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The use of disease-modifying therapies (DMT) has led to a paradigm shift in the management of multiple sclerosis. A comprehensive narrative review was conducted through an extensive literature search including Medline and Google Scholar to elucidate the link between DMT and the propensity of cutaneous malignancies. Sphingosine-1-phosphate receptor modulators, such as fingolimod and siponimod are associated with a higher risk of basal cell carcinoma (BCC), but not squamous cell carcinoma, or melanoma. The associated physiopathological mechanisms are not fully understood. Alemtuzumab and cladribine show isolated associations with skin cancer. Regarding other DMT, no increased risk has ever been found. Given the evidence currently available, it is of paramount importance to advocate for necessary dermatological assessments that should be individualized to the risk profile of each patient. Nonetheless, additional prospective studies are still needed to establish efficient dermatological follow-up protocols., (Copyright © 2024 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objectives: This study aimed to evaluate whether switching disease-modifying therapies (DMTs) from sphingosine-1 phosphate (S1P) receptor modulators to either natalizumab (NTZ) or dimethyl fumarate (DMF) could restore the effectiveness of SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis (MS)., Methods: This study included 9 controls and 33 patients with MS: 7 patients treated with DMF, 7 patients treated with NTZ, 9 patients treated with S1P receptor modulators, and 10 patients who had switched DMTs from S1P receptor modulators to DMF or NTZ by the second vaccine dose. The patients who had switched DMTs were classified into two groups, based on whether their lymphocyte counts were above or below 1000/μL at the time of vaccination. In addition, relapses within 6 months after switching DMTs were also evaluated in these patients. Six months after the second dose of the vaccination, anti-SARS-CoV-2 spike antibodies were evaluated in all participants, and spike specific CD4 + T cells were also assessed in patients who had switched DMTs from S1P receptor modulators., Results: Patients treated with S1P receptor modulators had lower levels of anti-SARS-CoV-2 spike antibodies than the controls and patients treated with DMF and NTZ. On the other hand, in patients who had switched DMTs from S1P receptor modulators, a recovery of lymphocyte counts above 1000/µL resulted in restored humoral and cellular immune responses to the vaccination. There were no neurological relapses in patients who had switched DMTs from S1P receptor modulators to NTZ., Conclusion: SARS-CoV-2 mRNA vaccination is expected to be effective in patients whose lymphocyte counts have recovered due to switching DMTs from S1P receptor modulators. Switching DMTs from S1P receptor modulators to NTZ before vaccination may be beneficial in achieving efficacy for SARS-CoV-2 mRNA vaccination, with a reduced risk of relapse., Competing Interests: Declaration of Competing Interest Tatsusada Okuno received research grants from Biogen and Mitsubishi Tanabe Pharma Corp. He has also received speaker fees from Biogen, Novartis and Mitsubishi Tanabe Pharma Corporation. Ichino Chinen is an employee of Biogen Japan and owns stocks of Biogen. Makoto Kinoshita has received speaker fees from Biogen and Novartis. Hisashi Murata has received payment for lectures from Alexion Pharmaceuticals Inc. and Mitsubishi Tanabe Pharma Corp. Hideki Mochizuki has received speaker fees from Biogen, Novartis and Mitsubishi Tanabe Pharma Corp., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

So far, only a small number of medications are effective in progressive multiple sclerosis (MS). The sphingosine-1-phosphate-receptor (S1PR)-1,5 modulator siponimod, licensed for progressive MS, is acting both on peripheral immune cells and in the central nervous system (CNS). So far it remains elusive, whether those effects are related to the neurotrophin brain derived neurotrophic factor (BDNF). We hypothesized that BDNF in immune cells might be a prerequisite to reduce disease activity in experimental autoimmune encephalomyelitis (EAE) and prevent neurotoxicity. MOG 35-55 immunized wild type (WT) and BDNF knock-out (BDNF ko ) mice were treated with siponimod or vehicle and scored daily in a blinded manner. Immune cell phenotyping was performed via flow cytometry. Immune cell infiltration and demyelination of spinal cord were assessed using immunohistochemistry. In vitro, effects on neurotoxicity and mRNA regulation were investigated using dorsal root ganglion cells incubated with EAE splenocyte supernatant. Siponimod led to a dose-dependent reduction of EAE scores in chronic WT EAE. Using a suboptimal dosage of 0.45 µg/day, siponimod reduced clinical signs of EAE independent of BDNF-expression in immune cells in accordance with reduced infiltration and demyelination. Th and Tc cells in secondary lymphoid organs were dose-dependently reduced, paralleled with an increase of regulatory T cells. In vitro, neuronal viability trended towards a deterioration after incubation with EAE supernatant; siponimod showed a slight rescue effect following treatment of WT splenocytes. Neuronal gene expression for CCL2 and CX3CL1 was elevated after incubation with EAE supernatant, which was reversed after siponimod treatment for WT, but not for BNDF ko . Apoptosis markers and alternative death pathways were not affected. Siponimod exerts both anti-inflammatory and neuroprotective effects, partially related to BDNF-expression. This might in part explain effectiveness during progression in MS and could be a target for therapy., (© 2024. The Author(s).)

Osteoporosis is the most common bone disorder, in which an imbalance between osteoclastic bone resorption and osteoblastic bone formation disrupts bone homeostasis. Osteoporosis management using anti-osteoclastic agents is a promising strategy; however, this remains an unmet need. Sphingosine-1-phosphate (S1P) and its receptors (S1PRs) are essential for maintaining bone homeostasis. Here, we identified that Siponimod, a Food and Drug Administration-approved S1PR antagonist for the treatment of multiple sclerosis, shows promising therapeutic effects against osteoporosis by inhibiting osteoclast formation and function. We found that Siponimod inhibited osteoclast formation in a dose-dependent manner without causing cytotoxicity. Podosome belt staining and bone resorption assays indicated that Siponimod treatment impaired osteoclast function. Western blot and qPCR assays demonstrated that Siponimod suppressed the expression of osteoclast-specific markers, including C-Fos, Nftac1, and Ctsk. Mechanistically, we validated that Siponimod downregulated receptor activator of nuclear factor kappa B ligand (RANKL)-induced Mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) signaling pathways during osteoclastogenesis. Moreover, in a preclinical mouse model, Siponimod prevented ovariectomy-induced bone loss by suppressing osteoclast activity in vivo. Collectively, these results suggest that Siponimod could serve as an alternative therapeutic agent for the treatment of osteoporosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Coronavirus disease 2019 (COVID-19) vaccination has been associated with a dampened humoral and/or cellular immune response in patients with multiple sclerosis (MS) who were concurrently on disease-modifying treatment (DMT) with B-cell depleting agents or sphingosine-1-phosphate receptor modulators (S1PRMs). Our main goal was to investigate the impact of these DMT classes on the clinical effectiveness of COVID-19 vaccination., Methods: Since March 2020, demographics and clinical data of patients with MS who developed COVID-19 have been collected at the Belgian National MS Centre in Melsbroek. Patients were considered to be 'protected by vaccination' if they were (i) fully vaccinated and (ii) tested positive for COVID-19 in the period ranging from 14 days to 6 months after the last administered vaccine., Results: On 19 December 2022, 418 COVID-19 cases were retrospectively identified in 389 individual patients. Hospitalization and mortality rates resulting from the infection were 10.8% and 2.4%, respectively. Being 'unprotected by vaccination' was significantly associated with a worse COVID-19 outcome (i.e., hospitalization and/or death) in the total cohort (N = 418, odds ratio [OR] 3.96), in patients on ongoing DMT other than anti-CD20 agents or S1PRMs (N = 123, OR 31.75) and in patients without DMT (N = 182, OR 5.60), but not in those receiving anti-CD20 agents (N = 91, OR 0.39); the S1PRMs subgroup was considered too small (22 infections) for any meaningful analysis., Conclusions: Coronavirus disease 2019 vaccination protects against severe infection in patients with MS but it was not possible to confirm this effect in those on DMT with B-cell depleting agents., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Maladjusted immune responses to the coronavirus disease 2019 (COVID-19), for example, cytokine release syndrome, may result in immunopathology and acute respiratory distress syndrome. Sphingosine-1-phosphate (S1P), a bioactive lipid mediator, and its S1P receptor (S1PR) are crucial in maintaining endothelial cell chemotaxis and barrier integrity. Apart from the S1P1 receptor-mediated mechanisms of sequestration of cytotoxic lymphocytes, including Th-17 and S1P1/2/3-mediated endothelial barrier functions, S1PR modulators may also attenuate cytokine release via activation of serine/threonine protein phosphatase 2A and enhance the pulmonary endothelial barrier via the c-Abl tyrosine kinase pathway. Chronic treatment with fingolimod (S1PR1,3,4,5 modulator) and siponimod (S1PR1,5 modulator) has demonstrated efficacy in reducing inflammatory disease activity and slowing down disease progression in multiple sclerosis. The decision to selectively suppress the immunity of a critically ill patient with COVID-19 remains a difficult choice. It has been suggested that treatment with fingolimod or siponimod may be appropriate to attenuate severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced hyperinflammation in patients with COVID-19 since these patients are already monitored in an intensive care setting. Here, we review the use of S1PR modulators, fingolimod and siponimod, in regulating the inflammatory response to SARS-CoV-2 with the aim of understanding their potential rationale use in patients with COVID-19.

Multiple sclerosis (MS) is a neurological, immune-mediated demyelinating disease that affects people in the prime of life. Environmental, infectious, and genetic factors have been implicated in its etiology, although a definitive cause has yet to be determined. Nevertheless, multiple disease-modifying therapies (DMTs: including interferons, glatiramer acetate, fumarates, cladribine, teriflunomide, fingolimod, siponimod, ozanimod, ponesimod, and monoclonal antibodies targeting ITGA4, CD20, and CD52) have been developed and approved for the treatment of MS. All the DMTs approved to date target immunomodulation as their mechanism of action (MOA); however, the direct effects of some DMTs on the central nervous system (CNS), particularly sphingosine 1-phosphate (S1P) receptor (S1PR) modulators, implicate a parallel MOA that may also reduce neurodegenerative sequelae. This review summarizes the currently approved DMTs for the treatment of MS and provides details and recent advances in the molecular pharmacology, immunopharmacology, and neuropharmacology of S1PR modulators, with a special focus on the CNS-oriented, astrocyte-centric MOA of fingolimod., Competing Interests: Declaration of Competing Interest Y.K. declares no competing financial interests. JC has received grant support from Janssen, Novartis, and Bristol Meyers Squibb., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Multiple sclerosis (MS) is an immune-mediated disorder of the CNS manifested by recurrent attacks of neurological symptoms (related to focal inflammation) and gradual disability accrual (related to progressive neurodegeneration and neuroinflammation). Sphingosine-1-phosphate-receptor (S1PR) modulators are a class of oral disease-modifying therapies (DMTs) for relapsing MS. The first S1PR modulator developed and approved for MS was fingolimod, followed by siponimod, ozanimod, and ponesimod. All are S1P analogues with different S1PR-subtype selectivity. They restrain the S1P-dependent lymphocyte egress from lymph nodes by binding the lymphocytic S1P-subtype-1-receptor. Depending on their pharmacodynamics and pharmacokinetics, they can also interfere with other biological functions., Areas Covered: Our narrative review covers the PubMed English literature on S1PR modulators in MS until August 2022. We discuss their pharmacology, efficacy, safety profile, and risk management recommendations based on the results of phase II and III clinical trials. We briefly address their impact on the risk of infections and vaccines efficacy., Expert Opinion: S1PR modulators decrease relapse rate and may modestly delay disease progression in people with relapsing MS. Aside their established benefit, their place and timing within the long-term DMT strategy in MS, as well as their immunological effects in the new and evolving context of the post-COVID-19 pandemic and vaccination campaigns warrant further study.

Background: Sphingosine-one phosphate receptor (S1PR) modulation inhibits S1PR1-mediated lymphocyte migration, lesion formation and positively-impacts on active multiple sclerosis (MS). These S1PR modulatory drugs have different: European Union use restrictions, pharmacokinetics, metabolic profiles and S1PR receptor affinities that may impact MS-management. Importantly, these confer useful properties in dealing with COVID-19, anti-viral drug responses and generating SARS-CoV-2 vaccine responses., Objective: To examine the biology and emerging data that potentially underpins immunity to the SARS-CoV-2 virus following natural infection and vaccination and determine how this impinges on the use of current sphingosine-one-phosphate modulators used in the treatment of MS., Methods: A literature review was performed, and data on infection, vaccination responses; S1PR distribution and functional activity was extracted from regulatory and academic information within the public domain., Observations: Most COVID-19 related information relates to the use of fingolimod. This indicates that continuous S1PR1, S1PR3, S1PR4 and S1PR5 modulation is not associated with a worse prognosis following SARS-CoV-2 infection. Whilst fingolimod use is associated with blunted seroconversion and reduced peripheral T-cell vaccine responses, it appears that people on siponimod, ozanimod and ponesimod exhibit stronger vaccine-responses, which could be related notably to a limited impact on S1PR4 activity. Whilst it is thought that S1PR3 controls B cell function in addition to actions by S1PR1 and S1PR2, this may be species-related effect in rodents that is not yet substantiated in humans, as seen with bradycardia issues. Blunted antibody responses can be related to actions on B and T-cell subsets, germinal centre function and innate-immune biology. Although S1P1R-related functions are seeming central to control of MS and the generation of a fully functional vaccination response; the relative lack of influence on S1PR4-mediated actions on dendritic cells may increase the rate of vaccine-induced seroconversion with the newer generation of S1PR modulators and improve the risk-benefit balance IMPLICATIONS: Although fingolimod is a useful asset in controlling MS, recently-approved S1PR modulators may have beneficial biology related to pharmacokinetics, metabolism and more-restricted targeting that make it easier to generate infection-control and effective anti-viral responses to SARS-COV-2 and other pathogens. Further studies are warranted., Competing Interests: Declaration of Competing Interest Although considered to be irrelevant, EF, GP, LKJ and ASK have nothing relevant to declare. In the past 3 years DB has received honoraria for teaching and consultancy, unrelated to this work from inMuneBio, Merck Serono, Novartis, Roche, Teva. GG has received honoraria and meeting support from AbbVie Biotherapeutics, Biogen, Novartis, Merck Sharp Dome, Merck Serono, Roche, Sanofi Genzyme, Synthon, Teva. He also serves as chief editor for Multiple Sclerosis and Related Disorders and has been an academic director of the Neurology Academy, supported by Roche. KS has received research support from: Biogen, Merck KGaA, and Novartis and speaking/consultancy honoraria from: Biogen, EMD Serono, Medscape; Merck KGaA, Novartis, Roche, Sanofi-Genzyme, and Teva, (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: S1P receptor modulators are oral Disease-Modifying Therapies (DMTs) for Multiple Sclerosis, which were associated with cases of basal cell carcinoma in clinical trials. This study aims at investigating in a real-world adverse event reporting system whether S1P receptor modulators increase the risk of skin cancer reporting, compared to other DMTs., Methods: Adverse event reports from the FDA Adverse Event Reporting System (FAERS) were extracted, cleaned, and analyzed from 2004Q1 until 2020Q4. The crude and adjusted Reported Odds Ratios (cROR, aROR) for the outcomes: basal cell carcinoma, squamous cell carcinoma, or melanoma were calculated for all DMTs. In a sensitivity analysis, we looked at each outcome separately., Results: The aROR (95%CI) of siponimod was: 9.68 (5.48-15.79) and of fingolimod 4.54 (3.86-5.32), indicating a safety signal of S1P receptor modulators for skin cancer. Ozanimod had only 52 complete reports without any cases. In the sensitivity analysis, siponimod showed a signal only for basal cell carcinoma: 22.83 (12.27-38.83), while fingolimod for all outcomes separately, including melanoma: 3.02 (2.31-3.89). Notably, among the other DMTs, alemtuzumab: 4.40 (2.98-6.25) and cladribine: 3.28 (1.17-7.13) presented also a signal for disproportionate reporting, while ocrelizumab showed a signal in the sensitivity analysis only for melanoma 2.55 (1.21-4.65)., Conclusions: S1P receptors seem to increase skin cancer reporting on FAERS, and the association is strongest for basal cell carcinomas. Therefore, close dermatologic surveillance before- and during therapy is needed. Whether fingolimod and ocrelizumab also increase the risk of melanoma needs further investigation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Pediatric-onset multiple sclerosis (POMS) is a rare neuroinflammatory and neurodegenerative disease that has a significant impact on long-term physical and cognitive patient outcomes. A small percentage of multiple sclerosis (MS) diagnoses occur before the age of 18 years. Before treatment initiation, a careful differential diagnosis and exclusion of other similar acquired demyelinating syndromes such as anti-aquaporin-4-associated neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody spectrum disorder (MOGSD) is warranted. The recent 2017 changes to the McDonald criteria can successfully predict up to 71% of MS diagnoses and have good specificity of 95% and sensitivity of 71%. Additional measures such as the presence of T1-weighted hypointense lesions and/or contrast-enhancing lesions significantly increase the accuracy of diagnosis. In adults, early use of disease-modifying therapies (DMTs) is instrumental to a better long-term prognosis, including lower rates of relapse and disability worsening, and numerous FDA-approved therapies for adult-onset MS are available. However, unlike their adult counterparts, the development, testing, and regulatory approval of POMS treatments have been significantly slower and hindered by logistic and/or ethical considerations. Currently, only two MS DMTs (fingolimod and teriflunomide) have been tested in large phase III trials and approved by regulatory agencies for use in POMS. First-line therapies not approved by the FDA for use in children (interferon-β and glatiramer acetate) are also commonly used and result in a significant reduction in inflammatory activity when compared with non-treated POMS patients. An increasing number of POMS patients are now treated with moderate efficacy therapies such as dimethyl fumarate and high-efficacy therapies such as natalizumab, anti-CD20 monoclonal antibodies, anti-CD52 monoclonal antibodies, and/or autologous hematopoietic stem cell transplantation. These high-efficacy DMTs generally provide additional reduction in inflammatory activity when compared with the first-line medications (up to 62% of relapse-rate reduction). Therefore, a number of phase II and III trials are currently investigating their efficacy and safety in POMS patients. In this review, we discuss potential changes in the regulatory approval process for POMS patients that are recommended for DMTs already approved for the adult MS population, including smaller sample size for pharmacokinetic/pharmacodynamic studies, MRI-centered primary outcomes, and/or inclusion of teenagers in the adult trials., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Ozanimod, a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity selectively to S1P receptor subtypes 1 (S1P 1 ) and 5 (S1P 5 ), is approved for the treatment of relapsing multiple sclerosis (MS) in multiple countries. Ozanimod profiling revealed a species difference in its potency for S1P 5 in mouse, rat, and canine compared with that for human and monkey. Site-directed mutagenesis identified amino acid alanine at position 120 to be responsible for loss of activity for mouse, rat, and canine S1P 5 , and mutation back to threonine as in human/monkey S1P 5 restored activity. Radioligand binding analysis performed with mouse S1P 5 confirmed the potency loss is a consequence of a loss of affinity of ozanimod for mouse S1P 5 and was restored with mutation of alanine 120 to threonine. Study of ozanimod in preclinical mouse models of MS can now determine the S1P receptor(s) responsible for observed efficacies with receptor engagement as measured using pharmacokinetic exposures of free drug. Hence, in the experimental autoimmune encephalomyelitis model, ozanimod exposures sufficient to engage S1P 1 , but not S1P 5 , resulted in reduced circulating lymphocytes, disease scores, and body weight loss; reduced inflammation, demyelination, and apoptotic cell counts in the spinal cord; and reduced circulating levels of the neuronal degeneration marker, neurofilament light. In the demyelinating cuprizone model, ozanimod prevented axonal degradation and myelin loss during toxin challenge but did not facilitate enhanced remyelination after intoxication. Since free drug levels in this model only engaged S1P 1, we concluded that S1P 1 activation is neuroprotective but does not appear to affect remyelination. SIGNIFICANCE STATEMENT: Ozanimod, a selective modulator of human sphingisone 1-phosphate receptor subtypes 1 and 5 (S1P 1/5 ), displays reduced potency for rodent and dog S1P 5 compared with human, which results from mutation of threonine to alanine at position 120. Ozanimod can thus be used as a selective S1P 1 agonist in mouse models of multiple sclerosis to define efficacies driven by S1P 1 but not S1P 5 . Based on readouts for experimental autoimmune encephalomyelitis and cuprizone intoxication, S1P 1 modulation is neuroprotective, but S1P 5 activity may be required for remyelination., (Copyright © 2021 The Author(s).)

The sphingosine 1-phosphate (S1P) signalling pathways have important and diverse functions. S1P receptors (S1PRs) have been proposed as a therapeutic target for various diseases due to their involvement in regulation of lymphocyte trafficking, brain and cardiac function, vascular permeability, and vascular and bronchial tone. S1PR modulators were first developed to prevent rejection by the immune system following renal transplantation, but the only currently approved indication is multiple sclerosis. The primary mechanism of action of S1PR modulators in multiple sclerosis is through binding S1PR subtype 1 on lymphocytes resulting in internalisation of the receptor and loss of responsiveness to the S1P gradient that drives lymphocyte egress from lymph nodes. The reduction in circulating lymphocytes presumably limits inflammatory cell migration into the CNS. Four S1PR modulators (fingolimod, siponimod, ozanimod, and ponesimod) have regulatory approval for multiple sclerosis. Preclinical evidence and ongoing and completed clinical trials support development of S1PR modulators for other therapeutic indications., Competing Interests: Declaration of interests JAC received personal compensation for consulting for Adamas, Atara, Bristol Myers Squibb, Convelo, MedDay, and Mylan, and for serving as an editor of Multiple Sclerosis Journal. MPM has served on scientific advisory boards for Genzyme and Genentech, received research funding from Novartis, and receives funding via a KL2 (KL2TR002547) grant from the Clinical and Translational Science Collaborative of Cleveland, from the National Center for Advancing Translational Sciences component of the National Institutes of Health., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. In recent years, many disease-modifying therapies (DMT) have been approved for MS treatment. For this reason, a profound knowledge of the characteristics and indications of the available compounds is required to tailor the therapeutic strategy to the individual patient characteristics. This should include the mechanism of action and pharmacokinetic of the drug, the safety and efficacy profile provided by clinical trials, as well as the understanding of possible side effects. Moreover, the evolving knowledge of the disease is paving the way to new and innovative therapeutic approaches, as well as the development of new biomarkers to monitor the therapeutic response and to guide the clinician's therapeutic choices. In this review we provide a comprehensive overview on currently approved therapies in MS and the emerging evidence-based strategies to adopt for initiating, monitoring, and eventually adapting a therapeutic regimen with DMT., (Copyright © 2021 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Multiple sclerosis is a major socio-economical burden as it represents the most common cause of non-traumatic neurological disability in young adults [1]. It affects also children with a lower prevalence and incidence but remains a major concern as disability may occur later during their adulthood. Therefore, there is an absolute need for earlier diagnosis and treatment. In this review, we would focus on how these objectives can be achieved., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Multiple sclerosis (MS) is an autoimmune inflammatory disease characterized by demyelination, axonal loss, and synaptic impairment in the central nervous system (CNS). The available therapies aim to reduce the severity of the pathology during the early inflammatory stages, but they are not effective in the chronic stage of the disease. In this phase, failure in endogenous remyelination is associated with the impairment of oligodendrocytes progenitor cells (OPCs) to migrate and differentiate into mature myelinating oligodendrocytes. Therefore, stimulating differentiation of OPCs into myelinating oligodendrocytes has become one of the main goals of new therapeutic approaches for MS. Different disease-modifying therapies targeting sphingosine-1-phosphate receptors (S1PRs) have been approved or are being developed to treat MS. Besides their immunomodulatory effects, growing evidence suggests that targeting S1PRs modulates mechanisms beyond immunomodulation, such as remyelination. In this context, this review focuses on the current understanding of S1PR modulators and their direct effect on OPCs and oligodendrocytes.

Background: In PARADIG MS , a double-blind phase III trial in 215 paediatric patients with multiple sclerosis (MS) (10 to <18 years), fingolimod administered for up to 2 years significantly reduced the annualised relapse rate (ARR) and rate of new/newly enlarged T2 (n/neT2) lesions compared with interferon (IFN) β-1a., Objectives: To investigate (1) differences between treatment groups across subpopulations (treatment-naïve, younger/prepubertal patients); (2) disability progression., Methods: ARRs at 10, 11 and 12 years were estimated based on predefined modelling extrapolations. Changes in Expanded Disability Status Scale (EDSS), and in 3 month (3M) and 6 month (6M) confirmed disability progression (CDP) were evaluated post hoc., Results: In the treatment-naïve subpopulation, fingolimod reduced ARR and n/neT2 lesions by 85.8% and 53.4%, respectively versus INF β-1a (both p<0.001), compared with 81.9% and 52.6% in the overall population. Model-based ARR reductions in younger patients (≤12 years) were 91.9%-94.6%. Twice as many IFN β-1a-treated than fingolimod-treated patients had worse EDSS scores at study end (20.6% vs 10.5%, p=0.043). Risk reductions in 3M-CDP and 6M-CDP were 77.2% (p=0.007) and 80.2% (p=0.040), respectively., Conclusions: Fingolimod in paediatric MS was associated with consistent control of disease activity versus IFN β-1a (including treatment-naïve and younger patients) and resulted in less disability progression for up to 2 years., Trial Registration Number: NCT01892722., Competing Interests: Competing interests: KD received personal compensation for speaker activities from Novartis. PH received compensation for serving on a scientific advisory board from Novartis, and for speaking from Bayer Health care. BB has served as a remunerated central MRI reviewer for the present trial (Novartis). EW volunteers on an advisory board for a Novartis trial. She is a site PI for clinical trials with Roche and Novartis. JG in the last 3 years has received honoraria for lectures and consultancy fees from Bayer, Teva and Novartis. LK has received personal compensation for activities as a speaker, consultant and/or participant on an advisory board from Biogen Idec, Novartis, Teva Neurosciences and Multicell. In addition, LK has received royalty or licence fees from ER Squibb & Sons, Avenir, Johnson & Johnson and Osmotica, and has received research support from Novartis, Biogen Idec, Celgene Corporation and Genentech. TC has received personal compensation for advisory boards/consulting for F. Hoffman-La Roche, Biogen and Novartis; TC has also received financial support for research activities from Biogen, Merck Serono, Verily and Novartis. TS, GLP and MM are employees of Novartis., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Siponimod fumarate (BAF-312) is a synthetic sphingosine 1- phosphate (S1P) receptor modulator, which exerts immunomodulating effects mediated by B- and T-cell sequestration in secondary lymphoid organs. S1P receptor modulators have consistently shown a significant benefit on relapse rate and other measures of disease activity in patients with relapsing multiple sclerosis (MS), compared with both placebo and active comparator. However, most clinical trials of S1P receptor modulators--as well as other therapies for MS--lack evidence of a significant benefit on disability progression. A phase III trial of siponimod for secondary progressive MS showed a significant effect of the active drug compared with placebo on reduction of disability progression. Siponimod exhibits selective affinity for types 1 and 5 S1P receptors, indicating a possible lower risk of bradycardia and vasoconstriction compared with modulators with type 3 S1P receptor affinity. Current evidence supporting siponimod efficacy for secondary progressive MS is reviewed in the present article., (Copyright 2020 Clarivate Analytics.)

Introduction : Fingolimod, the first oral disease-modifying treatment (DMT) in multiple sclerosis (MS), is a sphingosine 1-phosphate receptor (S1PR) ligand. Approved in 2010, fingolimod has been extensively studied and has been credited with several mechanisms of actions that contribute to its efficacy in MS, among which is the regulation of lymphocyte circulation between the central nervous system and the periphery. Concerns about toxicity, off-target effects, and real-life performance have been raised over time in post-marketing studies of such that next-generation sphingosine-1 phosphate receptor ligands are now being developed. Areas covered : Herein, the authors expand upon previous systematic reviews obtained via PubMed and through their expert opinion on fingolimod use in clinical practice. Long-term data including long-term efficacy, safety, tolerability, and management especially within growing DMT options and pre-treatment constellation in MS patients are discussed, together with the results of an increased understanding of the chemistry underlying the structure-activity relationship. Expert opinion : Despite the limitations illustrated in this article, fingolimod still constitutes a paradigm shift in MS treatment. However, although immunomodulation via S1PRs on lymphocytes has represented a major breakthrough in the clinical management of MS, modifying the evolution of progressive MS will likely require the development of approaches other than merely targeting S1PRs.

Siponimod (Mayzent ® ) is an oral selective sphingosine 1-phosphate receptor subtypes 1 and 5 (S1PR 1,5 ) modulator being developed by Novartis Pharmaceuticals for the treatment of multiple sclerosis (MS) and intracerebral haemorrhage. In March 2019, siponimod received its first global approval in the USA, for the treatment of adults with relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease and active secondary progressive disease. Siponimod is under regulatory review in the EU and Japan for secondary progressive MS. This article summarizes the milestone in the development of siponimod leading to this first global approval for MS in the USA.