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BACKGROUND AND PURPOSE Studies reporting the baseline determinants of cognitive performance and treatment effect on cognition in patients with multiple sclerosis (MS) are limited. We investigated the baseline correlates of cognition and the long-term treatment effects of fingolimod 0.5 mg once daily on cognitive processing speed and attention in patients with relapsing-remitting MS. METHODS This post hoc analysis pooled data from the phase 3 FREEDOMS and FREEDOMS II trials (N = 1556). We assessed the correlation between baseline patient demographic and disease characteristics and baseline 3-second Paced Auditory Serial Addition Test (PASAT-3) scores (Spearman's rank test) and the changes from baseline in PASAT-3 (mixed model repeated measures model) in the fingolimod and placebo (up to 24 months) or placebo-fingolimod switched (from Month 24 up to 120 months) groups. Additionally, the predictive value of PASAT-3 score for future disease outcomes was assessed (Cox or logistic regression models). RESULTS Among the variables assessed, lower PASAT-3 score at baseline correlated with higher disease burden (total brain volume, T2 lesion volume, and Expanded Disability Status Scale score), longer disease duration and older age (p

Background and purpose: Real-world data on alemtuzumab are limited and do not provide evidence of its effectiveness after various disease-modifying therapies (DMTs). Our aim was to provide real-world data on the impact of clinical variables and previous DMTs on clinical response to alemtuzumab. Methods: Sixteen Italian multiple sclerosis centers retrospectively included patients who started alemtuzumab from January 2015 to December 2018, and recorded demographics, previous therapies, washout duration, relapses, Expanded Disability Status Scale (EDSS) score, and magnetic resonance imaging data. Negative binomial regression models were used to assess the effect of factors on annualized relapse (ARR) after alemtuzumab initiation. Results: We studied 322 patients (mean age 36.8years, median EDSS score 3, median follow-up 1.94years). Previous treatments were: fingolimod (106), natalizumab (80), first-line oral agents (56), first-line injectables (interferon/glatiramer acetate; 30), and other drugs (15). Thirty-five patients were treatment-naïve. The pre-alemtuzumab ARR was 0.99 and decreased to 0.13 during alemtuzumab treatment (p&nbsp

The frequency of CD20+ T cells was reported to be increased in several inflammatory conditions. We report that in patients with multiple sclerosis (MS), CD20+ T cells display a distinct proinflammatory phenotype with pathogenic properties. Anti-CD20 treatment virtually extinguished CD20+ T cells, which might explain its broad effectiveness. Dimethyl fumarate dampened activity of differentiated CD20+ T cells, whereas fingolimod reduced their abundance only as part of its overall T cell suppressive capacity. Natalizumab increased the frequency of CD20+ effector T cells. Widely used MS therapeutics affect this proinflammatory T cell subset with assumed pathogenic potential in a surprisingly differential manner. ANN NEUROL 2021 ANN NEUROL 2021;90:834-839.

Study objective To compare the effectiveness of oral fingolimod and conventional injectable disease-modifying agents (DMAs) using the composite endpoint of relapse or DMA treatment switch in patients with multiple sclerosis (MS). Design A retrospective longitudinal cohort study. Data source IBM MarketScan Commercial Claims and Encounters Database from 2010-2012. Patients Adults (≥18 years) with MS diagnosis (ICD-9-CM:340) who newly initiated DMAs. Intervention Oral fingolimod and conventional injectable DMAs (interferon beta and glatiramer acetate). Measurements Composite endpoint of time to relapse or DMA treatment switch. Main results The incident study cohort consisted of 1997 MS patients who initiated oral fingolimod (15.6%) or injectable (84.4%) DMAs. The proportion of patients who had a composite endpoint (relapse/DMA treatment switch) in oral fingolimod and injectable DMA users was found to be 16.72% and 27.16%, respectively. The Cox PH regression model with stabilized IPTW revealed that fingolimod is equally effective as conventional injectable DMAs in reducing the risk of experiencing the composite endpoint of relapse or DMA switch (adjusted hazard ratio [aHR]: 0.67, 95% CI: 0.43-1.03). Additional analysis among patients who were adherent also found no significant difference in the composite endpoint (aHR: 0.70, 95% CI 0.49-1.15) between oral fingolimod and injectable DMA users. Conclusions Oral fingolimod has similar effectiveness as conventional injectable DMAs in reducing the risk of experiencing the composite endpoint (relapse or DMA treatment switch). In addition, when assessed independently, oral fingolimod showed no difference in reducing the time to relapse or DMA treatment switch compared to injectable DMAs.

The sphingosine-1-phosphate (S1P) receptor modulator regulates lymphocyte trafficking, resulting in its depletion from circulation, which ultimately causes immunosuppression. In this study, we investigated the preventive effect of fingolimod (FTY720) in the non-obese type 2 diabetic model, Spontaneously Diabetic Torii (SDT) rats. The S1P receptor modulator, FTY720 (0.3 mg/kg p.o.), was administered for 12 weeks to SDT rats from 5 to 17 weeks of age. Based on our findings, FTY720 could suppress the incidence of diabetes in SDT rats. Further, glucose intolerance was improved in FTY720-treated SDT rats at 14 weeks of age. Based on the haematological and histological analyses performed at 17 to 18 weeks of age, a decrease in lymphocytes and monocytes in the peripheral blood and a decrease in lymphocyte and atrophy in spleen occurred in the FTY720-treated SDT rats. Furthermore, the pancreatic changes, such as inflammation, atrophy, and fibrosis in islets observed in SDT rats were improved by FTY720 treatment. These findings suggest that the immunomodulatory effects of FTY720 reduced the pancreatic lesion in SDT rats, thereby demonstrating its preventive effect against diabetes. The development of diabetes in SDT rats is related to disorders of the immune system. However, the S1P receptor modulator may be useful for treating type 2 diabetes.

Introduction Limited comparative effectiveness data for rituximab (RTX) versus natalizumab (NTZ), fingolimod (FTY), and dimethyl fumarate (DMF) for the treatment of multiple sclerosis (MS) exist. Methods Clinician‐reported data on patients prescribed RTX, NTZ, FTY, or DMF for the treatment of MS at the Rocky Mountain MS Center at the University of Colorado were retrospectively collected. Outcomes included a composite effectiveness measure consisting of clinical relapse, contrast‐enhancing lesions, and/or new T2 lesions, individual effectiveness outcomes, and discontinuation. Logistic regression was used on patients matched by propensity scores and using average treatment effect on treated doubly robust weighting estimator. Results A total of 182, 451, 271, and 342 patients initiated RTX, NTZ, FTY, and DMF and were followed for 2 years. Before and after adjustment, the odds of experiencing disease activity was significantly higher for FTY [adjusted OR (aOR) = 3.17 (95% CI: 1.81–5.55), P

There are many different types of cardiovascular diseases, which impose a huge economic burden due to their extremely high mortality rates, so it is necessary to explore the underlying mechanisms to achieve better supportive and curative care outcomes. Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator with paracrine and autocrine activities that acts through its cell surface S1P receptors (S1PRs) and intracellular signals. In the circulatory system, S1P is indispensable for both normal and disease conditions; however, there are very different views on its diverse roles, and its specific relevance to cardiovascular pathogenesis remains elusive. Here, we review the synthesis, release and functions of S1P, specifically detail the roles of S1P and S1PRs in some common cardiovascular diseases, and then address several controversial points, finally, we focus on the development of S1P-based therapeutic approaches in cardiovascular diseases, such as the selective S1PR1 modulator amiselimod (MT-1303) and the non-selective S1PR1 and S1PR3 agonist fingolimod, which may provide valuable insights into potential therapeutic strategies for cardiovascular diseases.

Fingolimod is indicated for the treatment of patients with the relapsing-remitting form of multiple sclerosis. The primary study objective was to evaluate the bioequivalence of a test formulation, 0.5 mg fingolimod HCl capsule (Lebrina, Asofarma Sociedad Anónima Industrial y Comercial, Argentina) relative to a reference formulation, 0.5 mg fingolimod capsule (Gilenya, Novartis Pharmaceutical, Australia). In a single-center, randomized, single-dose, single-blinded, 2-way crossover study, 33 New Zealand healthy subjects of both sexes were enrolled to receive a 0.5-mg dose of 3 capsules of each fingolimod formulation under fasting conditions, with a 42-day washout period between administrations. Additional pharmacokinetic information regarding its main active metabolite, fingolimod phosphate, was also provided. The point estimate and 90% confidence intervals of the ratios of maximum concentration and area under the plasma concentration-time curve from time 0 to 72 hours were 99.07 (95.83-102.41) and 97.64 (95.33-100.00) for fingolimod, and 95.60 (90.95-100.49) and 98.54 (96.19-100.96), for fingolimod phosphate. Primary parameters, maximum concentration and area under the plasma concentration-time curve from time 0 to 72 hours for fingolimod and fingolimod phosphate were found to have no significant difference when test and reference formulations were compared. Fingolimod and fingolimod phosphate of both formulations were within the accepted 90% confidence interval limits of 80.00% and 125.00%. No significant differences between the test and reference drug products were detected in any of the pharmacokinetic parameters estimated. Notwithstanding the primary conclusion of bioequivalence is focused on the measurement of the parent compound, compliance with the same criteria by the active metabolite reinforces the comparability between the pharmacokinetic profiles of both formulations (ClinicalTrials.gov Identifier: NCT03757338).

Objective: Novel, highly effective disease-modifying therapies have revolutionized multiple sclerosis (MS) care. However, evidence from large comparative studies on important safety outcomes, such as cancer, is still lacking. Methods: In this nationwide register-based cohort study, we linked data from the Swedish MS register to the Swedish Cancer Register and other national health care and census registers. We included 4,187 first-ever initiations of rituximab, 1,620 of fingolimod, and 1,670 of natalizumab in 6,136 MS patients matched for age, sex, and location to 37,801 non-MS general population subjects. Primary outcome was time to first invasive cancer. Results: We identified 78 invasive cancers among treated patients: rituximab 33 (incidence rate [IR] per 10,000 person-years = 34.4, 95% confidence interval [CI] = 23.7–48.3), fingolimod 28 (IR = 44.0, 95% CI = 29.2–63.5), and natalizumab 17 (IR = 26.0, 95% CI = 15.1–41.6). The general population IR was 31.0 (95% CI = 27.8–34.4). Adjusting for baseline characteristics, we found no difference in risk of invasive cancer between rituximab, natalizumab, and the general population but a possibly higher risk with fingolimod compared to the general population (hazard ratio [HR] = 1.53, 95% CI = 0.98–2.38) and rituximab (HR = 1.68, 95% CI = 1.00–2.84). Interpretation: In this first large comparative study of 3 highly effective MS disease-modifying therapies, no increased risk of invasive cancer was seen with rituximab and natalizumab, compared to the general population. However, there was a borderline-significant increased risk with fingolimod, compared to both the general population and rituximab. It was not possible to attribute this increased risk to any specific type of cancer, and further studies are warranted to validate these findings.

Objective The purpose of this study was to investigate the effect of disease modifying therapies on immune response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines in people with multiple sclerosis (MS). Methods Four hundred seventy-three people with MS provided one or more dried blood spot samples. Information about coronavirus disease 2019 (COVID-19) and vaccine history, medical, and drug history were extracted from questionnaires and medical records. Dried blood spots were eluted and tested for antibodies to SARS-CoV-2. Antibody titers were partitioned into tertiles with people on no disease modifying therapy as a reference. We calculated the odds ratio of seroconversion (univariate logistic regression) and compared quantitative vaccine response (Kruskal Wallis) following the SARS-CoV-2 vaccine according to disease modifying therapy. We used regression modeling to explore the effect of vaccine timing, treatment duration, age, vaccine type, and lymphocyte count on vaccine response. Results Compared to no disease modifying therapy, the use of anti-CD20 monoclonal antibodies (odds ratio = 0.03, 95% confidence interval [CI] = 0.01–0.06, p [less than] 0.001) and fingolimod (odds ratio = 0.04; 95% CI = 0.01–0.12) were associated with lower seroconversion following the SARS-CoV-2 vaccine. All other drugs did not differ significantly from the untreated cohort. Both time since last anti-CD20 treatment and total time on treatment were significantly associated with the response to the vaccination. The vaccine type significantly predicted seroconversion, but not in those on anti-CD20 medications. Preliminary data on cellular T-cell immunity showed 40% of seronegative subjects had measurable anti-SARS-CoV-2 T cell responses. Interpretation Some disease modifying therapies convey risk of attenuated serological response to SARS-CoV-2 vaccination in people with MS. We provide recommendations for the practical management of this patient group. ANN NEUROL 2021

Finding novel and effective drugs for the treatment of ischemic stroke is warranted because there is not a definitive treatment for this prevalent disease. Due to the relevance between the sphingosine 1‐phosphate (S1P) receptor and several neurological diseases including ischemic stroke, it seems that fingolimod (FTY720), as an agonist of S1P receptor, can be a useful therapeutic strategy in these patients. FTY720 is the first oral drug approved by the US food and drug administration for the treatment of multiple sclerosis. Three important mechanisms for neuroprotective effects of FTY720 have been described. First, the functional antagonistic mechanism that is associated with lymphopenia and reduced lymphocytic inflammation. This effect results from the down‐regulation and degradation of lymphocytes' S1P receptors, which inhibits lymph node lymphocytes from entering the bloodstream. Second, a functional agonistic activity that is mediated through direct effects via targeting S1P receptors on the membrane of various cells including neurons, microglia, oligodendrocytes, astrocytes, and endothelial cells of blood vessels in the central nervous system (CNS), and the third, receptor‐independent mechanisms that are displayed by binding to specific cellular proteins that modulate intracellular signaling pathways or affect epigenetic transcriptions. Therefore, we review these mechanisms in more detail and describe the animal model and in clinical trial studies that support these three mechanisms for the neuroprotective action of FTY720 in ischemic stroke., Three important mechanisms for neuroprotective effects of FTY720 have been described. Functional antagonistic, functional agonistic and receptor‐independent mechanisms. Here, we review these mechanisms in more details and describe animal model and in clinical trial studies

Objectives To assess whether neurofilament light chain (NfL) could serve as an informative endpoint in Phase 2 studies in patients with relapsing–remitting multiple sclerosis (RRMS) and estimate the sample size requirements with NfL as the primary endpoint. Methods Using data from the Phase 3 FREEDOMS study, we evaluated correlation of NfL at Month 6 with 2‐year outcomes: relapses, confirmed disability worsening (CDW), new or enlarging T2 lesions (active lesions), and brain volume loss (BVL). We compared the proportion of treatment effect (PTE) on 2‐year relapses and BVL explained by 6‐month log‐transformed NfL levels with the PTE explained by the number of active lesions over 6 months. We estimated sample size requirements for different treatment effects. Results At Month 6, blood NfL levels (pg/mL, median [range]) were lower in the fingolimod arm (fingolimod (n = 132) 18 [8–247]; placebo (n = 114) 26 [8–159], P

Breakthrough disease on first-line injectables in relapsing-remitting multiple sclerosis (RRMS) is a common clinical situation where comparative studies between different escalation therapies are lacking. The aim of this study was to compare the efficacy, safety and medication persistence of natalizumab (NTZ), rituximab (RTX) and fingolimod (FGL) as escalation therapy in RRMS.Patients switching from interferon or glatiramer acetate to NTZ, RTX or FGL due to breakthrough disease were identified through the Swedish multiple sclerosis (MS) registry at four large MS centers in this retrospective observational study. Data were collected from the MS registry and medical charts. Hazard ratios (HRs) for relapses, adverse events and drug discontinuation with 95% confidence interval (CI) were calculated using multivariable confounder-adjusted Cox proportional hazard models.A total of 241 patients were included. The annualized relapse rates were 0.02 for NTZ, 0.03 for RTX and 0.07 for FGL. Compared with NTZ, the adjusted HR for relapse was 1.0 (95% CI, 0.2-5.6) for RTX and 3.4 (95% CI, 1.3-9.2) for FGL. The annualized drug discontinuation rates were 0.15, 0.01 and 0.15 for NTZ, RTX and FGL, respectively. The adjusted HR for drug discontinuation was 0.05 (95% CI, 0.01-0.38) for RTX and 1.0 (95% CI, 0.6-1.7) for FGL vs. NTZ.In patients with RRMS on interferon/glatiramer acetate with breakthrough disease, switching to NTZ or RTX was associated with less disease activity compared with FGL. RTX displayed superior medication persistence compared with both NTZ and FGL.

In this study, rat models of wound closure by first and second intention were developed to evaluate the influence that two immunosuppressants for treating multiple sclerosis (fingolimod, azathioprine) have on wound healing. Sixty-three Sprague-Dawley rats were daily treated with fingolimod (0.6 mg/kg), azathioprine (2.5 mg/kg), or placebo (saline). Following 6 weeks of treatment, a linear incision (1.5 cm) or a circular excisional defect (diameter 1.5 cm) was made on the dorsal skin. The treatments were uninterrupted and after 7 days (incisional) or 21 days (incisional, excisional), animals were euthanized (n = 7 per group and time-point). Morphometric (wound closure), histological (stainings), and immunofluorescent studies (macrophages) were performed to evaluate the healing process. For both the incisional and excisional defects, animals treated with fingolimod exhibited a healing process equivalent to that of placebo in terms of collagenization, wound closure, and macrophage response. By comparison, groups treated with azathioprine displayed a delay in healing times which was especially evident in the excisional defect, where inflammatory reaction and collagen deposition in the repair tissue remained active by day 21. These results show that immunosuppressants with a selective mechanism of action (fingolimod) can have less impact on wound healing than their classical nonselective counterparts (azathioprine).

Parkinson's disease (PD) is characterized by the loss of midbrain dopaminergic neurons and aggregates of α-synuclein termed Lewy bodies. Fingolimod (FTY720) is an agonist of sphingosine-1 phosphate receptors and an approved oral treatment for multiple sclerosis. Fingolimod elevates brain-derived neurotrophic factor (BDNF), an important neurotrophic factor for dopaminergic neurons. BDNF and fingolimod are beneficial in several animal models of PD. In order to validate the therapeutic potential of fingolimod for the treatment of PD, we tested its effect in the subacute MPTP mouse model of PD. MPTP or vehicle was applied i.p. in doses of 30 mg/kg MPTP on five consecutive days. In order to recapitulate the combination of dopamine loss and α-synuclein aggregates found in PD, MPTP was first administered in Thy1-A30P-α-synuclein transgenic mice. Fingolimod was administered i.p. at a dose of 0.1 mg/kg every second day. Nigrostriatal degeneration was assayed by stereologically counting the number of dopaminergic neurons in the substantia nigra pars compacta, by analysing the concentration of catecholamines and the density of dopaminergic fibres in the striatum. MPTP administration produced a robust nigrostriatal degeneration, comparable to previous studies. Unexpectedly, we found no difference between mice with and without fingolimod treatment, neither at baseline, nor at 14 or 90 days after MPTP. Also, we found no effect of fingolimod in the subacute MPTP mouse model when we used wildtype mice instead of α-synuclein transgenic mice, and no effect with an increased dose of 1 mg/kg fingolimod administered every day. In order to explain these findings, we analysed BDNF regulation by fingolimod. We did find an increase of BDNF protein after a single injection of fingolimod 0.1 or 1.0 mg/kg, but not after multiple injections, indicating that the BDNF response to fingolimod is unsustainable over time. Taken together we did not observe a neuroprotective effect of fingolimod in the subacute MPTP mouse model of PD. We discuss possible explanations for this discrepancy with previous findings and conclude fingolimod might be beneficial for the nonmotor symptoms of PD. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* and *Open Data* because it provided all relevant information to reproduce the study in the manuscript and because it made the data publicly available. The data can be accessed at https://osf.io/6xgfn/. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Multiple sclerosis is a neurological disorder in which the myelin sheaths of axons are damaged by the immune response. We report here a three-dimensional structural analysis of brain and spinal cord tissues of a mouse model of multiple sclerosis, known as experimental autoimmune encephalomyelitis (EAE). EAE-induced mice were raised with or without administration of fingolimod, which is used in the treatment of multiple sclerosis. Brains and spinal cords dissected from the EAE mice were lyophilized so as to reconstitute the intrinsic contrast of tissue elements, such as axons, in X-ray images. Three-dimensional structures of the brain hemispheres and spinal cords of the EAE mice were visualized with synchrotron radiation microtomography. Microtomographic cross sections reconstructed from the X-ray images revealed dilation of capillary vessels and vacuolation in the spinal cord of the EAE mice. Vacuolation was also observed in the cerebellum, suggesting that the neuroinflammatory response progressed in the brain. The vessel networks and vacuolation lesions in the spinal cords were modelled by automatically tracing the three-dimensional image in order to analyze the tissue structures quantitatively. The results of the analysis indicated that the distribution of vacuolations was not uniform but three-dimensionally localized. The mean vessel diameter showed a linear correlation with the clinical score, indicating that vasodilation is relevant to paralysis severity in the disease model. We suggest that vasodilation and vacuolation are related with neurological symptoms of multiple sclerosis., 22 pages, 5 figures, 1 table

BACKGROUND AND PURPOSE Evidence is needed to understand the effect of fingolimod on slowing down brain atrophy progression in multiple sclerosis (MS) patients in clinical practice. We investigated the effect of fingolimod on brain atrophy in MS patients with active disease (clinically and/or magnetic resonance imaging [MRI]) versus no evidence of active disease (NEAD). METHODS MS and clinical outcome and MRI in the United States (MS-MRIUS) is a multicenter, retrospective study that included 590 relapsing-remitting MS patients, who initiated fingolimod, and were followed for a median of 16 months. Patients with active disease at baseline (245, 41.5%) were defined as those who had one or more relapses in the year previous starting fingolimod, and/or displayed gadolinium enhancing lesions(s) at baseline MRI scan, whereas patients with NEAD at baseline (345, 58.5%) did not fulfill these criteria. Annualized percentage brain volume change (PBVC) and percentage lateral ventricle volume change (PLVVC) over the follow-up were analyzed in both groups. RESULTS Over the follow-up, the rate of PBVC was -.38% in active disease and -.25% in NEAD patients (P = .076), whereas PLLVC was 1.76% in active disease and .28% in NEAD patients (P = .046). No changes in timed 25-foot walk (P = .619) and Expanded Disability Status Scale (P = .275) scores or MRI lesion accumulation (P > 0.08) were detected, although the active disease group had a higher proportion of relapses during the follow-up period (P = .02). CONCLUSIONS The study provides real-world evidence that rate of brain atrophy in MS patients with underlying active disease and NEAD in fingolimod treated patients is below the established pathological cutoff for loss of whole brain volume (>-.4%) or expansion of lateral ventricles (> 3.5%).

This open‐label, single‐sequence study in healthy subjects investigated the effects of steady‐state carbamazepine on the pharmacokinetic (PK) profile of a single 2‐mg dose of fingolimod. In period 1, a single oral dose of fingolimod 2 mg (day 1) was followed by PK and safety assessments up to 36 days. In period 2, carbamazepine was administered in flexible, up‐titrated doses (600 mg twice daily maximum) for 49 days. Fingolimod was administered on day 35, followed by a study completion evaluation (day 71). The PK analysis included 23 of 26 of the enrolled subjects (88.5%). Coadministration of fingolimod at steady‐state carbamazepine concentrations resulted in increased fingolimod CL/F by 67% through the induction of CYP3A4, a cytochrome with negligible involvement in fingolimod clearance in an uninduced state. Fingolimod Cmax was reduced by 18% and AUCinf by 40%, as was T1/2 (106 vs 163 hours). A similar trend was observed for fingolimod‐P. Models linking fingolimod‐P blood concentrations to lymphocyte count or annual relapse rate suggest that such a decrease would have a low impact on the treatment effect. However, in the absence of efficacy data of fingolimod at doses lower than the therapeutic dose, their coadministration should be used with caution.

Fingolimod (FTY720) is used as an immunosuppressant for multiple sclerosis. Numerous studies indicated its neuroprotective effects in stroke. However, the mechanism remains to be elucidated. This study was intended to investigate the mechanisms of phosphorylated FTY720 (pFTY720), which was the principle active molecule in regulating astrocyte‐mediated inflammatory responses induced by oxygen‐glucose deprivation (OGD). Results demonstrated that pFTY720 could protect astrocytes against OGD‐induced injury and inflammatory responses. It significantly decreased pro‐inflammatory cytokines, including high mobility group box 1 (HMGB1) and tumour necrosis factor‐α (TNF‐α). Further, studies displayed that pFTY720 could prevent up‐regulation of Toll‐like receptor 2 (TLR2), phosphorylation of phosphoinositide 3‐kinase (PI3K) and nuclear translocation of nuclear factor kappa B (NFκB) p65 subunit caused by OGD. Sphingosine‐1‐phosphate receptor 3 (S1PR3) knockdown could reverse the above change. Moreover, administration of TLR2/4 blocker abolished the protective effects of pFTY720. Taken together, this study reveals that pFTY720 depends on S1PR3 to protect astrocytes against OGD‐induced neuroinflammation, due to inhibiting TLR2/4‐PI3K‐NFκB signalling pathway.

Genome wide-association studies have clearly shown the key roles of helper T (Th) cells and cellular immune responses for development of multiple sclerosis (MS). Novel medication for a “relapsing–remitting” form of MS (RR-MS) including natalizumab and fingolimod that targets immune cells, such as Th cells, is now available in clinics. However, a significant proportion of RR-MS patients subsequently develop a chronic progressive disease without obvious signs of relapses known as secondary progressive MS (SP-MS). Therapeutic agents for SP-MS are limited and pathogenesis of SP-MS remains elusive, partly because of the lack of experimental animal models that enable comprehensive and deep analysis of the disease. We have previously reported that an orphan nuclear receptor, NR4A2, plays critical roles in Th17 cells, a key Th cell subset associated with the pathogenesis of RR-MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Although EAE induced in mice lacking the NR4A2 gene in Th cells showed significantly milder signs of acute EAE, they unexpectedly developed a late/chronic EAE, in which atypical Th cells expressing Eomesodermin (Eomes) with cytotoxic properties were involved. Functional analysis revealed that Eomes+ Th cells are critically associated with the development of late/chronic EAE. Interestingly, similar Eomes+ Th cells were remarkably increased in the peripheral blood and cerebrospinal fluid from SP-MS patients, but not from RR-MS patients, implying that Eomes+ Th cells are selectively involved in the pathogenesis of SP-MS. Therefore, elimination or functional inhibition of Eomes+ Th cells could be considered as novel therapeutic strategies for SP-MS.

Background and purpose We have previously shown that patients with multiple sclerosis receiving immunomodulatory treatment have reduced seroprotection rates after influenza immunization. The aim of this study was to further investigate the influence of immunomodulatory therapies on the antibody response and seroprotection rates in patients immunized with seasonal influenza vaccine in 2012/2013 compared with healthy controls. Methods Ninety patients receiving fingolimod, glatiramer acetate, interferon beta-1a/1b, natalizumab or no therapy were compared with 62 healthy controls. All subjects received the inactivated split virus vaccine in 2012 and serum samples were collected pre-vaccination and 3, 6 and 12 months post-vaccination. The vaccine responses were evaluated by the hemagglutination inhibition assay and adjusted for age and gender. Results No significant differences in rates of protection against H1N1 for interferon beta-1a/1b and glatiramer acetate were observed as compared with controls at 3, 6 and 12 months. Fingolimod provided reduced protection at all time points post-vaccination, whereas natalizumab displayed reduced protection at 3 and 6 months. Patients without immunomodulation did not display protection rates that were significantly different from the controls at 3 and 12 months. Conclusion These findings suggest that patients with multiple sclerosis receiving fingolimod or natalizumab should be considered for a second dose of the vaccine in cases of insufficient protection. Our results further indicate that new immunomodulatory treatment regimens should be systematically evaluated for their influence on influenza-specific vaccine responses.

Aims Fingolimod hydrochloride is an effective immunomodulatory drug in improving relapsing-remitting multiple sclerosis (RRMS). However, data on the neuroradiologic effects on white matter (WM) have not been demonstrated. In this study, we aimed elucidating the impact of 1-year fingolimod treatment on WM integrity in patients with RRMS. Methods Diffusion tensor imaging (DTI) was applied to assess axonal and myelin integrity in specific WM tracts of patients with RRMS prior to and 1 year postfingolimod treatment (n = 30). The fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity, and mean diffusivity were analyzed using tract-based spatial statistics on specific regions of interest associated with impaired Expanded Disability Status Scale functional scores before treatment. Results In patients with impaired pyramidal function at baseline (average score 2.3 ± 0.2, n = 25), fingolimod induced a significant increase in FA (P = 0.002) and decrease in RD (P = 0.03) in the corticospinal tract. In patients with impaired cerebellar function at baseline (average score 2.0 ± 0.1, n = 19), significant increases in FA and decreases in RD were observed in the superior (P = 0.02, P = 0.01, respectively) and inferior (P = 0.03, P = 0.05, respectively) cerebellar peduncles. Conclusion The observed results suggest increased microstructural integrity and decreased demyelination of damaged WM tracts and support the possible direct mechanism of fingolimod action.