Drugs For Multiple Sclerosis Research Articles

Cladribine Treatment for MS Preserves the Differentiative Capacity of Subsequently Generated Monocytes, Whereas Its Administration In Vitro Acutely Influences Monocyte Differentiation but Not Microglial Activation.

Cladribine (2-chlorodeoxyadenosine, 2CdA) is one of the most effective disease-modifying drugs for multiple sclerosis (MS). Cladribine is a synthetic purine nucleoside analog that induces cell death of lymphocytes and oral cladribine treatment leads to a long-lasting disease stabilization, potentially attributable to immune reconstitution. In addition to its effects on lymphocytes, cladribine has been shown to have immunomodulatory effects on innate immune cells, including dendritic cells and monocytes, which could also contribute to its therapeutic efficacy. However, whether cladribine can modulate human macrophage/microglial activation or monocyte differentiation is currently unknown. The aim of this study was to determine the immunomodulatory effects of cladribine upon monocytes, monocyte-derived macrophages (MDMs) and microglia. We analyzed the phenotype and differentiation of monocytes from MS patients receiving their first course of oral cladribine both before and three weeks after the start of treatment. Flow cytometric analysis of monocytes from MS patients undergoing cladribine treatment revealed that the number and composition of CD14/CD16 monocyte subsets remained unchanged after treatment. Furthermore, after differentiation with M-CSF, such MDMs from treated MS patients showed no difference in gene expression of the inflammatory markers compared to baseline. We further investigated the direct effects of cladribine in vitro using human adult primary MDMs and microglia. GM-CSF-derived MDMs were more sensitive to cell death than M-CSF-derived MDMs. In addition, MDMs treated with cladribine showed increased expression of costimulatory molecules CD80 and CD40, as well as expression of anti-inflammatory, pro-trophic genes IL10 and MERTK, depending on the differentiation condition. Cladribine treatment in vitro did not modulate the expression of activation markers in human microglia. Our study shows that cladribine treatment in vitro affects the differentiation of monocytes into macrophages by modulating the expression of activation markers, which might occur similarly in tissue after their infiltration in the CNS during MS.

New drugs for multiple sclerosis: new treatment algorithms.

To discuss recent changes in the multiple sclerosis (MS) treatment algorithm and to present therapies currently in MS clinical trials. High efficacy disease modifying therapies are optimally beneficial when used in the early, inflammatory phase of MS. Bruton's tyrosine kinase has emerged as an important therapeutic target for both relapsing and progressive forms of MS. Multiple therapies targeting remyelination failed to provide conclusive evidence of broad therapeutic benefit; however, more targeted approaches offer hope that myelin repair might be achieved resulting in specific clinical improvements. Strategies targeting chronic Epstein-Barr virus infection and dysbiosis of the gut microbiome are the first to link microbial risk factors for MS and therapeutic interventions. A striking number of diverse treatments under investigation bodes well for development of better and more effective therapies in MS.

Therapeutic Strategy for Multiple Sclerosis Resistant to Standard Treatment: Refractory MS

In Japan, disease-modifying drugs for multiple sclerosis have amounted to eight, to date, providing us with various therapeutic choices. However, we still encounter difficult cases resistant to these drugs. This review summarizes the diagnostic and therapeutic strategies for refractory multiple sclerosis by presenting suggestive cases.

To each their own: Disparate abilities of Nrf2 activators to protect against various electrophilic and oxidative insults

Electrophilic and oxidative stress contribute to major diseases such as cancer and diabetes. Small‐molecule activators of the Nrf2 cytoprotective pathway show significant promise for prevention and amelioration of chronic diseases by combating these stressors through upregulation of detoxification and antioxidant enzymes. An understudied area is whether distinct small molecular Nrf2 activators can protect cells from all electrophilic and oxidative stressors, or whether certain molecules are better suited to protect against a particular type of stress.In this study, human keratinocyte HaCaT cells were preincubated for 24 h with one of four Nrf2 activators before different stressors were added for an additional 24 h and cell death was assessed. Three electrophiles were tested: sulforaphane (SFN), the subject of over 70 clinical trials, the multiple sclerosis drug Tecfidera (dimethyl fumarate, DMF), and bardoxolone methyl (BARD), in clinical trials for treatment of chronic kidney diseases and other conditions including COVID‐19. SFN, DMF, and BARD target C151 of the Keap1 protein, a negative regulator of Nrf2. Also tested was KI696, an inhibitor of the Keap1‐Nrf2 interaction. Three chemically distinct stressors—hydrogen peroxide, menadione (a quinone that rapidly generates ROS through one‐electron redox cycling), or chlorambucil (an alkylating chemotherapy agent)—were tested. Stressors were added to the cells at their LC50 concentration after pretreatment with a range of cytoprotective compound concentrations. Unexpectedly, SFN pretreatment showed little to no rescue for all stressors. However, DMF rescued the viability of cells stressed with hydrogen peroxide, menadione, and chlorambucil. BARD showed no rescue for hydrogen peroxide‐treated cells. KI696 improved the cell’s ability to survive chlorambucil. The ability of a given Nrf2 activator (or lack thereof) to protect against a given stressor points to a need to better understand the cytoprotective environment (specific enzymes upregulated, glutathione levels, etc.) that best protect against specific stressors.

Ethanol Inhibits the Metabolism of the Multiple Sclerosis Drug Dimethyl Fumarate to its Active Metabolite and Decreases Brain Exposure

HypothesisDimethyl fumarate is primarily metabolized to the monomethyl fumarate active metabolite by carboxylesterase 1 and is subject to inhibition by ethanol.MethodsA pharmacokinetic study was conducted to determine the effect of ethanol on dimethyl fumarate disposition in ES1e mice, a strain that is a better model of human carboxylesterase drug metabolism than typical rodent strains. The disposition of dimethyl fumarate and monomethyl fumarate, the purported active metabolite, was determined in a control group (n=30) receiving 100 mg/kg of dimethyl fumarate via oral gavage versus an ethanol group (n=30) receiving 3 g/kg of ethanol by oral gavage 10 minutes prior to dosing with 100 mg/kg of dimethyl fumarate. The area‐under‐the‐curve (AUC) and maximum plasma concentration (Cmax) were determined in plasma and brain tissue from the drug and metabolite concentrations determined by LC‐ mass spectrometry. The AUC and Cmax were compared between the control and ethanol group.ResultsLike dimethyl fumarate disposition in humans, only monomethyl fumarate concentrations were quantifiable in the plasma in the control group. In the ethanol group, dimethyl fumarate was quantifiable in both the plasma and brain tissue. Control Ethanol DMF MMF DMF MMF AUCPLASMA(ng/ml*min) ND 6072 4629 3948 CmaxPLASMA(ng/ml) ND 210 64 65 AUCBRAIN (ng/ml*min) ND 980 20 787 DMF=dimethyl fumarate; MMF=monomethyl fumarate (active metabolite); ND=not detectedThe terminal elimination half‐life of monomethyl fumarate in the control and ethanol groups was 14.4 and 44.3 minutes, respectively.ConclusionsEthanol inhibits the hydrolysis of dimethyl fumarate to active monomethyl fumarate by carboxylesterase 1 and has a drastic effect on the disposition of dimethyl fumarate and monomethyl fumarate. The therapeutic effect of dimethyl fumarate is likely to be significantly altered by the consumption of ethanol or other drug that inhibits carboxylesterase 1 potentially altering the beneficial effect of chronic dimethyl fumarate therapy on Relapsing‐Remitting Multiple Sclerosis.

Prescription trends of disease-modifying treatments for multiple sclerosis in Iran over the past 30 years

BackgroundIran, as a middle income country, is one of the places with high and rising prevalence of multiple sclerosis (MS). Regarding the substantial economic burden, reviewing the trend in prescribed disease modifying treatments (DMTs) could be of help. Here we studied the DMT information of nearly 14000 MS cases and its trends change for 30 years to improve health services to patients. MethodsThe population base of this descriptive-analytical (cross-sectional) study consisted of all MS patients in the nationwide MS registry of Iran (NMSRI), up to August 1, 2021. Registrars from 15 provinces, 24 cities, 13 hospitals,8 MS associations, 16 private offices, and 7 clinics had entered the data. ResultsOverall, 14316 cases were enrolled. The majority (76.1%) were female. The youngest and eldest patients were 5 and 78 years old, respectively. Diagnosis delay was under one year in most cases (median: 0, IQR: 0 – 1). Most (61.4%) had RRMS. Generally, platform injectables (IFN beta, glatiramer acetate) were the most used DMTs until 2010. It seems that introduction of newer agents (antiCD20s and oral DMTs) resulted in a decrease in the use of former drugs since around 2015. Some unusual practices are prominent such as using not approved DMTs for PPMS over the years, or administering high efficacy drugs like natalizumab for CIS. The results indicate the remaining popularity of first line injectable DMTs in female and pediatric patients. DiscussionMean age (SD) at onset in our study (29 ± 8.8) is near the statistics in Asia and Oceania (28 ± 0.7). Concerns about COVID-19 had a noticeable impact on administering high efficacy drugs like rituximab and fingolimod. However, in male patients this approach has not been the case. It may be related to more aggressive disease course in this group. The other possible explanation could be planning for pregnancy in female cases. The popularity of platform injectable drugs in pediatric MS may be related to its favorable safety profile over the years. Another point in this group, is the superiority of rituximab over other highly efficient medications.

Multiple Sclerosis and Microbiome.

The composition of microbiota and the gut-brain axis is increasingly considered a factor in the development of various pathological conditions. The etiology of multiple sclerosis (MS), a chronic autoimmune disease affecting the CNS, is complex and interactions within the gut-brain axis may be relevant in the development and the course of MS. In this article, we focus on the relationship between gut microbiota and the pathophysiology of MS. We review the contribution of germ-free mouse studies to our understanding of MS pathology and its implications for treatment strategies to modulate the microbiome in MS. This summary highlights the need for a better understanding of the role of the microbiota in patients’ responses to disease-modifying drugs in MS and disease activity overall.

The Shared Mechanism and Candidate Drugs of Multiple Sclerosis and Sjögren's Syndrome Analyzed by Bioinformatics Based on GWAS and Transcriptome Data.

ObjectiveThis study aimed to explore the shared mechanism and candidate drugs of multiple sclerosis (MS) and Sjögren’s syndrome (SS).MethodsMS- and SS-related susceptibility genes and differentially expressed genes (DEGs) were identified by bioinformatics analysis based on genome-wide association studies (GWAS) and transcriptome data from GWAS catalog and Gene Expression Omnibus (GEO) database. Pathway enrichment, Gene Ontology (GO) analysis, and protein–protein interaction analysis for susceptibility genes and DEGs were performed. The drugs targeting common pathways/genes were obtained through Comparative Toxicogenomics Database (CTD), DrugBank database, and Drug–Gene Interaction (DGI) Database. The target genes of approved/investigational drugs for MS and SS were obtained through DrugBank and compared with the common susceptibility genes.ResultsBased on GWAS data, we found 14 hub common susceptibility genes (HLA-DRB1, HLA-DRA, STAT3, JAK1, HLA-B, HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB5, HLA-DPA1, HLA-DPB1, TYK2, IL2RA, and MAPK1), with 8 drugs targeting two or more than two genes, and 28 common susceptibility pathways, with 15 drugs targeting three or more than three pathways. Based on transcriptome data, we found 3 hub common DEGs (STAT1, GATA3, PIK3CA) with 3 drugs and 10 common risk pathways with 435 drugs. “JAK-STAT signaling pathway” was included in common susceptibility pathways and common risk pathways at the same time. There were 133 overlaps including JAK-STAT inhibitors between agents from GWAS and transcriptome data. Besides, we found that IL2RA and HLA-DRB1, identified as hub common susceptibility genes, were the targets of daclizumab and glatiramer that were used for MS, indicating that daclizumab and glatiramer may be therapeutic for SS.ConclusionWe observed the shared mechanism of MS and SS, in which JAK-STAT signaling pathway played a vital role, which may be the genetic and molecular bases of comorbidity of MS with SS. Moreover, JAK-STAT inhibitors were potential therapies for MS and SS, especially for their comorbidity.

Azathioprine in the Treatment of Multiple Sclerosis: A Single Center Experience from Nepal

Introduction: Azathioprine is used as an off - label drug for the treatment of multiple sclerosis. It is one of the oldest and most widely used immunosuppressants that targets T and B lymphocytes and thus reduces the relapse and slows down the disease progression with the almost same efficacy as the other disease modifying drugs for multiple sclerosis. But due to its side effect profile it isn’t used as a standard choice of treatment. However, its cost effectiveness and oral route of administration makes it a drug of choice in a low socioeconomic country. This paper highlights the diagnosis of Multiple Sclerosis based on McDonald’s criteria and treatment with Azathioprine.
 Methods: It is a retrospective analysis was conducted among 32 patients suffering from Multiple sclerosis and treated with Azathioprine at tertiary neurological institue.Patients outcome was also documented reaching them individually.
 Results: Among 19 patients all were female with highest prevalence among age group of 30-39 years old. 60% had relapsing remitting Multiple sclerosis, 45% of the patients present with ocular symptoms followed by 31% patients with lower limb weakness and spasticity. 30% did not develop any relapse, 15.8% patients developed one episode of relapse, 21.1% patients relapsed twice while 21.1% patients relapsed thrice during the study period. 85% patients showed signs of improvements with Azathioprine therapy in terms of decreased neurological residual deficits and less complication.
 Conclusion: Azathioprine shows improvement, slows the rate of relapse with minimal evidence of side effects and no evidence of malignancy in patients with multiple sclerosis.

Distinct gene expression in demyelinated white and grey matter areas of patients with multiple sclerosis.

Demyelination of the central nervous system is a prominent pathological hallmark of multiple sclerosis and affects both white and grey matter. However, demyelinated white and grey matter exhibit clear pathological differences, most notably the presence or absence of inflammation and activated glial cells in white and grey matter, respectively. In order to gain more insight into the differential pathology of demyelinated white and grey matter areas, we micro-dissected neighbouring white and grey matter demyelinated areas as well as normal-appearing matter from leucocortical lesions of human post-mortem material and used these samples for RNA sequencing. Our data show that even neighbouring demyelinated white and grey matter of the same leucocortical have a distinct gene expression profile and cellular composition. We propose that, based on their distinct expression profile, pathological processes in neighbouring white and grey matter are likely different which could have implications for the efficacy of treating grey matter lesions with current anti-inflammatory-based multiple sclerosis drugs.

Disease-Modifying Drug Uptake and Health Service Use in the Ageing MS Population.

BackgroundEvidence regarding the efficacy or effectiveness of the disease-modifying drugs (DMDs) in the older multiple sclerosis (MS) population is scarce. This has contributed to a lack of evidence-based treatment recommendations for the ageing MS population in practice guidelines. We examined the relationship between age (<55 and ≥55 years), DMD exposure and health service use in the MS population.MethodsWe conducted a population-based observational study using linked administrative health data from British Columbia, Canada. We selected all persons with MS and followed from the most recent of their first MS or demyelinating event, 18th birthday or 01-January-1996 (index date) until the earliest of emigration, death or 31-December-2017 (study end). We assessed DMD exposure status over time, initially as any versus no DMD, then by generation (first or second) and finally by each individual DMD. Age-specific analyses were conducted with all-cause hospitalizations and number of physician visits assessed using proportional means model and negative binomial regression with generalized estimating equations.ResultsWe included 19,360 persons with MS (72% were women); 10,741/19,360 (56%) had ever reached their 55th birthday. Person-years of follow-up whilst aged <55 was 132,283, and 93,594 whilst aged ≥55. Any DMD, versus no DMD in the <55-year-olds was associated with a 23% lower hazard of hospitalization (adjusted hazard ratio, aHR0.77; 95%CI 0.72-0.82), but not in the ≥55-year-olds (aHR0.95; 95%CI 0.87-1.04). Similar patterns were observed for the first and second generation DMDs. Exposure to any (versus no) DMD was not associated with rates of physician visits in either age group (<55 years: adjusted rate ratio, aRR1.02; 95%CI 1.00-1.04 and ≥55 years: aRR1.00; 95%CI 0.96-1.03), but variation in aRR was observed across the individual DMDs.ConclusionOur study showed beneficial effects of the DMDs used to treat MS on hospitalizations for those aged <55 at the time of exposure. In contrast, for individuals ≥55 years of age exposed to a DMD, the hazard of hospitalization was not significantly lowered. Our study contributes to the broader understanding of the potential benefits and risks of DMD use in the ageing MS population.

Inhalation of dimethyl fumarate-encapsulated solid lipid nanoparticles attenuate clinical signs of experimental autoimmune encephalomyelitis and pulmonary inflammatory dysfunction in mice.

The FDA-approved Dimethyl Fumarate (DMF) as an oral drug for Multiple Sclerosis (MS) treatment based on its immunomodulatory activities. However, it also caused severe adverse effects mainly related to the gastrointestinal system. Investigated the potential effects of solid lipid nanoparticles (SLNs) containing DMF, administered by inhalation on the clinical signs, central nervous system (CNS) inflammatory response, and lung function changes in mice with experimental autoimmune encephalomyelitis (EAE). EAE was induced using MOG35-55 peptide in female C57BL/6J mice and the mice were treated via inhalation with DMF-encapsulated SLN (CTRL/SLN/DMF and EAE/SLN/DMF), empty SLN (CTRL/SLN and EAE/SLN), or saline solution (CTRL/saline and EAE/saline), every 72 h during 21 days. After 21 days post-induction, EAE mice treated with DMF-loaded SLN, when compared with EAE/saline and EAE/SLN, showed decreased clinical score and weight loss, reduction in brain and spinal cord injury and inflammation, also related to the increased influx of Foxp3+ cells into the spinal cord and lung tissues. Moreover, our data revealed that EAE mice showed signs of respiratory disease, marked by increased vascular permeability, leukocyte influx, production of TNF-α and IL-17, perivascular and peribronchial inflammation, with pulmonary mechanical dysfunction associated with loss of respiratory volumes and elasticity, which DMF-encapsulated reverted in SLN nebulization. Our study suggests that inhalation of DMF-encapsulated SLN is an effective therapeutic protocol that reduces not only the CNS inflammatory process and disability progression, characteristic of EAE disease, but also protects mice from lung inflammation and pulmonary dysfunction.

A Simple Computational Approach to Identify Potential Drugs for Multiple Sclerosis and Cognitive Disorders from Expert Curated Resources.

Multiple sclerosis, a disease of central nervous system leads to potential disability. In the USA, one million cases are diagnosed with multiple sclerosis in 2019. Multiple sclerosis is identified as one of the diseases causing global burden. Cognitive disorder is highly prevalent among 43-70% of multiple sclerosis patients. However, treating cognitive disorder in multiple sclerosis patients is mostly ignored and this leads to several complications. We utilized various expert curated resources to identify potential drugs for multiple sclerosis and cognitive disorder, with specific focus on identifying drugs that are capable of treating both the conditions. We used simple text mining techniques to compile two databases, disease-drug association database and gene-drug interaction database from various existing standard resources. Our study suggests four drugs, Baclofen, Levodopa, Minocycline, and Vitamin B12, for treating both multiple sclerosis and cognitive disorder. In addition, our approach suggests six drugs for multiple sclerosis and 10 drugs for cognitive disorder. We obtained pharmacologist opinion on the drugs suggested for each condition and provided literature evidence for our claim. Here, we present our computational approach as a protocol such that it can be applied to other comorbid diseases that did not gain much attention so far.

Disease modifying drugs (DMDs) for multiple sclerosis (MS) : Factors to consider for optimizing treatment’

Disease modifying drugs (DMDs) for multiple sclerosis (MS) : Factors to consider for optimizing treatment’

Disease-modifying drugs for multiple sclerosis and subsequent health service use

Objective: We assessed the relationship between the multiple sclerosis (MS) disease-modifying drugs (DMDs) and healthcare use. Methods: Persons with MS (aged ⩾18 years) were identified using linked population-based health administrative data in four Canadian provinces and were followed from the most recent of their first MS/demyelinating event or 1 January 1996 until the earliest of death, emigration, or study end (31 December 2017 or 31 March 2018). Prescription records captured DMD exposure, examined as any DMD, then by generation (first-generation (the injectables) or second-generation (orals/infusions)) and individual DMD. The associations with subsequent all-cause hospitalizations and physician visits were examined using proportional means model and negative binomial regression. Results: Of 35,894 MS cases (72% female), mean follow-up was 12.0 years, with person-years of DMD exposure for any, or any first- or second-generation DMD being 63,290, 54,605 and 8685, respectively. Any DMD or any first-generation DMD exposure (versus non-exposure) was associated with a 24% lower hazard of hospitalization (adjusted hazard ratio, aHR: 0.76; 95% confidence intervals (CIs): 0.71–0.82), rising to 29% for the second-generation DMDs (aHR: 0.71; 95% CI: 0.58–0.88). This ranged from 18% for teriflunomide (aHR: 0.82; 95% CI: 0.67–1.00) to 44% for fingolimod (aHR: 0.56; 95% CI: 0.36–0.87). In contrast, DMD exposure was generally not associated with substantial differences in physician visits. Conclusion: Findings provide real-world evidence of a beneficial relationship between DMD exposure and hospitalizations.

The QOSMOS Study: Pharmacist-Led Multicentered Observational Study on Quality of Life in Multiple Sclerosis.

Health-related quality of life is frequently included in patient-reported outcomes aimed at evaluating the effectiveness of disease-modifying drugs for multiple sclerosis, but recent data about Italian patients are missing. A multicenter observational and cross-sectional study was performed by students of hospital pharmacy to update existing data on quality of life and to correlate it with the pharmacological and medical history of patients. Quality of life (QoL) was assessed using the MS-QoL54 questionnaire, and the pharmacist collected patients’ characteristics, medical and pharmacological history, and Expanded Disability Status Scale (EDSS). Three hundred and forty-nine patients with multiple sclerosis were recruited from 16 centers between May 2018 and June 2019 (median age = 44.1 years; 68.9% women). The composite indexes of physical and mental well-being showed direct correlation with each other (R = 0.826; p < 0.001), and EDSS disability was an independent negative predictor of both indexes (R2 = 35.08% p < 0.001 and R2 = 15.74% p < 0.001, respectively). A trend of association between Physical Health Composite Score and different classes of oral disease-modifying drugs (DMDs) was observed. Our study found a decrease in QoL correlated with teriflunomide, which deserves further investigation. This experience demonstrates that joint action between scientific society and students association can be successful in conducting a no-profit multicenter observational study in a real-world setting.

Transcriptomics, metabolomics, lipidomics, metabolic flux and mGWAS analyses of sphingolipid pathway highlights novel drugs for Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) related neurodegeneration has been correlated with metabolic dysfunction. Sphingomyelins (SM), a class of lipids found in the cell membranes especially myelin sheath, have been shown to be disrupted in AD and in other neurodegenerative diseases. Ceramides, the simplest of the sphingolipids, are known to be associated with Aβ production and inflammation. In order to characterize the SM pathway for its molecular links to AD pathogenesis we used complementary multi‐omics approach and identified targets that can be used for intervention.MethodIn this study we used post‐mortem brain transcriptome data of 1000 AD and cognitively normal individuals from ROS/MAP, Mayo clinic and Mount Sinai Brain bank cohort and identified differentially expressed genes in SM pathway. We also used the information derived from metabolic networks of brain and carried out metabolic flux analysis to identify reactions and genes that are altered in SM pathway. We performed multimodal neuroimaging analysis and identified genetic variants linked to genes in SM pathway and associated with AD pathogenesis. Lipidomic analyses and genetic association studies were also carried out to study the SM pathway dysregulation in AD.ResultThe multi‐omics analysis suggested increase in ceramide and depletion of sphingosine‐1‐phosphate that alters sphingolipid homeostasis in AD. To test our hypothesis, we used APP/PS1 mice and modulated S1P activity by targeting the receptor using Fingolimod, an FDA‐approved drug for multiple sclerosis. Our study showed that altering S1P signaling rescues cognitive deficits in the treated mice and Fingolimod and other modulators of S1P metabolism might be potent drug repositioning candidates for AD.ConclusionThis study demonstrates the power of using diverse types of data to inform about underlying mechanisms of AD pathogenesis. It also raises the possibility of employing powerful new approaches to the repurposing of existing drugs used for treatment of other diseases.

Characteristics of COVID-19 in patients with multiple sclerosis

BackgroundRegarding the high prevalence of multiple sclerosis (MS) and COVID-19 in Iran, a multicenter study of COVID-19 in Iranian MS patients with is carried out to address the concerns of this population. MethodsData on MS patients with COVID-19 from nine provinces of Iran were entered in a web-based registry system, between July 2020 and March 2021. Among the COVID-19 symptoms, dyspnea, altered mental status, or those resulting in hospital admission were considered severe. ResultsA total of 397 eligible patients were identified. In addition, 310 (78%) were female. The mean age was 36.5 ± 9.5. 294 (74%) patients had relapsing- remitting form. Also, four patients (1%) expired due to COVID-19 infection. The mean duration of admission in hospitalized patients was 9 (± 5.3) days. MRI was performed on 111 (28%) patients after developing COVID-19. MRI changes were observed in 27 (24%) of these cases. MS drug was changed in 26 (6%) patients. Steroid use in the past three months (OR: 2.43, 95% CI: 1.003–5.88) (p value: 0.049) and antiCD20s (OR: 4.03, 95% CI: 2.41–6.68) (p value < 0.001) showed significant association with severe COVID-19 symptoms. ConclusionThe death rate of COVID-19 among MS patients (1%) is lower than the overall death rate of the pandemic in Iran (3%). Those who received steroid in the past three months may be at increased risk of more severe forms of COVID-19. There are still doubts about the effect of anti CD20s on COVID-19 severity.

Paediatric multiple sclerosis: a lesson from TERIKIDS

Biological plausibility and convincing evidence from subgroup analyses indicate that the treatments proven efficacious for adults with multiple sclerosis are generally as effective, or more, in patients who are younger and have more active disease; 1 Signori A Schiavetti I Gallo F Sormani MP Subgroups of multiple sclerosis patients with larger treatment benefits: a meta-analysis of randomized trials. Eur J Neurol. 2015; 22: 960-966 Google Scholar such findings give a rationale for use of these drugs in paediatric multiple sclerosis. To put it another way, there is no apparent reason why effective treatments for adults who have relapsing-remitting multiple sclerosis should be not effective in children. Arguably the most important requirement to advance the care of paediatric patients with multiple sclerosis is the assessment of long-term safety, to ensure that treatment during childhood and adolescence does not expose patients to future risk. The ways in which the safety and efficacy of drugs might be investigated in patients with paediatric multiple sclerosis have been discussed extensively in a consensus paper from the International Paediatric Multiple Sclerosis Study Group (IPMSSG). 2 Waubant E Banwell B Wassmer E et al. Clinical trials of disease-modifying agents in pediatric MS: opportunities, challenges, and recommendations from the IPMSSG. Neurology. 2019; 92: e2538-e2549 Google Scholar Safety and efficacy of teriflunomide in paediatric multiple sclerosis (TERIKIDS): a multicentre, double-blind, phase 3, randomised, placebo-controlled trialNo significant difference in time to first confirmed clinical relapse was found, possibly because more patients than expected switched from the double-blind to the open-label treatment period because of high MRI activity. Key secondary imaging analyses and a prespecified sensitivity analysis of probability of relapse or high MRI activity suggest that teriflunomide might have beneficial effects in children with relapsing multiple sclerosis by reducing the risk of focal inflammatory activity. Full-Text PDF

Evaluating Effects of Glatiramer Acetate Treatment on Amyloid Deposition and Tau Phosphorylation in the 3xTg Mouse Model of Alzheimer's Disease.

Neuroinflammation driven by the accumulation of amyloid β (Aβ) can lead to neurofibrillary tangle formation in Alzheimer’s Disease (AD). To test the hypothesis that an anti-inflammatory immunomodulatory agent might have beneficial effects on amyloid and tau pathology, as well as microglial phenotype, we evaluated glatiramer acetate (GA), a multiple sclerosis drug thought to bias type 2 helper T (Th2) cell responses and alternatively activate myeloid cells. We administered weekly subcutaneous injections of GA or PBS to 15-month-old 3xTg AD mice, which develop both amyloid and tau pathology, for a period of 8 weeks. We found that subcutaneous administration of GA improved behavioral performance in novel object recognition and decreased Aβ plaque in the 3xTg AD mice. Changes in tau phosphorylation were mixed with specific changes in phosphoepitopes seen in immunohistochemistry but not observed in western blot. In addition, we found that there was a trend toward increased microglia complexity in 3xTg mice treated with GA, suggesting a shift toward homeostasis. These findings correlated with subtle changes in the microglial transcriptome, in which the most striking difference was the upregulation of Dcstamp. Lastly, we found no evidence of changes in proportions of major helper T cell (Th) subtypes in the periphery. Overall, our study provides further evidence for the benefits of immunomodulatory therapies that alter the adaptive immune system with the goal of modifying microglia responses for the treatment of Alzheimer’s Disease.