Effects Of Fingolimod Research Articles

Влияние финголимода на сурфактант и гемостаз-регулирующую активность лёгких при экспериментальном аутоиммунном энцефаломиелите

Экспериментальный аутоиммунный энцефаломиелит (ЭАЭ) является общепризнанной экспериментальной моделью для изучения клинических проявлений рассеянного склероза (РС). Нарушение нереспираторных функций лёгких при РС является одной из актуальных и малоизученных проблем. При этом была выявлена высокая эффективность применения финголимода в терапии РС, что обусловило цель исследования - изучение влияния финголимода на сурфактант и гемостаз-регулирующую активность лёгких при экспериментальном аутоиммунном энцефаломиелите (ЭАЭ). Материалы и методы. Экспериментальные исследования выполнены на 95 половозрелых белых беспородных крысах-самцах. Животные были разделены на группы: 1-я - ЭАЭ (энцефалитогенная смесь в полном адъюванте Фрейнда (ПАФ) подкожно, n = 25); 2-я - ЭАЭ на фоне введения финголимода (FTY 720, «SIGMA», 1мг/кг, n = 18), 3-я - интактные животные (n = 25), 4-я - животные с введением только ПАФ (n = 27). У животных определяли биохимические и функциональные параметры сурфактанта лёгких (содержание общих фосфолипидов, их фракционный спектр, поверхностную активность сурфактанта), а также показатели коагуляционного гемостаза (АЧТВ и ПВ) венозной («до лёгких») и артериальной («после лёгких») крови. Результаты. Показано, что ЭАЭ сопровождается снижением содержания альвеолярных фосфолипидов и изменением их фракционного состава, в том числе уменьшением фосфатидилхолина и увеличением лизофосфатидилхолина, что вызывает ухудшение поверхностной активности лёгких. Помимо этого, при ЭАЭ наблюдаются гипокоагуляционные изменения АЧТВ и ПВ как в артериальной, так и в венозной крови. Введение финголимода полностью нивелирует изменения сурфактанта лёгких и частично восстанавливает изменения АЧТВ и ПВ артериальной и венозной крови. Заключение. Полученные результаты свидетельствуют о корригирующем влиянии финголимода на сурфактант и гемостаз-регулирующую активность лёгких, изменённые при ЭАЭ. Experimental autoimmune encephalomyelitis (EAE) is a common animal model for studying clinical manifestations of multiple sclerosis (MS). Alterations in non-respiratory functions of the lungs in MS is a relevant but understudied issue. A high effectiveness of fingolimod in the treatment of MS has been demonstrated in clinical practice. The aim of this study was to evaluate the effect of fingolimod on the pulmonary surfactant (PS) and the hemostasis-regulating activity of the lungs in EAE. Methods. Experiments were performed on 95 adult male outbred albino rats. The animals were divided into the following groups: 1, EAE (subcutaneous injections of the encephalitogenic mixture in Freund’s complete adjuvant, n = 25); 2, EAE with intraperitoneal administration of fingolimod (FTY 720, SIGMA, 1 mg/kg, n = 18); 3, intact animals (n = 27); and 4, intraperitoneal administration of Freund’s complete adjuvant without the encephalitogenic mixture (n = 27). Functional and biochemical characteristics of pulmonary surfactant (surface activity, content of total phospholipids and their fractions) and indexes of coagulation hemostasis (APTT and PT) in venous (“before lung”) and arterial (“after lung”) blood were determined. Results. EAE was associated with a decrease in the content of alveolar phospholipids and changes in their fractional composition, including a decrease in phosphatidylcholine and an increase in lysophosphatidylcholine, which is known to impair the pulmonary surfactant activity. In addition, a hypocoagulative shift in APTT and PT was observed in the “before lung” and “after lung” blood of EAE rats. The fingolimod treatment completely reversed the surfactant changes and partially restored APTT and PT in both arterial and venous blood of animals with EAE. Conclusion. The results showed a correcting effect of fingolimod on PS and the hemostasis-regulating activity of lungs affected by EAE.

Differential Effects of Fingolimod and Natalizumab on B Cell Repertoires in Multiple Sclerosis Patients.

Natalizumab and fingolimod are effective multiple sclerosis (MS) therapies that disrupt lymphocyte migration but have differential effects on B cell maturation and trafficking. We investigated their effects on peripheral blood (PB) and cerebrospinal fluid (CSF) B cell repertoires using next-generation deep sequencing. Paired CSF and PB B cell subsets (naïve, CD27+ memory, and CD27-IgD- double-negative B cells and plasmablasts) were collected by applying flow cytometry at baseline and after 6months of treatment and their respective heavy-chain variable region repertoires assessed by Illumina MiSeq. Treatment with fingolimod contracted, whereas natalizumab expanded circulating PB B cells. CSF B cell numbers remained stable following fingolimod treatment but decreased with natalizumab therapy. Clonal overlap between CSF and PB B cells was reduced with natalizumab treatment but remained stable with fingolimod therapy. Lineage analyses of pre- and posttreatment CSF B cell repertoires revealed large, clonally expanded B cell clusters in natalizumab-treated MS patients but no intrathecal clonal expansion following fingolimod therapy. Our findings suggest that natalizumab diminishes the exchange of peripheral and intrathecal B cells without impacting intrathecal clonal expansion. In contrast, fingolimod treatment fails to alter blood-brain barrier B cell exchange but diminishes intrathecal clonal expansion. Sphingosine-1 phosphate receptor inhibition may alter intrathecal B cell biology in MS.

Occurrence and microstructural features of slowly expanding lesions on fingolimod or natalizumab treatment in multiple sclerosis

Background: In multiple sclerosis (MS), up to 57% of white matter lesions are chronically active. These slowly expanding lesions (SELs) contribute to disability progression. Objective: The aim of this study is to compare fingolimod and natalizumab effects on progressive linearly enlarging lesions (i.e. SELs), a putative biomarker of smouldering inflammation. Methods: Relapsing-remitting MS patients starting fingolimod (n = 24) or natalizumab (n = 28) underwent 3T brain magnetic resonance imaging (MRI) at baseline, months 6, 12 and 24. SELs were identified among baseline-visible lesions showing ⩾ 12.5% of annual increase, calculated by linearly fitting the Jacobian of the nonlinear deformation field between timepoints obtained combining T1- and T2-weighted scans. SEL burden, magnetization transfer ratio (MTR) and T1 signal intensity were compared using linear models. Results: The prevalences of fingolimod (75%) and natalizumab patients (46%) with ⩾ 1 SEL were not significantly different (adjusted-p = 0.08). Fingolimod group had higher SEL number and volume (adjusted-p ⩽ 0.047, not false discovery rate (FDR) survived). In both groups, SELs versus non-SELs showed lower MTR and T1 signal intensity (adjusted-p ⩽ 0.01, FDR-survived). Longitudinally, non-SEL MTR increased in both treatment groups (adjusted-p ⩽ 0.005, FDR-survived). T1 signal intensity decreased in SELs with both treatments (adjusted-p ⩽ 0.049, FDR-survived in fingolimod group) and increased in natalizumab non-SELs (adjusted-p = 0.03, FDR-survived). Conclusion: The effects of natalizumab and fingolimod on SEL occurrence seem modest, with natalizumab being slightly more effective. Both treatments may promote reparative mechanisms in stable or chronic inactive lesions.

From the Molecular Mechanism to Pre-clinical Results: Anti-epileptic Effects of Fingolimod.

Epilepsy is a devastating neurological condition characterized by long-term tendency to generate unprovoked seizures, affecting around 1-2% of the population worldwide. Epilepsy is a serious health concern which often associates with other neurobehavioral comorbidities that further worsen disease conditions. Despite tremendous research, the mainstream anti-epileptic drugs (AEDs) exert only symptomatic relief leading to 30% of untreatable patients. This reflects the complexity of the disease pathogenesis and urges the precise understanding of underlying mechanisms in order to explore novel therapeutic strategies that might alter the disease progression as well as minimize the epilepsy-associated comorbidities. Unfortunately, the development of novel AEDs might be a difficult process engaging huge funds, tremendous scientific efforts and stringent regulatory compliance with a possible chance of end-stage drug failure. Hence, an alternate strategy is drug repurposing, where anti-epileptic effects are elicited from drugs that are already used to treat non-epileptic disorders.Herein, we provide evidence of the anti-epileptic effects of Fingolimod (FTY720), a modulator of sphingosine-1-phosphate (S1P) receptor, USFDA approved already for Relapsing-Remitting Multiple Sclerosis (RRMS). Emerging experimental findings suggest that Fingolimod treatment exerts disease-modifying anti-epileptic effects based on its anti-neuroinflammatory properties, potent neuroprotection, anti-gliotic effects, myelin protection, reduction of mTOR signaling pathway and activation of microglia and astrocytes. We further discuss the underlying molecular crosstalk associated with the anti-epileptic effects of Fingolimod and provide evidence for repurposing Fingolimod to overcome the limitations of current AEDs.

Fingolimod reduces salivary infiltrates and increases salivary secretion in a murine Sjögren's model

Sjögren's Syndrome (SjS) is a chronic, systemic autoimmune disease causing xerostomia, xerophthalmia, and systemic symptoms. The principal pathological finding in SjS is the accumulation of lymphocytes in exocrine glandular tissue and elsewhere, leading to secretory dysfunction and other abnormalities. A rational therapeutic approach might be to interfere with lymphocyte migration to the periphery from central lymphoid tissues. We thus examined in an animal model of SjS the effects of Fingolimod (FTY720, Gilenya™), which interferes with migration of lymphocytes to peripheral sites. Fingolimod induces sequestration of lymphocytes in lymphoid organs by altering lymphocyte expression of sphingosine-1-phosphate receptors. In the C57Bl/6. NOD.Aec1Aec2 (AEC) model of SjS, Fingolimod reduced circulating T and B cell numbers. Treatment of AEC mice with Fingolimod increased salivary output and decreased the size of salivary gland infiltrates. Oral Fingolimod thus merits further consideration in the management of SjS in humans.

The sphingosine-1-phosphate receptor modulator, FTY720, prevents the incidence of diabetes in Spontaneously Diabetic Torii rats.

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 (0.3mg/kg p.o.), was administered for 12weeks to SDT rats from 5 to 17weeks 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 14weeks of age. Based on the haematological and histological analyses performed at 17 to 18weeks 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.

REALMS study: real-world effectiveness and safety of fingolimod in patients with relapsing-remitting multiple sclerosis in Portugal

BackgroundFingolimod, an oral sphingosine 1-phosphate receptor modulator, is approved by EMA for relapsing-remitting multiple sclerosis (RRMS).ObjectivesTo assess the effectiveness and safety of fingolimod in patients with RRMS in real-world clinical practice in Portugal.MethodsRetrospective, multicentre, non-interventional study, reporting 3 years follow-up of data collected from October 2015 to July 2016. Sociodemographic data and previous treatments at baseline and data regarding disease evolution, including number of relapses, annualised relapse rates (ARR) and Expanded Disability Status Scale (EDSS), were collected.ResultsTwo-hundred and seventy-five participants were enrolled in the REALMS study. Results showed that the main reason to switch to fingolimod was failure of previous treatment (56.7%) and only 3.6% were naïve patients. In the total population, there was a significant decrease in ARR of 64.6% in the first year of treatment, 79.7% in the second year and 82.3% in the third year, compared with baseline. More than 67.0% of patients had no relapses during the 3 years after switching to fingolimod. EDSS remained stable throughout the study.ConclusionsTherapy with fingolimod showed a sustained effectiveness and safety over the 3 years, particularly on patients switched from first-line drugs (BRACE). No new safety issues were reported.

Selective modulation of trans-endothelial migration of lymphocyte subsets in multiple sclerosis patients under fingolimod treatment

Multiple sclerosis (MS) is an autoimmune disorder where auto-aggressive T cells target the central nervous system (CNS), causing demyelination. The trans-endothelial migration of leucocytes across the blood-brain barrier (BBB) is one of the earliest CNS events in MS pathogenesis. We examined the effect of the disease state and treatment with fingolimod on the transmigration of peripheral blood mononuclear cells (PBMCs) in an in vitro BBB model. Patients' leucocyte numbers, subsets and phenotypes were assessed by flow cytometry. As expected, fingolimod treatment induced a significant reduction in T cell and B cell numbers compared to untreated MS patients and healthy controls. Interestingly fingolimod led to a marked reduction of CD4+ and a significant increase in CD8+ cell numbers. In migrated cells, only CD3+ cell numbers were reduced in fingolimod-treated, compared to untreated patients; it had no effect on B cell or monocyte transmigration. T cells were then differentiated into naïve, effector and memory subsets based on their expression of CCR7. This showed that MS patients had increased numbers of effector memory CD4+ cells re-expressing CD45RA (TEMRA) and a decrease in central memory (CM) CD8+ cells. The former was corrected by fingolimod, while the latter was not. CM CD4+ and CD8+ cells migrated across BBB more efficiently in fingolimod-treated patients. We found that while fingolimod reduced the proportions of naïve CD19+ B cells, it significantly increased the proportions of these cells which migrated. When B cells were further stratified based on CD24, CD27 and CD38 expression, the only effect of fingolimod was an enhancement of CD24hiCD27+ B cell migration, compared to untreated MS patients. The migratory capacities of CD8hi Natural Killer (NK), CD8dim NK and NK-T cells were also reduced by fingolimod. While the disease-modifying effects of fingolimod are currently explained by its effect on reducing circulating auto-aggressive lymphocytes, our data suggests that fingolimod may also have a direct though differential effect on the trans-endothelial migration of circulating lymphocyte populations.

Comparative analysis of dimethyl fumarate and fingolimod in relapsing\u2013remitting multiple sclerosis

BackgroundDimethyl fumarate and fingolimod are oral disease modifying treatments (DMTs) that reduce relapse activity and slow disability worsening in relapsing–remitting multiple sclerosis (RRMS).ObjectiveTo compare the effectiveness of dimethyl fumarate and fingolimod in a real-world setting, where both agents are licensed as a first-line DMT for the treatment of RRMS.MethodsWe identified patients with RRMS commencing dimethyl fumarate or fingolimod in the Swiss Federation for Common Tasks of Health Insurances (SVK) Registry between August 2014 and July 2019. Propensity score-matching was applied to select subpopulations with comparable baseline characteristics. Relapses and disability outcomes were compared in paired, pairwise-censored analyses.ResultsOf the 2113 included patients, 1922 were matched (dimethyl fumarate, n = 961; fingolimod, n = 961). Relapse rates did not differ between the groups (incident rate ratio 1.0, 95%CI 0.8–1.2, p = 0.86). Moreover, no difference in the hazard of 1-year confirmed disability worsening (hazard ratio [HR] 0.9; 95%CI 0.6–1.6; p = 0.80) or disability improvement (HR 0.9; 95%CI 0.6–1.2; p = 0.40) was detected. These findings were consistent both for treatment-naïve patients and patients switching from another DMT.ConclusionDimethyl fumarate and fingolimod have comparable effectiveness regarding reduction of relapses and disability worsening in RRMS.

Immunohistochemical analysis of protective effects of maternal fingolimod on the placenta and fetal lung and brain in chorioamnionitis-induced preterm birth rat model

Objectives Fingolimod (FIN) is used for multiple sclerosis treatment and has potential antiapoptotic and anti-inflammatory effects. We aimed at expanding our knowledge on various immunohistochemical markers for elucidating the possible mechanisms of action of fingolimod in the placenta and fetal lung and brain. Methods Sixteen pregnant rats were divided into four groups. On gestational day 17, lipopolysaccharide (LPS) was injected intraperitoneally to induce preterm fetal injury followed by intraperitoneal injection of fingolimod. Hysterotomy for preterm delivery was performed 6 h after fingolimod was injected. The study groups included (1) control, (2) LPS (1 mg/kg), (3) FIN (4 mg/kg), and (4) FIN + LPS. Fetal brain and lung and placenta samples were collected for histopathological examination. Moreover, fetal lungs (surfactant protein-A (SP-A), SP-B, SP-D, caspase-3, and caspase-8), fetal brains (interleukin-10, interleukin-1β, TNF-α, caspase-8, glial fibrillary acidic protein, vimentin, myelin basic protein, and receptor activator of nuclear factor kappa), and placenta tissues (interleukin-10, interleukin-1β, TNF-α, caspase-3, and caspase-8) were immunohistochemically evaluated. Results Maternal fingolimod treatment led to attenuation of LPS-induced fetal brain, lung, and placental injury, as indicated by lower immunoexpression of inflammatory markers compared to LPS group (p < .0001 for all comparisons). Conclusion The findings of the present study confirm the neuroprotective effects of antenatally administered fingolimod, which also significantly improved preterm fetal lung injury and placental inflammation in LPS-exposed preterm pregnancies by possible antiapoptotic and anti-inflammatory effects.

Effects of fingolimod, a sphingosine-1-phosphate (S1P) receptor agonist, on white matter microstructure, cognition and symptoms in schizophrenia.

Several lines of evidence have implicated white matter (WM) deficits in schizophrenia, including microstructural alterations from diffusion tensor (DTI) brain imaging studies. It has been proposed that dysregulated inflammatory processes, including heightened activity of circulating lymphocytes, may contribute to WM pathology in this illness. Fingolimod is a sphingosine-1-phosphate (S1P) receptor agonist that is approved for the treatment of relapsing multiple sclerosis (MS). Fingolimod robustly decreases the number of circulating lymphocytes through sequestration of these cells in lymph tissue. In addition, this agent improved WM microstructure as shown by increases in DTI fractional anisotropy (FA). In this pilot study, we assessed the effects of fingolimod on WM microstructure, cognition and symptoms in an eight-week, double-blind trial. Forty subjects with schizophrenia or schizoaffective disorder were randomized 1:1 to fingolimod (0.5mg/day) and placebo. Fingolimod caused significant reductions in circulating lymphocytes (p < .001). In addition, there was a statistically non-significant association (p = .089) between DTI-FA change in the WM skeleton and fingolimod. There were significant relationships between the degree of lymphocyte reductions and increases in FA in the corpus collosum (p = .004) and right superior longitudinal fasciculus ( p = .02), and a non-significant correlation with the WM skeleton. There were no significant fingolimod versus placebo interactions on cognitive or symptom measures. There were no serious adverse events related to fingolimod treatment. Future studies with larger samples and treatment durations are needed to further establish fingolimod's potential therapeutic effects in schizophrenia.

Fingolimod increases oligodendrocytes markers expression in epidermal neural crest stem cells

Epidermal neural crest stem cells (EPI-NCSCs) are propitious candidates for cell replacement therapy and supplying neurotrophic factors in the neurological disorders. Considering the potential remyelinating and regenerative effects of fingolimod, in this study, we evaluated its effects on EPI-NCSCs viability and the expression of neurotrophic and oligodendrocyte differentiation factors. EPI-NCSCs, extracted from the bulge of rat hair follicles, were characterized and treated with fingolimod (0, 50, 100, 200, 400, 600, 1000, and 5000 nM). The cell viability was evaluated by MTT assay at 6, 24 and 72 h. The expression of neurotrophic and differentiation factors in the cells treated with 100 and 400 nM fingolimod were measured at 24 and 120 h. Fingolimod at 50–600 nM increased the cells viability after 6 h, with no change at the higher concentrations. The highest concentration (5000nM) induced toxicity at 24 and 72 h. NGF and GDNF genes expression were decreased at 120 h, but on the contrary, brain derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) were increased by both concentrations at both time points. Oligodendrocyte markers including platelet-derived growth factor receptor A (PDGFRα), neuron-glial antigen 2 (NG2) and growth associated protein 43 (GAP43) were elevated at 120 h, which was accompanied with reduce in stemness markers (Nestin and early growth response 1 (EGR1)). Fingolimod increased the expression of neurotrophic factors in EPI-NCSCs, and guided them to oligodendrocyte fate. Therefore, fingolimod in combination with EPI-NCSCs, can be considered as a promising approach for demyelinating neurological disorders.

Fingolimod and tumor-infiltrating lymphocytes in checkpoint-inhibitor treated cancer patients

Immune checkpoint inhibitors (ICIs) are emerging as the new standard of care for treating various metastatic cancers. It is known that effective anti-tumor immune responses are associated with a stronger presence of tumor-infiltrating lymphocytes (TILs) in solid tumor tissue. Cancer patients with relapsing–remitting multiple sclerosis (RRMS) are often under continuous treatment with fingolimod, an immune-modulating drug that inhibits lymphocyte egress from secondary lymphatic organs. Little is known about the effect of fingolimod on ICI cancer therapy, as fingolimod may limit the number of TILs. Here we present three patients with RRMS, who developed various cancers during fingolimod treatment. Histology of all tumors consistently showed low numbers of TILs. A second biopsy taken from one of the tumors, a melanoma, revealed a significant increase of TILs after stopping fingolimod and starting pembrolizumab, indicating a surge in the number and re-invigoration of T cells. Our study suggests that fingolimod limits the number of TILs in solid tumors and may, thus, inhibit anti-cancer immune responses.

Clinical effectiveness of reduced fingolimod dose in relapsing remitting multiple sclerosis-a Portuguese cohort.

Fingolimod is an oral daily treatment for relapsing remitting multiple sclerosis (RRMS). A decrease in lymphocytes count is a common side effect, whereby clinicians occasionally propose a reduced dose rather than its discontinuation. However, current data on the effectiveness of these regimens are scarce and contradictory. Our objective was to investigate if the fingolimod effectiveness is maintained with reduction in dosing frequency. Retrospective and observational study of RRMS patients taking fingolimod-nondaily (FTY-ND) for at least 6months. Propensity score-based matching was performed to select patients taking daily dose (FTY-ED) with comparable baseline characteristics: age, sex, disease duration, annualized relapse rate (ARR), and expanded disability status scale (EDSS). Afterwards, clinical and laboratorial assessment was evaluated in both groups. Thirty-six patients were included in each group (FTY-ED vs. FTY-ND). Decrease in lymphocytes count was the main reason for switching to FTY-ND (88.9%). Previous treatment with natalizumab was inversely associated with risk of reducing dose (OR 0.253, 95%CI = 0.08-0.807, p = 0.016). There were no significant differences in clinical disease activity between patients FTY-ED vs. FTY-ND: mean ARR 0.4 vs. 0.3 (p = 0.247), median EDSS 2.0 vs. 2.0 (p = 0.687), and proportion of patients with EDSS increase 8.3% vs. 13.9% (p = 0.453). FTY-ND was overall well tolerated and was associated with an increase in the mean lymphocytes count (362 ± 103 cells/mm3 to 541 ± 183 cells/mm3, p < 0.001). These data suggest that the effectiveness of FTY is maintained despite the reduction of the dose, minimizing the most common adverse events. These findings warrant further confirmation, ideally with randomized clinical trials.

Fingolimod administration improves neurological functions of mice with subarachnoid hemorrhage

PurposeTo investigate the brain protective effects of fingolimod on inflammatory response of SAH mice. MethodsWe utilized an endovascular mouse perforation model of SAH. Mice were divided into three groups: sham group, SAH group and SAH + Fingolimod group. Mice received either saline or fingolimod (1 mg/kg) intraperitoneally 2 h after sham surgery or SAH. The modified neurological severity score (mNSS) and Morris water maze were respectively used to evaluate the influence of nerve function. Evens blue (EB) extravasation was used to detect the permeability of blood-brain barrier, and water content in brain tissue was also detected. Flow cytometry, ELISA kits and western blotting were used to detect inflammatory factors in brain tissue. ResultsThe results showed that compared with SAH group, after treatment, the delay time of locating the hidden platform was shorter. The mNSS results showed that fingolimod improved the behavior of SAH mice. In addition, fingolimod could reduce the water content in brain. Flow cytometry results showed that after 3 d of treatment, fingolimod significantly increased Treg cells and down-regulated NK cells. Western blotting results showed fingolimod inhibited the expression of inflammatory cytokines in brain tissue. ELISA kit results showed that fingolimod could down-regulate IL-6 and TNF-α and up-regulate IL-10 and TGF-β1 in serum. ConclusionsFingolimod could regulate the inflammatory response to alleviate SAH-induced brain damage and promote neurological recovery, which provides a new therapeutic strategy for SAH treatment.

Real-world evidence on the safety and effectiveness of fingolimod in patients with multiple sclerosis from Taiwan

Multiple sclerosis is classified as a rare disease in Taiwan. This study evaluated the safety and effectiveness of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS) from routine clinical practice in Taiwan. In this retrospective, multicentre, observational study, we collected clinical data of patients treated with fingolimod 0.5mg/day in routine clinical practice between September 2012 and December 2015. Primary outcome was the overall safety of fingolimod; secondary outcome was the annualized relapse rate (ARR). Overall, 62/69 (86.1%) patients were on fingolimod by the end of data collection period. Mean age (±standard deviation [SD]) at inclusion was 37.7±10.10 years; mean duration of MS was 5.4±4.52 years and mean duration of fingolimod exposure was 135.8 patient-years. The most common adverse events (AEs) were bradycardia (21.7%; first-dose related), upper respiratory tract infection, dizziness, and hypoaesthesia (numbness) (11.6% each), followed by urinary tract infection and back pain (7.2% each). Seven patients had liver enzyme-related AEs. Eight patients had absolute lymphocyte counts <0.2×103/uL over the study period. One patient developed second degree AV block after first-dosing. Serious AEs were observed in 11 patients (15.9%; mild-to-moderate). No newly developed macular oedema was detected. The ARR was 0.3±0.74 in fingolimod-treated patients and 66.7% of patients were relapse-free. The mean (SD) change from baseline in expanded disability status scale score was -0.30±1.353. Fingolimod 0.5mg/day treatment with an average of 2 years of exposure was associated with a manageable safety profile, and maintained/improved effectiveness in RRMS patients from Taiwan.

Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy in paediatric patients with multiple sclerosis: Results from the PARADIGMS study

Background: Reduction in absolute lymphocyte count (ALC) is expected with fingolimod treatment. Objective: To evaluate the effect of fingolimod 0.5 mg versus intramuscular interferon β-1a (30 μg) on ALC and its relationship with infections in paediatric-onset multiple sclerosis (POMS) up to 4 years. Methods: We assessed ALC at baseline, monthly till 3 months, and every 3 months (core phase) and with variable periodicity (extension phase) of Phase 3 PARADIGMS study (N = 215). Incidence rates (IRs) of infection-related adverse events (infAEs)/100 patient-years were analysed by on-study nadir ALC. Results: With fingolimod, ALC rapidly reduced to 29.9%–34.4% of baseline values within 2 weeks and remained stable thereafter; no relevant changes observed with interferon. IRs of infAEs were 67.6 with fingolimod and 61.8 with interferon; IR ratios with respect to interferon, overall: 1.09, by nadir ALC 0.2–0.4 × 109/L: 1.13 and >0.4 × 109/L: 0.91. Three patients had a single episode of ALC <0.2 × 109/L (core phase). No opportunistic infections were observed and infection risk did not increase during the extension phase. Conclusion: In paediatric patients, the overall incidence of infections was comparable between fingolimod and interferon. No association was observed between nadir ALC and infections in POMS, although sample size may have been too small to rule an association.

The efficacy and safety of oral disease-modifying therapies for relapsing-remitting multiple sclerosis: A systematic review

Background: Although widely used, first-line injectable medicines for the treatment of multiple sclerosis (MS) remain an issue of efficacy and adherence. Recently, new oral medications for MS have contributed to dramatic improvements in MS treatment. This study aims to evaluate the safety and efficacy of oral disease-modifying drugs (DMDs) used in relapsing-remitting MS (RRMS). Methods: A systematic review was conducted on related databases including PubMed, Scopus, Cochrane, and Web of Science up to April 2020. The screening of the studies and their quality assessment was carried out independently by the two authors. Results: Three studies fulfilled the predefined criteria of inclusion. One of them compared teriflonomide with subcutaneous interferon beta-1a (IFN β-1a), another compared oral fingolimod with intramuscular (IM) IFN β-1b, and the third article compared oral fingolimod with IM IFN β-1a. No eligible study was found for dimethyl fumarate (DMF). The results indicated that while the efficacy of fingolimod was more than IFN β (IM β-1a and β-1b), teriflunomide 7 mg had less efficacy than subcutaneous IFN β-1a. Regarding safety, the results indicated that the proportion of diabetic patients with adverse events (AEs) in the fingolimod group was higher than in the IFN β-1b group and the overall occurrence of AEs was similar between teriflunomide and IFN β-1a groups. Conclusion: There is evidence for the effectiveness of fingolimod in reducing annualized relapse rates (ARRs) and improving magnetic resonance imaging (MRI) findings, but the evidence does not support the effectiveness of teriflunomide and further studies are required to determine its efficacy. Also, fingolimod is associated with more side effects than IFN β-1b, but there is no evidence to suggest any difference in side effects between teriflunomide and IFN β-1a.

Evaluation of the effect of fingolimod (FTY720) on macular perfusion by swept-source optical coherence tomography angiography in patients with multiple sclerosis

Aim To determine changes in retinal microcirculation, caused by fingolimod (FTY720) use, via swept-source optical coherence tomography angiography (SS-OCTA) in relapsing-remitting multiple sclerosis (RR-MS) patients. Materials and methods 80 patients with RR-MS, who were using fingolimod, and 50 healthy control subjects were included in the study. Group 1 consisted of 40 eyes from 40 RR-MS patients, who had been using fingolimod for less than six months, and Group 2 consisted of 40 eyes from 40 RR-MS patients, who had been using fingolimod for longer than six months. All participants underwent SS-OCTA via DRI OCT Triton (Topcon, Tokyo, Japan), analysing their central macular thickness (CMT) (µm), subfoveal choroidal thickness (SFCT) (µm), superficial (VDs) (%) and deep vascular plexuses (VDd) (%), choriocapillaris (VDcc) (%), and superficial and deep foveal avascular zones (FAZs, FAZd, respectively) (%) in mean values. Results The mean follow-up times for patients in Groups 1 and 2 were 2.9 ± 1.5 months and 22.5 ± 11.3 months, respectively. The FAZs value in Group 2 was found to be significantly higher than that in both Group 1 and the control group (p = 0.034, p = 0.042, respectively). The VDs central value in Group 2 did not differ significantly from that in Group 1 or the control group (p > 0.05), while the VDs central value was higher in Group 1 than in the control group (p = 0.008). In Group 1, the VDd central value was significantly higher than in Group 2 and the control group (p = 0.047; p = 0.020, respectively). The CMT measurement for Group 2 was significantly lower than in Group 1 and the control group (p = 0.008, p = 0.003, respectively). Conclusion Fingolimod use seems to remarkably increase VDs and VDd measurements in the early period of administration and decrease CMT over a longer period of administration in patients with RR-MS.

Comparison of first-line and second-line use of fingolimod in relapsing MS: The open-label EARLIMS study.

BackgroundTreatment of MS often begins with low-efficacy injectable disease-modifying therapy (iDMT).ObjectivesTo compare the effect of fingolimod 0.5 mg/day on clinical, MRI, patient-reported, and safety outcomes, in treatment-naïve and previously treated (≥1 iDMT) patients with early MS.MethodsEARLIMS was a multicentre, open-label, non-randomized, parallel-group phase 3 b/4 study in Australia and Spain. Patients with relapsing–remitting MS, Expanded Disability Status Scale (EDSS) score <4.0, and ≥1–5 years since diagnosis, received daily fingolimod for 48 weeks. The primary endpoint was annualized relapse rate (ARR).ResultsOf 347 patients enrolled at 51 sites (treatment-naïve, 200 [57.6%]; previously treated, 147 [42.4%]), 320 completed the study (treatment-naïve, 184 [92.0%]; previously treated, 136 [92.5%]), but the study remained underpowered (planned enrolment, n = 432). Fingolimod reduced ARR to similar levels in both treatment-naïve (mean ARR [95% confidence interval], 0.21 [0.14, 0.29]) and previously treated groups (0.30 [0.20, 0.41]; p = 0.1668). There were no new safety signals.ConclusionsFingolimod appeared equally effective as first- or second-line therapy in relapsing MS. There was a trend for better outcomes with fingolimod in treatment-naïve patients than in those previously treated with >1 iDMT.