Epstein-Barr virus-encoded BART9 and BART15 miRNAs are elevated in exosomes of cerebrospinal fluid from relapsing-remitting multiple sclerosis patients.

Epstein-Barr virus (EBV) infection is approved as the main environmental trigger of multiple sclerosis (MS). In this path, we quantified ebv-miR-BART9-3p and ebv-miR-BART15 in exosomes of cerebrospinal fluid (CSF) of untreated relapsing-remitting MS (RRMS) patients in comparison with the control group. Interestingly, patients displayed significant upregulation of ebv-miR-BART9-3p (18.4-fold) and ebv-miR-BART15 (3.1-fold) expression in CSF exosomes. Moreover, the expression levels of hsa-miR-21-5p and hsa-miR-146a-5p were found to be significantly elevated in the CSF samples obtained from the patient group compared to those obtained from the HC group. The levels of Interferon-gamma (IFN-γ), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-17 (IL-17), interleukin-23 (IL-23), transforming growth factor beta (TGF-ß), and tumor necrosis factor-alpha (TNF-α) were observed to be significantly elevated in the serum and CSF exosomes of the patients. The highest increase was observed in TGF-ß (8.5-fold), followed by IL-23 (3.9-fold) in CSF exosomes. These findings are in agreement with the association between EBV infection and inflammatory cytokines induction. Furthermore, the ratios of TGF-ß: TNF-α and TGF-ß: IFN-γ attained values of 4 to 16.4 and 1.3 to 3.6, respectively, in the CSF exosomes of the patients, in comparison to those of the control group. These findings show EBV activity in RRMS patients is different from that of healthy ones. Elevation of ebv-miR-BART9-3p, ebv-miR-BART15, and inflammatory cytokines expression in CSF exosomes in RRMS patients provides a substantial link between EBV activity and the onset of the disease, as well as the transition from EBV infection to MS.

Identification of Key Ferroptosis-Related Genes in the Peripheral Blood of Patients with Relapsing-Remitting Multiple Sclerosis and Its Diagnostic Value.

Multiple sclerosis (MS) is a neurodegenerative disease with a complex pathogenesis. Re-lapsing-remitting multiple sclerosis (RRMS) is the most common subset of MS, accounting for approximately 85% of cases. Recent studies have shown that ferroptosis may contribute to the progression of RRMS, but the underlying mechanism remains to be elucidated. Herein, this study intended to explore the molecular network of ferroptosis associated with RRMS and establish a predictive model for efficacy diagnosis. Firstly, RRMS-related module genes were identified using weighted gene co-expression network analysis (WGCNA). Secondly, the optimal machine learning model was selected from four options: the generalized linear model (GLM), random forest model (RF), support vector machine model (SVM), and extreme gradient boosting model (XGB). Subsequently, the predictive efficacy of the diagnostic model was evaluated using receiver operator characteristic (ROC) analysis. Finally, a SVM diagnostic model based on five genes (JUN, TXNIP, NCOA4, EIF2AK4, PIK3CA) was established, and it demonstrated good predictive performance in the validation dataset. In summary, our study provides a systematic exploration of the complex relationship between ferroptosis and RRMS, which may contribute to a better understanding of the role of ferroptosis in the pathogenesis of RRMS and provide promising diagnostic strategies for RRMS patients.

Defective Induction of IL-27-Mediated Immunoregulation by Myeloid DCs in Multiple Sclerosis.

The purpose of this study was to examine whether myeloid dendritic cells (mDCs) from patients with multiple sclerosis (MS) and healthy controls (HCs) become similarly tolerogenic when exposed to IL-27 as this may represent a potential mechanism of autoimmune dysregulation. Our study focused on natural mDCs that were isolated from HCs and MS patient peripheral blood mononuclear cells (PBMCs). After a 24-h treatment with IL-27 ± lipopolysaccharide (LPS), the mDCs were either harvested to identify IL-27-regulated gene expression or co-cultured with naive T-cells to measure how the treated DC affected T-cell proliferation and cytokine secretion. mDCs isolated from HCs but not untreated MS patients became functionally tolerogenic after IL-27 treatment. Although IL-27 induced both HC and untreated MS mDCs to produce similar amounts of IL-10, the tolerogenic HC mDCs expressed PD-L2, IDO1, and SOCS1, while the non-tolerogenic untreated MS mDCs expressed IDO1 and IL-6R. Cytokine and RNA analyses identified two signature blocks: the first identified genes associated with mDC tolerizing responses to IL-27, while the second was associated with the presence of MS. In contrast to mDCs from untreated MS patients, mDCs from HCs and IFNb-treated MS patients became tolerogenic in response to IL-27. The genes differentially expressed in the different donor IL-27-treated mDCs may contain targets that regulate mDC tolerogenic responses.

Inner Retinal Layer Changes Reflect Changes in Ambulation Score in Patients with Primary Progressive Multiple Sclerosis.

The establishment of surrogate markers to detect disability progression in persons with multiple sclerosis (PwMS) is important to improve monitoring of clinical deterioration. Optical coherence tomography (OCT) could be such a tool. However, sufficient longitudinal data of retinal neuroaxonal degeneration as a marker of disease progression exist only for PwMS with a relapsing-remitting course (RRMS) so far. In contrast, longitudinal data of retinal layers in patients with primary-progressive MS (PPMS) are inconsistent, and the association of OCT parameters with ambulatory performance in PwMS has rarely been investigated. We aimed to investigate the relative annual rates of change in retinal layers in PwMS (RRMS and PPMS) compared with healthy controls (HC) using OCT and to evaluate their association with ambulatoryfunctionalscore (AS) worsening in PPMS. A retrospective analysis of a longitudinal OCT dataset of the retinal layers of PwMS and HC from two MS centers in Germany was performed. Walking ability was measured over a standardized distance of 500 m, and changes during the observation period were categorized using the AS and the expanded disability status scale (EDSS). 61 HC with 121 eyes and 119 PwMS (PPMS: 57 patients with 108 eyes; RRMS: 62 patients with 114 eyes) were included. The median follow-up time for PwMS was 3 years. The relative annual change of pRNFL (peripapillary retinal nerve fiber layer) and INL (inner nuclear layer) was significantly different in PwMS compared with HC. RRMS and PPMS subgroups did not differ in the annual atrophy rates. In patients with PPMS, worsening of the AS was significantly associated with increased thinning of the TMV (total macular volume), GCIP (ganglion cell and inner plexiform layer), and ONPL (outer nuclear and outer plexiform layer) (all p-value < 0.05, r > 0.30). For every -0.1% decrease in the TMV, GCIP, and ONPL, the risk of a deterioration in the AS increased by 31% (hazard ratio (HR): 1.309), 11% (HR: 1.112), and 16% (HR: 1.161), respectively. In addition, worsening EDSS in PPMS was significantly associated with the relative annual atrophy rates of pRNFL, TMV, and GCIP (all p-value < 0.05). Disability progression in PPMS can be measured using OCT, and increasing annual atrophy rates of the inner retinal layers are associated with worsening ambulation. OCT is a robust and side-effect-free imaging tool, making it suitable for routine monitoring of PwMS.

Narrative recall in relapsing-remitting multiple sclerosis: A potentially useful speech task for detecting subtle cognitive changes.

Our research studied relapsing-remitting multiple sclerosis (RRMS). In half of the RRMS cases, mild cognitive difficulties are present, but often remain undetected despite their adverse effects on individuals' daily life. Detecting subtle cognitive alterations using speech analysis have rarely been implemented in MS research. We applied automatic speech recognition technology to devise a speech task with potential diagnostic value. Therefore, we used two narrative tasks adjusted for the neural and cognitive characteristics of RRMS; namely narrative recall and personal narrative. In addition to speech analysis, we examined the information processing speed, working memory, verbal fluency, and naming skills. Twenty-one participants with RRMS and 21 gender-, age-, and education-matched healthy controls took part in the study. All the participants with RRMS achieved a normal performance on Addenbrooke's Cognitive Examination. The following parameters of speech were measured: articulation and speech rate, the proportion, duration, frequency, and average length of silent and filled pauses. We found significant differences in the temporal parameters between groups and speech tasks. ROC analysis produced high classification accuracy for the narrative recall task (0.877 and 0.866), but low accuracy for the personal narrative task (0.617 and 0.592). The information processing speed affected the speech of the RRMS group but not that of the control group. The higher cognitive load of the narrative recall task may be the cause of significant changes in the speech of the RRMS group relative to the controls. Results suggest that narrative recall task may be effective for detecting subtle cognitive changes in RRMS.

Spatial distribution of white matter degenerative lesions and cognitive dysfunction in relapsing-remitting multiple sclerosis patients.

AIM: The aim of this study was to assess degenerative lesion localisation in the course of relapsing-remitting multiple sclerosis (RRMS) and to identify the association between localisation and the frequency of T1-hypointense lesions (black holes) with cognitive dysfunction. We also searched for neuroradiological predictors of cognitive dysfunction in patients. The clinical rationale for the study was previous research, and our own findings suggest that lesion localisation plays an important role in cognitive performance and neurological disability of MS patients. MATERIAL AND METHODS: Forty-two patients were included in the study. All subjects underwent neuropsychological examination using Raven's Coloured Progressive Matrices, a naming task from the Brief Repeatable Battery of Neuropsychological Tests, and attention to detail tests. Magnetic resonance imaging (MRI) was acquired on 1.5 Tesla scanner and black holes were manually segmented on T1-weighted volumetric images using the FMRIB Software Library. Linear regression was applied to establish a relationship between black hole volume per lobe and cognitive parameters. Bonferroni correction of voxelwise analysis was used to correct for multiple comparisons. RESULTS: The following associations between black hole volume and cognition were identified: frontal lobes black hole volume was associated with phonemic verbal fluency (t = -4.013, p < 0.001), parietal black hole volume was associated with attention (t = -3.776, p < 0.001), and parietal and temporal black hole volumes were associated with nonverbal intelligence (p < 0.001). The volume of parietal black holes was the best predictor of cognitive dysfunction. CONCLUSIONS: Our approach, including measurement of focal axonal loss based on T1-volumetric MRI sequence and brief neuropsychological assessment, might improve personalised diagnostic and therapeutic decisions in clinical practice.

Immune-cell BDNF expression in treatment-naïve relapsing-remitting multiple sclerosis patients and following one year of immunomodulation therapy.

Although neurons are the main source of neurotrophins in the healthy brain, neurotrophins can also be expressed in the immune system. We have previously shown that in relapsing-remitting multiple sclerosis (RRMS) lower immune-cell neurotrophin levels are associated with brain atrophy and cognitive impairment. The aim of the present study was to assess if immune-cell neurotrophin expression is impaired in MS as compared with the healthy controls, and to describe if these levels change in treatment-naïve RRMS patients, following one year of immunomodulation. Fifty treatment-naïve RRMS patients were assessed at baseline and after one year of immunomodulation (beta-interferons/glatiramer acetate). The control group included 39 healthy subjects matched according to age and gender. Peripheral blood mononuclear cells (PBMCs) were isolated from heparinized blood using Ficoll-Histopaque gradient. The levels of brain-derived-neurotrophic-factor (BDNF), beta-nerve-growth-factor (beta-NGF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) were measured in PBMC lysates with ELISA. BDNF levels were significantly lower in MS than in the healthy controls (median 613 vs. 1657pg/mg protein, p<0.001). After one year of immunomodulation, BDNF expression did not change significantly (p=0.06) on the group level. In 70% of patients there was no increase in BDNF level, and in 30% it increased. We observed no differences between treatment groups. Other neurotrophins were detected in a minority of MS samples (as opposed to the controls). To conclude, we have shown that immune-cell production of neurotrophins is impaired in MS patients. In our MS cohort standard immunomodulation failed to restore normal BDNF levels in PBMCs within one year of therapy.

Predictive factors and treatment challenges in malignant progression of relapsing-remitting multiple sclerosis.

Objective: Our objective was to uncover the predictive factors that can help anticipate the malignant progression of individuals with Relapsing-Remitting Multiple Sclerosis (RRMS). Additionally, we sought to analyze and compare the response to treatment between patients with benign and malignant forms of RRMS. Methods: This cohort study included RRMS patients categorized as benign (≥10 years since disease onset, Expanded Disability Status Scale (EDSS) ≤ 1) or malignant (≤5 years since disease onset, EDSS ≥6). Patients' data, including demographics, medical history, treatment, and MRI (Magnetic Resonance Imaging) scans, were collected and statistically analyzed. Results: Among the 254 patients diagnosed with RRMS, 174 were found to have benign RRMS, while the remaining 80 were diagnosed with malignant RRMS. Notably, patients with malignant RRMS exhibited a significantly higher mean age of onset (32.00 ± 7.96 vs. 25.70 ± 17.19; P < 0.001) and a greater prevalence of males (40% vs. 18.4%; P = 0.014). Additionally, within the initial five years of diagnosis, patients with malignant RRMS experienced a higher number of relapses (median: 4 vs. 2; P < 0.001) and hospitalizations (median: 2 vs. 1; P = 0.006) compared to those with benign RRMS. Clinical presentations of malignant RRMS were predominantly characterized by multifocal attacks, whereas unifocal attacks were more prevalent in patients with benign RRMS. MRI scans revealed that malignant RRMS patients displayed a higher burden of plaques in the infratentorial and cord regions, as well as a greater number of black hole lesions. Conversely, benign RRMS patients exhibited a higher number of Gadolinium-enhanced lesions. Utilizing Disease-Modifying Therapies (DMTs) with an escalating approach has shown effectiveness in managing benign RRMS. However, it has proven insufficient in addressing malignant RRMS, resulting in frequent transitions to higher-line DMTs. As a result, it places a considerable burden on patients with malignant RRMS, consuming valuable time and resources, and ultimately yielding subpar outcomes. Conclusion: Our study identifies prognostic factors for malignant progression in RRMS, including older age of onset, male gender, increased relapses and hospitalizations, multifocal attacks, higher plaque load, and black hole lesions. The current escalation strategy for DMTs is insufficient for managing malignant RRMS, requiring alternative approaches for improved outcomes. In other words, MS is a spectrum rather than a single disease, and some patients progress to a malignant phenotype of MS that is not effectively treated by the current approach.

Two Cases of Acute Diverticulitis Following Ocrelizumab Infusion in Patients With Multiple Sclerosis.

Ocrelizumab is an anti-CD20 monoclonal antibody used to treat primary progressive and relapsing-remitting multiple sclerosis. Several prior case reports have demonstrated colitis in association with ocrelizumab infusion, and one case report has shown ocrelizumab-associated diverticulitis. We report on two cases in which ocrelizumab treatment of multiple sclerosis was complicated by acute diverticulitis. A 50-year-old woman and a 41-year-old man, both with relapsing-remitting multiple sclerosis, presented with acute abdominal pain. One patient had no known gastrointestinal history while the other had a history of laparoscopic sleeve gastrectomy. Both patients had received an ocrelizumab infusion one month prior to presentation. The woman underwent exploratory laparotomy, which revealed perforated sigmoid diverticulitis. The man was initially suspected of appendicitis and was treated with appendectomy, but a pathology review demonstrated diverticular disease in the appendix. In patients with multiple sclerosis on ocrelizumab, presentation with diverticulitis should include ocrelizumab-induced diverticulitis in the differential diagnosis.

Establishing clinically meaningful within-individual improvement thresholds for eight patient-reported outcome measures in people with relapsing-remitting multiple sclerosis.

BACKGROUND: As disease-modifying therapies do not reverse the course of multiple sclerosis (MS), assessment of therapeutic success involves documenting patient-reported outcomes (PROs) concerning health-related quality of life, disease and treatment-related symptoms, and the impact of symptoms on function. Interpreting PRO data involves going beyond statistical significance to calculate within-patient meaningful change scores. These thresholds are needed for each PRO in order to fully interpret the PRO data. This analysis of PRO data from the PROMiS AUBAGIO study, which utilized 8 PRO instruments in teriflunomide-treated relapsing-remitting MS (RRMS) patients, was designed to estimate clinically meaningful within-individual improvement thresholds in the same manner, for 8 PRO instruments. RESULTS: The analytical approach followed a triangulation exercise that considered results from anchor- and distribution-based methods and graphical representations of empirical cumulative distribution functions in PRO scores in groups defined by anchor variables. Data from 8 PRO instruments (MSIS-29 v2, FSMC, MSPS, MSNQ, TSQM v1.4, PDDS, HRPQ-MS v2, and HADS) were assessed from 434 RRMS patients. For MSIS-29 v2, FSMC, MSPS, and MSNQ total scores, available anchor variables enabled both anchor- and distribution-based methods to be applied. For instruments with no appropriate anchor available, distribution-based methods were applied. A recommended value for meaningful within-individual improvement was defined by comparing mean change in PRO scores between participants showing improvement of one or two categories in the anchor variable or those showing no change. A "lower bound" estimate was calculated using distribution-based methods. An improvement greater than the lower-bound estimate was considered "clinically meaningful". CONCLUSION: This analysis produced estimates for assessing meaningful within-individual improvements for 8 PRO instruments used in MS studies. These estimates should be useful for interpreting scores and communicating study results and should facilitate decision-making by regulatory and healthcare authorities where these 8 PROs are commonly employed.

Vaginal Herpes Zoster While Under Treatment for Relapsing-Remitting Multiple Sclerosis With Diroximel Fumarate.

Multiple sclerosis (MS) is an autoimmune demyelinating disorder that disproportionately affects middle-aged women, and is capable of resulting in severe disability. However, the use of disease-modifying therapies has profoundly contributed to the improvement in the morbidity of the disorder. Diroximel fumarate (DRF) is a second-generation drug that has seen success in the treatment of relapsing-remitting MS (RRMS). While its relatively mild side effects of gastrointestinal discomfort are known, the less common complications are often missed in clinical settings. This includes a resulting susceptibility to opportunistic infections. In this case report, we describe a patient who experienced lymphopenia, recurrent yeast infections, and labial shingles while on the medication. This case highlights the side effects and the rare complications of the immunomodulator, DRF.

Enlarged choroid plexus related to iron rim lesions and deep gray matter atrophy in relapsing-remitting multiple sclerosis.

BACKGROUND: Choroid plexus (CP) is considered to be linked to inflammation of multiple sclerosis (MS), but its connection with markers of inflammation in vivo in MS is unclear, the markers such as lesions load and brain atrophy, particularly the white matter lesions (WMLs) edge surrounded by an iron rim, termed as iron rim lesions (IRLs). PURPOSE: To investigate the association between CP volume and brain lesions load, especially IRLs load and atrophy in MS, and its relationship with clinical characteristics. METHODS: 3.0 T brain MRI images were acquired from 99 relapsing-remitting MS (RRMS) and 60 healthy controls (HCs) to obtain the volumes of CP, whole brain and lesions. Volumes were expressed as a ratio of intracranial volume. Expanded Disability Status Scale (EDSS), Montreal Cognitive Assessment (MoCA) and Symbol Digit Modalities Test (SDMT) were used to assess the severity of disability and cognitive function. Student's t-test and Multivariable regression analyses were performed to evaluate the difference of CP volumes between RRMS and HC and the association between CP volume and lesions load, brain volumes and clinical scale scores in RRMS. RESULTS: CP volume was 30% larger in patients with RRMS than HCs (p < 0.001) and was 20% larger in patients with IRLs than those without IRLs (p = 0.007). Moreover, the larger CP volume was related to greater WMLs volume in the whole RRMS (r = 0.46, p < 0.001). Further analysis in patients with IRLs showed a positive correlation between CP volume and WMLs volume (r = 0.45, p = 0.003), and IRLs volume (r = 0.51, p < 0.001). Meanwhile, enlarged CP was related to lower volumes in the whole brain (r = -0.30, p = 0.006), deep gray matter (r = -0.51, p < 0.001) and most regional deep gray matter nuclei (except amygdala), but no correlation with cortical lesions or cortex volume (both p > 0.05). In addition, CP volume was significantly higher in patients with cognitive impairment than those with cognitive preservation by MoCA scores (p = 0.011); the larger CP volume was associated with higher EDSS scores (r = 0.25, p = 0.014) and lower SDMT Z scores in RRMS (r = -0.26, p = 0.014). CONCLUSION: The enlargement of CP in RRMS had close correlations with inflammatory lesions, especially IRLs and deep gray matter atrophy, but not the cortex. Meanwhile, the larger CP volume was associated with higher disability and lower cognitive scores. CP volume may be a surrogate imaging marker for MS disease activity.

Health economic outcomes of switching to alemtuzumab from other disease-modifying therapies in people with multiple sclerosis in the USA.

Aim: Describe demographics, clinical characteristics, healthcare resource utilization (HCRU) and costs in people with multiple sclerosis (pwMS) switching to alemtuzumab from other disease-modifying therapies (DMTs). Patients & methods: Retrospective, observational study of IBM®MarketScan® claims database. PwMS previously treated with DMTs and initiating alemtuzumab (1 January 2013 to 31 December 2019) were identified. "Index" was date of alemtuzumab initiation (prescription filled). Results: The study cohort (n = 341) was primarily female (72%) with (mean ± standard deviation) age 45.1 ± 9.5 years. At index, duration of MS was 5.3 ± 2.8 years. HCRU (inpatient/outpatient services), outpatient costs (including MS-specific MRI and emergency room visits) and annualized relapse rate significantly reduced over the 2 years following initiation of alemtuzumab. DMT costs reduced over the same period. Conclusion: Health economic and clinical benefits were seen following switching to alemtuzumab from other DMTs for treatment of MS, in this cohort from the USA.

A Case of Prolonged Fever in a Patient Infected With COVID-19 on Ofatumumab.

We discuss a case of a 53-year-old woman with multiple sclerosis on monthly ofatumumab injections, who was infected with SARS-CoV-2 with persistent fevers for seven weeks. She was hospitalized for fever with diagnostic workup being unremarkable with negative SARS-CoV-2 IgM and undetectable nucleocapsid IgG antibodies four weeks out from the initial infection, indicating she may not have mounted an appropriate immune response to the infection. Patients on immunosuppression therapy may have a prolonged course of disease given that medications such as ofatumumab can take up to 24 weeks of B-cell recovery post-treatment discontinuation and a longer road to recovery.

Fatigue in Multiple Sclerosis Is Associated with Reduced Expression of Interleukin-10 and Worse Prospective Disease Activity.

In multiple sclerosis (MS), fatigue is a frequent symptom that negatively affects quality of life. The pathogenesis of fatigue is multifactorial and inflammation may play a specific role. To explore the association between fatigue, central inflammation and disease course in MS in 106 relapsing-remitting (RR)-MS patients, clinical characteristics, including fatigue and mood, were explored at the time of diagnosis. NEDA (no evidence of disease activity)-3 status after one-year follow up was calculated. Cerebrospinal fluid (CSF) levels of a set of proinflammatory and anti-inflammatory molecules and peripheral blood markers of inflammation were also analyzed. MRI structural measures were explored in 35 patients. A significant negative correlation was found at diagnosis between fatigue measured with the Modified Fatigue Impact Scale (MFIS) and the CSF levels of interleukin (IL)-10. Conversely, no significant associations were found with peripheral markers of inflammation. Higher MFIS scores were associated with reduced probability to reach NEDA-3 status after 1-year follow up. Finally, T2 lesion load showed a positive correlation with MFIS scores and a negative correlation with CSF IL-10 levels at diagnosis. CSF inflammation, and particularly the reduced expression of the anti-inflammatory molecule IL-10, may exacerbate fatigue. Fatigue in MS may reflect subclinical CSF inflammation, predisposing to greater disease activity.

Real-world application of autologous hematopoietic stem cell transplantation in 507 patients with multiple sclerosis.

OBJECTIVE: To investigate the results of real-world application of non-myeloablative autologous HSCT for multiple sclerosis (MS). METHODS: Between July 2003 and October 2019 at a single center (Northwestern University), 414 patients with relapsing remitting MS (RRMS) and 93 patients with newly diagnosed secondary progressive MS (SPMS) underwent non-myeloablative HSCT. RESULTS: There was one treatment-related death (0.19%) due to hospital-acquired legionella pneumonia, and one patient developed neutropenic bacteremia (Klebsiella pneumonia) without sepsis. Overall 5-year survival was 98.8%. Post HSCT secondary autoimmune diseases (2nd ADs) were idiopathic thrombocytopenia (ITP) and hypo or hyperthyroidism. ITP was highest with alemtuzumab (14%) and 0 to 2.8% for the non-alemtuzumab regimens. After HSCT, 16 patients developed hypothyroidism (3.5%) and 15 developed hyperthyroidism / Grave's disease (3.3%). Relapse free survival (RFS) at 5 years for RRMS and SPMS was 80.1% and 98.1%, respectively, while progression free survival (PFS) at 4 years for RRMS and SPMS was 95% versus 66%, respectively. For patients with RRMS, the EDSS significantly improved (p < 0.0001) at each follow-up from a pre-HSCT mean of 3.87 to 2.51, 2.50, 2.41, 2.33, and 2.19 at 1, 2, 3, 4, and 5 years, respectively. For SPMS, the EDSS improved significantly only at 1 year but not thereafter. For SPMS, the mean baseline EDSS of 5.09 changed post-HSCT to 4.85 (p = 0.04), 4.88 (p = 0.2), 4.92 (p = .27), 4.72 (p = 0.07), and 4.2 (p = 0.21) at 1, 2, 3, 4, 5 years, respectively. CONCLUSION: In patients with RRMS, autologous non-myeloablative HSCT is an effective one-time therapy, while HSCT appears of less benefit for newly diagnosed SPMS.

Health Economic Impact of Software-Assisted Brain MRI on Therapeutic Decision-Making and Outcomes of Relapsing-Remitting Multiple Sclerosis Patients-A Microsimulation Study.

AIM: To develop a microsimulation model to assess the potential health economic impact of software-assisted MRI in detecting disease activity or progression in relapsing-remitting multiple sclerosis (RRMS) patients. METHODS: We develop a simulated decision analytical model based on a hypothetical cohort of RRMS patients to compare a baseline decision-making strategy in which only clinical evolution (relapses and disability progression) factors are used for therapy decisions in MS follow-up, with decision-making strategies involving MRI. In this context, we include comparisons with a visual radiologic assessment of lesion evolution, software-assisted lesion detection, and software-assisted brain volume loss estimation. The model simulates clinical (EDSS transitions, number of relapses) and subclinical (new lesions and brain volume loss) disease progression and activity, modulated by the efficacy profiles of different disease-modifying therapies (DMTs). The simulated decision-making process includes the possibility to escalate from a low efficacy DMT to a high efficacy DMT or to switch between high efficacy DMTs when disease activity is detected. We also consider potential error factors that may occur during decision making, such as incomplete detection of new lesions, or inexact computation of brain volume loss. Finally, differences between strategies in terms of the time spent on treatment while having undetected disease progression/activity, the impact on the patient's quality of life, and costs associated with health status from a US perspective, are reported. RESULTS: The average time with undetected disease progression while on low efficacy treatment is shortened significantly when using MRI, from around 3 years based on clinical criteria alone, to 2 when adding visual examination of MRI, and down to only 1 year with assistive software. Hence, faster escalation to a high efficacy DMT can be performed when MRI software is added to the radiological reading, which has positive effects in terms of health outcomes. The incremental utility shows average gains of 0.23 to 0.37 QALYs over 10 and 15 years, respectively, when using software-assisted MRI compared to clinical parameters only. Due to long-term health benefits, the average annual costs associated with health status are lower by $1500-$2200 per patient when employing MRI and assistive software. CONCLUSIONS: The health economic burden of MS is high. Using assistive MRI software to detect and quantify lesions and/or brain atrophy has a significant impact on the detection of disease activity, treatment decisions, health outcomes, utilities, and costs in patients with MS.

Assessing Lumbar Plexus and Sciatic Nerve Damage in Relapsing-Remitting Multiple Sclerosis Using Magnetisation Transfer Ratio.

Background: Multiple sclerosis (MS) has traditionally been regarded as a disease confined to the central nervous system (CNS). However, neuropathological, electrophysiological, and imaging studies have demonstrated that the peripheral nervous system (PNS) is also involved, with demyelination and, to a lesser extent, axonal degeneration representing the main pathophysiological mechanisms. Aim: The purpose of this study was to assess PNS damage at the lumbar plexus and sciatic nerve anatomical locations in people with relapsing-remitting MS (RRMS) and healthy controls (HCs) in vivo using magnetisation transfer ratio (MTR), which is a known imaging biomarker sensitive to alterations in myelin content in neural tissue, and not previously explored in the context of PNS damage in MS. Method: Eleven HCs (7 female, mean age 33.6 years, range 24-50) and 15 people with RRMS (12 female, mean age 38.5 years, range 30-56) were recruited for this study and underwent magnetic resonance imaging (MRI) investigations together with clinical assessments using the expanded disability status scale (EDSS). Magnetic resonance neurography (MRN) was first used for visualisation and identification of the lumbar plexus and the sciatic nerve and MTR imaging was subsequently performed using identical scan geometry to MRN, enabling straightforward co-registration of all data to obtain global and regional mean MTR measurements. Linear regression models were used to identify differences in MTR values between HCs and people with RRMS and to identify an association between MTR measures and EDSS. Results: MTR values in the sciatic nerve of people with RRMS were found to be significantly lower compared to HCs, but no significant MTR changes were identified in the lumbar plexus of people with RRMS. The median EDSS in people with RRMS was 2.0 (range, 0-3). No relationship between the MTR measures in the PNS and EDSS were identified at any of the anatomical locations studied in this cohort of people with RRMS. Conclusion: The results from this study demonstrate the presence of PNS damage in people with RRMS and support the notion that these changes, suggestive of demyelination, maybe occurring independently at different anatomical locations within the PNS. Further investigations to confirm these findings and to clarify the pathophysiological basis of these alterations are warranted.

Strain and sex differences in somatosensation and sociability during experimental autoimmune encephalomyelitis.

Multiple Sclerosis (MS) is an immune-mediated disease that results in major locomotor deficits. However, recent studies have revealed that fatigue, slow processing speed, and memory impairment are the top variables impacting employment status for MS patients. These suggest that cognitive effects may have a greater impact on productivity, lifestyle, and quality of life than do disease-related motor deficits. However, these debilitating non-locomotive effects have been largely overlooked in rodent models of the disease, such as experimental autoimmune encephalomyelitis (EAE). We hypothesized that murine EAE can also be used to assess non-locomotive dysfunctions (mood, sociability, muscle strength, and balance), as well as potential biases in these dysfunctions due to sex and/or strain. We actively immunized male and female C57BL/6 (B6) and SJL mice for EAE and evaluated their performance on the Deacon's weight grip test, Kondziela's inverted screen test, Hall's rope grip test, manual von Frey test for somatic nociception, and a three-chamber social preference paradigm. We hypothesized that EAE progression is associated with changes in muscle strength, balance, pain, and sociability and that these variations are linked to sex and/or strain. Our results indicate that strain but not sex influenced differences in muscle strength and balance during EAE, and both sex and strain have an impact on mechanical nociception, regardless of EAE disease status. Furthermore, both sex and strain had complex effects on differences in sociability. In conclusion, testing these additional modalities during EAE helps to unveil other signs and symptoms that could be used to determine the efficacy of a drug or treatment in the modulation of a MS-like behavior.

Treatment With Cladribine Selects IFNγ+IL17+ T Cells in RRMS Patients - An In Vitro Study.

Background: Multiple sclerosis (MS) is an incurable autoimmune disease mediated by a heterogeneous T cell population (CD3+CD161+CXCR3-CCR6+IFNγ-IL17+, CD3+CXCR3+CCR6+IFNγ+IL17+, and CD3+CXCR3+IFNγ+IL17- phenotypes) that infiltrates the central nervous system, eliciting local inflammation, demyelination and neurodegeneration. Cladribine is a lymphocyte-depleting deoxyadenosine analogue recently introduced for MS therapy as a Disease Modifying Drug (DMD). Our aim was to establish a method for the early identification and prediction of cladribine responsiveness among MS patients. Methods: An experimental model was designed to study the cytotoxic and immunomodulatory effect of cladribine. T cell subsets of naïve relapsing-remitting MS (RRMS) patients were analyzed ex vivo and in vitro comparatively to healthy controls (HC). Surviving cells were stimulated with rh-interleukin-2 for up to 14days. Cell proliferation and immunophenotype changes were analyzed after maximal (phorbol myristate acetate/ionomycin/monensin) and physiological T-cell receptor (CD3/CD28) activation, using multiparametric flow cytometry and xMAP technology. Results: Ex vivo CD161+Th17 cells were increased in RRMS patients. Ex vivo to in vitro phenotype shifts included: decreased CD3+CCR6+ and CD3+CD161+ in all subjects and increased CD3+CXCR3+ in RRMS patients only; Th17.1 showed increased proliferation vs Th17 in all subjects; CD3+IL17+ and CD3+IFNγ+IL17+ continued to proliferate till day 14, CD3+IFNγ+ only till day 7. Regarding cladribine exposure: RRMS CD3+ cells were more resistant compared to HC; treated CD3+ cells proliferated continuously for up to 14 days, while untreated cells only up to 7 days; both HC/RRMS CD3+CXCR3+ populations increased from baseline till day 14; in RRMS patients vs HC, IL17 secretion from cladribine-treated cells increased significantly, in line with the observed proliferation of CD3+IL17+ and CD3+IFNγ+IL17+ cells; in both HC/RRMS, cladribine led to a significant increase in CD3+IFNγ+ cells at day 7 only, having no further effect at day14. IFNγ and IL17 secreted in culture media decreased significantly from ex vivo to in vitro. Conclusions: CD3+ subtypes showed different responsiveness due to selectivity of cladribine action, in most patients leading to in vitro survival/proliferation of lymphocyte subsets known as pathogenic in MS. This in vitro experimental model is a promising tool for the prediction of individual responsiveness of MS patients to cladribine and other DMDs.