Treatment Of Multiple Sclerosis Patients Research Articles

The role of multiple sclerosis therapies on the dynamic of human gut microbiota

Gut microbiota, the total microorganisms in our gastrointestinal tract, might have an implication in multiple sclerosis (MS), a demyelinating neurological disease. Our study included 50 MS patients and 21 healthy controls (HC). Twenty patients received a disease modifying therapy (DMT), interferon beta1a or teriflunomide, 19 DMT combined with homeopathy and 11 patients accepted only homeopathy. We collected in total 142 gut samples, two for each individual: at the study enrolment and eight weeks after treatment. We compared MS patients' microbiome with HC, we analysed its evolution in time and the effect of interferon beta1a, teriflunomide and homeopathy. There was no difference in alpha diversity, only two beta diversity results related to homeopathy. Compared to HC, untreated MS patients had a decrease of Actinobacteria, Bifidobacterium, Faecalibacterium prauznitzii and increased Prevotella stercorea, while treated patients presented lowered Ruminococcus and Clostridium. Compared to the initial sample, treated MS patients had a decrease of Lachnospiraceae and Ruminococcus and an increased Enterococcus faecalis. Eubacterium oxidoreducens was reduced after homeopathic treatment. The study revealed that MS patients may present dysbiosis. Treatment with interferon beta1a, teriflunomide or homeopathy implied several taxonomic changes. DMTs and homeopathy might influence the gut microbiota.

Cannabinoids and Multiple Sclerosis: A Critical Analysis of Therapeutic Potentials and Safety Concerns.

Multiple sclerosis (MS) is a complicated condition in which the immune system attacks myelinated axons in the central nervous system (CNS), destroying both myelin and axons to varying degrees. Several environmental, genetic, and epigenetic factors influence the risk of developing the disease and how well it responds to treatment. Cannabinoids have recently sparked renewed interest in their therapeutic applications, with growing evidence for their role in symptom control in MS. Cannabinoids exert their roles through the endogenous cannabinoid (ECB) system, with some reports shedding light on the molecular biology of this system and lending credence to some anecdotal medical claims. The double nature of cannabinoids, which cause both positive and negative effects, comes from their actions on the same receptor. Several mechanisms have been adopted to evade this effect. However, there are still numerous limitations to using cannabinoids to treat MS patients. In this review, we will explore and discuss the molecular effect of cannabinoids on the ECB system, the various factors that affect the response to cannabinoids in the body, including the role of gene polymorphism and its relation to dosage, assessing the positive over the adverse effects of cannabinoids in MS, and finally, exploring the possible functional mechanism of cannabinoids in MS and the current and future progress of cannabinoid therapeutics.

Repurposing drugs against Alzheimer's disease: can the anti-multiple sclerosis drug fingolimod (FTY720) effectively tackle inflammation processes in AD?

Therapeutic approaches providing effective medication for Alzheimer's disease (AD) patients after disease onset are urgently needed. Previous studies in AD mouse models and in humans suggested that physical exercise or changed lifestyle can delay AD-related synaptic and memory dysfunctions when treatment started in juvenile animals or in elderly humans before onset of disease symptoms. However, a pharmacological treatment that can reverse memory deficits in AD patients was thus far not identified. Importantly, AD disease-related dysfunctions have increasingly been associated with neuro-inflammatory mechanisms and searching for anti-inflammatory medication to treat AD seems promising. Like for other diseases, repurposing of FDA-approved drugs for treatment of AD is an ideally suited strategy to reduce the time to bring such medication into clinical practice. Of note, the sphingosine-1-phosphate analogue fingolimod (FTY720) was FDA-approved in 2010 for treatment of multiple sclerosis patients. It binds to the five different isoforms of Sphingosine-1-phosphate receptors (S1PRs) that are widely distributed across human organs. Interestingly, recent studies in five different mouse models of AD suggest that FTY720 treatment, even when starting after onset of AD symptoms, can reverse synaptic deficits and memory dysfunction in these AD mouse models. Furthermore, a very recent multi-omics study identified mutations in the sphingosine/ceramide pathway as a risk factor for sporadic AD, suggesting S1PRs as promising drug target in AD patients. Therefore, progressing with FDA-approved S1PR modulators into human clinical trials might pave the way for these potential disease modifying anti-AD drugs.

In-depth characterization of long-term humoral and cellular immune responses to COVID-19m-RNA vaccination in multiple sclerosis patients treated with teriflunomide or alemtuzumab

The impact of disease-modifying therapies on the efficacy to mount appropriate immune responses to COVID-19 vaccination in patients with multiple sclerosis (MS) is currently under investigation. To characterize long-term humoral and cellular immunity in mRNA-COVID-19 MS vaccinees treated with teriflunomide or alemtuzumab. We prospectively measured SARS-COV-2 IgG, memory B-cells specific for SARS-CoV-2 RBD, and memory T-cells secreting IFN-γ and/or IL-2, in MS patients vaccinated with BNT162b2-COVID-19 vaccine before, 1, 3 and 6 months after the second vaccine dose, and 3-6 months following vaccine booster. Patients were either untreated (N=31, 21 females), under treatment with teriflunomide (N=30, 23 females, median treatment duration 3.7 years, range 1.5-7.0 years), or under treatment with alemtuzumab (N=12, 9 females, median time from last dosing 15.9 months, range 1.8-28.7 months). None of the patients had clinical SARS-CoV-2 or immune evidence for prior infection. Spike IgG titers were similar between untreated, teriflunomide and alemtuzumab treated MS patients both at 1 month (median 1320.7, 25-75 IQR 850.9-3152.8vs. median 901.7, 25-75 IQR 618.5-1495.8, vs. median 1291.9, 25-75 IQR 590.8-2950.9, BAU/ml, respectively), at 3 months (median 1388.8, 25-75 1064.6-2347.6vs. median 1164.3 25-75 IQR 726.4-1399.6, vs. median 837.2, 25-75 IQR 739.4-1868.5 BAU/ml, respectively), and at 6 months (median 437.0, 25-75 206.1-1161.3vs. median 494.3, 25-75 IQR 214.6-716.5, vs. median 176.3, 25-75 IQR 72.3-328.8 BAU/ml, respectively) after the second vaccine dose. Specific SARS-CoV-2 memory B cells were detected in 41.9%, 40.0% and 41.7% of subjects at 1 month, in 32.3%, 43.3% and 25% at 3 months, and in 32.3%, 40.0%, 33.3% at 6 months following vaccination in untreated, teriflunomide treated and alemtuzumab treated MS patients, respectively. Specific SARS-CoV-2 memory T cells were found in 48.4%, 46.7% and 41.7 at 1 month, in 41.9%, 56.7% and 41.7% at 3 months, and in 38.7%, 50.0%, and 41.7% at 6 months, of untreated, teriflunomide-treated and alemtuzumab -treated MS patients, respectively. Administration of a third vaccine booster significantly increased both humoral and cellular responses in all patients. MS patients treated with teriflunomide or alemtuzumab achieved effective humoral and cellular immune responses up to 6 months following second COVID-19 vaccination. Immune responses were reinforced following the third vaccine booster.

Effectiveness of exercise interventions in animal models of multiple sclerosis.

Multiple sclerosis (MS) is associated with an impaired immune system that severely affects the spinal cord and brain, and which is marked by progressive inflammatory demyelination. Patients with MS may benefit from exercise training as a suggested course of treatment. The most commonly used animal models of studies on MS are experimental autoimmune/allergic encephalomyelitis (EAE) models. The present review intends to concisely discuss the interventions using EAE models to understand the effectiveness of exercise as treatment for MS patients and thereby provide clear perspective for future research and MS management. For the present literature review, relevant published articles on EAE animal models that reported the impacts of exercise on MS, were extracted from various databases. Existing literature support the concept that an exercise regimen can reduce the severity of some of the clinical manifestations of EAE, including neurological signs, motor function, pain, and cognitive deficits. Further results demonstrate the mechanisms of EAE suppression with information relating to the immune system, demyelination, regeneration, and exercise in EAE. The role for neurotrophic factors has also been investigated. Analyzing the existing reports, this literature review infers that EAE is a suitable animal model that can help researchers develop further understanding and treatments for MS. Besides, findings from previous animal studies supports the contention that exercise assists in ameliorating MS progression.

Real-world cost of care and site of care in patients with multiple sclerosis initiating infused disease-modifying therapies

AimEvaluate the real-world costs over two years and costs by site of care for ocrelizumab (OCR), natalizumab (NTZ), and alemtuzumab (ATZ) in patients with multiple sclerosis (MS).MethodsThis retrospective study used HealthCore Integrated Research Database and included continuously enrolled adults with MS initiating OCR, NTZ, and ATZ between April 2017 and July 2019 (i.e. patient identification period). Annual total cost of care (pharmacy and medical costs) was evaluated for the first- and second-year of follow-up, further stratified by site of care. Costs were measured using health plan allowed amount and adjusted to 2019 US dollars. Sensitivity analyses were conducted in patients who completed yearly dosing schedule according to Food and Drug Administration approved prescribing information.ResultsOverall, 1,058, 166, and 46 patients were included in OCR, NTZ, and ATZ cohorts, respectively. Mean (standard deviation [SD]) total cost of care during first- and second-year follow-up were $125,597 ($72,274) and $109,618 ($75,085) for OCR, $117,033 ($57,102) and $106,626 ($54,872) for NTZ, and $179,809 ($97,530) and $108,636 ($77,973) for ATZ. Infusible drug cost was the main driver in all three cohorts accounting for >78% of the total costs. Annual total cost of care increased substantially after patients started/switched to infusible DMTs. Across site of care, hospital outpatient infusion was common (OCR 58%, NTZ 37%, ATZ 49%) and expensive followed by physician office infusion (OCR 28%, NTZ 40%, ATZ 16%); home infusion was the least common (<10%) and least expensive.LimitationsThe results were limited to commercially insured patients (specifically those with Anthem-affiliated health plans).ConclusionsReal-world costs increased after patients started/switched to infusible DMTs. Drug cost is the main driver for the total costs, which varied substantially by site of care. Controlling drug cost markups and using home setting for infusion can reduce costs in the treatment of MS patients.

Thyroid autoimmunity following alemtuzumab treatment in multiple sclerosis patients: a prospective study.

Autoimmune thyroid disease (AITD) is the most common adverse effect in alemtuzumab (ALZ)treated relapsing-remitting (RR) multiple sclerosis (MS) patients. The objective of this prospective study was to analyze the occurrence, timing of onset, clinical course, and laboratory characteristics of AITD post-ALZ. We evaluated 35 RRMS patients treated with ALZ at a single academic MS center; clinical and laboratory data were collected before ALZ initiation and thereafter quarterly on follow-up with a median of 43.5months. Seventeen out of 31 patients (54.8%) with no prior history of thyroid dysfunction developed AITD with a mean onset of 19.4months ± 10.2 (SD) after the first ALZ cycle; Graves' disease (GD) (n = 9); hypothyroidism with positive stimulating thyrotropin receptor antibodies (TRAb) (n = 1); Hashimoto thyroiditis (HT) (n = 6); HT with hypothyroidism (n = 1). Interestingly, seven of nine (77.7%) GD patients showed a fluctuating course. Three out of four patients with preexisting thyroid disease remained stable, whereas one with prior HT and hypothyroidism developed fluctuating GD. All patients with GD commenced antithyroid drugs (ATDs); five continued on "block and replace" treatment; one required radioactive iodine, and one total thyroidectomy. Our analysis showed earlier onset of ALZ-induced AITD in comparison to most other ALZ cohorts; overall, these patients required complex therapeutic approaches of the AITD. We observed a higher rate of fluctuating GD, with earlier onset and lower remission rate than previously reported, which in the majority of patients required prolonged "block and replace" therapy in the minimum dose of each therapeutic agent or more definitive interventions.

High-dose chemotherapy with autologous hematopoietic stem cell transplantation in multiple sclerosis: intermediate results of 3 years research

Relevance. Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease of the central nervous system with progressive course. High-dose chemotherapy (HDCT) with autologous haematopoietic stem cell transplantation (AHSCT) is a promising course of treatment-refractory MS. The study aimed to assess the effi cacy and safety of treating MS patients with HDCT + AHSCT.Material and methods. Were studied 10 people (5 women and 5 men) with relapsing-remitting (30%), secondary progressive (60%) and primary progressive MS (10%). Patients underwent AHSCT using cyclophosphamide + rituximab chemotherapeutic regimen.Results. In 90% of cases, at least a stabilizing eff ect is shown after the procedure. Only 10% was showed signs of demyelinating activity on MRI of the spinal cord 2 years after HDCT + AHSCT. All patients had a response to therapy according to median Expanded Disability Status Scores (EDSS). We found a positive dynamics of the average EDSS score: before treatment — 5.9 points, 6 months and 1 year after treatment — 5.1 points. There was shown a positive eff ect on dynamics of neurological status, quality of life and emotional state of patients. No treatment-related mortality and uncontrolled complications were revealed.Conclusion. Timely AHSCT contributes to minimizing the level of disability and signifi cantly improves the quality of life of patients.

Efficacy and safety of divozilimab during 24-week treatment of multiple sclerosis patients in randomized double-blind placebo-controlled clinical trial BCD-132-2

To find the optimal therapeutic dose of the anti-B cell mAb divozilimab (DIV) based on the efficacy and safety data of intravenous administration at a dose of 125 mg or 500 mg in patients with relapsing remitting multiple sclerosis (RRMS) compared to placebo (PBO) and teriflunomide (TRF). To study the efficacy and safety of DIV within 24 weeks of treatment. A multicenter, randomized, double-blind and double-masked, placebo-controlled phase 2 clinical trial (CT) BCD-132-2 involved 271 adult patients with RRMS from 25 centres In Russia. Patients were randomly assigned (2:2:2:1) into 4 groups: TRF, DIV 125 mg, DIV 500 mg and PBO. After screening patients entered to the main period, which consisted of one cycle of therapy for 24 weeks. The primary endpoint was the total number of gadolinium-enhancing T1 lesions (Gd+) observed on brain MRI scans after 24 weeks (per scan - involves estimating the mean value of the score from all the MRI assessments performed for each participant in the study). 263 patients completed 24 weeks of treatment. Most of the patients in the DIV groups had no lesions on T1-weighted MRI after 24 weeks of treatment (94.44% on 125 mg and 93.06% on 500 mg). In the TRF and PBO groups the values were significantly lower: 68.06% and 56.36% respectively (both p<0.05). The proportions of relapse-free patients in the DIV groups were 93.06% and 97.22% (125 mg and 500 mg, respectively). As expected, DIV reduced the CD19+ B-cells. However, the repopulation rate of CD19+ B-cells in the 125 mg group was more pronounced (mainly due to the recovering pool of CD27-naive B-cells) compared to the 500 mg group. DIV showed a favorable safety profile at both doses. Thus, the assessment of 24 weeks treatment demonstrated that DIV is a highly effective, safe and convenient option for the treatment of RRMS patients, both naive and previously treated with disease modifying therapy. A dose of 500 mg is recommended for further efficacy and safety evaluation during phase 3 CT.

Effect of MS14® on physical activity of multiple sclerosis patients: A randomized triple-blind placebo-controlled clinical trial.

Multiple Sclerosis (MS) is a neurological disorder with an increasing global prevalence and severe complications. MS14® is a Persian-medicine-derived natural product with herbal and marine origin which has shown beneficial effects in the management of MS complications. In this study, its effect on physical activity of MS patients was investigated. A triple-blind placebo-controlled clinical trial was conducted. Participants used either MS14 capsule or placebo 3 times a day for 3 weeks. At baseline and end of the study, physical activity indices were assessed using international physical activity questionnaire (IPAQ). Secondary outcome measures were Fatigue Severity Scale (FSS), timed 10m walk, Ashworth scale, and Timed Get up and Go. A total number of 80 MS patients completed the study. At the end of study, improvement of general physical activity (p-value=0.047) and Timed 10m walk index (p-value=0.003) in the MS14 group was significant when compared to placebo. No serious adverse effects were observed in this study. Considering the improvement of some physical activity indices, MS14® is seems to be a safe natural product which could be considered as a supplementary treatment in MS patients. Future larger trials are suggested to further evaluate its efficacy.

Placental Extract and Exosomes Derived from Pregnant Mice Attenuate the Development of Experimental Autoimmune Encephalomyelitis.

Placental extract (PE) and exosomes from pregnant mice appear to have immunomodulatory and neuroprotective effects. In this study, we assessed the potential therapeutic effects of PE and exosomes obtained from pregnant mice in experimental autoimmune encephalomyelitis (EAE) mouse models. C57BL/6 mice, 8 to 12 weeks of age, were prepared and administered PE, exosomes, and glatiramer acetate (GA), as an FDA-approved treatment for multiple sclerosis (MS), after EAE induction. Thereafter, the therapeutic effects of treatment were evaluated by measuring the clinical courses of the mice as well as determining the number of regulatory T (Treg) cells using flow cytometry, cytokine levels, and microRNA-326 expression via real-time PCR. GA, PE, and exosomes reduced clinical severity, the extent of spinal cord demyelination, and the infiltration of inflammatory cells into the spinal cord. The frequency of CD4+CD25+FoxP3+ Treg cells increased after treatment of EAE mice with GA, PE, and exosomes. The mRNA expression of the inflammatory cytokines (interleukin-17 and interferon-gamma), as well as miR-326 expression, decreased significantly in the EAE mice after treatment with GA and exosomes. PE and exosomes from pregnant mice are involved in the modulation of Treg/Th17 balance and provide a therapeutic approach for MS. Further clinical studies will hopefully confirm the safety and efficacy of such treatments in MS patients.

Demographic and disease-related factors impact on cerebrospinal fluid neurofilament light chain levels in multiple sclerosis.

Neurofilament light (NfL) levels reflect inflammatory disease activity in multiple sclerosis (MS), but it is less clear if NfL also can serve as a biomarker for MS progression in treated patients without relapses and focal lesion accrual. In addition, it has not been well established if clinically effective treatment re-establishes an age and sex pattern for cerebrospinal fluid NfL (cNfL) as seen in controls, and to what degree levels are affected by disability level and magnetic resonance imaging (MRI) atrophy metrics. We included subjects for whom cNfL levels had been determined as per clinical routine or in clinical research, classified as healthy controls (HCs, n = 89), MS-free disease controls (DCs, n = 251), untreated MS patients (uMS; n = 296), relapse-free treated MS patients (tMS; n = 78), and ProTEct-MS clinical trial participants (pMS; n = 41). Using linear regression, we found a positive association between cNfL and age, as well as lower concentrations among women, in all groups, except for uMS patients. In contrast, disability level in the entire MS cohort, or T1 and T2 lesion volumes, brain parenchymal fraction, thalamic fraction, and cortical thickness in the pMS trial cohort, did not correlate with cNfL concentrations. Furthermore, the cNfL levels in tMS and pMS groups did not differ. In participants with MS lacking signs of inflammatory disease activity, disease modulatory therapy reinstates an age and sex cNfL pattern similar to that of control subjects. No significant association was found between cNfL levels and clinical worsening, disability level, or MRI metrics.

Peripheral myeloid-derived suppressor cells are good biomarkers of the efficacy of fingolimod in multiple sclerosis

BackgroundThe increasing number of treatments that are now available to manage patients with multiple sclerosis (MS) highlights the need to develop biomarkers that can be used within the framework of individualized medicine. Fingolimod is a disease-modifying treatment that belongs to the sphingosine-1-phosphate receptor modulators. In addition to inhibiting T cell egress from lymph nodes, fingolimod promotes the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs), whose monocytic subset (M-MDSCs) can be used as a biomarker of disease severity, as well as the degree of demyelination and extent of axonal damage in the experimental autoimmune encephalomyelitis (EAE) model of MS. In the present study, we have assessed whether the abundance of circulating M-MDSCs may represent a useful biomarker of fingolimod efficacy in EAE and in the clinical context of MS patients.MethodsTreatment with vehicle or fingolimod was orally administered to EAE mice for 14 days in an individualized manner, starting the day when each mouse began to develop clinical signs. Peripheral blood from EAE mice was collected previous to treatment and human peripheral blood mononuclear cells (PBMCs) were collected from fingolimod to treat MS patients’ peripheral blood. In both cases, M-MDSCs abundance was analyzed by flow cytometry and its relationship with the future clinical affectation of each individual animal or patient was assessed.ResultsFingolimod-treated animals presented a milder EAE course with less demyelination and axonal damage, although a few animals did not respond well to treatment and they invariably had fewer M-MDSCs prior to initiating the treatment. Remarkably, M-MDSC abundance was also found to be an important and specific parameter to distinguish EAE mice prone to better fingolimod efficacy. Finally, in a translational effort, M-MDSCs were quantified in MS patients at baseline and correlated with different clinical parameters after 12 months of fingolimod treatment. M-MDSCs at baseline were highly representative of a good therapeutic response to fingolimod, i.e., patients who met at least two of the criteria used to define non-evidence of disease activity-3 (NEDA-3) 12 months after treatment.ConclusionOur data indicate that M-MDSCs might be a useful predictive biomarker of the response of MS patients to fingolimod.

Involvement of NINJ2 Protein in Inflammation and Blood-Brain Barrier Transmigration of Monocytes in Multiple Sclerosis.

Multiple sclerosis (MS) is an inflammatory neurodegenerative disorder of the central nervous system (CNS). The migration of immune cells into the CNS is essential for its development, and plasma membrane molecules play an important role in triggering and maintaining the inflammation. We previously identified ninjurin2, a plasma membrane protein encoded by NINJ2 gene, as involved in the occurrence of relapse under Interferon-β treatment in MS patients. The aim of the present study was to investigate the involvement of NINJ2 in inflammatory conditions and in the migration of monocytes through the blood-brain barrier (BBB). We observed that NINJ2 is downregulated in monocytes and in THP-1 cells after stimulation with the pro-inflammatory cytokine LPS, while in hCMEC/D3 cells, which represent a surrogate of the BBB, LPS stimulation increases its expression. We set up a transmigration assay using an hCMEC/D3 transwell-based model, finding a higher transmigration rate of monocytes from MS subjects compared to healthy controls (HCs) in the case of an activated hCMEC/D3 monolayer. Moreover, a positive correlation between NINJ2 expression in monocytes and monocyte migration rate was observed. Overall, our results suggest that ninjurin2 could be involved in the transmigration of immune cells into the CNS in pro-inflammatory conditions. Further experiments are needed to elucidate the exact molecular mechanisms.

A Randomized Study of b3 Agonists versus Anticholinergics Administration in Patients with Multiple Sclerosis and Lower Urinary Tract Dysfunction

Abstract Introduction and Objective: Multiple sclerosis (MS) is the most frequent autoimmune demyelinating disease of the central nervous system usually affecting lower urinary tract function. In the present study, we compare the efficacy and safety of either a b3 agonist (mirabegron) or anticholinergics in treating MS patients with lower urinary tract dysfunction (LUTD) and assess the LUTD symptom improvement. Evidence Acquisition: A multi-center, single-blinded, comparative study was designed, including MS patients with LUTD. Patients were administered either mirabegron or anticholinergics in combination with standard MS treatment. All cases underwent clinical examination and completed urination diaries and validated questionnaires (Neurogenic Bladder Symptom Score and MS International Quality of Life). Furthermore, urine test analysis, as well as abdominal ultrasound imaging examination, was performed. Data on several clinical and imaging parameters were collected between the two groups at the first visit and after 3 months of treatment. Evidence Synthesis: A total of 61 patients with LUTD participated in the survey. An improvement regarding LUTD was noted in all patients. However, no statistical difference was recorded between the mirabegron and the anticholinergic group. Medical treatment was well tolerated, and no patient discontinued medication due to side effects. Conclusions: Both mirabegron and anticholinergic therapy can be administered for LUTD in MS patients. In terms of drug efficacy, no statistical difference was noted between the two cohorts at 3 months.

Evidence for novel cell defense mechanisms sustained by dimethyl fumarate in multiple sclerosis patients: the HuR/SOD2 cascade

BackgroundDimethyl fumarate (DMF) is an effective treatment for relapsing remitting Multiple Sclerosis (MS) and its mechanisms of action encompass immunomodulatory and cytoprotective effects. Despite DMF is known to activate the Nrf2 pathway, Nrf2-independent mechanisms have been also reported and new insights on the underlying molecular mechanisms are still emerging including transcriptional and post-transcriptional events.At this regard, we focused on a small family of RNA-binding proteins, the ELAV-like proteins, that play a pivotal role in post-transcriptional mechanisms and are involved in the pathogenesis of several psychiatric and neurologic disorders. HuR, the ubiquitously expressed member of the family, is implicated in many cellular functions, including survival, inflammation and proper functioning of the immune system. We previously documented the potential entanglement of HuR in MS pathogenesis. In the present work, we explored HuR protein levels in peripheral blood mononuclear cells (PBMCs) from MS patients before and after DMF treatment compared to healthy controls (HC). Considering that HuR may act on various targets, playing a protective role against oxidative stress, our main goals were to evaluate whether manganese-dependent superoxide dismutase transcript (SOD2) could represent a new molecular target of HuR and to study the potential influence of DMF treatment on this interaction. MethodsPBMCs from 20 patients with MS and 20 frequency-matched HC by sex and age were used to evaluate HuR, MnSOD (the protein coded by SOD2) and Nrf2 protein content by Western blot, before and after 12 months of DMF treatment.Immunoprecipitation experiments coupled with RNA extraction in PBMCs were performed to explore whether SOD2 mRNA could be physically bound by HuR and whether the expression of MnSOD protein could be affected by 12 months of DMF treatment. ResultsIn PBMCs, HuR protein binds SOD2 transcript in HC and in MS patients naïve to disease modifying treatment. The expression of MnSOD protein is positively affected by 12 months of DMF treatment. PBMCs from MS patients have a lower HuR and MnSOD protein content compared to matched HC (HuR: p<0.01, MnSOD: p<0.01). Of interest, 12 months of DMF treatment in MS patients restores the amount of both HuR protein and MnSOD enzyme to the levels observed in HC. We also confirmed that Nrf2 is an HuR target, and we report that its levels are significantly increased in MS patients naïve to disease modifying treatment and remain elevated following DMF administration. ConclusionSOD2 transcript is a new target of HuR protein. DMF induces an increased expression of HuR protein, which ultimately interacts more strongly with SOD2 transcript promoting the expression of this antioxidant protein. The activation of this molecular cascade can constitute an additional tool that the cells can exploit to counteract the oxidative stress associated with MS development, and can account for the multifaceted molecular mechanisms underlying DMF efficacy in MS.

In-silico studies of glutathione peroxidase4 activators as candidate for multiple sclerosis management

Multiple sclerosis (MS) is an autoimmune and inflammatory demyelinating disease of the central nervous system (CNS) that affects approximately 2.8 million people worldwide. Although numerous studies have been conducted to investigate novel therapeutic targets and lead compounds, few drug choices are available to treat MS patients. The etiology of this disease is still poorly understood. However, oxidative stress is proposed as one of the underlining pathology. The neuronal antioxidant enzyme glutathione peroxidase 4 (GPx4) is responsible for scaffolding toxic peroxide phospholipids and reducing neuronal death within the CNS. Therefore, screening for lead compounds able to activate this essential enzyme might protect neuronal cells from damage and slow the disease progression. This study aimed to identify potential activators of GPx4, an essential inhibitor to ferroptosis, as a novel neuroprotective strategy in MS treatment. For understanding the binding of the four selected compounds to GPX4 protein showing the mechanism of the interaction, molecular docking analysis and molecular dynamic (MD) simulation were used. The study was carried out through various computational methods using Autodock Vina for docking of the protein and ligand and Desmond for MD simulation. The four tested compounds used to activate GPx4 are as follows: ferrostatin, lapatinib, liproxstatin-1, and PKUMDL-LDL-102. Results showed that the lapatinib had greater log P value (6.17) which indicates higher permeability through blood brain barrio (BBB) to exirt the proposed neurological effect. In the molecular docking analysis, the best docking scores was displayed by Lapatinib (−7.6 kcal/mol). Ferrostatin, Lapatinib, and Liproxstatin-1 almost bind in the similar sites of the target protein, while PKUMDL-LC-102 binds at a different site. Furthermore, MD simulation study showed a stable system for lapatinib and liproxstatin-1 as confirmed by RMSD and RMSF values during 100 ns trajectories. Additionally, the most negative ΔG Bind score (the lowest) which considered the best was exhibited by lapatinib (−47.52 Kcal/mol). The test compounds were further inspected for their intersction with GPx4 in terms of hydrophobic, hydrogen and other bonding types beside the stability of these bonds by observing the protein–ligand contact within 100 ns trajectories. Interestingly, the receptor–ligand complex showed deep continuous bands for Lapatinib with Lys127 and Gly128. In conclusion, among the four studied compounds Lapatinib could be a promising scaffold for developing effective leads capable of activating GPx4 and assist in the treatment of MS.

Immune response in ofatumumab treated multiple sclerosis patients after SARS-CoV-2 vaccination.

ObjectiveThe pandemic induced by SARS-CoV-2 has huge implications for patients with immunosuppression that is caused by disorders or specific treatments. Especially approaches targeting B cells via anti-CD20 therapy are associated with impaired humoral immune response but sustained cellular immunity. Ofatumumab is a human anti-CD20 directed antibody applied in low dosages subcutaneously, recently licensed for Multiple Sclerosis (MS). Effects of early ofatumumab treatment on alterations of immune cell composition and immune response towards SARS-CoV-2 are incompletely understood.MethodsWe here investigated immune cell alterations in early ofatumumab (Ofa) treated patients and effects on humoral (titer, neutralization capacity against wild type, Delta and Omicron) and cellular immune responses in Ofa treated MS patients following a third vaccination against SARS-CoV-2 compared to healthy controls.ResultsWe show that a mean treatment duration of three months in the Ofa group led to near complete B cell depletion in line with altered composition of certain CD4+ T cell subpopulations such as enhanced frequencies of naive and a decrease of non-suppressive regulatory T cells (Tregs). Titer and neutralization capacity against SARS-CoV-2 variants was impaired while cellular immune response was sustained, characterized by a strong T helper 1 profile (Th1).InterpretationIn summary, low dosage ofatumumab treatment elicits sustained depletion of B cells in line with alterations of immune cells, mainly Tregs. This is associated with impaired humoral immune response towards SARS-CoV-2 vaccination but preserved, Th1 driven cellular immunity adding crucial information regarding early effects of low dosage anti-CD20 therapy on humoral and cellular immunity.

Recent advances in the management of multiple sclerosis

Every 5 minutes, someone somewhere in the world is diagnosed with an inflammatory, demyelinating, neurodegenerative disorder known as multiple sclerosis (MS). MS was historically known as "La sclèrose en plaques" which involves the central nervous system (the brain and the spinal cord). It is always considered to be a disease of adulthood but nowadays pediatric MS is also gaining popularity. It is the most common non-traumatic chronic disabling disease of adults. MS is said to have etiology of multifactorial origin. of the myelin structure thereby producing a dysregulated immune system. MS is an ongoing disease with episodes of relapses and remissions whereas the basic pathophysiology remains increasing over time. Since the pathophysiology of MS is very complex, it makes the pharmacotherapy part bit difficult. MS therapy is disease subtype-specific. The drugs which were previously approved for MS lacks efficacy and sometimes possess serious adverse effects and thereby creating lacunae in treating MS patients include the need for a drug with better efficacy especially it should be evidence-based. There are several new drugs approved for the treatment of MS in recent times especially over the past 5-8 years and 'n' number of new molecules being tried in clinical trials. In this review, an effort was made to discuss MS epidemiology, potential etiological factors, pathophysiology, clinical aspects of MS before moving on to pharmacotherapy and other non-pharmacological management of MS. A special elaborative note on recently approved drugs and drugs under pipeline has been discussed in this review.

“I would stress less if I knew that the nurse is taking care of it”: Multiple Sclerosis inpatients’ and health care professionals’ views of their nursing-experience and nursing consultation in rehabilitation—a qualitative study

BackgroundNurses play a crucial role in the multidisciplinary team in the rehabilitation of multiple sclerosis (MS) patients. However, little is known about patients' and health care professionals’ (HCP) experiences (physicians, therapists) with nurses in rehabilitation. The aim of this qualitative study is (i) to describe the rehabilitation nursing care from the perspective of MS patients and HCPs and their view of a nursing consultations (ii) to elaborate similarities and differences of patients’ and HCP’s views.MethodsWe used a qualitative approach and selected the participants purposively. We conducted semi-structured individual MS patient (n = 15) and two focus groups interviews with HCPs (n = 8) in an inpatient rehabilitation clinic in Switzerland. We analysed the data using a structuring content analysis approach. First, we analysed patients’ and HCPs’ perspectives separately. Afterwards we elaborated similarities and differences descriptively.ResultsMain categories of patients’ perspectives were “need for nursing care” and “relationship between nurses and MS patient”. MS patients have mentioned the following points according to a nursing consultation: (i) nurses as advocates, (ii) involvement of relatives (iii) peer groups (iv) contact person.“Nurses in their scope of practice”, “nurses as a part of the multidisciplinary team” and “the specifications in the treatment of MS patients” were main categories of HCPs’ perspective.MS patients and HCPs demonstrated similarly the importance to have a nurse as a contact person in the multidisciplinary team and the need to integrate a nurse-led peer group in a nursing consultation. While HCPs prefer that relative always be included in nursing consultations, patients provided reasons when inclusion was not desirable.ConclusionThe results indicate that continuity in the nursing care for MS patients could contribute to a trusting nurse-patient relationship. This facilitates nurses to create a deeper understanding of MS patients and their needs in daily rehabilitation. The need for MS patients to share their concerns and receive scientifically proven knowledge from peers could addressed with a nurse-led peer group.