Treatment Of Multiple Sclerosis Research Articles

The Evolving Role of Monomethyl Fumarate Treatment as Pharmacotherapy for Relapsing-Remitting Multiple Sclerosis.

Multiple sclerosis is the most common autoimmune disease affecting the central nervous system (CNS) worldwide. Multiple sclerosis involves inflammatory demyelination of nerve fibers in the CNS, often presenting with recurrent episodes of focal sensory or motor deficits associated with the region of the CNS affected. The prevalence of this disease has increased rapidly over the last decade. Despite the approval of many new pharmaceutical therapies in the past 20 years, there remains a growing need for alternative therapies to manage the course of this disease. Treatments are separated into two main categories: management of acute flare versus long-term prevention of flares via disease-modifying therapy. Primary drug therapies for acute flare include corticosteroids to limit inflammation and symptomatic management, depending on symptoms. Several different drugs have been recently approved for use in modifying the course of the disease, including a group of medications known as fumarates (e.g., dimethyl fumarate, diroximel fumarate, monomethyl fumarate) that have been shown to be efficacious and relatively safe. In the present investigation, we review available evidence focused on monomethyl fumarate, also known as Bafiertam®, along with bioequivalent fumarates for the long-term treatment of relapsing-remitting multiple sclerosis.

Efficacy and Safety of PEGylated Interferons for Relapsing-Remitting Multiple Sclerosis in Adult Patients: Results of Matching-Adjusted Indirect Comparison

Introduction. Beta interferons are effective and safe agents for the treatment of relapsing-remitting multiple sclerosis (RRMS). PEGylated interferons have been developed in order to increase patient adherence. Direct comparisons of the efficacy and safety of PEGylated interferons have not yet been conducted.
 Our objective was to evaluate the efficacy and safety of SamPEG-IFN-β1a versus PEG-IFN-β1a in adult patients with RRMS.
 Materials and methods. We conducted a systematic search of randomized clinical trials (RCTs) using the PubMed, Embase and eLIBRARY.RU databases. Efficacy was assessed based on the proportion of patients with disease relapses and the annualized relapse rate (ARR) during the 1st and the 2nd years of treatment. Safety was assessed by the number of patients with adverse events (AEs), serious AEs (SAEs), and any AEs that led to the treatment discontinuation. We conducted pairwise matching-adjusted indirect comparison (MAIC) to assess comparative efficacy of PEGylated IFNs. To evaluate the efficacy, hypotheses of non-inferiority of SamPEG-IFN-β1a to PEG-IFN-β1a and superiority of SamPEG-IFN-β1a over PEG-IFN-β1a were tested.
 Results. Based on results of the systematic review, four articles were selected wherein the results of phase 3 clinical trial of PEG-IFN-β1a and phase 2–3 clinical trial of SamPEG-IFN-β1a were described. In PEG-IFN-β1a group (n = 512) the agent was administered once every 2 weeks, in SamPEGIFN-β1a group (n = 114) the agent was administered at a dose of 240 μg. The analysis results confirmed the hypothesis of SamPEG-IFN-β1a non-inferiority to PEG-IFN-β1a in efficacy, while SamPEG-IFN-β1a superiority over PEG-IFN-β1a in efficacy was not confirmed. The hypothesis of SamPEG-IFN-β1a superiority over PEG-IFN-β1a in safety was also confirmed based on a significantly lower incidence of SAEs and any AEs that led to treatment discontinuation.
 Conclusions. The proportion of patients with relapses and the ARR in 1 year and in 2 years of therapy indicates that SamPEG-IFN-β1a is non-inferior to PEG-IFN-β1a in efficacy. SamPEG-IFN-B1a demonstrated a more favourable safety profile than PEG-IFN-B1a as showing less odds of SAEs and AEs leading to treatment discontinuation.

Infiltration by monocytes of the central nervous system and its role in multiple sclerosis: reflections on therapeutic strategies.

Mononuclear macrophage infiltration in the central nervous system is a prominent feature of neuroinflammation. Recent studies on the pathogenesis and progression of multiple sclerosis have highlighted the multiple roles of mononuclear macrophages in the neuroinflammatory process. Monocytes play a significant role in neuroinflammation, and managing neuroinflammation by manipulating peripheral monocytes stands out as an effective strategy for the treatment of multiple sclerosis, leading to improved patient outcomes. This review outlines the steps involved in the entry of myeloid monocytes into the central nervous system that are targets for effective intervention: the activation of bone marrow hematopoiesis, migration of monocytes in the blood, and penetration of the blood-brain barrier by monocytes. Finally, we summarize the different monocyte subpopulations and their effects on the central nervous system based on phenotypic differences. As activated microglia resemble monocyte-derived macrophages, it is important to accurately identify the role of monocyte-derived macrophages in disease. Depending on the roles played by monocyte-derived macrophages at different stages of the disease, several of these processes can be interrupted to limit neuroinflammation and improve patient prognosis. Here, we discuss possible strategies to target monocytes in neurological diseases, focusing on three key aspects of monocyte infiltration into the central nervous system, to provide new ideas for the treatment of neurodegenerative diseases.

Latent tuberculosis prevalence, diagnosis and treatment in Multiple Sclerosis as a strategy for reducing infection reactivation during immunosuppressant therapy

BackgroundTuberculosis is an infectious disease with a risk of reactivation in Multiple Sclerosis patients on immunosuppressant therapy. Diagnosis and treatment of Latent Tuberculosis Infection (LTBI) prevents the infection. ObjectiveTo diagnose and treat LTBI in Multiple Sclerosis (MS). MethodsCross-sectional study of the prevalence and treatment of LTBI in MS, between February 2021 and June 2023. LTBI was defined as an absence of symptoms, positive PPD or IGRA and normal chest X-ray. ResultsOf the 58 patients with MS, 17 (29.3 %) were diagnosed with LTBI, 15 with PPD > 5 mm and 2 with positive IGRA, 10 (58.8 %) female and 7 (41.1 %) male, mean age of 41.3 (SD ±13.4) years. All patients with LTBI were treated with immunomodulators or immunosuppressants: Fingolimod 5 (29.4 %), Natalizumab 5 (29.4 %), Cladribine 2 (11.8 %), Glatiramer 2 (11.8 %), Ocrelizumab 2 (11.8 %), and Interferon beta 1 (5.9 %). Steroids therapy for relapses, were used in 5/17 (93.8 %) with LTBI and 30/37 (81.1 %) without LTBI. To treat LTBI, 11 (64.7 %) received Isoniazid and 6 (35.3 %) Isoniazid plus Rifapentine. Hepatotoxicity occurred in 3 (17.6 %) with INH. There were no interruptions of ILTB treatment during the study. ConclusionThe prevalence of LTBI was found to be high and treatment proved safe.

The patient-reported wearing-off phenomenon with monoclonal antibody treatments for multiple sclerosis

The patient-reported wearing-off phenomenon with monoclonal antibody treatments for multiple sclerosis

Dysbiosis in Multiple Sclerosis: Can Immunoglobulin Y Supplements Help?

The role of gut microbiota in autoimmune disorders like multiple sclerosis is gaining attention. Multiple sclerosis is characterized by inflammation, demyelination, and neurodegeneration in the central nervous system. Alterations in gut microbiota have been linked to multiple sclerosis development, with decreased beneficial bacteria and increased harmful species. The gut-brain axis is a complex interface influencing bidirectional interactions between the gut and the brain. Dysbiosis, an imbalance in gut microbiota, has been associated with autoimmune diseases. The influence of gut microbiota in multiple sclerosis is reversible, making it a potential therapeutic target. Probiotics, prebiotics, and fecal microbiota transplantation have shown promise in multiple sclerosis treatment, with positive effects on inflammation and immune regulation. Immunoglobulin Y (IgY) supplements derived from chicken egg yolk have potential as nutraceuticals or dietary supplements. IgY technology has been effective against various infections, and studies have highlighted its role in modulating gut microbiota and immune responses. Clinical trials using IgY supplements in multiple sclerosis are limited but have shown positive outcomes, including reduced symptoms, and altered immune responses. Future research directions involve understanding the mechanisms of IgY's interaction with gut microbiota, optimal dosage determination, and long-term safety assessments. Combining IgY therapy with other interventions and investigating correlations between microbiota changes and clinical outcomes are potential avenues for advancing multiple sclerosis treatment with IgY supplements.

Ocrelizumab B cell depletion has no effect on HERV RNA expression in PBMC in MS patients

BackgroundEpstein barr virus (EBV) infection of B cells is now understood to be one of the triggering events for the development of Multiple Sclerosis (MS), a progressive immune-mediated disease of the central nervous system. EBV infection is also linked to expression of human endogenous retroviruses (HERVs) of the HERV-W group, a further risk factor for the development of MS. Ocrelizumab is a high-potency disease-modifying treatment (DMT) for MS, which depletes B cells by targeting CD20. ObjectivesWe studied the effects of ocrelizumab on gene expression in peripheral blood mononuclear cells (PBMC) from paired samples from 20 patients taken prior to and 6 months after beginning ocrelizumab therapy. We hypothesised that EBV and HERV-W loads would be lower in post-treatment samples. MethodsSamples were collected in Paxgene tubes, subject to RNA extraction and Illumina paired end short read mRNA sequencing with mapping of sequence reads to the human genome using Salmon and differential gene expression compared with DeSeq2. Mapping was also performed separately to the HERV-D database of HERV sequences and the EBV reference sequence. ResultsPatient samples were more strongly clustered by individual rather than disease type (relapsing/remitting or primary progressive), treatment (pre and post), age, or sex. Fourteen genes, all clearly linked to B cell function were significantly down regulated in the post treatment samples. Interestingly only one pre-treatment sample had detectable EBV RNA and there were no significant differences in HERV expression (of any group) between pre- and post-treatment samples. ConclusionsWhile EBV and HERV expression are clearly linked to triggering MS pathogenesis, it does not appear that high level expression of these viruses is a part of the ongoing disease process or that changes in virus load are associated with ocrelizumab treatment.

Targeting Vascular Impairment, Neuroinflammation, and Oxidative Stress Dynamics with Whole-Body Cryotherapy in Multiple Sclerosis Treatment.

Multiple sclerosis (MS), traditionally perceived as a neurodegenerative disease, exhibits significant vascular alternations, including blood-brain barrier (BBB) disruption, which may predispose patients to increased cardiovascular risks. This vascular dysfunction is intricately linked with the infiltration of immune cells into the central nervous system (CNS), which plays a significant role in perpetuating neuroinflammation. Additionally, oxidative stress serves not only as a byproduct of inflammatory processes but also as an active contributor to neural damage. The synthesis of these multifaceted aspects highlights the importance of understanding their cumulative impact on MS progression. This review reveals that the triad of vascular damage, chronic inflammation, and oxidative imbalance may be considered interdependent processes that exacerbate each other, underscoring the need for holistic and multi-targeted therapeutic approaches in MS management. There is a necessity for reevaluating MS treatment strategies to encompass these overlapping pathologies, offering insights for future research and potential therapeutic interventions. Whole-body cryotherapy (WBCT) emerges as one of the potential avenues for holistic MS management approaches which may alleviate the triad of MS progression factors in multiple ways.

Immunosenescence and vaccine efficacy revealed by immunometabolic analysis of SARS-CoV-2-specific cells in multiple sclerosis patients

Disease-modifying therapies (DMT) administered to patients with multiple sclerosis (MS) can influence immune responses to SARS-CoV-2 and vaccine efficacy. However, data on the detailed phenotypic, functional and metabolic characteristics of antigen (Ag)-specific cells following the third dose of mRNA vaccine remain scarce. Here, using flow cytometry and 45-parameter mass cytometry, we broadly investigate the phenotype, function and the single-cell metabolic profile of SARS-CoV-2-specific T and B cells up to 8 months after the third dose of mRNA vaccine in a cohort of 94 patients with MS treated with different DMT, including cladribine, dimethyl fumarate, fingolimod, interferon, natalizumab, teriflunomide, rituximab or ocrelizumab. Almost all patients display functional immune response to SARS-CoV-2. Different metabolic profiles characterize antigen-specific-T and -B cell response in fingolimod- and natalizumab-treated patients, whose immune response differs from all the other MS treatments.

Disease-modifying therapies in managing disability worsening in paediatric-onset multiple sclerosis: a longitudinal analysis of global and national registries

High-efficacy disease-modifying therapies have been proven to slow disability accrual in adults with relapsing-remitting multiple sclerosis. However, their impact on disability worsening in paediatric-onset multiple sclerosis, particularly during the early phases, is not well understood. We evaluated how high-efficacy therapies influence transitions across five disability states, ranging from minimal disability to gait impairment and secondary progressive multiple sclerosis, in people with paediatric-onset multiple sclerosis. Longitudinal data were obtained from the international MSBase registry, containing data from people with multiple sclerosis from 151 centres across 41 countries, and the Italian Multiple Sclerosis and Related Disorders Register, containing data from people with multiple sclerosis from 178 Italian multiple sclerosis centres. People younger than 18 years at the onset of multiple sclerosis symptoms were included, provided they had a confirmed diagnosis of relapsing-remitting multiple sclerosis and at least four Expanded Disability Status Scale (EDSS) scores recorded within 12-month intervals. The primary outcome was the time to change in disability state: minimal disability (EDSS scores 0, 1·0, and 1·5), mild disability (EDSS scores 2·0 and 2·5), moderate disability (EDSS scores 3·0 and 3·5), gait impairment (EDSS scores ≥4·0), and clinician diagnosed secondary progressive multiple sclerosis. A multi-state model was constructed to simulate the natural course of multiple sclerosis, modelling the probabilities of both disability worsening and improvement simultaneously. The impact of high-efficacy disease-modifying therapies (alemtuzumab, cladribine, daclizumab, fingolimod, mitoxantrone, natalizumab, ocrelizumab, rituximab, or autologous haematopoietic stem cell transplantation) and low-efficacy disease-modifying therapies (dimethyl fumarate, glatiramer acetate, interferon beta, or teriflunomide), compared with no treatment, on the course of disability was assessed. Apart from recruitment, individuals with lived experience of multiple sclerosis were not involved in the design and conduct of this study. A total of 5224 people (3686 [70·6%] female and 1538 [29·4%] male) with mean age at onset of multiple sclerosis 15·24 years (SD 2·52) were included. High-efficacy therapies reduced the hazard of disability worsening across the disability states. The largest reduction (hazard ratio 0·41 [95% CI 0·31-0·53]) was observed in participants who were treated with high-efficacy therapies while in the minimal disability state, compared with those remained untreated. The benefit of high-efficacy therapies declined with increasing disability. Young people with minimal disability who received low-efficacy therapy also experienced a reduced hazard (hazard ratio 0·65 [95% CI 0·54-0·77]) of transitioning to mild disability, in contrast to those who remained untreated. Treatment of paediatric-onset relapsing-remitting multiple sclerosis with high-efficacy therapy substantially reduces the risk of reaching key disability milestones. This reduction in risk is most pronounced among young people with minimal or mild disability when treatment began. Children with relapsing-remitting multiple sclerosis should be treated early with high-efficacy therapy, before developing significant neurological impairments, to better preserve their neurological capacity. National Health and Medical Research Council, Australia; MSBase Foundation Fellowship; MS Australia Postdoctoral Fellowship.

Comparative Analysis of the Two Innovative Vaccines

Multiple sclerosis (MS), one of the most prevalent autoimmune diseases, poses a significant challenge for therapeutic advancements. Among these, antigen-specific therapies (ASTs) utilizing therapeutic vaccines have emerged as highly promising. Designed to induce antigen-specific tolerance without compromising the overall immune system, these vaccines offer a glimmer of hope for MS patients, despite many still being in the preclinical trial phase. This research provides an elaborate comparison of two distinct vaccine types: m1Ψ mRNA vaccines and ROS-scavenging CeNP MSN vaccines. As AST vaccines targeting MS, they exhibit notable similarities across various facets, ranging from superficial aspects such as the models employed to evaluate therapeutic effects to deeper considerations like their anti-inflammatory characteristics and key mechanistic factors. Beneath these similarities, significant differences are identified and analyzed within this article. Additionally, the advantages, disadvantages, and noteworthy features of each vaccine are thoroughly compared, accompanied by corresponding suggestions for improvement. Through this comparative analysis of the two innovative vaccines, the paper aims to enhance readers' comprehension of MS treatments. By offering humble insights, it aspires to make a positive impact on related research, ultimately contributing to the advancement of MS therapeutic approaches.

Treatment of Multiple Sclerosis with Cladribine Tablets: Literature Review and the Guidance of the Lithuanian Association of Neurologists

Cladribine is a disease-modifying drug used for the treatment of the highly active relapsing-remitting form of multiple sclerosis. Cladribine is a purine nucleoside analogue which selectively targets lymphocyte subpopulations involved in the pathogenesis of multiple sclerosis, and therefore it is classified as an immune reconstitution therapy drug. Two short courses of cladribine tablets given over two years significantly reduce the multiple sclerosis relapse rate and disability progression. For most patients, the effect persists in the third and the fourth year. This makes cladribine convenient for patients with multiple comorbidities, difficulties in adhering to their prescribed treatment regimen, those planning a pregnancy, or those for whom long-term immunosuppression is undesirable. Cladribine tablets are denoted by good safety characteristics, with the most prominent adverse effect being lymphopenia, which does not lead to an increased risk of infections other than Herpes zoster.However, in clinical practice, there are a number of issues related both to the initial administration of cladribine tablets and the strategy of treatment in different clinical situations during the first-to-fourth years of treatment, and particularly after the fourth year. Although there are no contraindications for additional courses of cladribine tablets, the product information does not provide detailed guidance on their continued use. During more than five years after the approval of the medicinal product, the new clinical trial data and the Real-World Evidence (RWE) on the efficacy and safety of cladribine tablets have become available, based on which, several national and international expert panels, as well as the Lithuanian Association of Neurologists, have issued guidance on the use of cladribine tablets reviewed in this article. Upon reactivation of the disease, additional courses of cladribine tablets or other disease-modifying therapies may be prescribed, depending on various factors related to the severity of the relapse, patient characteristics, and previously used medications. If the patient’s condition remains stable after the fourth year, extension of the treatment-free period with the structured monitoring approach could be appropriate.

Is there anything beyond addiction psychotherapy in patients with cannabis use disorder? A rationale for prescribing medical marihuana as a harm reduction strategy

Marihuana has been known to people for hundreds of years. Today, marihuana is either legal or decriminalized in many countries, particularly in Europe and the Americas, which may encourage use of the drug. Cannabis and its derivatives are used in medicine on the recommendation of doctors, including for the treatment of multiple sclerosis or drug-resistant epilepsy. There is a group of people who turn to marihuana on the street without regard to contraindications and side effects, and these are the recreational users who struggle with problematic use or addiction . Buying marihuana outside of the medical market means that the user may not realize the negative health effects of their use, and there are serious risks associated with the negative effects of the natural substances found in marihuana or the numerous and common marihuana contaminants, such as mercury and pesticides, among others. This review justifies the prescription of pharmaceutical-grade medical marihuana as part of health harm reduction for a group of cannabis use disorder patients who are unlikely to stop using marihuana from untested or illicit sources, while also discussing ethical and economic issues.

Naujųjų anti-CD20 monokloninių antikūnų vaidmuo gydant itin aktyvią recidyvuojančiąją remituojančiąją išsėtinę sklerozę: ofatumumabo klinikinis efektyvumas ir saugumas

Multiple sclerosis is the most common chronic demyelinating neurodegenerative central nervous system disease among young adults. Considering its extent in a relatively young population, multiple sclerosis determines a significant socioeconomic burden to the society due to the cost of disease modifying treatment and a lower working capacity of patients and their caregivers. It is important to control neuroinflammation in the central nervous system caused by the pathologic activity of immune cells by considering a high efficacy treatment early in the disease course in order to prevent accumulation of neurological damage and to improve long term outcomes. According to the newest clinical studies, anti-CD20 therapies have proven their effectiveness and safety in active relapsing multiple sclerosis treatment: since 2018, ocrelizumab, and, since 2023, ofatumumab have both been available as treatment options in Lithuania. Because of its high potency and safety, as well as the specific mechanism of action, ofatumumab is effective in lower doses, and, after initial training at a health care facility, it can be self-administered through subcutaneous injection. This article reviews the efficacy, safety data and treatment indications of the latest available anti-CD20 monoclonal antibodies.

Multi-actor system dynamics in access to disease-modifying treatments for multiple sclerosis in Southeast Asia: A regional survey and suggestions for improvement

BackgroundDespite the global availability of multiple sclerosis (MS) treatments, accessing and financing them in Southeast Asia (SEA) remains a challenge. This descriptive survey-based study aimed to describe the current state of MS treatment access and local access dynamics within this region. MethodsThe survey questionnaire, comprising of 15 closed-ended and five open-ended questions, was developed by three neurologists with expertise in MS and routine MS patient management, or had training in neuroimmunology. Questionnaire development was guided by the recent Atlas of MS and in alignment with the Access to Treatment framework, focusing on MS diagnosis and treatment issues in SEA. Fifteen neurologists experienced in managing MS across the region were identified as key informants for this study. ResultsAll fifteen neurologists participated in the survey via email and videoconferencing between January 2020 and February 2023, which included the following countries: Brunei, Cambodia, Indonesia, Malaysia, Myanmar, Lao PDR, Philippines, Singapore, Thailand, Timor-Leste, and Vietnam. All had at least five years of experience in managing MS patients and six had previously completed a neuroimmunology fellowship programme. SEA countries showed disparities in healthcare financing, availability of neurologists, MS treatments, and investigative tools. Access to MS disease-modifying treatments (DMTs) is hindered by high cost, lack of MS specialists, and weak advocacy efforts. On-label DMTs are not listed as essential medicines regionally except for interferon beta1a and teriflunomide in Malaysia. On-label monoclonals are available only in Malaysia, Singapore, and Thailand. Generic on-label DMTs are unavailable due to lack of distributorship and expertise in using them. Off-label DMTs (azathioprine, methotrexate, and rituximab) predominate in most SEA countries. Other challenges include limited access to investigations, education, and knowledge about DMTs among general neurologists, and absence of registries and MS societies. Patient champions, communities, and MS organisations have limited influence on local governments and pharmaceutical companies. Despite its increasing prevalence, there is a lack of concerted priority setting due to MS being perceived as a rare, non-communicable disease. ConclusionThis study highlights the distinct dynamics, challenges, and research gaps within this region, and provides suggestions to improve MS diagnosis, education, and medicine access.

Magnetic Resonance Imaging Evidence Supporting the Efficacy of Cladribine Tablets in the Treatment of Relapsing-Remitting Multiple Sclerosis.

Numerous therapies are currently available to modify the disease course of multiple sclerosis (MS). Magnetic resonance imaging (MRI) plays a pivotal role in assessing treatment response by providing insights into disease activity and clinical progression. Integrating MRI findings with clinical and laboratory data enables a comprehensive assessment of the disease course. Among available MS treatments, cladribine is emerging as a promising option due to its role as a selective immune reconstitution therapy, with a notable impact on B cells and a lesser effect on T cells. This work emphasizes the assessment of MRI's contribution to MS treatment, particularly focusing on the influence of cladribine tablets on imaging outcomes, encompassing data from pivotal and real-world studies. The evidence highlights that cladribine, compared with placebo, not only exhibits a reduction in inflammatory imaging markers, such as T1-Gd+, T2 and combined unique active (CUA) lesions, but also mitigates the effect on brain volume loss, particularly within grey matter. Importantly, cladribine reveals early action by reducing CUA lesions within the first months of treatment, regardless of a patient's initial conditions. The selective mechanism of action, and sustained efficacy beyond year 2, combined with its early onset of action, collectively position cladribine tablets as a pivotal component in the therapeutic paradigm for MS. Overall, MRI, along with clinical measures, has played a substantial role in showcasing the effectiveness of cladribine in addressing both the inflammatory and neurodegenerative aspects of MS.

Peripheral oedema as an adverse effect of treatment of secondary progressive multiple sclerosis with siponimod: A case series

Siponimod is a sphingosine 1-phosphate receptor (S1P) modulator used to treat secondary progressive multiple sclerosis (SPMS). We report 3 SPMS patients treated with siponimod who developed new or worsening peripheral oedema soon after commencing treatment. In one case, peripheral oedema resulted in immobility. Siponimod-related peripheral oedema deserves wider recognition due to the potential for morbidity and over-investigation. Clinicians should assess for pre-existing oedema and coexisting conditions that may predispose to developing peripheral oedema prior to commencing siponimod.

Therapeutic applicability of cannabidiol and other phytocannabinoids in epilepsy, multiple sclerosis and Parkinson's disease and in comorbidity with psychiatric disorders.

Studies have demonstrated the neuroprotective effect of cannabidiol (CBD) and other Cannabis sativa L. derivatives on diseases of the central nervous system caused by their direct or indirect interaction with endocannabinoid system-related receptors and other molecular targets, such as the 5-HT1A receptor, which is a potential pharmacological target of CBD. Interestingly, CBD binding with the 5-HT1A receptor may be suitable for the treatment of epilepsies, parkinsonian syndromes and amyotrophic lateral sclerosis, in which the 5-HT1A serotonergic receptor plays a key role. The aim of this review was to provide an overview of cannabinoid effects on neurological disorders, such as epilepsy, multiple sclerosis and Parkinson's diseases, and discuss their possible mechanism of action, highlighting interactions with molecular targets and the potential neuroprotective effects of phytocannabinoids. CBD has been shown to have significant therapeutic effects on epilepsy and Parkinson's disease, while nabiximols contribute to a reduction in spasticity and are a frequent option for the treatment of multiple sclerosis. Although there are multiple theories on the therapeutic potential of cannabinoids for neurological disorders, substantially greater progress in the search for strong scientific evidence of their pharmacological effectiveness is needed.

Ocrelizumab use in multiple sclerosis: a real-world experience in a changing therapeutic scenario.

CD20-depleting therapies are a real milestone in the treatment ofmultiple sclerosis (MS). This study examined the ocrelizumab (OCR) use in patients with primary progressive (PP) and relapsing remitting (RR) MS, also evaluating the predictors of treatment response. Patients with MS treated with OCR between 2017 and 2022 were included, and OCR use trends examined. The patients' characteristics were assessed at baseline and after 24months of OCR to assess the NEDA-3 status. This study included 421 patients: 33 (7.9%) with PP and 388 (92.1%) with RR MS. Among these, 67 (17.3%) were naïve, while switchers from first- and second-line disease-modifying therapies (DMTs) were 199 (51.3%) and 122 (31.4%), respectively. An increasing trend in OCR use was reported. For six patients treated with rituximab, OCR was chosen to improve tolerability; for 390 switcher patients, the choice was due to ineffectiveness; and for 25, as an exit strategy from natalizumab due to JC virus positivity. NEDA-3 status was calculated for subjects exposed to 24months of OCR and was achieved by 163/192 (84.9%) RR patients and 9/16 (56%) PP patients, with younger age (p = 0.048) and annualized relapse rate in the year previous to OCR (p = 0.005) emerging as determinants. For the 25 patients who switched to OCR after natalizumab, no clinical or MRI activity after 12months was reported. OCR has been confirmed to be a highly efficacious option for patients with PP and RR MS, even proving to be a valid exit strategy for natalizumab.

Ozanimod-mediated remission in experimental autoimmune encephalomyelitis is associated with enhanced activity of CNS CD27low/- NK cell subset.

Ozanimod (RPC1063) is an immunomodulator that has been recently approved by the FDA (2020) for the treatment of relapsing-remitting multiple sclerosis (RRMS). It is a selective agonist of the sphingosine-1-phophate receptors 1 and 5, expressed on naïve and central memory T and B cells, as well as natural killer (NK) cells, and is involved in lymphocyte trafficking. Oral administration of ozanimod was reported to result in rapid and reversible reduction in circulating lymphocytes in multiple sclerosis (MS) patients, however, only minimal effect on NK cells was observed. In this study, we sought to investigate the effect of ozanimod on NK cells and assess whether they play any role in ozanimod-induced remission in experimental autoimmune encephalomyelitis (EAE), the animal model of MS. Active EAE induction was done in C57BL/6 female mice, followed by daily oral treatment with ozanimod (0.6mg/kg) starting at disease onset (score 1). Flow cytometry of blood and CNS was performed 24 hours after the last oral dose of ozanimod treatment in diseased mice. Histological analysis of lumbar spinal cord was performed for evaluating the level of inflammation and demyelination. Depletion of peripheral NK cells was done using anti-NK1.1 mouse antibody (mAb) at day 5 post-EAE induction. Ozanimod was effective in reducing the clinical severity of EAE and reducing the percentage of autoreactive CD4+ and CD8+ T cells along with significant inhibition of lymphocyte infiltration into the spinal cord, accompanied by reversed demyelination. Furthermore, ozanimod treatment resulted in a significant increase in the frequency of total NK cells in the blood and CNS along with upregulation of the activating receptor NKG2D on CD27low/- NK cell subset in the CNS. The effectiveness of ozanimod treatment in inhibiting the progression of the disease was reduced when NK cells were depleted using anti-NK1.1 mAb. The current study demonstrated that ozanimod treatment significantly improved clinical symptoms in EAE mice. Ozanimod and anti-NK1.1 mAb appear to function in opposition to one another. Collectively, our data suggest that ozanimod-mediated remission is associated with an increased percentage of total NK cells and CD27low/- NK cells expressing the activating receptor, NKG2D in the CNS.