Fingolimod In Multiple Sclerosis Research Articles

An observational study of alemtuzumab following fingolimod for multiple sclerosis.

Objective:To describe a series of patients with relapsing multiple sclerosis (MS) who experienced significant and unexpected disease activity within the first 12 months after switching from fingolimod to alemtuzumab.Methods:Patients with relapsing MS treated sequentially with fingolimod then alemtuzumab who experienced significant subsequent disease activity were identified by personal communication with 6 different European neuroscience centers.Results:Nine patients were identified. Median disease duration to alemtuzumab treatment was 94 (39–215) months and follow-up from time of first alemtuzumab cycle 20 (14–21) months. Following first alemtuzumab infusion cycle, 8 patients were identified by at least 1 clinical relapse and radiologic disease activity and 1 by significant radiologic disease activity alone.Conclusions:We acknowledge the potential for ascertainment bias; however, these cases may illustrate an important cause of reduced efficacy of alemtuzumab in a vulnerable group of patients with MS most in need of disease control. We suggest that significant and unexpected subsequent disease activity after alemtuzumab induction results from prolonged sequestration of autoreactive lymphocytes following fingolimod withdrawal, allowing these cells to be concealed from the usual biological effect of alemtuzumab. Subsequent lymphocyte egress then provokes disease reactivation. Further animal studies and clinical trials are required to confirm these phenomena and in the meantime careful consideration should be given to mode of action of individual therapies and sequential treatment effects in MS when designing personalized treatment regimens.

VP214 Criteria That Influence The Brazilian Public Decision-Making

INTRODUCTION:In Brazil, the National Committee for Health Technology Incorporation in the public health system (CONITEC) advises the Ministry of Health about incorporation, exclusion and alteration of health technologies in Brazilian public health system (SUS). Decision making considers multiple criteria, included or not in legislation. This analysis was the first step for a multiple-criteria decision analysis (MCDA) building. This study aims to identify criteria that influence Health Technology Assessment (HTA) for SUS.METHODS:Five real cases of controversial recommendations of technology incorporation made by CONITEC were reviewed by listening to the plenary recordings and reviewing committee minutes. The choice was guided by convenience, with prioritization according to CONITEC's members, using a pre-defined standardized form. Weight in decision making was also raised and identified. Selected technologies judgments were: Trastuzumab for metastatic/advanced Breast Cancer; Fingolimod for Multiple Sclerosis; Clozapine, Lamotrigine, Olanzapine, Quetiapine and Risperidone for Bipolar Affective Disorder; Hematopoietic stem cell transplantation for Sickle Cell Disease; and Positron Emission Computed Tomography (PET-CT) for Lung Cancer and for hepatic metastasis from Colorectal Cancer.RESULTS:The choice of different technologies allowed verifying specific criteria used for the incorporation of each type of technology, as well as the similar criteria discussed and used by all these technology types. In addition, some identified criteria were specific to the Brazilian reality, such as: “Incorporation by other countries”, “Potential technologies without registration in Brazil” and “Off-label use”. These criteria were not previously identified in studies conducted in other countries. Some criteria have been identified in all decisions, such as: efficacy, disease severity, quality and confidence in the evidences, logistic challenges for implementation, unmet needs, budget impact and treatment costs. Relative impact of cost-effectiveness was considered low.CONCLUSIONS:CONITEC's recordings are an important source to understand the Brazilian decision-making process. To identify the important criteria can help to standardize and improve the HTA process.

PP086 Horizon Scanning In Multiple Sclerosis Decisions In Brazil

INTRODUCTION:In Brazil, the pharmaceutical sector has requested an individual incorporation in the Brazilian public health system (SUS) for each new drug for multiple sclerosis that receives sanitary authorization for marketing. Horizon Scanning within Brazilian Ministry of Health has played a key role in the recommendations made by the National Committee for Health Technology Incorporation (CONITEC). Horizon Scanning seeks to predict which technologies have potential to impact health care in SUS, before their formal request. This study aims to present the impact of horizon scanning in two assessments made by CONITEC on drugs to treat Multiple Sclerosis.METHODS:Grey literature was searched to find new and emerging drugs for multiple sclerosis treatment. Regulatory agencies were also searched: European Medicines Agency (EMA), Food and Drug Administration (FDA) and Brazilian Regulation and Health Surveillance Agency (Anvisa). A pre-defined standardized form was used. Information extracted about each drug was identified as: drugs name, mechanism of action, indication, administration route, finished phases of clinical trial and registration in other countries.RESULTS:In 2014, horizon scanning identified seven drugs while CONITEC was assessing Fingolimod for multiple sclerosis. In this case, the drug's administration route was a differential, as only three new drugs identified were also orally administrated. Thus, Fingolimod received a positive recommendation for incorporation. In 2016, horizon scanning identified fourteen drugs while Teriflunomide was under assessment. At this moment, the orally administrated Fingolimod was already available and it was identified other eight new drugs with the same route. Therefore, the initial recommendation was against its incorporation.CONCLUSIONS:Horizon scanning has proved to be of major importance for assisting recommendation-making process of the committee. In the two cases presented, horizon scanning information could predict which technologies were being developed and could be registered in Brazil. These new technologies had influenced the recommendations made by CONITEC's members. As a result, a horizon scanning section in all CONITEC's reports became mandatory.

Fingolimod for Multiple Sclerosis; Mechanism of Action, Safety and Toxicity

Context: From the year 2010, for patients with highly active relapsing-remitting (RR) multiple sclerosis (MS), fingolimod could be justified for prescription as an oral medication. Previous published clinical trials identified that the drug could reduce auto-aggressive lymphocyte infiltration into the central nervous system (CNS) through the blood brain barrier (BBB), by stoppage of lymphocyte passage from lymphoid tissues. Evidence Acquisition: The aim of this study was to provide a comprehensive review related to the pharmacotherapy of fingolimod for MS, by gathering data related to previous clinical and laboratory trials. The key words relevant to the topic were searched through the United States national library of medicine. Significant manuscripts associated with fingolimod pharmacotherapy for MS were nominated and studied completely. Results: In patients with MS due to multifactorial pathogenesis, in both white and gray matter of CNS, multifocal lesions might be recognized. CD4+ and CD8+ effector T cells, sensitive to CNS myelin antigens, are assumed to facilitate the preliminary stage of injury formation. Fingolimod -therapy in patients at the RRMS phase, reserve lymphocyte egress from lymphocyte nodes and disturb its’ recirculation in the CNS. Previous clinical trials confirmed that once-daily oral administration of 0.5 mg fingolimod for one year causes a decrease in annualized relapse rate. Reduction in the annualized relapse rate has been reported, related to the study of 249 patients with RRMS. Reduction in disability progression after three and six months has been reported, respectively. The numbers of new or newly enlarged T2 lesions were shown to have reduced. Head cold, headache, fatigue, macular edema, herpes and zoster infections, bradycardia, relapse and basal-cell carcinoma have been reported as side-effects related to finglimod-therapy for MS. Conclusions: However, fingolimod-therapy could provide flexibility regarding the ease of oral use for patients with RRMS, but rationalization related to the prescription are largely based on inter- and intra- individual variation. Due to unpredictability in disease manifestation and its’ progression, caution must be taken with drug prescription. Additional studies based on advanced pharmacotherapy trials appear to be valuable.

Alternatives for reducing relapse rate when switching from natalizumab to fingolimod in multiple sclerosis

ABSTRACTNatalizumab is a therapeutic option for treating multiple sclerosis (MS) and is particularly efficacious for patients with highly active disease. A long washout period has been recommended between withdrawal of natalizumab and start of fingolimod (another option for treating MS). This long washout period has been associated with a significant increase in MS activity. In the present study, a group of 96 patients who were switched from natalizumab to fingolimod had short washout periods between drugs, or monthly corticosteroid pulse therapy if longer washout periods were recommended. This therapeutic approach led to the lowest reported relapse rate so far, among patients with MS switching from natalizumab to fingolimod (8.3%). No complications from short withdrawal were observed in this group of patients.

Fingolimod for multiple sclerosis and emerging indications: appropriate patient selection, safety precautions, and special considerations

Fingolimod (FTY720), an immunotherapeutic drug targeting the sphingosine-1-phosphate receptor, is a widely used medication for relapsing-remitting multiple sclerosis (MS). Apart from the pivotal Phase III trials demonstrating efficacy against placebo and interferon-β-1a once weekly, sufficient clinical data are now available to assess its real-world efficacy and safety profile. Approved indications of fingolimod differ between countries. This discrepancy, to some extent, reflects the intermediate position of fingolimod in the expanding lineup of MS medications. With individualization of therapy, appropriate patient selection gets more important. We discuss various scenarios for fingolimod use in relapsing-remitting MS and their pitfalls: as first-line therapy, as escalation therapy after failure of previous immunotherapies, and as de-escalation therapy following highly potent immunotherapies. Potential side effects such as bradycardia, infections, macular edema, teratogenicity, and progressive multifocal leukoencephalopathy as well as appropriate safety precautions are outlined. Disease reactivation has been described upon fingolimod cessation; therefore, patients should be closely monitored for MS activity for several months after stopping fingolimod. Finally, we discuss preclinical and clinical data indicating neuroprotective effects of fingolimod, which might open the way to future indications such as stroke, Alzheimer’s disease, and other neurodegenerative disorders.

Long-term (up to 4.5 years) treatment with fingolimod in multiple sclerosis: results from the extension of the randomised TRANSFORMS study

ObjectiveThe 12-month (M), phase 3, double-blind, randomised TRANSFORMS study demonstrated significant benefits of fingolimod 0.5 or 1.25 mg over interferon β-1a (IFNβ-1a) in patients with relapsing–remitting multiple sclerosis. We report...

Long-term cardiac safety and tolerability of fingolimod in multiple sclerosis: A postmarketing study.

Fingolimod is the first oral disease-modifying therapy approved for multiple sclerosis (MS). The risks associated with the use of fingolimod include cardiovascular adverse events (AEs). First-dose observation (FDO) is required for all patients for at least 6 hours. We describe FDO data and long-term cardiac tolerability in a cohort of fingolimod-treated relapsing MS patients. Two hundred and twelve patients started fingolimod 0.5 mg once daily. Before the first administration, all subjects had an electrocardiogram (ECG) with cardiologist interpretation. Following administration they were monitored for 6 hours and underwent a cardiac monitoring every 3 months. In this cohort, there was a heart rate reduction at the VI hour of 9.6 ± 8 beats per minute (P < .001). Fifty-four individuals (25.5%) presented an abnormal ECG during the 6 hours. We experienced 1 case (0.22%) of symptomatic second-degree atrioventricular block. The mean follow-up period was 1.5 ± 0.7 years. During this period, 1 patient showed atrial fibrillation that needed to be treated. We also observed 5 cases of persistent increase in blood pressure. This postmarketing study shows that fingolimod is well tolerated and tha tcardiologic AEs are generally self-limited in the long term.

Fingolimod effects on left ventricular function in multiple sclerosis

Background: Cardiovascular side effects such as bradycardia and atrioventricular block were observed during the early clinical trials of fingolimod in multiple sclerosis, and one cardiovascular- linked death has been reported in the post-marketing period. Objective: To investigate the medium-term effects of fingolimod on heart function in order to obtain further insights into its cardiac safety profile. Methods: The study involved 53 patients starting treatment with fingolimod 0.5 mg daily and 25 patients treated with natalizumab 300 mg monthly. Cardiac function was assessed by means of echocardiography at baseline (T0), and after one (T1), six (T6), and (in the case of the fingolimod group) 12 months (T12). Results: Mean left ventricular ejection fraction significantly decreased and end-systolic volume increased from T0 to T1 (p=0.005) and T6 (p=0.0001) in the fingolimod but not the natalizumab group, although a slight increase was observed at T12. A similar decrease in ejection fraction was also observed after six months in nine patients switched from natalizumab to fingolimod. Conclusion: Fingolimod significantly reduces left ventricular systolic function in MS patients. This effect has no clinical consequences in subjects without previous cardiac disorders, but suggests that more caution is required in patients with current or previous heart failure.

Spotlight on the April 14 Issue

#### Notable in Neurology This issue features articles on nocturnal frontal lobe epilepsy with paroxysmal arousals due to CHRNA2 loss of function and on refining the phenotype variability and identifying factors that explain the clinical severity of the symptoms observed in Unverricht-Lundborg disease. Other featured articles focus on the recurrence of reversible cerebral vasoconstriction syndrome and on the long-term effects of fingolimod in multiple sclerosis. ### Memory fMRI predicts verbal memory decline after anterior temporal lobe resection![Graphic][1] The authors performed an fMRI word memory encoding paradigm and an out-of-scanner recognition assessment in 50 patients with … [1]: /embed/inline-graphic-1.gif

Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial.

Objective:To assess long-term safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS).Methods:Patients completing FTY720 Research Evaluating Effects of Daily Oral Therapy in MS (FREEDOMS) were eligible for this dose-blinded, parallel-group extension study, continuing fingolimod 0.5 mg/day or 1.25 mg/day, or switching from placebo to either dose, randomized 1:1. Efficacy variables included annualized relapse rate (ARR), brain volume loss (BVL), and confirmed disability progression (CDP). Between-group analyses were conducted in the intent-to-treat (ITT) population from FREEDOMS baseline to end of study. Within-group analyses compared years 0–2 (FREEDOMS) and years 2–4 (extension) in the extension ITT population.Results:Of 1,272 patients (FREEDOMS ITT population), 1,033 were eligible, and 920 enrolled in the extension study (continuous-fingolimod: 0.5 mg [n = 331], 1.25 mg [n = 289]; placebo–fingolimod: 0.5 mg [n = 155], 1.25 mg [n = 145]); 916 formed the extension ITT population (n = 330; n = 287; n = 154; n = 145) and 773 (84%) completed. In the continuous-fingolimod groups, ARR was lower (p < 0.0001), BVL was reduced (p < 0.05), and proportionately more patients were free from 3-month CDP (p < 0.05) than in a group comprising all placebo–fingolimod patients. Within each placebo–fingolimod group, ARR was lower (p < 0.001, both) and BVL was reduced after switching (p < 0.01, placebo–fingolimod 0.5 mg). Rates and types of adverse events were similar across groups; no new safety issues were reported.Conclusion:Efficacy benefits of fingolimod during FREEDOMS were sustained during the extension; ARR and BVL were reduced after switching.Classification of evidence:This study provides Class IV evidence that long-term fingolimod treatment is well-tolerated and reduces relapse rates, disability progression, and MRI effects in patients with RRMS.

Fingolimod prevents blood-brain barrier disruption induced by the sera from patients with multiple sclerosis.

ObjectiveEffect of fingolimod in multiple sclerosis (MS) is thought to involve the prevention of lymphocyte egress from lymphoid tissues, thereby reducing autoaggressive lymphocyte infiltration into the central nervous system across blood-brain barrier (BBB). However, brain microvascular endothelial cells (BMECs) represent a possible additional target for fingolimod in MS patients by directly repairing the function of BBB, as S1P receptors are also expressed by BMECs. In this study, we evaluated the effects of fingolimod on BMECs and clarified whether fingolimod-phosphate restores the BBB function after exposure to MS sera.MethodsChanges in tight junction proteins, adhesion molecules and transendothelial electrical resistance (TEER) in BMECs were evaluated following incubation in conditioned medium with or without fingolimod/fingolimod-phosphate. In addition, the effects of sera derived from MS patients, including those in the relapse phase of relapse-remitting (RR) MS, stable phase of RRMS and secondary progressive MS (SPMS), on the function of BBB in the presence of fingolimod-phosphate were assessed.ResultsIncubation with fingolimod-phosphate increased the claudin-5 protein levels and TEER values in BMECs, although it did not change the amount of occludin, ICAM-1 or MelCAM proteins. Pretreatment with fingolimod-phosphate restored the changes in the claudin-5 and VCAM-1 protein/mRNA levels and TEER values in BMECs after exposure to MS sera.ConclusionsPretreatment with fingolimod-phosphate prevents BBB disruption caused by both RRMS and SPMS sera via the upregulation of claudin-5 and downregulation of VCAM-1 in BMECs, suggesting that fingolimod-phosphate is capable of directly modifying the BBB. BMECs represent a possible therapeutic target for fingolimod in MS patients.

P027 - Severe reactivation of multiple sclerosis after discontinuation of fingolimod: An IRIS-associated phenomenon

Background Data on the mechanism of rebound activity post-withdrawal of fingolimod in multiple sclerosis (MS) patients is scarce. Objectives To describe a patient with multiple sclerosis (MS) who developed severe reactivation after discontinuation of fingolimod. Method Case report and review of literature. Results A 36-year old woman with aggressive MS since 1998 was switched to fingolimod due to JC virus seropositivity after receiving 24 infusions of natalizumab. The 8-week natalizumab washout period was unremarkable. While on fingolimod, she developed severe lymphopenia (0.2×109/L) necessitating withdrawal of fingolimod. Seven weeks later, she presented with dysarthria and right-sided pyramidal weakness, which rapidly progressed to drowsiness and coma within few days. The clinical presentation and radiological features were suspicious for progressive multifocal leukoencephalopathy (PML). CSF JCV DNA was negative. She received plasmapheresis and maintenance corticosteroids afterwards. A clinical improvement was observed within 14 days but she sustained significant hemiparesis requiring extensive rehabilitation. The final diagnosis of severe reactivation of MS post-withdrawal of fingolimod was established. It is postulated that the significant reactivation of MS was due to its association with an Immune Reconstitution Inflammatory Syndrome (IRIS) given the abrupt rise in lymphocyte count after fingolimod withdrawal. Conclusion Our case highlighted the diagnostic dilemma in JC virus seropositive patients who developed relapses after discontinuing potent immunomodulators. Patients who discontinued fingolimod might be at risk of developing IRIS resulting in disease reactivation in the washout period. Data on the mechanism of rebound activity post-withdrawal of fingolimod in multiple sclerosis (MS) patients is scarce. To describe a patient with multiple sclerosis (MS) who developed severe reactivation after discontinuation of fingolimod. Case report and review of literature. A 36-year old woman with aggressive MS since 1998 was switched to fingolimod due to JC virus seropositivity after receiving 24 infusions of natalizumab. The 8-week natalizumab washout period was unremarkable. While on fingolimod, she developed severe lymphopenia (0.2×109/L) necessitating withdrawal of fingolimod. Seven weeks later, she presented with dysarthria and right-sided pyramidal weakness, which rapidly progressed to drowsiness and coma within few days. The clinical presentation and radiological features were suspicious for progressive multifocal leukoencephalopathy (PML). CSF JCV DNA was negative. She received plasmapheresis and maintenance corticosteroids afterwards. A clinical improvement was observed within 14 days but she sustained significant hemiparesis requiring extensive rehabilitation. The final diagnosis of severe reactivation of MS post-withdrawal of fingolimod was established. It is postulated that the significant reactivation of MS was due to its association with an Immune Reconstitution Inflammatory Syndrome (IRIS) given the abrupt rise in lymphocyte count after fingolimod withdrawal. Our case highlighted the diagnostic dilemma in JC virus seropositive patients who developed relapses after discontinuing potent immunomodulators. Patients who discontinued fingolimod might be at risk of developing IRIS resulting in disease reactivation in the washout period.

Fingolimod for multiple sclerosis: a review for the specialist nurse.

The availability of treatments for multiple sclerosis (MS) has increased substantially over the past decade. Once-daily fingolimod 0.5mg capsules (Gilenya, Novartis Pharma) were approved in the European Union in March 2011 as the first oral disease-modifying therapy for patients with relapsing MS. This review summarises the efficacy and safety of fingolimod, and discusses practical considerations for MS specialist nurses. Fingolimod has demonstrated efficacy in the treatment of relapsing-remitting MS, as assessed by relapse measures, inflammatory disease activity and brain volume loss. Evaluation of its safety profile suggests a need for monitoring procedures for specific adverse events, including transient, mostly asymptomatic, reductions in heart rate, blood pressure increases, macular oedema and liver enzyme elevations. The MS nurse is likely to be involved in monitoring treatment initiation, providing support in the case of adverse events and promoting patient adherence to the prescribed treatment regimen.

The influence of patient demographics, disease characteristics and treatment on brain volume loss in Trial Assessing Injectable Interferon vs FTY720 Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS), a phase 3 study of fingolimod in multiple sclerosis

Background: Patients with multiple sclerosis (MS) lose brain volume (BV) faster than healthy individuals. Objective: Our purpose, within the 12-month phase 3 TRANSFORMS study, was to examine the effect of treatment on BV loss in patient subgroups, establish correlations between baseline normalized BV (NBV) and baseline disease parameters, to identify variables predictive of baseline NBV and on-study percentage BV change (PBVC), and to establish correlations between on-study PBVC and on-study efficacy outcomes. Methods: Patients received fingolimod 0.5 mg or 1.25 mg, or intramuscular (IM) interferon β-1a (IFNβ-1a) for 12 months. The effect of treatment on PBVC was examined in patient demographic, disease and magnetic resonance imaging (MRI) characteristic subgroups. Pearson’s correlation analyses and a stepwise linear regression model were used to identify variables predictive of NBV and PBVC. Results: Fingolimod reduced BV loss over 12 months versus IFNβ-1a IM in all patient subgroups assessed, including individuals with or without gadolinium (Gd)-enhancing lesions at baseline. Baseline T1 hypointense lesion volume had the strongest correlation with baseline NBV. Baseline Gd-enhancing T1 lesion count was most predictive of change in PBVC over 12 months. Conclusions: Our results improve understanding of the contributions of different baseline demographic, clinical and MRI characteristics to NBV, including factors that may be predictive of future BV loss

Switching From Natalizumab to Fingolimod in Multiple Sclerosis

The safety and efficacy of switching from natalizumab to fingolimod have not yet been evaluated in a large cohort of patients with multiple sclerosis (MS) to our knowledge. To collect data from patients with MS switching from natalizumab to fingolimod. The Enquête Nationale sur l'Introduction du Fingolimod en Relais au Natalizumab (ENIGM) study, a survey-based, observational multicenter cohort study among MS tertiary referral centers. Participants were patients for whom a switch from natalizumab to fingolimod was planned. Clinical data were collected on natalizumab treatment, duration and management of the washout period (WP), and relapse or adverse events during the WP and after the initiation of fingolimod. Occurrence of MS relapse during the WP or during a 6-month follow-up period after the initiation of fingolimod. Thirty-six French MS tertiary referral centers participated. In total, 333 patients with MS switched from natalizumab to fingolimod after a mean of 31 natalizumab infusions (female to male ratio, 2.36; mean age, 41 years; and Expanded Disability Status Scale score at the initiation of natalizumab, 3.6). Seventy-one percent were seropositive for the JC polyomavirus. The Expanded Disability Status Scale score remained stable for patients receiving natalizumab. Twenty-seven percent of patients relapsed during the WP. A WP shorter than 3 months was associated with a lower risk of relapse (odds ratio, 0.23; P = .001) and with less disease activity before natalizumab initiation (P = .03). Patients who stopped natalizumab because of poor tolerance or lack of efficacy also had a higher risk of relapse (odds ratio, 3.20; P = .004). Twenty percent of patients relapsed during the first 6 months of fingolimod therapy. Three percent stopped fingolimod for efficacy, tolerance, or compliance issues. In the multivariate analysis, the occurrence of relapse during the WP was the only significant prognostic factor for relapse during fingolimod therapy (odds ratio, 3.80; P = .05). In this study, switching from natalizumab to fingolimod was associated with a risk of MS reactivation during the WP or shortly after fingolimod initiation. The WP should be shorter than 3 months.

Suppressed pro-inflammatory properties of circulating B cells in patients with multiple sclerosis treated with fingolimod, based on altered proportions of B-cell subpopulations

The chief therapeutic mechanism of fingolimod in multiple sclerosis (MS) is considered to be sequestration of pathogenic lymphocytes into secondary lymphoid tissues. B cells have recently been recognized as important immune regulators in MS. In this study, the effects of fingolimod on B cells in MS patients were analyzed. MS patients treated with fingolimod (MS-F) had a significantly lower number of B cells in the circulation. The remaining B cells in the blood of MS-F had a reduced proportion of memory B cells and an increased proportion of naïve B cells, expressed lower levels of the costimulatory molecule CD80, and produced less tumor necrosis factor-α and more interleukin-10. These observations in MS-F were based on an increased proportion of the transitional B-cell subpopulation within the naïve B-cell compartment. The observed findings in B cells of MS-F might be related to the therapeutic effect of this drug in MS.

Mechanisms of action of fingolimod in multiple sclerosis

AbstractFingolimod is a sphingosine 1‐phosphate receptor (S1PR) modulator approved as a therapy for multiple sclerosis. The present review will describe how interactions of fingolimod with S1PR, can induce the dual effects of inhibiting signaling and functional responses induced by S1P, the natural ligand for the S1PR, while continuing itself to induce active signaling and functional responses. These dual effects of fingolimod will be considered in terms of their mechanisms of actions on the systemic immune system, the blood–brain barrier, and within the central nervous system.

Future directions in the study of fingolimod in multiple sclerosis

AbstractThe efficacy of fingolimod treatment for multiple sclerosis (MS) has been shown, but its exact mechanism remains unclear. Fingolimod is an oral disease‐modifying drug that prevents the entry of autoreactive T cells into the central nervous system (CNS) by inhibiting the egress of T cells from the lymph nodes. It binds sphingosine‐1‐phosphate (S1P) receptors on a variety of cells, including cells in the CNS, where it exerts diverse effects. In addition to its immune mechanisms, recent studies suggested that non‐immune mechanisms might play a role in the efficacy of fingolimod for the treatment of MS. Herein, we explore the underlying mechanisms of fingolimod in MS, which will therefore improve the understanding of its beneficial and adverse effects.

Japanese guidelines for fingolimod in multiple sclerosis: Putting into practice

AbstractFingolimod functions as a modulator of sphingosine‐1‐phosphate (S1P) receptors expressed on the surface of T and B lymphocytes, leading to their internalization. Loss of S1P receptors results in sequestration of central memory T cells enriched by Th17 cells in lymph nodes. After successful treatment of an animal model of multiple sclerosis (MS), clinical trials of oral fingolimod in patients with relapsing‐remitting MS showed a 60% reduction in the annualized rate of relapse. The United States Food and Drug Administration approved fingolimod as a first‐line drug for MS treatment in 2010, and data have been accumulated thereafter. However, MS experts recommend that the drug should remain as a second‐line option, because the long‐term risks for infection and malignancy have not been fully elucidated. Also, because of different genetic backgrounds, Asian MS patients might require special attention regarding other infectious agents and secondary cancer as compared with those reported in Caucasian patients. Furthermore, some Japanese patients who developed severe symptoms were later shown to be positive for the anti‐aquaporin‐4 antibody. In addition, reports of some Western MS patients have noted worsening after initiation, as well as discontinuation of fingolimod treatment. Finally, the optic spinal type of MS and neuromyelitis optica spectrum disorders are more prevalent in Asian than Western countries. Thus, establishment of criteria for determining which Asian MS patients would benefit from fingolimod treatment is mandatory.