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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., Competing Interests: Declaration of competing interest EHC has no disclosures. TAH has received honoraria for talks, advisory boards or support for scientific meetings from Bayer-Schering, Novartis, Biogen Idec, Merck, Teva, Merck, Alexion, Bristol Myers Squibb and Sanofi-Genzyme. He was the principal investigator on the phase IV study “Onboarding of siponimod in secondary progressive multiple sclerosis patients in Australia: Novel, real world evidence from the MSGo digital support program” study funded by Novartis. He is Co-Editor of Advances in Clinical Neuroscience and Rehabilitation and serves on the editorial boards of Journal of Neuroimmunology and Frontiers in Neurology., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Cladribine is an oral disease-modifying drug authorized by the European Medicine Agency for the treatment of highly active relapsing multiple sclerosis (MS)., Objectives: To provide real-world evidence of cladribine's effectiveness and safety in people with MS (pwMS)., Methods: A retrospective observational multi-center, multi-national study of pwMS who were started on cladribine tablets in ten centers from five European countries., Results: We identified 320 pwMS treated with cladribine tablets. The most common comorbidities were arterial hypertension and depression. Three patients had resolved hepatitis B infection, while eight had positive Quantiferon test prior to cladribine commencement. There were six pwMS who had malignant diseases, but all were non-active. During year 1, 91.6% pwMS did not have EDSS worsening, 86.9% were relapse-free and 72.9% did not have MRI activity. During the second year, 90.2% did not experience EDSS worsening, 86.5% were relapse-free and 75.5% did not have MRI activity. NEDA-3 was present in 58.0% pwMS in year 1 and in 54.2% in year 2. In a multivariable logistic regression model age positively predicted NEDA-3 in year 1. The most common adverse events were infections and skin-related adverse events. Lymphopenia was noted in 54.7% of pwMS at month 2 and in 35.0% at month 6. Two pwMS had a newly discovered malignant disease, one breast cancer, and one melanoma, during the first year of treatment., Conclusion: Our real-world data on the effectiveness and safety of cladribine tablets are comparable to the pivotal study and other real-world data with no new safety signals., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

We investigated the impact of dimethyl fumarate (DMF), an oral therapy for relapsing multiple sclerosis (MS), on blood microRNA (miRNA) signatures and neurofilament light (NFL) levels. DMF normalized miR-660-5p and modulated various miRNAs associated with the NF-kB pathway. These alterations reached a peak 4-7 months after treatment. Notably, particular miRNAs correlated with high or low NFL levels, implying their potential role as markers of treatment efficacy. Our findings broaden the understanding of DMF's immunomodulatory effects and may aid in predicting treatment responses., Competing Interests: Declaration of Competing Interest The authors declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article. MLE is grateful for financial support from Lundbeckfonden (R347-2020-2454). TS has received travel grants from Biogen, Merck, Novartis, and Roche, has received research grants from Biogen and Roche, has served on advisory boards for Biogen, Merck, Novartis and Roche. ZI is grateful for financial support from Biogen (DK-BGT-11542), from Scleroseforeningen (A25341, A29926, A31829, A33600), University of Southern Denmark (14/24200), Odense University Hospital (5798002573633)., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objectives: Immune responses in the central nervous system (CNS) are highly compartmentalized and cerebrospinal fluid (CSF) in particular often reflects CNS pathology better than peripheral blood. While CSF leukocytes are known to be distinct from blood, the immediate effects of peripheral leukocyte depletion on CSF leukocytes have not been studied in humans., Methods: We here analyzed CSF and blood from two relapsing-remitting multiple sclerosis (RRMS) patients early after peripheral leukocyte depletion with the anti-CD52 antibody alemtuzumab compared to untreated RRMS and control patients using single cell RNA-sequencing., Results: As expected for alemtuzumab, most leukocyte lineages including T cells were synchronously depleted from CSF and blood, while - surprisingly - pDCs were maintained in CSF but depleted from blood by alemtuzumab. Transcriptionally, genes associated with migration were elevated only in the CSF after alemtuzumab. Predicted cellular interactions indicated a central role of pDCs and enhanced migration signaling in the CSF after alemtuzumab., Discussion: The CSF and blood compartments are thus partially uncoupled, emphasizing that the CNS is only partially accessible even for treatments profoundly affecting the blood., Competing Interests: Declaration of Competing Interest GMzH received compensation for serving on scientific advisory boards (LFB) and speaker honoraria (Alexion). HW is acting as a paid consultant for AbbVie, Actelion, Biogen, IGES, Johnson & Johnson, Novartis, Roche, Sanofi-Aventis, and the Swiss Multiple Sclerosis Society. The remaining authors declare no financial interests or conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Gut microbiota, the total microorganisms in our gastrointestinal tract, might have an implication in multiple sclerosis (MS), a demyelinating neurological disease. Our study included 50 MS patients and 21 healthy controls (HC). Twenty patients received a disease modifying therapy (DMT), interferon beta1a or teriflunomide, 19 DMT combined with homeopathy and 11 patients accepted only homeopathy. We collected in total 142 gut samples, two for each individual: at the study enrolment and eight weeks after treatment. We compared MS patients' microbiome with HC, we analysed its evolution in time and the effect of interferon beta1a, teriflunomide and homeopathy. There was no difference in alpha diversity, only two beta diversity results related to homeopathy. Compared to HC, untreated MS patients had a decrease of Actinobacteria, Bifidobacterium, Faecalibacterium prauznitzii and increased Prevotella stercorea, while treated patients presented lowered Ruminococcus and Clostridium. Compared to the initial sample, treated MS patients had a decrease of Lachnospiraceae and Ruminococcus and an increased Enterococcus faecalis. Eubacterium oxidoreducens was reduced after homeopathic treatment. The study revealed that MS patients may present dysbiosis. Treatment with interferon beta1a, teriflunomide or homeopathy implied several taxonomic changes. DMTs and homeopathy might influence the gut microbiota., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Cigarette smoking is the most prominent significant cause of death and morbidity. It is recognised as a risk factor for a number of immune mediated, inflammatory diseases including multiple sclerosis (MS). Here, we review the complex immunological effects of smoking on the immune system, which include enhancement of inflammatory responses with a parallel reduction of some immune defences, resulting in an increased susceptibility to infection and a persistent proinflammatory environment. We discuss the effect of smoking on the susceptibility, clinical course, disability, and mortality in MS, the likely benefits of smoking cessation, and the specific immunological effects of smoking in MS. In conclusion, smoking is an important environmental risk factor for MS occurrence and outcome, and it acts in significant part through immunological mechanisms., (Copyright © 2018. Published by Elsevier B.V.)

The detrimental effects of a high-salt diet on human health have received much attention in the past few years. While it has been well established that high dietary salt intake is related to cardiovascular diseases, there is growing evidence that excess salt also affects the immune system and might be considered as a risk factor in autoimmune diseases such as multiple sclerosis (MS). Several studies have implicated T helper 17 cells (Th17) in the pathogenesis of MS. We and others recently demonstrated that excessive salt enhances the differentiation of Th17 cells, inducing a highly pathogenic phenotype that aggravates experimental neuroinflammation. Moreover, a diet rich in sodium affects intestinal microbiota alongside increased intestinal Th17 cells, thus linking the detrimental effects of high salt consumption to the gut-immune axis. First human studies revealed an association of increased MS disease activity with elevated sodium chloride consumption, while more recent epidemiology studies in larger cohorts suggest no correlation between salt intake and MS. However, it is known that ordinary urinary sodium analyses and nutritional questionnaires do not necessarily correspond to the actual sodium load and more sophisticated analyses are needed. Moreover, studies revealed that sodium can temporarily be stored in the body. This review summarizes recent findings on the impact of salt on the immune system and discusses potential challenges investigating dietary salt intake as a risk factor in MS., (Copyright © 2018 Elsevier B.V. All rights reserved.)

High mobility group box 1 (HMGB1), a nonhistone chromatin associated protein, plays different roles according to the expression pattern such as the amount, cell location and sub-cellular location. It has been recently demonstrated that the systemic HMGB1 is associated with autoimmune encephalomyelitis. However, the dynamic change of HMGB1 expression pattern in spinal cords that may be involved in the progression of disease is not fully understood. In this study, the amount, cell location and subcellular location of HMGB1 in adult mice spinal cords during various stages of experimental autoimmune encephalomyelitis (EAE) are investigated. HMGB1 is expressed in the nuclei of spinal cord resident cells such as some astrocytes, microglia and a few neurons in normal situation. During EAE progression, the total and extracellular HMGB1 in the spinal cord are increased, more HMGB1 positive astrocytes and microglia are observed, and the intra-neurons HMGB1 in the ventral horn and around the central canal localize majorly in the cytoplasm accompanied by the increasing extracellular HMGB1. Blockade of HMGB1 in central nervous system (CNS) locally attenuates the severity of EAE significantly. Our findings indicate that the HMGB1 expression pattern in the spinal cord is associated with the progression of EAE. HMGB1 may be a potential target for autoimmune encephalomyelitis (multiple sclerosis in human) therapy., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Th17 cells play an important role in multiple sclerosis (MS) and its autoimmune model, experimental autoimmune encephalomyelitis (EAE). However, studies have not addressed how enhanced Th17 immune responses can affect demyelinating diseases. We induced EAE with MOG in RORγt transgenic C57BL/6 mice that overexpress a Th17 inducing transcription factor. RORγt transgenic mice developed more severe EAE than wild-type mice with more robust anti-MOG Th17 immune responses. In contrast, mice overexpressing T-bet, a Th1-inducing transcription factor, were resistant to EAE. Therefore, a genetic bias toward Th17 immune responses could contribute to CNS immunopathology., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Recent studies suggest that, beside focal lesions, diffuse inflammatory and degenerative processes take place throughout the MS brain. Especially, molecular alterations in the so-called normal appearing white matter suggest the induction of neuroprotective mechanisms against oxidative stress preserving cellular homeostasis and function. In this study we investigated whether in an animal model for MS, namely in experimental autoimmune encephalomyelitis (EAE), similar changes occur. We isolated normal appearing white and grey matter from the corpus callosum and the above lying cerebral cortex from DA rats with rMOG-induced EAE and carried out a gene expression analysis. Examination of corpus callosum revealed only minor changes in EAE rats. In contrast, we identified a number of gene expression alterations in the cerebral cortex even though morphological and cellular alterations were not evident. One of the most striking observations was the downregulation of genes involved in mitochondrial function as well as a whole set of genes coding for different glutamate receptors. Our data imply that molecular alterations are present in neurons far distant to inflammatory demyelinating lesions. These alterations might reflect degenerative processes induced by lesion-mediated axonal injury in the spinal cord. Our results indicate that the MOG-induced EAE in DA rats is a valuable model to analyze neuronal alterations due to axonal impairment in an acute phase of a MS-like disease, and could be used for development of neuroprotective strategies.

There have been significant advances in the treatment of multiple sclerosis (MS) in recent years, but further improvement in therapy is required as not all patients have responded optimally. An approach to enhancing MS treatment is to combine drugs that impact on different aspects of the disease process. We have described that the tetracycline derivative, minocycline, attenuates the severity of experimental autoimmune encephalomyelitis (EAE), a model of MS. Here, we have evaluated the combination of minocycline and glatiramer acetate (GA), a current therapy in MS, on the course of EAE in mice. This combination resulted in a significant reduction of disease severity and disease burden with attenuation of the inflammation, axonal loss and demyelination.

Chronic relapsing-remitting experimental autoimmune encephalomyelitis (CREAE) induced with myelin oligodendrocyte glycoprotein peptides 35-55 (MOG(35-55)) in NOD mice was successfully treated with brain-derived gangliosides (GA). The GA treatment suppressed the development and severity of CREAE, both clinically and histologically. Spleen cells from the GA-treated mice displayed markedly inhibited levels of MOG(35-55) specific proliferation and interferon-gamma production. Delayed-type hypersensitivity reactions to MOG(35-55) were suppressed by the GA treatment. GA modulate various T cell effector functions in CREAE and may be an effective therapeutic agent for autoimmune demyelinating diseases such as multiple sclerosis.