Comment on "Plasma neurofilament light chain to evaluate response during cladribine treatment in multiple sclerosis".

McAlpine's Multiple Sclerosis

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.

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.

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.

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.

Introduction

Cladribine is a new type of drug with properties of selective lymphocyte suppression that appear to favorably alter the clinical course of progressive multiple sclerosis (MS). The history of the development of cladribine treatment in chronic progressive MS is discussed, and the application of cladribine treatment to progressive multiple sclerosis in a double-blind, placebo crossover study is reviewed. Cladribine selectively targets both resting and dividing lymphocytes and may be able to destroy the activated lymphocytes that induce CNS demyelination, thus producing stabilization or improvement in chronic MS. Although the role of cladribine has not yet been fully defined, additional studies are underway to evaluate the efficacy and safety of cladribine in both progressive MS and relapsing-remitting MS.

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

Glatiramer acetate (GA) has been used as an immunomodulatory agent for the treatment of relapsing-remitting multiple sclerosis (MS) in the United States since 1996. It is currently one of two first-line agents for use in the treatment of relapsing-remitting MS. GA was the first agent to be used in the treatment of MS that was developed using the animal model of MS called experimental autoimmune encephalomyelitis. In this commentary, we examine the development of GA as a treatment for MS and discuss its mechanism of action as suggested by recent studies using modern immunologic methods.

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

Exosome microRNA is closely related to the pathological processes of multiple sclerosis. Recent studies have shown that exosome microRNA is not only involved in the pathogenesis of multiple sclerosis, but also plays an important role in the early diagnosis, the identification of relapses, the prediction of subtypes and the treatment of multiple sclerosis. Therefore, exosome microRNA is expected to be a new diagnostic biomarker as well as treatment target for multiple sclerosis. In this article, the advances of exosome microRNA in multiple sclerosis are reviewed. Key words: Exosomes; MicroRNAs; Multiple sclerosis

The research emphasis has grown into the role of B cells in multiple sclerosis since the accumulation of oligoclonal bands has been detected in the patient's cerebrospinal fluid.The efficiency of anti-B cell therapy is distinct among different stages, suggesting a dual function of B cells.It has been confirmed in animal models that the function of B cells includes not only producing antibodies, but also secreting of a variety of pro-inflammatory and anti-inflammatory cytokines, which contribute to the antibody-independent regulation of other cellular immune responses and changing the course of the disease.However, there are still some problems and limitations in the clinical application of B cell deletion therapy domestically and overseas.The specific roles and mechanisms of B-cells involved in multiple sclerosis are described in this review to elucidate the significance of B-cells in the treatment of multiple sclerosis and the research directions in the future. Key words: B cell; Multiple sclerosis; B-cell depletion

This paper’s objective is to develop a model for the appropriate and equitable use of disease‐modifying treatments in multiple sclerosis. The prevalence and incidence of multiple sclerosis was established in Leeds. A specialist multiple sclerosis team with two consultant neurologists and a multiple sclerosis support nurse was based at one centre. The team co‐operated with purchasers to develop a model of care. This included a referral protocol, strict prescribing criteria, counselling and education of patients, the use of patient‐centred outcome measures and training and feedback to other neurologists. A total of 217 people with multiple sclerosis were assessed from April 1997 to March 2000. Our experience suggests that a centralised multi‐district clinic developed by close collaboration between clinicians and health purchasers and operating under agreed rules is a feasible and effective model for the managed introduction of new treatments to the NHS.

Objective:To evaluate the influence of oral laquinimod, a candidate multiple sclerosis (MS) treatment, on induction of T follicular helper cells, development of meningeal B cell aggregates, and clinical disease in a spontaneous B cell–dependent MS model.Methods:Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice by immunization with recombinant myelin oligodendrocyte glycoprotein (rMOG) protein. Spontaneous EAE was evaluated in C57BL/6 MOG p35-55–specific T cell receptor transgenic (2D2) × MOG-specific immunoglobulin (Ig)H-chain knock-in (IgHMOG-ki [Th]) mice. Laquinimod was administered orally. T cell and B cell populations were examined by flow cytometry and immunohistochemistry.Results:Oral laquinimod treatment (1) reduced CD11c+CD4+ dendritic cells, (2) inhibited expansion of PD-1+CXCR5+BCL6+ T follicular helper and interleukin (IL)-21–producing activated CD4+CD44+ T cells, (3) suppressed B cell CD40 expression, (4) diminished formation of Fas+GL7+ germinal center B cells, and (5) inhibited development of MOG-specific IgG. Laquinimod treatment not only prevented rMOG-induced EAE, but also inhibited development of spontaneous EAE and the formation of meningeal B cell aggregates. Disability progression was prevented when laquinimod treatment was initiated after mice developed paralysis. Treatment of spontaneous EAE with laquinimod was also associated with increases in CD4+CD25hiFoxp3+ and CD4+CD25+IL-10+ regulatory T cells.Conclusions:Our observations that laquinimod modulates myelin antigen–specific B cell immune responses and suppresses both development of meningeal B cell aggregates and disability progression in spontaneous EAE should provide insight regarding the potential application of laquinimod to MS treatment. Results of this investigation demonstrate how the 2D2 × Th spontaneous EAE model can be used successfully for preclinical evaluation of a candidate MS treatment.