Research advances in exosome microRNA for multiple sclerosis

McAlpine's Multiple Sclerosis

Abstract—It is well known that vitamins are essential micronutrients for the normal functioning of all body systems and must be supplied in sufficient quantities with food. The role of vitamins produced by the gut microbiota for host health is largely undefined. The review discusses the properties of eight water-soluble B vitamins, their complex effects on the functioning of the nervous system. Attention is paid to a little-studied issue - the synthesis of B vitamins by the intestinal microbiota and its role in vitamin deficiency in the body. It is proposed that interrelated factors – “Western diet”, altered composition (dysbiosis) of the intestinal microbiota and deficiency of B vitamins are involved in the pathogenesis of multiple sclerosis, a severe autoimmune demyelinating disease that affects people of working age. The available studies on the evaluation of the level of B vitamins in patients with multiple sclerosis and the use of high doses of these vitamins for the treatment of progressive forms of multiple sclerosis are presented. In addition, the idea of the possibility of using probiotic bacteria producing B vitamins in the treatment of multiple sclerosis is being put forward.

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) that represents one of the first causes of neurological disability in young adults. Although the pathogenesis of MS is still unclear, an autoimmune mechanism has been demonstrated. According to this evidence in the last 15 years different treatments acting on the immune system have been developed. Current disease-modifying drugs (DMDs) for MS require regular and frequent parenteral administration and are associated with limited long-term treatment adherence. Moreover the clinical efficacy of these disease-modifying drugs is suboptimal. Thus, there is an important need for the development of new therapeutic strategies. Several oral therapies (fingolimod, fumaric acid, teriflunomide, laquinimod) are in development; Among these cladribine is the only therapy with the potential for short-course dosing. Cladribine is an immunosuppressant that offers sustained regulation of the immune system through a preferential lymphocyte depleting action. Cladribine has a well-characterized and well-known safety profile, derived from more than 15 years of use of the parenteral formulation both in the oncology field and in MS. This paper reviews the new oral emerging treatments and presents the available data about the use of cladribine in MS and the future perspective of its clinical use.

Objective To assess the efficiency and safety of mycophenolate mofetil (MMF) in patients with multiple sclerosis (MS) and neuromyelitis optica (NMO). Methods Twenty-seven patients with MS or NMO were selected, and the patients were divided into 2 groups: MMF group (MMF combined with glucocorticoid treatment group, 10 cases) and glucocorticoid group (only glucocorticoid treatment group, 17 cases). There were 5 cases with MS and 5 cases with NMO in MMF group. There were 13 cases with MS and 4 cases with NMO in glucocorticoid group. The therapeutic efficacy 6 months after treatment, expanded disability status scale (EDSS) before treatment and 6 months after treatment, and annualized relapse rate (ARR) were compared; and the safety was observed. Results There was no statistical difference in efficacy rate 6 months after treatment between MMF group and glucocorticoid group: 9/10 vs. 11/17, P>0.05. The EDSS scores 6 months after treatment in MMF group and glucocorticoid group were significantly lower than those before treatment: (2.41 ± 2.05) scores vs. (3.40 ± 2.05) scores and (1.17 ± 0.92) scores vs. (2.38 ± 1.28) scores, and there were statistical differences (P <0.05), particularly for the patients with MS. The ARR 6 months after treatment in MMF group was significantly lower than that before treatment: 0 time/year vs. 0.75 times/year, and there was statistical difference (P <0.05). The difference of ARR before and after treatment in MMF group was significantly higher than that in glucocorticoid group: 0.75 times/year vs.-0.46 times/year, and there was statistical difference (P<0.01), particularly for the patients with MS. Only 1 female patient had myalgia when taking higher dosage of MMF, and the symptom tended to relieve after the dosage was reduced. Conclusions MMF is effective in the treatment of MS and NMO. MS can improve the neurological function and reduce the recurrence of the disease; and the safety is high. Key words: Multiple sclerosis; Neuromyelitis optica; Glucocorticoids; Mycophenolate mofetil; Retrospective studies

In recent years, the incidence of multiple sclerosis (MS) has increased in the pediatric population. As there are no separate clinical guidelines for the treatment of pediatric MS and therapeutic options have expanded, it is important to discuss and establish new protocols for the treatment of MS in children and adolescents. This article presents a series of clinical cases of the use of ofatumumab in patients under 18 years of age with a relapsing-remitting MS (RRMS).In the first observation, a 16-year-old female patient with RRMS was switched to ofatumumab therapy due to persistent clinical and radiological activity of the disease during dimethyl fumarate therapy. After the first injection, hyperthermia of up to 38.6 °C and cephalgia were observed, which resolved on the background of symptomatic therapy. No adverse events occurred with subsequent injections, and the patient had clinical and radiological remission during the six-month use of the drug.In the second observation, a 17-year-old female patient with a four-year history of the disease showed resistance to first-line therapy (interferon β1a and glatiramer acetate), so therapy was switched to ofatumumab. After the first injection, persistent hyperthermia of up to 39.3 °C was observed for two days, therefore, premedication with antipyretic and antihistamine medication was performed for the next two injections. No further adverse events were recorded, the therapy was well tolerated, and premedication was not required. The clinical remission of the disease lasted for six months and the results of the control MRI showed no signs of disease activity.In the third observation, ofatumumab therapy was initiated in a 17-year-old patient with rapidly progressive MS. No adverse events were recorded during the 9-month treatment, no signs of the disease activity were detected on the control MRI, and a decrease in the size of some foci was observed. Thus, high short-term efficacy, good tolerability and safety of ofatumumab in the treatment of MS in patients under 18 years of age were demonstrated, which are consistent with the results of the use of the drug in the adult population; no unexpected adverse events were observed. The subcutaneous route of administration contributed to improved patients’ adherence to therapy.

Significant advances in magnetic resonance imaging (MRI) technology and treatment of multiple sclerosis (MS) have been made during the past decade. These advances have revealed evidence of profound heterogeneity in MS. There is a clear need to revisit the key issues in MS pathogenesis and treatment strategies, taking new data into consideration. This paper provides an overview of recent progress in MS research, including (a) a review of clinical, pathologic, and immunologic aspects of MS, (b) a discussion of the mechanism of action of currently available disease-modifying drugs for MS, (c) an account of the role of MRI in clinical management and clinical trials in MS, and (d) an overview of some emerging treatments for MS.

Treatment for multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system, has changed drastically in the last 30 years. Several different disease-modifying therapies are now available, with off-label use of the B-cell-depleting antibody rituximab becoming an increasingly popular choice, as more and more studies report on its effectiveness. The objective of this study was to summarize the current state of evidence for rituximab as a treatment for relapsing-remitting MS (RRMS). A structured literature search was conducted in PubMed, focusing on peer-reviewed studies of adult populations with RRMS. Ongoing trials with rituximab in MS were identified through Clinicaltrials.gov and additional references were identified through review articles. Despite promising results for rituximab as a treatment of MS, the market-authorization holder switched focus from rituximab and discontinued the industry-sponsored trials programme. However, several observational studies, smaller clinical trials and one large investigator-initiated randomized-controlled trial have continued to report fewer clinical relapses, fewer contrast-enhancing lesions on magnetic resonance imaging and better drug survival with rituximab, compared with MS-approved alternatives. Rituximab should be considered as both a first- and second-line therapy option for most MS patients with active, non-progressive disease. However, as an off-label therapy for MS, regulatory approval remains a barrier for wider adoption in many countries.

Should Spinal MRI Be Routinely Performed in Patients With Clinically Isolated Optic Neuritis?

Mycophenolate mofetil (MMF) is an affordable and tolerable drug reported to be beneficial in the treatment of multiple sclerosis (MS). To determine efficacy of MMF as first line disease modifying drug (DMD) in 40 patients with MS seen in our demyelinating disease registry. The annualized relapse rate (ARR) for 1 year prior to starting MMF therapy and 1 year post treatment was calculated. Pre- and post-treatment expanded disability status scores (EDSS), age at onset of treatment, disease duration, and type of MS were recorded. Wilcoxon rank sum test was used for comparison of ARRs and EDSS before and after treatment. Forty patients included 27 females and 13 males. Mean duration of MMF therapy was 24 months (range 14-33 months). Pre-treatment mean ARR of 0.95 was significantly different from post treatment mean ARR of 0.11 (P=0.0001). Pre-treatment mean EDSS 3.80 (inter quartile range [IQR] 3.5-4.5) was significantly different from post-treatment mean EDSS 2.66 (IQR 1.5-3.0, P=0.0001). No adverse effects were reported that required stopping of medication. Five patients discontinued treatment 6-11 months after starting therapy, two of whom relapsed subsequently. Our preliminary results support the use of MMF, a cheap and well-tolerated drug, as first line disease modifying drug in MS. Long-term results in a larger patient cohort is required for validating our preliminary conclusions.

MicroRNA (miRNA) is a class of endogenous non-coding small RNA with regulatory activities, which generally regulates the expression of target genes at the post-transcriptional level. Multiple Sclerosis (MS) is thought to be an autoimmune-mediated chronic inflammatory demyelinating disease of the central nervous system (CNS) that typically affect young adults. T lymphocytes play an important role in the pathogenesis of MS, and studies have suggested that miRNAs are involved in regulating the proliferation, differentiation, and functional maintenance of T lymphocytes in MS. Dysregulated expression of miRNAs may lead to the differentiation balance and dysfunction of T lymphocytes, and they are thus involved in the occurrence and development of MS. In addition, some specific miRNAs, such as miR-155 and miR-326, may have potential diagnostic values for MS or be useful for discriminating subtypes of MS. Moreover, miRNAs may be a promising therapeutic strategy for MS by regulating T lymphocyte function. By summarizing the recent literature, we reviewed the involvement of T lymphocytes in the pathogenesis of MS, the role of miRNAs in the pathogenesis and disease progression of MS by regulating T lymphocytes, the possibility of differentially expressed miRNAs to function as biomarkers for MS diagnosis, and the therapeutic potential of miRNAs in MS by regulating T lymphocytes.

Targets of the humoral autoimmune response in multiple sclerosis

Computer design, synthesis, and bioactivity analyses of drugs like fingolimod used in the treatment of multiple sclerosis

Since COVID-19 has emerged as a word public health problem, attention has been focused on how immune-suppressive drugs used for the treatment of autoimmune disorders influence the risk for SARS-CoV-2 infection and the development of acute respiratory distress syndrome (ARDS). Here, we discuss the disease-modifying agents approved for the treatment of multiple sclerosis (MS) within this context. Interferon (IFN)-β1a and -1b, which display antiviral activity, could be protective in the early stage of COVID-19 infection, although SARS-CoV-2 may have developed resistance to IFNs. However, in the hyperinflammation stage, IFNs may become detrimental by facilitating macrophage invasion in the lung and other organs. Glatiramer acetate and its analogues should not interfere with the development of COVID-19 and may be considered safe. Teriflunomide, a first-line oral drug used in the treatment of relapsing-remitting MS (RRMS), may display antiviral activity by depleting cellular nucleotides necessary for viral replication. The other first-line drug, dimethyl fumarate, may afford protection against SARS-CoV-2 by activating the Nrf-2 pathway and reinforcing the cellular defenses against oxidative stress. Concern has been raised regarding the use of second-line treatments for MS during the COVID-19 pandemic. However, this concern is not always justified. For example, fingolimod might be highly beneficial during the hyperinflammatory stage of COVID-19 for a number of mechanisms, including the reinforcement of the endothelial barrier. Caution is suggested for the use of natalizumab, cladribine, alemtuzumab, and ocrelizumab, although MS disease recurrence after discontinuation of these drugs may overcome a potential risk for COVID-19 infection.

Since the first approved parenteral drug for the treatment of multiple sclerosis (MS) in 1993 (interferon [IFN] beta, and later glatiramer acetate [GA]), today there are both parenteral and oral treatment options for MS. After IFN beta preparations, glatiramer acetate was developed; and, until the approval of natalizumab in 2006, those dominated the treatment of MS. Later on, among oral drug options, cladribine made a promising entry; however, due to safety concerns, it was withdrawn soon. Afterwards, with the understanding of the role of sphingosine-1 phosphate (S1P) receptors in the pathogenesis of MS, fingolimod was approved in 2010, which was followed by other oral agents such as teriflunomide and dimethyl fumarate. Recently newer IV treatment options such as alemtuzumab, rituximab and ocrelizumab have widened the treatment arena. Recently, after submitting new efficacy and safety data, cladribine was approved for MS by EMA, in 2017. Moreover, seven years after its rejection due to safety reasons, in August 2018 FDA accepted to re-evaluate the data of cladribine as a treatment option for relapsing remitting MS (RRMS). Another oral treatment option, Laquinimod, was not approved because it could not be shown to slow disability progression despite favourable effect in relapsing MS. Newer generation S1P receptor modulators are being investigated currently, and they are expected to come into the treatment arena soon. In this article, mechanisms of actions, clinical trial results, and side effects of the newer drugs used for MS, are reviewed. IFN beta and glatiramer acetate were not included since they have clinical experience nearing 30 years.

There is increasing evidence that human herpes viruses and human endogenous retroviruses (HERV) are involved in the aetiology and pathogenesis of multiple sclerosis (MS). In order to acquire the ultimate evidence to confirm such a relationship, it is probably required to use specific antiviral drugs in clinical trials of MS. The results of published antiviral clinical trials in patients with MS are summarized in this review. None of them showed statistically significant effects on primary outcomes of disease activity or on disability development. However, given their small sample sizes, the strong trends and effects observed in subgroup analysis of antiherpes virus treatment in patients with MS warrant further studies. The possible involvement of HERV in MS is intriguing, and drugs have been developed that could reduce the impact of HERV in MS. However, larger studies are needed as the phase I and II trials were not designed to show clinical efficacy in MS.