National Multiple Sclerosis Society Research Articles

Lifetime stressors relate to invisible symptoms of multiple sclerosis

Aim: Childhood stressors can increase adult stress perception and may accumulate over the lifespan to impact symptoms of multiple sclerosis (MS). Growing evidence links childhood stressors (e.g., abuse, neglect) to fatigue, pain, and psychiatric morbidity in adults with MS; yet literature in this area is lacking a comprehensive lifespan approach. The aim of this cross-sectional study was to examine contributions of childhood and adulthood stressor characteristics (i.e., count, severity), on three individual outcomes: fatigue, pain interference, and psychiatric morbidity in People with MS (PwMS). Methods: An online survey was distributed through the National MS Society. Hierarchical block regression modeling was used to sequentially assess baseline demographics, childhood stressors, and adult stressors per outcome. We hypothesized that child and adult stressors would significantly contribute to fatigue, pain interference, and psychiatric morbidity. Results: Overall, 713 PwMS informed at least one final analytic model. Both childhood and adult stressors significantly contributed to pain interference and psychiatric morbidity. Adult stressor severity independently correlated with psychiatric morbidity (P < 0.0001). Childhood stressors significantly contributed to fatigue (LR test P < 0.0001). Childhood stressor severity independently significantly correlated with both fatigue likelihood (P = 0.03) and magnitude (P < 0.001). Conclusions: This work supports a relationship between stressors across the lifespan and fatigue, pain, and psychiatric morbidity in PwMS. Stressor severity may have an important role which may not be captured in count-based trauma measurement tools. Clinicians and researchers should consider lifetime stress when addressing fatigue, pain, and psychiatric morbidity among PwMS.

Rituximab for Multiple Sclerosis: Hiding in Plain Sight

In February 2023, following extensive discussions with stakeholders and data review, the Institute for Clinical and Economic Review issued final policy recommendations for treatment of relapsing multiple sclerosis (RMS)1: "All stakeholders have a responsibility and an important role to play in ensuring that all effective treatment options for patients with RMS, including off-label use of rituximab, are utilized in ways to help improve affordability and access and reduce health inequities." The report calls on payers to remove barriers to rituximab coverage, the American Academy of Neurology and the National MS Society to publicly endorse rituximab for RMS, and clinicians to advocate for coverage of rituximab and its biosimilars. In July 2023, the World Health Organization listed rituximab as an essential medicine for MS.2 Yet not much has changed. Food and Drug Administration (FDA)-approved MS disease-modifying therapies continue to generate enormous profits for pharma, and rituximab remains hidden in plain sight.

Direct and Indirect Care of Patients With Multiple Sclerosis: Burden on Providers and Impact of Portal Messages.

Multiple sclerosis (MS) indirect patient-care time is often underreported and uncompensated. Data on time spent on indirect and direct care by MS providers is lacking. A survey was designed to understand the practice patterns among MS providers in the United States, including time spent on direct and indirect patient care, as well as managing electronic medical record portal messages. The National MS Society and the American Academy of Neurology facilitated the distribution of the survey to MS providers. Most providers spent at least 1 hour on new and at least 30 minutes on follow-up direct patient care. For indirect patient care, 77% of providers spent more than 1 hour and 57% spent more than 2 hours per day. While some providers have support staff to help with portal messages, many do not have protected time or compensation for portal messages. Multiple sclerosis providers spent a higher-than-average time on direct and indirect patient care tasks, including portal messages, and most lack protected time or compensation for portal messages. These results highlight the potential impact of indirect patient care (notably portal messages) on provider workload and burnout. Better support, protected time and/or compensation for indirect patient care can help ease physician burden and decrease burnout.

Subjective well-being of adults with multiple sclerosis during COVID-19: Evaluating stress-appraisal-coping and person-environment factors.

People with multiple sclerosis (MS) have been coping with high levels of stress during the ongoing coronavirus pandemic, affecting their employment, physical, and mental health, and overall life satisfaction. This study evaluated constructs of the stress-appraisal-coping theory and positive person-environment factors as predictors of subjective well-being for adults with MS. Participants included 477 adults with MS recruited through the National Multiple Sclerosis Society. Hierarchical regression analysis was used to determine the incremental variance in subjective well-being accounted for by demographic covariates, functional disability, perceived stress, stress appraisal, coping styles, and positive person-environment contextual factors. Positive stress appraisal and coping flexibility were significantly associated with subjective well-being at the bivariate correlation level and at the step they were entered into the regression model. Marital status, household income, functional disability, perceived stress, hope, core self-evaluations, and social support were significant predictors in the final model, accounting for 60% of the variance in subjective well-being scores (R² = .60, f² = 1.48; large effect size). Findings from this study support a stress management and well-being model based on constructs of Lazarus and Folkman's stress-appraisal-coping theory and positive person-environment contextual factors, which can inform the development of theory-driven and empirically supported stress management and well-being interventions for people with MS during the ongoing global health crisis. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Internet-delivered cognitive behavioural therapy programme to reduce depressive symptoms in patients with multiple sclerosis: a multicentre, randomised, controlled, phase 3 trial

Depression is three to four times more prevalent in patients with neurological and inflammatory disorders than in the general population. For example, in patients with multiple sclerosis, the 12-month prevalence of major depressive disorder is around 25% and it is associated with a lower quality of life, faster disease progression, and higher morbidity and mortality. Despite its clinical relevance, there are few treatment options for depression associated with multiple sclerosis and confirmatory trials are scarce. We aimed to evaluate the safety and efficacy of a multiple sclerosis-specific, internet-based cognitive behavioural therapy (iCBT) programme for the treatment of depressive symptoms associated with the disease. This parallel-group, randomised, controlled, phase 3 trial of an iCBT programme to reduce depressive symptoms in patients with multiple sclerosis was carried out at five academic centres with large outpatient care units in Germany and the USA. Patients with a neurologist-confirmed diagnosis of multiple sclerosis and depressive symptoms were randomly assigned (1:1:1; automated assignment, concealed allocation, no stratification, no blocking) to receive treatment as usual plus one of two versions of the iCBT programme Amiria (stand-alone or therapist-guided) or to a control condition, in which participants received treatment as usual and were offered access to the iCBT programme after 6 months. Masking of participants to group assignment between active treatment and control was not possible, although raters were masked to group assignment. The predefined primary endpoint, which was analysed in the intention-to-treat population, was severity of depressive symptoms as measured by the Beck Depression Inventory-II (BDI-II) at week 12 after randomisation. This trial is registered at ClinicalTrials.gov, NCT02740361, and is complete. Between May 3, 2017, and Nov 4, 2020, we screened 485 patients for eligibility. 279 participants were enrolled, of whom 101 were allocated to receive stand-alone iCBT, 85 to receive guided iCBT, and 93 to the control condition. The dropout rate at week 12 was 18% (50 participants). Both versions of the iCBT programme significantly reduced depressive symptoms compared with the control group (BDI-II between-group mean differences: control vs stand-alone iCBT 6·32 points [95% CI 3·37-9·27], p<0·0001, effect size d=0·97 [95% CI 0·64-1·30]; control vs guided iCBT 5·80 points [2·71-8·88], p<0·0001, effect size d=0·96 [0·62-1·30]). Clinically relevant worsening of depressive symptoms was observed in three participants in the control group, one in the stand-alone iCBT group, and none in the guided iCBT group. No occurrences of suicidality were observed during the trial and there were no deaths. This trial provides evidence for the safety and efficacy of a multiple sclerosis-specific iCBT tool to reduce depressive symptoms in patients with the disease. This remote-access, scalable intervention increases the therapeutic options in this patient group and could help to overcome treatment barriers. National Multiple Sclerosis Society (USA).

Prior cycles of anti-CD20 antibodies affect antibody responses after repeated SARS-CoV-2 mRNA vaccination.

BACKGROUNDWhile B cell depletion is associated with attenuated antibody responses to SARS-CoV-2 mRNA vaccination, responses vary among individuals. Thus, elucidating the factors that affect immune responses after repeated vaccination is an important clinical need.METHODSWe evaluated the quality and magnitude of the T cell, B cell, antibody, and cytokine responses to a third dose of BNT162b2 or mRNA-1273 mRNA vaccine in patients with B cell depletion.RESULTSIn contrast with control individuals (n = 10), most patients on anti-CD20 therapy (n = 48) did not demonstrate an increase in spike-specific B cells or antibodies after a third dose of vaccine. A third vaccine elicited significantly increased frequencies of spike-specific non-naive T cells. A small subset of B cell-depleted individuals effectively produced spike-specific antibodies, and logistic regression models identified time since last anti-CD20 treatment and lower cumulative exposure to anti-CD20 mAbs as predictors of those having a serologic response. B cell-depleted patients who mounted an antibody response to 3 vaccine doses had persistent humoral immunity 6 months later.CONCLUSIONThese results demonstrate that serial vaccination strategies can be effective for a subset of B cell-depleted patients.FUNDINGThe NIH (R25 NS079193, P01 AI073748, U24 AI11867, R01 AI22220, UM 1HG009390, P01 AI039671, P50 CA121974, R01 CA227473, U01CA260507, 75N93019C00065, K24 AG042489), NIH HIPC Consortium (U19 AI089992), the National Multiple Sclerosis Society (CA 1061-A-18, RG-1802-30153), the Nancy Taylor Foundation for Chronic Diseases, Erase MS, and the Claude D. Pepper Older Americans Independence Center at Yale (P30 AG21342).

Serum neurofilament light chain reference database for individual application in paediatric care: a retrospective modelling and validation study

Neurological conditions represent an important driver of paediatric disability burden worldwide. Measurement of serum neurofilament light chain (sNfL) concentrations, a specific marker of neuroaxonal injury, has the potential to contribute to the management of children with such conditions. In this context, the European Medicines Agency recently declared age-adjusted reference values for sNfL a top research priority. We aimed to establish an age-adjusted sNfL reference range database in a population of healthy children and adolescents, and to validate this database in paediatric patients with neurological conditions to affirm its clinical applicability. To generate a paediatric sNfL reference dataset, sNfL values were measured in a population of healthy children and adolescents (aged 0-22 years) from two large cohorts in Europe (the Coronavirus Antibodies in Kids from Bavaria study, Germany) and North America (a US Network of Paediatric Multiple Sclerosis Centers paediatric case-control cohort). Children with active or previous COVID-19 infection or SARS-CoV-2 antibody positivity at the time of sampling, or a history of primary systemic or neurological conditions were excluded. Linear models were used to restrospectively study the effect of age and weight on sNfL concentrations. We modelled the distribution of sNfL concentrations as a function of age-related physiological changes to derive reference percentile and Z score values via a generalised additive model for location, scale, and shape. The clinical utility of the new reference dataset was assessed in children and adolescents (aged 1-19 years) with neurological diseases (epilepsy, traumatic brain injury, bacterial CNS infections, paediatric-onset multiple sclerosis, and myelin oligodendrocyte glycoprotein antibody-associated disease) from the paediatric neuroimmunology clinic at the University of California San Francisco (San Francisco, CA, USA) and the Children's Hospital of the University of Regensburg (Regensburg, Germany). Samples from 2667 healthy children and adolescents (1336 [50·1%] girls and 1331 [49·9%] boys; median age 8·0 years [IQR 4·0-12·0]) were used to generate the reference database covering neonatal age to adolescence (target age range 0-20 years). In the healthy population, sNfL concentrations decreased with age by an estimated 6·8% per year until age 10·3 years (estimated multiplicative effect per 1 year increase 0·93 [95% CI 0·93-0·94], p<0·0001) and was mostly stable thereafter up to age 22 years (1·00 [0·52-1·94], p>0·99). Independent of age, the magnitude of the effect of weight on sNfL concentrations was marginal. Samples from 220 children with neurological conditions (134 [60·9%] girls and 86 [39·1%] boys; median age 14·7 years [IQR 10·8-16·5]) were used to validate the clinical utility of the reference Z scores. In this population, age-adjusted sNfL Z scores were higher than in the reference population of healthy children and adolescents (p<0·0001) with higher effect size metrics (Cohen's d=1·56) compared with the application of raw sNfL concentrations (d=1·28). The established normative sNfL values in children and adolescents provide a foundation for the clinical application of sNfL in the paediatric population. Compared with absolute sNfL values, the use of sNfL Z score was associated with higher effect size metrics and allowed for more accurate estimation of the extent of ongoing neuroaxonal damage in individual patients. Swiss National Science Foundation, US National Institutes of Health, and the National Multiple Sclerosis Society.

Diffusion-Weighted Images and Contrast-Enhanced MRI in the Diagnosis of Different Stages of Multiple Sclerosis of the Central Nervous System.

Introduction Multiple sclerosis (MS) is one of the most prevalent disorders of the central nervous system (CNS), and it can be observed in the field of radiological cross-sectional magnetic resonance imaging (MRI). The prevalence of MS in Saudi Arabia has increased as compared to the past few years. MRI is the gold standard non-invasive modality of choice in MS diagnosis according to the National Multiple Sclerosis Society (NMSS), New York City. This study aimed to highlight the significance of using diffusion-weighted images (DWIs) and the use of contrast media in the MS protocol, as well as the importance of identifying the suitable time of imaging after contrast enhancement to detect active lesions. Methods A retrospective cross-sectional study was conducted of 100 MS patients with an age range of 17 to 56 years. The data set included 41 active cases and 59 inactive cases. All patients had an MRI standard protocol of both the brain and spine in addition to DWI sequence and contrast agent (CA) injection, with images taken in early and delayed time. Results Of the patients, 71% were female and 29% were male. Active MS disease was more significant at younger ages than at older ages. Active lesions were significantly enhanced in delayed contrast images and showed high signal intensity in both the DWI and apparent diffusion coefficient (ADC) map, while inactive lesions showed no enhancement after contrast injection and showed an iso-signal intensity in both the DWI and ADC map. Conclusion The use of CA has developed over the years in the diagnosis of MS patients. In this study, the relationship between active lesions, DWI, and delayed contrast enhancement is very strong. In future research, we recommend adding a DWI sequence for the suspected active MS spine lesions in addition to delayed enhancement time in active MS after contrast injection to increase MRI sensitivity toward active MS lesions of the brain and spinal cord as well.

Risk of new disease activity in patients with multiple sclerosis who continue or discontinue disease-modifying therapies (DISCOMS): a multicentre, randomised, single-blind, phase 4, non-inferiority trial

Multiple sclerosis typically has onset in young adults and new disease activity diminishes with age. Most clinical trials of disease-modifying therapies for multiple sclerosis have not enrolled individuals older than 55 years. Observational studies suggest that risk of return of disease activity after discontinuation of a disease-modifying therapies is greatest in younger patients with recent relapses or MRI activity. We aimed to determine whether risk of disease recurrence in older patients with no recent disease activity who discontinue disease-modifying therapy is increased compared to those who remain on disease-modifying therapy. DISCOMS was a multicentre, randomised, controlled, rater-blinded, phase 4, non-inferiority trial. Individuals with multiple sclerosis of any subtype, 55 years or older, with no relapse within the past 5 years or new MRI lesion in the past 3 years while continuously taking an approved disease-modifying therapy were enrolled at 19 multiple sclerosis centres in the USA. Participants were randomly assigned (1:1 by site) with an interactive response technology system to either continue or discontinue disease-modifying therapy. Relapse assessors and MRI readers were masked to patient assignment; patients and treating investigators were not masked. The primary outcome was percentage of individuals with a new disease event, defined as a multiple sclerosis relapse or a new or expanding T2 brain MRI lesion, over 2 years. We assessed whether discontinuation of disease-modifying therapy was non-inferior to continuation using a non-inferiority, intention-to-treat analysis of all randomly assigned patients, with a predefined non-inferiority margin of 8%. This trial is registered at ClinicalTrials.gov, NCT03073603, and is completed. 259 participants were enrolled between May 22, 2017, and Feb 3, 2020; 128 (49%) were assigned to the continue group and 131 (51%) to the discontinue group. Five participants were lost to follow-up (continue n=1, discontinue n=4). Six (4·7%) of 128 participants in the continue group and 16 (12·2%) of 131 in the discontinue group had a relapse or a new or expanding brain MRI lesion within 2 years. The difference in event rates was 7·5 percentage points (95% CI 0·6-15·0). Similar numbers of participants had adverse events (109 [85%] of 128 vs 104 [79%] of 131) and serious adverse events (20 [16%] vs 18 [14%]), but more adverse events (422 vs 347) and serious adverse events (40 vs 30) occurred in the discontinue group. The most common adverse events were upper respiratory infections (20 events in 19 [15%] participants in the continue group and 37 events in 30 [23%] participants in the discontinue group). Three participants in the continue group and four in the discontinue group had treatment-related adverse events, of which one in each group was a serious adverse event (multiple sclerosis relapse requiring admission to hospital). One participant in the continue group and two in the discontinue group died; no deaths were deemed to be related to treatment. We were unable to reject the null hypothesis and could not conclude whether disease-modifying therapy discontinuation is non-inferior to continuation in patients older than 55 years with multiple sclerosis and no recent relapse or new MRI activity. Discontinuation of disease-modifying therapy might be a reasonable option in patients older than 55 years who have stable multiple sclerosis, but might be associated with a small increased risk of new MRI activity. Patient-Centered Outcomes Research Institute and the National Multiple Sclerosis Society.

0905 Factors Associated with Sleep Quality among Men with Multiple Sclerosis

Abstract Introduction Multiple sclerosis (MS), a neurodegenerative disease with typical onset in young to middle adulthood, results in disrupted sleep more commonly than the general population. There are known sex differences in MS onset and clinical course. MS, however, affects approximately three times more women than men, resulting in less attention to the male experience. Thus, there is a lack of information on disrupted sleep among men with MS. The purpose of this study was to examine the relationships between personal factors, behaviors, and sleep quality among men with MS. Methods Men with MS aged 20 to 90 years participated in an online anonymous survey recruited through the National MS Society website. Pearson’s correlations and linear regression were used to examine relationships between personal factors (age (years), type of MS, years since MS was diagnosed by a physician and race), sleep promoting behaviors (Sleep Behavior Self-Rating Scale), and sleep quality (Sleep Impact Short-Form total score). Results Four hundred ninety-six men with MS (mean age=53 years; SD=12.8; range 22-81 years) completed the survey. The majority were white (n=428; 86%) and married (n=358; 72%), with relapsing-remitting MS (n=323; 65%). Sleep quality ranged widely (mean=43.2; SD=3; range 27.9-59.9) with 90% reporting poor sleep. Pearson correlation results indicated a significant positive association between sleep quality and sleep promoting behaviors (r=.339) and negative associations with age (r=-234) and race (r=-.148). Multiple regression showed that sleep promoting behaviors and age statistically significantly predicted sleep quality (F(5,399) =15.51,p&amp;lt;.001,R2=.152). MS type, years passed since MS diagnoses and race did not add significantly to the prediction. Conclusion These findings suggest that poor sleep quality was strongly associated with sleep promoting behaviors among in older men with MS. Improving sleep promoting behaviors may substantially improve sleep quality. Further qualitative research is required to address the lack of information on understanding factors that disturb sleep among men with MS. Support (if any) This study was supported by National Heart, Lung, and Blood Institute (NHLBI) UB Clinical Scholar Program in Implementation Science to Achieve Triple Aims -NIH K12 Faculty Scholar Program in Implementation Science (NHLBI) Award

Randomized Clinical Trial of Intermittent Calorie Restriction in People with Multiple Sclerosis: Effects on Immunometabolic and Cognitive Measures

Abstract BACKGROUND: Intermittent calorie restriction (iCR) reduces inflammation in preclinical models and in people with Multiple Sclerosis (pwMS). Mechanisms could be related to changes in levels of adipose tissue-derived adipokines with reduced systemic inflammation and gut microbiota composition. AIMS: Evaluate the effects of iCR on adipokines levels, metabolic and immune/inflammatory biomarkers compared to a control unrestricted diet (Ctr) in pwMS. METHODS: PwMS (relapsing Remitting MS) were randomly assigned to the iCR or Ctr groups for 12 weeks. Blood was collected at baseline, 6 and 12 weeks. Leptin and adiponectin levels, peripheral blood metabolic and immunologic profiling, anthropometric and total body fat measures, and clinical and cognitive measures were evaluated. Differences between iCR and Ctr were examined using a linear, repeated measures mixed model and adjusted for baseline levels, age, sex and DMTs. RESULTS: 42 pwMS were randomized (iCR=22 and Ctr=20). 34 pwMS completed the study (iCR=17 and Ctr=17). PwMS on iCR showed a significant reduction of anthropometric (weight and BMI) and body adiposity measures (waist circumference and fat mass) over the 12 weeks. Leptin levels decreased and were significantly lower in the iCR group at 6 weeks and approaching significance at 12 weeks. Adiponectin increased from baseline in the iCR group at 6 and 12 weeks. The iCR group showed a significant decrease in Th1 cells and an increase in CD45RO+ regulatory T cells after 6 weeks. Cognitive testing using symbol digit modality test showed significantly greater improvement in the iCR group versus Ctr at 12 weeks. CONCLUSIONS: Short term iCR is safe and feasible in pwMS, and it can ameliorate metabolic, immunologic, and cognitive profiles. National Multiple Sclerosis Society # RG-1607-25158

Nitric Oxide (NO) regulation of Dendritic cells (DC) metabolism and immune effector functions

Abstract Dendritic cell (DC) activation is characterized by a sustained commitment to glycolysis, a requirement for survival in DC subsets expressing inducible nitric oxide synthase (iNOS, encoded by Nos2 gene). Nitric oxide (NO) can mediate both host-protective and host-cytotoxic effects by interfering with pathogen replication and/or by inhibiting the host mitochondrial respiration, resulting in metabolic rewiring in DCs. These phenomena primarily have been studied in DCs from the classic laboratory inbred mouse strain C57BL/6J (B6), where DCs experience a loss of mitochondrial function due to NO accumulation. To assess the conservation of NO-driven metabolic regulation in DCs, we compared B6 mice to the wild-derived genetically divergent PWD/PhJ (PWD) strain. We show preserved mitochondrial respiration and enhanced post-activation survival in LPS-stimulated PWD DCs due to attenuated NO production. To genetically map PWD’s NO phenotype, we used a congenic mouse strain (B6.PWD-Chr11.2; 11.2) that carries a PWD-derived portion of chromosome 11, including Nos2, on a B6 background. The 11.2 DCs show comparable iNOS expression with lower NO production levels than B6 DCs. We demonstrate that activated 11.2 DCs maintain mitochondrial respiration and TCA cycle carbon flux, compared with B6 DCs. However, reduced NO production by the PWD Nos2 allele results in impaired cellular control of Listeria monocytogenes replication. These studies establish a natural genetic model for restrained endogenous NO production and suggest a useful model to investigate the contribution/regulation of NO in DC metabolism and immune function. This work was supported by the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (P30GM118228, 1R21AI135385-01A, T32AI055402-15, and R21 AI145306), the NIH, National Institute of Neurological Disorders and Stroke (R01 NS097596), and the National Multiple Sclerosis Society (RG-1901-33309).

Harnessing the Full Potential of Regulatory T Cells by mRNA-induced Antigen Specificity

Abstract Regulatory T cells (Tregs) are crucial in inducing and maintaining tolerance, and already have shown clinical potential. In this study, we describe an efficient non-viral engineering method by TCR-encoding mRNA electroporation, while also exploring the potential of further promoting on-target effects by disrupting the endogenous TCR using a fully RNA-based CRISPR/Cas9 technology. Endogenous TCR disruption prior to TCR-transfection resulted in more than 90% blockade of the endogenous TCR expression and a similar high (&amp;gt;85%) but more homogenous expression of the transgenic TCR. Importantly, following antigen-specific TCR-induced stimulation, both engineered Tregs significantly increased the expression of multiple activation and suppression markers. Moreover, the engineered Tregs outcompeted polyclonal Tregs in suppressing antigen-specific effector T cell proliferation and performed better in blocking moDC maturation, even in the presence of antigen-activated effector T cells. Secretome screening revealed a distinct anti-inflammatory profile for TCR-Tregs. On the other hand, TCR-engineered KO Tregs co-expressed anti-inflammatory cytokines together with some pro-inflammatory cytokines, but qualitatively different from their effector Th counterparts. Hence, an anti-inflammatory profile with Th cell features is seen with TCR-engineered KO Tregs. In conclusion, we show that this versatile approach can be used to induce the functional expression of a transgenic TCR, but also for CRISPR/Cas9-mediated disruption of endogenous TCRs with high efficiency using an RNA-based platform. Comparison between polyclonal Tregs and TCR engineered Tregs in EAE using an HLA-transgenic mouse model is now being investigated. National Multiple Sclerosis Society (RG-1612-26484)

Investigating molecular mimicry by microbial peptides in the induction of experimental autoimmune encephalomyelitis

Abstract Multiple sclerosis (MS) is an incurable neuroinflammatory autoimmune disease in which a patient’s immune system targets the myelin sheath of neurons. This impairs neuronal signaling to the periphery, manifesting as severe pain, loss of vision, and partial paralysis. Several environmental and genetic risk factors such as the DRB1*1501 haplotype have been identified, but the exact etiology of this disease remain unclear. It is thought that MS is primarily mediated by myelin-reactive CD4 +T cells, however, the autoantigen epitopes targeted are diverse and vary between patients. Furthermore, certain peptides from these autoantigens share amino acid sequence similarities with those of microbial peptides. This is the basis for a phenomenon known as “molecular mimicry”, in which these similarities are sufficient to activate autoreactive CD4 +T cells. Previous work in our lab using the mouse model of MS, experimental autoimmune encephalomyelitis (EAE), found that immunization of DRB1*1501 mice with a peptide from M. avium generates both M. avium- and myelin basic protein (MBP)-reactive CD4 +T cells, though the presence of these cells failed to induce disease. We have previously demonstrated that immunization with suboptimal amounts of multiple myelin-derived peptides, which would not induce EAE individually, result in EAE if combined. We therefore hypothesize that there is a threshold effect in which the concurrent presence of multiple microbial peptides with structural similarity to myelin can contribute to induction of EAE in transgenic DRB1*1501 mice. With the data from this study, we hope to clarify the role of microbial infection in the pathogenesis of MS. This work was supported by grant RG1602 from the National Multiple Sclerosis Society (T.G.F.), support by the Jesse H. &amp; Mary Jones Gibbs Endowed Chair (T.G.F.), support by grant G12MD007591 from the National Institute on Minority Health and Health Disparities, and NIH/NIBIB ESTEEMED grant R25EB027605 (LS), support by NIH grant R01NS117742 (T.G.F.).

Pro-resolution lipid mediator maresin-1 reduces inflammation, promotes neuroprotection, and prevents disease progression in multiple sclerosis model of autoimmunity

Abstract Multiple sclerosis (MS) is the most common inflammatory neurodegenerative disease in young adults, resulting in neurological defects and disability. The endogenous mechanisms for resolving inflammation are intact but become defective in patients, resulting in a lack of resolution mediators and unresolved inflammation. Because DHA metabolism is impaired in MS, we hypothesize that supplementing its downstream metabolite maresin 1 (MaR1) will alleviate inflammation and demyelination in animal model of MS called experimental allergic encephalomyelitis (EAE). EAE was induced in SJL mice, followed by treatment with MaR1 (300ng, 200ul in PBS/animal/day ip) on day 6 after disease induction. Monitoring the disease course, recall response by ELISA, cytokine expression analysis by qPCR and western blotting, and immune profiling by flow cytometry were used to assess the effect of MaR1 treatment in EAE. The neuroprotective effect of MaR1 was also assessed using single molecule array (SIMOA), histopathology, and IHC. Statistical analysis was done using Graph-Pad Prism. Restoration of MaR1 had a protective effect on neurological deficits, prevented disease progression, and reduced disease severity in EAE by reducing immune cell infiltration (CD4 +IL17 +and CD4 +IFN +) into the CNS (P&amp;lt;0.001). It significantly reduced the proinflammatory cytokine IL17 (P&amp;lt;0.01) and promoted an anti-inflammatory response via IL10 and IL4 (P&amp;lt;0.001). Furthermore, it exerted neuroprotective effects as evidenced by higher MBP expression in the brain from the MaR1 treated group. Overall, MaR1 supplementation has anti-inflammatory and neuroprotective effects in preclinical animal models, implying that it could be a new therapeutic molecule in MS. Supported by grants from National Multiple Sclerosis Society (US) Research Grant (RG-2111-38733, RG-1807–31964 and RG-1508– 05912), the US National Institutes of Health Grant (NS112727 and AI144004), and Henry Ford Hospital Internal Grant (A10270 and A30967) to SG.

Mucus sialylation determines intestinal host-commensal homeostasis

Abstract Intestinal mucus forms the first line of defense against bacterial invasion while providing nutrition to support microbial symbiosis. How the host controls mucus barrier integrity and commensalism is unclear. We show that terminal sialylation of glycans on intestinal mucus by ST6GALNAC1 (ST6), the dominant sialyltransferase specifically expressed in goblet cells and induced by microbial pathogen-associated molecular patterns, is essential for mucus integrity and protecting against excessive bacterial proteolytic degradation. Glycoproteomic profiling and biochemical analysis of ST6 mutations identified in patients show that decreased sialylation causes defective mucus proteins and congenital inflammatory bowel disease (IBD). Mice harboring a patient ST6 mutation have compromised mucus barriers, dysbiosis, and susceptibility to intestinal inflammation. Based on our understanding of the ST6 regulatory network, we show that treatment with sialylated mucin or a Foxo3 inhibitor can ameliorate IBD. Supported by the Intramural Research Program of the NIAID, NIH, United States and by National Multiple Sclerosis Society Career Transition Award, United States (TA 3059-A-2 to C.W.).

Obesity Modulated Gut Microbiota Exacerbate Disease Severity in HLA-Class II Transgenic Mouse Model of Multiple Sclerosis

Abstract Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the CNS where interaction among multiple environmental and genetic factors influence disease outcome. HLA class II alleles such as HLA-DR2 and –DR3 are considered strongest genetic factors linked with MS, whereas recently gut microbiota have emerged as an important environmental factor linked to MS. Additionally, obesity has been shown to promote MS disease severity. However, the mechanistic link between gut microbiota and obesity in pathobiology of MS is unknown. HLA-DR3 transgenic mice on a high-fat diet (HFD) to induce obesity, resulted in severe EAE compared to normal chow diet (NCD). Antibiotic-mediated gut microbiota depletion and fecal transplant studies established that the microbiota is necessary and sufficient for obesity to potentiate EAE severity. Obesity-associated microbiota alterations included increases in bacterial genes linked with hydrogen sulfide (H 2S)-metabolism, with concordant increases in fecal H 2S. Further, mice on HFD showed increased gut permeability and systemic inflammation compared with NCD group. Altogether, this study provides evidence for involvement of the gut microbiome and associated H 2S-metabolism microbial genes in obesity induced modulation of EAE severity. Dissection of these pathways will help to identify novel therapeutic targets to reduce disease severity in obese patients. The Author acknowledge funding from the National Multiple Sclerosis Society grant (RG 5138A1/1T), National Institutes of Health/NIAID (1R01AI137075), the University of Iowa Environmental Health Sciences Research Center, NIEHS/NIH (P30 ES005605), and a gift from P. Heppelmann and M. Wacek to AM.

Imaging Chronic Active Lesions in Multiple Sclerosis: a Consensus Statement from the North America Imaging in Multiple Sclerosis Cooperative (P11-3.009)

Imaging Chronic Active Lesions in Multiple Sclerosis: a Consensus Statement from the North America Imaging in Multiple Sclerosis Cooperative (P11-3.009)

Longitudinal Cognitive Screening Findings in Pediatric MS vs. Pediatric Controls and Adult MS in a Multi-center Cohort (S31.008)

Longitudinal Cognitive Screening Findings in Pediatric MS vs. Pediatric Controls and Adult MS in a Multi-center Cohort (S31.008)

Real-world effectiveness of switching treatment after initial platform injectable disease-modifying therapies in pediatric multiple sclerosis in the US (P14-3.008)

Real-world effectiveness of switching treatment after initial platform injectable disease-modifying therapies in pediatric multiple sclerosis in the US (P14-3.008)