. More than 28,000 MS subjects participating in trials of 13 categories of immunomodulatory drugs are included in the meta-analysis. The efficacy of immunomodulatory DMTs on MS disability strongly decreased with advancing age (R2 = 0.6757, p = 6.39e-09). Inclusion of baseline EDSS did not significantly improve the model. The regression predicts zero efficacy beyond approximately age 53 years. The comparative efficacy rank derived from the regression residuals differentiates high- and low-efficacy drugs. High-efficacy drugs outperform low-efficacy drugs in inhibiting MS disability only for patients younger than 40.5 years. The meta-analysis supports the notion that progressive MS is simply a later stage of the MS disease process and that age is an essential modifier of a drug efficacy. Higher efficacy treatments exert their benefit over lower efficacy treatments only during early stages of MS, and, after age 53, the model suggests that there is no predicted benefit to receiving immunomodulatory DMTs for the average MS patient.

Multiple Sclerosis: A Systemic Review of Drugs and Therapeutics

Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease of the central nervous system. It affects approximately 400,000 people in the United States and onset is usually during young adulthood. There are four clinical forms of MS, of which relapsing remitting type is the most common. As the etiology of MS is unknown, finding a cure will remain challenging. The main mechanism of injury appears to be inflammation and 8 agents are now FDA approved to help control MS. These agents for relapsing forms of MS target different parts of the immune system, with the end goal of decreasing and avoiding further inflammation. No agents are FDA approved for the primary progressive version of MS. FDA approved agents include four preparations of interferon β (Avonex, Rebif, Betaseron and Extavia), glatiramer acetate (Copaxone), mitoxantrone (Novantrone), natalizumab (Tysabri) and fingolimod (Gilenya). There are several drug undergoing phase II and III trials. The heterogeneity of the MS disease process, individual patient response, and medication toxicities continue to challenge the treating physician.

Role of SLAMF immunoregulatory molecules in MS disease processes

Abstract In our proteomic analysis of cerebrospinal fluid (CSF) we found signaling lymphocyte activation molecules family (SLAMF) upregulated in multiple sclerosis (MS) patients in comparison to controls. The goal of this project is to explore the role of SLAMF molecules in MS. To identify immune cells that express and secrete SLAMF molecules in the intrathecal (CSF) environment, we performed immunophenotyping of matched blood and CSF leukocytes and dynamic in-vitro experiments, co-culturing leukocytes with EBV and CMV viral lysates. This antigen-specific activation of a sizeable proportion of T and B cells allowed the investigating of changes in surface expression and secretion of SLAMF molecules. SLAMF2 was broadly expressed, however CSF CD8+ T cells and monocytes had higher SLAMF2 expression in comparison to blood. Stimulation down-modulated SLAMF2 on T cells, but upregulated it on B cells. SLAMF3 was expressed on cells of adaptive, but not innate immunity and CD4+ T cells expressed higher levels of SLAMF3 in CSF than in blood. Upon activation, SLAMF3 expression did not change and the soluble form did not accumulate in supernatants. SLAMF5 was broadly expressed, with particularly higher levels on cells of innate immunity (monocytes and dendritic cells). CSF T and B cells had lower SLAMF5 levels than blood T&amp;B cells. SLAMF6 was strongly expressed on T, B and NK cells; its expression levels did not vary between compartments or upon activation. Finally, SLAMF7 was expressed on cytotoxic T cells, NK cells and plasma cells, with significant upregulation on all antigen-presenting cells upon activation. We explored its role in cytotoxicity, but found no effect of SLAMF7 blockade or sSLAMF7 addition on NK-mediated killing of MHC-I-deficient targets.

Natalizumab stabilizes physical, cognitive, MRI, and OCT markers of disease activity: A prospective, non-randomized pilot study.

Natalizumab is an effective therapy for multiple sclerosis (MS). Its effectiveness has been demonstrated in several clinical and imaging studies. The objective of this study was to further demonstrate the efficacy of natalizumab using a comprehensive battery of clinical and imaging markers in the same cohort of patients followed longitudinally, hence capturing the multi-faceted nature of the MS disease process. A prospective, open-label, pilot study of 20 MS patients treated with natalizumab was conducted. High resolution MRI, Symbol-Digit Modalities Test (SDMT), and Optical Coherence Tomography (OCT) scans were obtained at baseline, 48, and 96 weeks. 15 patients completed the study. Natalizumab treatment decreased Expanded Disability Status Scale score (EDSS) and no change in SDMT, Brain Parenchymal Fraction (BPF), or any of the OCT markers of retinal degeneration was observed. Thalamic and whole brain volume as assessed by Percentage Brain Volume Change (PBVC) showed continuous deterioration. Higher baseline T2 lesion load correlated with increased rate of PBVC at 96-weeks (r = 0.566, R2 = 0.320, p = 0.035) and thalamic volume loss (r = -0.586, R2 = 0.344, p = 0.027). Most patients, 93%, achieved no evidence of disease activity (NEDA) at 2 years, likely due to early disease duration and lower initial baseline lesion load. This study further demonstrates stabilization of clinical and imaging markers of disease activity during natalizumab treatment.

Causal Effect of Genetic Variants Associated With Body Mass Index on Multiple Sclerosis Susceptibility.

Multiple sclerosis (MS) is an autoimmune disease with both genetic and environmental risk factors. Recent studies indicate that childhood and adolescent obesity double the risk of MS, but this association may reflect unmeasured confounders rather than causal effects of obesity. We used separate-sample Mendelian randomization to estimate the causal effect of body mass index (BMI) on susceptibility to MS. Using data from non-Hispanic white members of the Kaiser Permanente Medical Care Plan of Northern California (KPNC) (2006-2014; 1,104 cases of MS and 10,536 controls) and a replication data set from Sweden (the Epidemiological Investigation of MS (EIMS) and the Genes and Environment in MS (GEMS) studies, 2005-2013; 5,133 MS cases and 4,718 controls), we constructed a weighted genetic risk score using 97 variants previously established to predict BMI. Results were adjusted for birth year, sex, education, smoking status, ancestry, and genetic predictors of MS. Estimates in KPNC and Swedish data sets suggested that higher genetically induced BMI predicted greater susceptibility to MS (odds ratio=1.13, 95% confidence interval: 1.04, 1.22 for the KPNC sample; odds ratio = 1.09, 95% confidence interval: 1.03, 1.15 for the Swedish sample). Although the mechanism remains unclear, to our knowledge, these findings support a causal effect of increased BMI on susceptibility to MS for the first time, and they suggest a role for inflammatory pathways that characterize both obesity and the MS disease process.