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Background: Progressive Multifocal Leukoencephalopathy (PML) is an opportunistic infection caused by John Cunningham virus (JCV) reactivation, potentially associated with natalizumab (NTZ) treatment for Multiple Sclerosis (MS). The anti-JCV antibodies titre (JCV index) increases during NTZ treatment; however, the effects of other disease-modifying therapies (DMTs) on the JCV index have not been fully explored. Objective: The aim of the study was to evaluate changes in the JCV index during treatment with several DMTs. Methods: This longitudinal study evaluated the JCV index before starting DMT (T0) and during treatment with DMT (T1). Results: A total of 260 participants (65.4 % females, mean age 43 ± 11.3 ) were enrolled: 68 (26.2 %) treated with fingolimod (FTY), 65 (25 %) rituximab or ocrelizumab (RTX/OCR), 37 (14.2 %) dimethyl-fumarate (DMF), 29 (11.2 %) cladribine (CLD), 23 (8.8 %) teriflunomide (TFM), 20 (7.7 %) interferon or glatiramer acetate (IFN/GA), and 18 (6.9 %) alemtuzumab (ALM). At T1, the percentage of patients with JCV index 1.51 was found to be significantly reduced in the RTX/OCR group (51.6 % versus 37.5 %, p = 0.04). In the FTY group, a significant reduction in the percentage of patients with JCV index Conclusion: DMTs with a T and/or B depleting mechanism of action induced a significant reduction in the JCV index. These results may suggest new possible sequencing strategies potentially maximizing disease control while reducing the PML risk.

Postoperative cystoid macular oedema (CMO) is a recognised complication of cataract surgery, occurring in around 1.5% of cases. It is generally managed with topical steroids or non-steroidal anti-inflammatory medications. We present a case of a patient who developed bilateral sequential CMO following bilateral sequential cataract surgery which was non-responsive to topical therapy and worsened following sub-Tenons administration of steroid. The patient took fingolimod for multiple sclerosis both prior to and during the period of cataract surgery which is known to result in the development of macular oedema in some patients. On fingolimod cessation, the oedema resolved over a period of 5 months with good visual recovery. We present this case to inform cataract surgeons of the risk of fingolimod-associated macular oedema in patients undergoing cataract surgery and to inform neurologists of the potential need to adjust treatment for patients undergoing cataract surgery.

OBJECTIVE Progressive multifocal leukoencephalopathy (PML) is a serious viral infection associated with disease-modifying therapies (DMT) for multiple sclerosis (MS) including sphingosine 1-phosphate receptor (S1PR) modulators. The objective of this review was to investigate the characteristics of PML in MS patients associated with drugs of the S1PR modulator. METHODS We conducted a literature review and analysis of 24 patients from 12 publications in PubMed, SCOPUS and EMBASE. This is a descriptive analysis and study of characteristics of PML associated fingolimod and related S1PR modulator group of DMT. RESULTS A total of 24 cases of PML in MS patients treated with fingolimod were identified. Of these, 21 cases contained data regarding changes in the expanded disability status scale (EDSS). One case of PML in association with ozanimod treatment in a clinical trial was also identified. In PML cases associated with fingolimod, the mean age at the time of PML diagnosis was 50.91 ± 11.5 years. All patients were treated with fingolimod for more than 24 months. Compared to patients who improved or were stable, in terms of EDSS, after symptomatic management of PML, the non-improved groups were significantly older. There were no fatalities in either group during the reported follow-up period. CONCLUSION The incidence of PML appears to be extremely low in MS patients treated with S1PR modulators. Risk of PML increases with increase in duration of treatment with S1PR modulators like fingolimod, and increased age at the time of PML diagnosis is associated with worse prognosis.

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

We have previously reported that the long-term exposure of Isocarbophos, a kind of organophosphorus compounds, induces vascular dementia (VD) in rats. Studies have also shown that organophosphorus compounds have adverse effects on offsprings. Vitamin B6 is a coenzyme mainly involved in the regulation of metabolism and has been demonstrated to ameliorate VD. Sphingosine-1-phosphate (S1P), a biologically active lipid, plays a vital role in the cardiovascular system. However, whether S1P is involved in the therapeutic effects of Vitamin B6 on posterior cerebral artery injury has yet to be further answered. In the present study, we aimed to explore the potential influence of Vitamin B6 on Isocarbophos-induced posterior cerebral artery injury in offspring rats and the role of the S1P receptor in this process. We found that Vitamin B6 significantly improves the vasoconstriction function of the posterior cerebral artery in rats induced by Isocarbophos by the blood gas analysis and endothelium-dependent relaxation function assay. We further demonstrated that Vitamin B6 alleviates the Isocarbophos-induced elevation of ICAM-1, VCAM-1, IL-1, and IL-6 by using the enzyme-linked immunosorbent assay kits. By performing immunofluorescence and the western blot assay, we revealed that Vitamin B6 prevents the down-regulation of S1P in posterior cerebral artery injury. It is worth noting that Fingolimod, the S1P inhibitor, significantly inhibits the Vitamin B6-induced up-regulation of S1P in posterior cerebral artery injury. Collectively, our data indicate that Vitamin B6 may be a novel drug for the treatment of posterior cerebral artery injury and that S1P may be a drug target for its treatment.

Introduction Multiple sclerosis (MS) is a disease of unknown etiology. Diagnosis of MS is primarily based on detection of myelin damage by magnetic resonance imaging (MRI) and classification of demyelination according to the McDonald Criteria. Cholecalciferol (vitamin D3) has been shown to affect the onset and progression of MS via its immunomodulating properties. The role of vitamin D in MS pathogenesis and treatment deserves further investigation, as there is sufficient evidence to suggest a correlation between vitamin D blood level and brain MRI lesion load. State of knowledge Elevated blood vitamin D concentration is linked with demyelination, as determined by T2-weighted and gadolinium-enhanced MRI. Blood vitamin D blood levels are affected by sun exposure, among other factors; however, there is no evident connection between abnormalities in myelination and seasonality. Vitamin D supplementation among MS patients has been associated with a lower probability of new lesions and loss of existing lesion volume, as observed seen in T1-weighted MRI scans (p=0.03). An increase in TGF-beta levels was noted among patients using vitamin D supplementation, which may suggest a mechanism by which cholecalciferol may improve MS prognosis. Patients with clinically isolated syndrome (CIS) exhibited an inverse correlation between vitamin D concentration and risk of new lesions as seen in T2-weighted MRI scans. Moreover, vitamin D intake among these patients lowered the risk of progression to clinically definite multiple sclerosis (CDMS). Daily intake of vitamin D during fingolimod treatment correlated strongly with lower numbers of new lesions. High dose vitamin D supplementation during interferon beta-1a treatment was linked to lower mean percentage of lesions compared with volume pre-treatment seen by T2-weighted MRI. Results Recent findings advocate for the monitoring of vitamin D blood levels in MS patients. Vitamin D supplementation should be considered in both MS patients and patients with CIS, where other signs of disease may be delayed. Moreover, vitamin D supplementation appears to lower the likelihood of new demyelination changes apparent in MRI examinations.

Neurodegenerative diseases are clinical manifestations that depend on the anatomy and function of the affected areas. Amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are some of these diseases, but they are also autoimmune and their etiology makes treatments limited and of little therapeutic efficacy. Currently, some clinical research advances can be pillars for the development of new treatments for these diseases. Therefore, the objective of this review is to describe the latest clinical advances in ALS and MS as well as their results in clinical recovery in randomized clinical trials, meta-analyzes, and full-text systematic reviews conducted in humans and rats, published in English and Spanish in the last 5 years, using PubMed, SciELO, and Cochrane. For clinical trials to be included, they had to provide a detailed breakdown of randomization methods, diagnostic criteria, intervention details, and efficacy evaluation. The results show that, so far, available medications, like riluzole and edaravone for ALS and fingolimod, dimethyl fumarate, and IFN β-1b for MS, only prolong the life of the patient. Among these drugs are also glutamate neurotransmitter antagonists, immunomodulators and even antioxidants; each of them showed significant improvement in the reviewed trials. Similarly, other non-pharmaceutical treatments, as the 600-mg dose of curcumin in the diet for ALS, showed improvement of the patients’ conditions. Regarding MS, more studies should be carried out on autotransplantation with adiposederived mesenchymal stem cells (AdMSCs) to investigate the potential therapeutic benefit of this technique in phases prior to secondary-progressive (SPMS).

The risk of cancer associated with persons with multiple sclerosis (pwMS) prescribed with disease modifying therapies (DMTs) is not well established. This observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from the World Health Organization database: VigiBase®. All consecutive reports of DMTs prescribed to pwMS (alemtuzumab, dimethyl fumarate, fingolimod, glatiramer acetate, interferon-β, natalizumab, ocrelizumab, and teriflunomide), and their serious adverse event cases were eligible, excluding those reporting immunosuppressant DMTs used as anticancer therapies. The primary outcome was the multivariate odds ratio of cancer reporting (r-OR) for DMTs prescribed to pwMS after imputation of missing data. There were 5966 cancer cases from 240,993 reports of DMTs prescribed to pwMS. After adjustments on age, sex, and geographical region, natalizumab (r-OR 1.74, 95% CI 1.63–1.87), interferon-β (r-OR 1.39, 95% CI 1.30–1.49), dimethyl fumarate (r-OR 1.35, 95% CI 1.25–1.46), and fingolimod (r-OR 1.15, 95% CI 1.06–1.24) were significantly associated with a greater cancer reporting, whereas alemtuzumab, glatiramer acetate, ocrelizumab, and teriflunomide were not, in the disproportionality analysis. As exploratory analyses, upper aerodigestive tract, breast, urinary including the male genitourinary tract, and nervous system cancers were associated with natalizumab, interferon-β, and dimethyl fumarate. Fingolimod was only associated with skin cancer types. Cancer cases reporting these four DMTs prescribed to pwMS were younger in age than for non-pwMS drugs in the VigiBase® (p

PURPOSE OF THE REVIEW: To provide the latest evidence and treatment advances of multiple sclerosis in women of childbearing age prior to conception, during pregnancy and postpartum. RECENT FINDINGS: Recent changes permitting interferon beta (IFN-β) use in pregnancy and breastfeeding has broadened the choices of disease modifying treatments (DMTs) for patients with high relapse rates. Natalizumab may also be continued until 34 weeks of pregnancy for patients requiring persisting treatment. Drugs with a known potential of teratogenicity such as fingolimod or teriflunomide should be avoided and recommended wash-out times for medications such as cladribine, alemtuzumab or ocrelizumab should be considered. Teriflunomide and fingolimod are not recommended during breastfeeding, however, glatiramer acetate and IFN-β are considered to be safe. SUMMARY: The evidence of potential fetotoxicities and adverse pregnancy outcomes associated with DMTs is increasing, although more research is needed to evaluate the safety of drugs and to track long-term health outcomes for the mother and the child.

Background Recent observations suggest a lack of humoral response after SARS-CoV-2 vaccination in multiple sclerosis (MS) patients treated with fingolimod or ocrelizumab Objectives To assess serological response to SARS-CoV-2 vaccination in MS patients receiving these disease-modifying treatments (DMTs) in a real-life setting. Methods Retrospective clinical data collection from MS patients followed at San Raffaele Hospital MS Centre (Milan, Italy). All patients treated with fingolimod or ocrelizumab who had received a complete anti-COVID-19 vaccination course, with no clinical history suggestive of previous SARS-CoV-2 infection and with an available post-vaccination serological assay obtained at least 14 days after vaccination completion were considered for the study. Results We collected data from 32 MS patients, 16 treated with fingolimod and 16 receiving ocrelizumab. Among the fingolimod group 10 patients (62.5%) had a positive serological response after vaccination and among ocrelizumab-treated patients a positive serological test was found in six cases (37.5%). No relation between serological response and clinical features (i.e., treatment duration, time between vaccination and last treatment dose, and white blood cells count) was identified. Conclusions Our initial real-life experience suggests a variable antibody production in MS patients receiving these DMTs. At present, there are no sufficient data to do not recommend anti-SARS-CoV-2 vaccine in these patients.

To analyse the course of multiple sclerosis (MS) after fingolimod withdrawal in a multicentre cohort. Patients who discontinued fingolimod were included. Relapses, Expanded Disability Status Scale (EDSS), and new/gadolinium-enhancing lesions on magnetic resonance imaging (MRI) were assessed during the last year on fingolimod, and in the year after discontinuation. Wilcoxon test was used to analyse the difference in EDSS and relapses between the two periods, and to compare lymphocyte counts at discontinuation and 3 months later. Demographic and clinical variables were evaluated using univariable and multivariable logistic regression analyses. Patients were 230 (females 66.1%; mean age 38 years; median EDSS 3). Fingolimod was discontinued due to inefficacy in 57%, and 87.4% started another treatment. Relapse was observed in 33% of the patients in the year after discontinuation. Severe reactivation was observed in 15%. During the first 6 months after discontinuation, new/enhancing lesions were seen in 62/116 patients. Higher age at the fingolimod discontinuation was found to be associated with a lower probability of inflammatory activity (p = 0.001) and severe reactivation (p = 0.007) during the year after discontinuation. Lower lymphocyte count was a risk factor for clinical, radiological, and severe activity (p = 0.02, p = 0.002, p = 0.01, respectively). The main reason for the discontinuation of fingolimod was inefficacy. One-third of the patients had a relapse during the year after discontinuation, 15% experienced a severe reactivation, and approximately 50% of patients with available MRI scan had new/enhancing lesions. The risk factors for disease activity after discontinuation were low lymphocyte count and younger age.

Recently, more and more attention has been paid to the problem of drug‑induced (DI) atrial fibrillation (AF). It is known that the development of DI AFcan be associated with the intake of cardiovascular and anticancer drugs, drugs that affect the central nervous system or respiratory organs. However,there are other drugs that can provoke DI AF, which practitioners are less aware of. This article is a review of the current literature on DI AF associated withthe intake of other groups of drugs and individual drugs that are not included in the above groups. Analysis of the available literature has shown that theincidence of DI AF reaches 6.9% when taking zoledronic acid and 1.5% when taking alendronate, although data from different authors regarding thecausal relationship between bisphosphonate therapy and the development of AF are ambiguous. The use of high doses of glucocorticosteroids (at a dailydose of ≥ 7.5 mg in terms of prednisolone) is also associated with an increased risk of AF (OR = 6.07; 95% CI: 3.90–9.42). Treatment with non‑steroidal anti‑inflammatory drugs is also associated with a higher risk of developing DI AF compared to those who do not use it – the incidence rate is 1.17 (95% CI:1.10–1.24) for nonselective and 1.27 (95% CI: 1.20–1.34) for cyclooxygenase‑2 inhibitors. The literature contains a description of clinical cases of DI AF whiletaking immunosuppressants (azathioprine, methotrexate + etanercept, fingolimod, cyclosporine), drugs that affect the genitourinary system (vardenafil,sildenafil, yohimbine hydrochloride, hexoprenaline), local anesthetics, bupacaero testosterone, stanozolol, testosterone cypionate, nandrolone decanoateextraboline) and nicotine‑containing products (nicotine‑containing chewing gum).

Background: Ofatumumab, an FDA-approved fully-human anti-CD20 monoclonal antibody with a 20 mg subcutaneous (s.c.) monthly dosing regimen, is indicated for the treatment of relapsing forms of multiple sclerosis (MS) in adults, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. ARTIOS is a Phase 3b study exploring the treatment outcomes in relapsing MS (RMS) patients with disease activity that are switching from commonly used oral disease-modifying therapies. This patient population was relatively under-represented in the ASCLEPIOS I/II studies. Objectives: To present the innovative design of the ARTIOS study in RMS patients. Methods: ARTIOS is a single-arm, prospective, multicenter, open-label study in RMS patients aged 18-60 years with an Expanded Disability Status Scale score of 0-4 and breakthrough disease activity (defined as 1 relapse or 1 disease activity on MRI) after 6 months (m) of treatment with dimethyl fumarate or fingolimod. The study comprises of a screening and transition period (60 days), a treatment period (96 weeks) and a safety follow-up and/or extension period (9m). Ofatumumab 20 mg s.c. is self-administered monthly via an auto-injector. Treatment effectiveness (primary endpoint) will be evaluated as the annualized relapse rate over 96 weeks. Safety evaluations (secondary endpoint) include the proportion of patients with adverse events, laboratory/vital sign results meeting abnormal criteria, and treatment discontinuations. Exploratory endpoints include disability, MRI activity, no evidence of disease activity (NEDA-3) and patient-reported outcomes (MS impact, fatigue, treatment satisfaction and anxiety/depression). This innovative study design employs digital tools such as FloodlightTM (smartphone application), Actigraphy (activity-tracking watch), and an eCOA handheld for electronic diary to allow collection of data on the patient's activity (daily activity, sleep quality and injection reactions). Biomarkers of disease activity (neurofilament light chain [NfL] and glial fibrillary acidic protein [GFAP]) will also be evaluated. Results: The study plans to enroll ~550 patients across 25 countries. The first patient first visit was achieved on 14 July 2020 and study completion is expected in 2023. To account for COVID-19 associated restrictions, the original study was modified to provide more flexibility to patients visiting the clinic only to perform procedures which cannot be done at home with the support of home nurses (e.g., MRI and EDSS). An interim analysis is planned after completion of 1 year of treatment. Conclusions: The ARTIOS study will provide clinical data for the selected MS patient population that was not studied in the pivotal ofatumumab trials. ARTIOS leverages various digital technologies to collect unique and comprehensive data which may enrich treatment outcomes in this patient population.

Introduction. The aim of this study was to report the course and outcome of SARS-CoV-2 infection in multiple sclerosis (MS) patients treated with disease-modifying therapies (DMTs) in Poland. A major concern for neurologists worldwide is the course and outcome of SARS-CoV-2 infection in patients with MS treated with different DMTs. Although initial studies do not suggest an unfavourable course of infection in this group of patients, the data is limited. Materials and methods. This study included 396 MS patients treated with DMTs and confirmed SARS-CoV-2 infection from 28 Polish MS centres. Information concerning patient demographics, comorbidities, clinical course of MS, current DMT use, as well as symptoms of SARS-CoV-2 infection, need for pharmacotherapy, oxygen therapy, and/or hospitalisation, and short-term outcomes was collected up to 30 January 2021. Additional data about COVID-19 cases in the general population in Poland was obtained from official reports of the Polish Ministry of Health. Results. There were 114 males (28.8%) and 282 females (71.2%). The median age was 39 years (IQR 13). The great majority of patients with MS exhibited relapsing-remitting course (372 patients; 93.9%). The median EDSS was 2 (SD 1.38), and the mean disease duration was 8.95 (IQR 8) years. Most of the MS patients were treated with dimethyl fumarate (164; 41.41%). Other DMTs were less frequently used: interferon beta (82; 20.70%), glatiramer acetate (42; 10.60%), natalizumab (35;8.84%), teriflunomide (25; 6.31%), ocrelizumab (20; 5.05%), fingolimod (16; 4.04), cladribine (5; 1.26%), mitoxantrone (3; 0.76%), ozanimod (3; 0.76%), and alemtuzumab (1; 0.25%). The overall hospitalisation rate due to COVID-19 in the cohort was 6.81% (27 patients). Only one patient (0.3%) died due to SARS-CoV-2 infection, and three (0.76%) patients were treated with mechanical ventilation; 106 (26.8%) patients had at least one comorbid condition. There were no significant differences in the severity of SARS-CoV-2 infection regarding patient age, duration of the disease, degree of disability (EDSS), lymphocyte count, or type of DMT used. Conclusions and clinical implications. Most MS patients included in this study had a favourable course of SARS-CoV-2 infection. The hospitalisation rate and the mortality rate were not higher in the MS cohort compared to the general Polish population. Continued multicentre data collection is needed to increase the understanding of SARS-CoV-2 infection impact on the course of MS in patients treated with DMTs.

Lymphocytes and innate immune cells are key drivers of multiple sclerosis (MS) and are the main target of MS disease modifying therapies (DMT). Ex vivo analyses of MS lesions have revealed cellular heterogeneity and variable T-cell levels, which may have important implication for patient stratification and choice of DMT. Although magnetic resonance imaging (MRI) has proven valuable to monitor DMT efficacy, its lack of specificity for cellular subtypes highlights the need for complementary methods to improve lesion characterization. Here, we evaluated the potential of 2’-deoxy-2’-[18F]fluoro-9-β-D-arabinofuranosylguanine (18F-FAraG) PET imaging to non-invasively assess infiltrating T-cells and to provide, in combination with MRI, a novel tool to determine lesion types. Methods: We used a novel MS mouse model that combines cuprizone and experimental autoimmune encephalomyelitis (EAE) to reproducibly induce two brain inflammatory lesion types, differentiated by their T-cell content. 18F-FAraG PET imaging, T2-weighted MRI, and T1-weighted contrast-enhanced MRI were performed prior to disease induction, during demyelination with high levels of innate immune cells, and following T-cell infiltration. Fingolimod immunotherapy was used to evaluate the ability of PET and MRI to detect therapy response. Ex vivo immunofluorescence analyses for T-cells, microglia/macrophages, myelin and blood brain barrier (BBB) integrity were performed to validate the in vivo findings. Results:18F-FAraG signal was significantly increased in brain and spinal cord at the time point of T-cell infiltration. 18F-FAraG signal from white matter (corpus callosum), and grey matter (cortex, hippocampus) further correlated with T-cell density. T2-weighted MRI detected white matter lesions independently of T-cells. T1-weighted contrast-enhanced MRI indicated BBB disruption at the time point of T-cell infiltration. Fingolimod treatment prevented motor deficits and decreased T-cell and microglia/macrophage levels. In agreement, 18F-FAraG signal was decreased in brain and spinal cord of Fingolimod-treated mice, T1-weighted contrast-enhanced MRI revealed intact BBB, while T2-weighted MRI remained unchanged. Conclusion: The combination of MRI and 18F-FAraG PET enables detection of inflammatory demyelination and T-cell infiltration in a MS mouse model, providing a new way to evaluate lesion heterogeneity during disease progression and following DMT. Upon clinical translation, these methods hold great potential for patient stratification, monitoring MS progression and therapy responses.

“Real-world” data on the nationwide epidemiology and treatment patterns of multiple sclerosis (MS) is very scarce in Asia. This study is aim to evaluate the 10-years trends in epidemiology and treatment patterns of MS with Taiwan’s National Health Insurance Database (NHIRD). Patients aged 20 years or older and were newly diagnosed with MS between 2007 and 2016 were identified. The crude incidences of MS were presented annually and stratified by sex and age. Baseline characteristics and treatment patterns, particularly disease-modifying drugs (DMDs), were also analyzed. This study included 555 MS patients (mean age was 36.9 and 74.4% were female). The crude incidence rate of MS decreased slightly from 0.43 per 100,000 persons in 2007 to 0.24 per 100,000 persons in 2015. The female to male ratios remained mainly between 2 to 3. Approximately 80% of MS patients received initial DMDs, with interferon β-1a as the dominant one. Furthermore, 37.5% of MS patients received subsequent DMDs, with fingolimod being the most frequently used. The median times from diagnosis to initial and to subsequent DMDs were 77 and 1239 days, respectively. This nationwide study provides up-to-date and sophisticated estimates of MS epidemiology and treatment pattern in “real-world” setting in Taiwan.

Background: Disease-modifying therapies (DMTs) can reduce the risk of disability worsening in patients with relapsing forms of multiple sclerosis (RMS). High-efficacy DMTs can lead to confirmed or sustained disability improvement (CDI and SDI). Objective and Methods: Post hoc analyses of data from the TRANSFORMS, FREEDOMS, and FREEDOMS II trials and their extensions assessed the effects of fingolimod (0.5–1.25 mg/day) on stabilizing or improving disability over ⩽8 years in participants with RMS. CDI and SDI rates were compared between participants initially randomized to fingolimod, interferon (IFNβ-1a), or placebo. Results: At 8 years’ follow-up in TRANSFORMS, 35.1% (95% confidence interval [CI], 28.2%–43.1%) of assessed participants in the IFNβ-1a–fingolimod switch group and 41.9% (36.6%–47.6%) on continuous fingolimod experienced CDI; disability did not worsen in approximately 70%. Similar results were seen in the combined FREEDOMS population. Proportionally fewer TRANSFORMS participants achieved SDI in the IFNβ-1a–fingolimod switch group than on continuous fingolimod (5.4% [3.0%–9.5%] vs 14.2% [10.8%–18.4%], p = 0.01). Conclusion: CDI and SDI are outcomes of interest for clinical trials and for long-term follow-up of participants with RMS. Monitoring CDI and SDI in addition to disability worsening may facilitate understanding of the therapeutic benefit of RMS treatments.

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.

ObjectivesAlemtuzumab is effective in patients with active multiple sclerosis but has a complex safety profile, including the development of secondary autoimmunity. Most of patients enrolled in randomised clinical trials with alemtuzumab were either treatment naïve or pretreated with injectable substances. Other previous disease-modifying treatments (DMTs) were not used in the study cohorts, and therefore, associated risks might yet remain unidentified.MethodsWe retrospectively evaluated a prospective dual-centre alemtuzumab cohort of 170 patients. We examined the baseline characteristics as well as safety and effectiveness outcomes, including the time to first relapse, the time to 3 months confirmed disability worsening and the time to secondary autoimmunity.ResultsThe regression analysis showed that, among all previously used DMTs, the pretreatment with fingolimod (n=33 HRs for the time to first relapse (HR 5.420, 95% CI 2.520 to 11.660; pConclusionIn the real-world setting, we demonstrated suboptimal disease control and increased risk of secondary autoimmunity following alemtuzumab, among patients previously treated with fingolimod. These data can provide guidance for improving MS therapeutic management.

Data suggest that patients with pediatric-onset multiple sclerosis (POMS) should initiate treatment with a disease-modifying therapy early to slow progression. The PARADIGMS trial demonstrated that oral fingolimod reduced the annual rate of relapse by 82% compared with intramuscular interferon beta-1a in children with POMS. The PARADIGMS study had a follow-up of 2 years, but no data are available about the safety and efficacy of fingolimod for longer periods in children with POMS. Here we present two cases of children with POMS who achieved sustained clinical benefit from treatment with fingolimod for more than 2 years. The first patient, an 11-year-old male, who participate in the PARADIGMS study, was treatment naïve at the time of fingolimod initiation. His clinical condition remained stable over 5 years of treatment, with no relapses and no radiological lesion progression. The second patient was a female who initiated fingolimod at the age of 12 years, 2 years after her POMS diagnosis and after an 8-month trial of interferon beta-1a. The patient had experienced two relapses during interferon beta-1a but had no relapses in more than 2 years of treatment with fingolimod, and her MRI scans showed no new or active lesions. These data show that prolonged treatment with fingolimod can be safe and effective during long-term treatment as first- or second-line therapy in children with POMS.

Background Comparative effectiveness of natalizumab and fingolimod over a follow-up longer than 2 years has been not addressed yet. Objectives To compare the effect on no evidence of disease activity (NEDA-3) in relapsing-remitting multiple sclerosis (RRMS) patients treated with natalizumab or fingolimod for at least 4 years. Methods We included RRMS patients switched from first-line agents to natalizumab or fingolimod. Patients were propensity score (PS)-matched on a 1-to-1 basis. Percentages of patients reaching NEDA-3 status at 2 and 4 years of follow-up were compared using the chi-square test. The risk of not achieving NEDA-3 at 4 years was explored in matched samples by Cox regression models. Results We evaluated 174 PS-matched patients. Patients receiving natalizumab reached a NEDA-3 status at 2 and 4 years more frequently than those exposed to fingolimod (63% vs 44%, p=0.037; 45.7% vs 25.8%, p=0.015, respectively). Patients receiving natalizumab were at a significant lower risk of not achieving the NEDA-3 status at 4 years compared to those exposed to fingolimod (hazard ratio (95% confidence interval): 0.54 (0.36–0.80), p=0.002). Conclusions Although both medications were effective in patients non-responding to first-line agents, natalizumab seems to be superior to fingolimod in RRMS in obtaining NEDA-3 status at 4 years.

Introduction: Fingolimod is the first confirmed oral immune-modulator to treat Relapsing-Remitting Multiple Sclerosis (RRMS). This study aimed to investigate the safety and efficacy of fingolimod therapy in Iranian patients with RRMS. Methods: In our trial, 50 patients resistant to conventional interferon therapy were assigned to receive fingolimod 0.5 mg per day for 12 months. The number of Dadolinium (Gd)-enhanced lesions, enlarged T2 lesions, and relapses over 12 months were considered as endpoints and compared to baseline. Liver biochemical evaluations and lymphocyte count were done at baseline and in months 3, 6, and 12 of the study. Patients were also monitored for possible cardiovascular events within the first 24 h and other side effects routinely. Results: Among the patients who completed the trial, the number of Gd-enhanced and enlarged T2 lesions over 12 months significantly decreased (P=0.03 and P

Fingolimod is used to treat relapsing–remitting multiple sclerosis. It has an immunosuppressive effect that predisposes to skin malignancies. The Summary of Product Characteristics recommends that persons receiving Fingolimod be educated regarding photoprotection and vigilance of skin lesions and should undergo a dermatological evaluation at initiation of treatment and 6–12 monthly thereafter. The incidence of keratinocytic carcinomas in those on long-term immunosuppression following solid organ transplantation is declining. This trend coincided with temporal changes in immunosuppressive protocols and the introduction of skin cancer prevention programmes suggesting that the risk of developing these malignancies may be mitigated by the provision of education to patients amongst other measures. The aim of our study was to assess if health care professionals are explaining skin advice and documenting the discussion when prescribing Fingolimod in a University Hospital outpatient setting. Clinical records of consecutive patients on Fingolimod were reviewed. Data on demographics, documented provision of advice on skin protection and who provided the advice was collected. Fifty patients with multiple sclerosis were identified. Median age was 40.5 years (range 25–63). Forty-two were female (42/50, 84%). Provision of advice regarding skin protection was documented in 20% (10/50). This was provided by nurse specialists in 14% (7/50), doctors in 10% (5/50) and both in 4% (2/50). The risk of developing skin cancers can be reduced by the adoption of simple preventative measures; patients on Fingolimod are at an increased risk of developing these cancers. This study demonstrates a need for improvement in the documentation of advice around skin protection.

Background and Objectives: Multiple sclerosis (MS) is a disease that involves an individualchr('39')s central nervous system and can affect many aspects of his/her life. This study was conducted to evaluate the safety and efficacy of fingolimod compared to placebo in the treatment of relapsing MS. Methods: A detailed research was carried out on Medline, Web of Sciences, the Cochran Library, Embase, and Scopus databases within January-December 2020. The studies were evaluated regarding the effectiveness of the Expanded Disability Status Scale (EDSS) and the safety of complications. A random model with a 95% confidence interval was used for data analysis. To evaluate the heterogeneity of the studies I2 test was used in this research. The Cochrane risk of bias tool checklist was applied to assess the quality of the study methodology. Results: The results indicated that in 3 and 1 studies fingolimod was used at a dose of 1.25 and 0.5 mg, respectively. Based on the findings, the use of fingolimod at a dose of 0.59 mg was effective in improving patients. The patients receiving fingolimod 1.25 mg were more likely to have lymphopenia than patients taking placebo. Conclusion: Finally, the findings of this study showed that the use of fingolimod was effective on the EDSS index, compared to placebo. Doctors can use this drug to improve EDSS and the quality of life of patients.

Treatment for pediatric-onset multiple sclerosis (POMS) currently reflects treatment for adult-onset MS, despite some differences in its clinical course. First-choice treatment of POMS generally consists of interferon β-1a or glatiramer acetate, with therapies such as natalizumab or fingolimod reserved for second-choice treatment. In cases of severe disease, both fingolimod and natalizumab can be considered first-choice therapy. This paper presents three case histories of patients with POMS and highlights the different uses of fingolimod within the POMS treatment algorithm. The first and third cases are examples of escalation therapy, both in females aged 16 to 17 years, with fingolimod administering as second choice following disease progression. The second case is an example of using fingolimod as first-choice therapy, given to a 12-year-old male with severe disease. In all three cases, over a period of approximately 1 year after the initiation of fingolimod treatment, there was no further disease progression and no adverse events were recorded.

Treatment of pediatric multiple sclerosis (MS) has been increasingly debated in the last few years due to limited knowledge of treatment strategies and therapeutic options. When MS develops at a young age, it usually has a very inflammatory disease course, with many relapses and disease activity as seen in magnetic resonance imaging (MRI). Therefore, treatment with immunomodulatory drugs may be beneficial in these patients. However, limited data are available to date on the treatment of pediatric MS. Although observational, prospective, and retrospective studies provide some information on its treatment course, only one clinical trial in pediatric patients has been published, the PARADIGMS trial, which showed an 82% reduction in relapse rate with fingolimod (0.5 mg/day) versus interferon β-1a (30 μg once weekly intramuscularly). Here, we present the case of a pediatric patient with MS (age of onset, 13 years), who was initially treated with interferon β-1a for 2 years and subsequently switched to fingolimod, owing to clinical and radiological activity despite treatment with interferon β-1a.

BackgroundSwitching between first-line disease-modifying therapies in patients with clinically stable relapsing–remitting multiple sclerosis (RRMS) due to reasons other than disease activity is frequent, but evidence on the effect of this practice is limited. We investigated the effect of switching patients with stable RRMS on occurrences of disability accumulation, relapses and future treatment discontinuation.MethodsUsing the Danish Multiple Sclerosis Registry, we identified patients with RRMS without disease activity who either (1) stayed on injectable platform therapy (interferon-β or glatiramer acetate) or (2) switched to dimethyl fumarate (DMF) or teriflunomide (TFL) and compared treatment outcomes using propensity-score-based methods and marginal structural models (MSM).ResultsWe included 3206 patients in the study. We found no change in risk of 6-month confirmed Expanded Disability Status Scale score worsening in patients switching to DMF (HR: 1.15, 95% CI 0.88 to 1.50) or TFL (HR: 1.16, 95% CI 0.92 to 1.46). The risk of suffering any relapse tended to decrease when switching to DMF (HR: 0.73, 95% CI 0.51 to 1.04) and tended to increase when switching to TFL (HR: 1.25, 95% CI 0.96 to 1.63). Absolute risk differences were small. MSM analyses showed similar results but did not find an increased relapse risk in TFL switchers.ConclusionSwitching from injectable platform therapies to oral first-line therapies in patients with clinically stable RRMS does not increase the risk of disability accumulation. While the postswitch risk of relapses trended towards marginally higher on TFL, this trend was eliminated by adjustment for time-variant confounders.

BACKGROUND The current treated MS population is very different from that of patients in randomized clinical trials. OBJECTIVES To study the long-term efficacy and tolerance of fingolimod (FTY) and dimethyl fumarate (DMF), both available as first-line treatment in early-treated treatment-naive MS patients. METHODS Retrospective analysis of 75 patients from our prospective MS registry fulfilling the inclusion criteria: FTY or DMF as first-line treatment, treatment initiation within 36months of disease onset and treatment duration>12months. RESULTS Demographics and MRI characteristics at baseline were similar in both groups (FTY 55 patients, DMF 20), but patients on FTY had higher pretreatment clinical activity (P=0.008). Twenty-two percent of patients in the FTY group and 15% in the DMF group had highly active disease. At last follow-up (mean: 44.2, SD: 17.3months), the majority of the patients were still on treatment while 54.5% of FTY and 65% of DMF patients reached NEDA 3 status (P=0.444). Both treatments significantly decreased relapses and occurrence of new T1 Gd-enhancing lesions (P

Background and purpose Initial cardiovascular fingolimod effects might compromise baroreflex responses to rapid blood pressure (BP) changes during common Valsalva-like maneuvers. This study evaluated cardiovascular responses to Valsalva maneuver (VM)-induced baroreceptor unloading and loading upon fingolimod initiation. Patients and methods Twenty-one patients with relapsing-remitting multiple sclerosis performed VMs before and 0.5, 1, 2, 3, 4, 5, and 6 hours after fingolimod initiation. We recorded heart rate (HR) as RR intervals (RRI), systolic and diastolic BP (BPsys, BPdia) during VM phase 1, VM phase 2 early, VM phase 2 late, and VM phase 4. Using linear regression analysis between decreasing BPsys and RRI values during VM phase 2 early, we determined baroreflex gain (BRG) reflecting vagal withdrawal and sympathetic activation upon baroreceptor unloading. To assess cardiovagal activation upon baroreceptor loading, we calculated Valsalva ratios (VR) between maximal and minimal RRIs after strain release. Analysis of variance or Friedman tests with post hoc analysis compared corresponding parameters at the eight time points (significance: p Results RRIs at VM phase 1, VM phase 2 early, and VM phase 2 late were higher after than before fingolimod initiation, and maximal after 4 hours. Fingolimod did not affect the longest RRIs upon strain release, but after 3, 5, and 6 hours lowered the highest BPsys values during overshoot and all BPdia values, and thus reduced VRs. BRG was slightly higher after 3 and 5 hours, and significantly higher after 4 hours than before fingolimod initiation. Conclusions VR-decreases 3–6 hours after fingolimod initiation are physiologic results of fingolimod-associated attenuations of BP and HR increases at the end of strain and do not suggest impaired cardiovagal activation upon baroreceptor loading. Stable and at the time of HR nadir significantly increased BRGs indicate improved responses to baroreceptor unloading. Thus, cardiovascular fingolimod effects do not impair autonomic responses to sudden baroreceptor loading or unloading but seem to be mitigated by baroreflex resetting.

Background/Purpose: 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. Methods: In this retrospective, multicentre, observational study, we collected clinical data of patients treated with fingolimod 0.5 mg/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). Results: 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

Background Nine oral disease-modifying therapies (DMTs) have been approved for the treatment of multiple sclerosis (MS) in the United States. Few studies have examined self-reported quality of life (QoL) and functional status outcomes among patients who switch to oral medications from injectable MS therapies. This study compares self-reported QoL and disability status between participants switching from injectable to oral DMTs, to those who stay on injectable DMTs continuously for the same time period. Methods Longitudinal data were assessed from relapsing MS participants in the Pacific Northwest MS Registry completing a minimum of two surveys between 2012 and 2018 with a maximum of 36 months between surveys. Stayers were defined as those who remained on injectable DMTs continuously from Time 1 to Time 2; switchers were those who switched from injectable to either fingolimod, teriflunomide or dimethyl fumarate during the same time interval. Outcomes of interest were physical and psychological QoL, measured by the Multiple Sclerosis Impact Scale (MSIS-29), and disability, measured by the Patient Determined Disease Steps (PDDS). To analyze the effect of switching to oral DMT on outcomes at Time 2, a one-to-two propensity score matching (PSM) was used to match switchers to stayers. Outcomes at Time 2 were analyzed using paired t-test for QoL scores, and Stuart Maxwell test for PDDS as a categorical variable. Results Among 2385 participants who returned consecutive yearly surveys, 413 met the inclusion criteria for stayers and 66 for switchers. After one-to-two PSM, 124 stayers were matched to 62 switchers. Paired t-test showed no differences between switchers and stayers for physical (mean difference: − 0.41; [95% confidence interval CI: − 3.3-2.4]; p = 0.78) or psychological (mean difference: − 0.23; [95% CI, − 1.6- 1.1]; p = 0.74) QoL. Additionally, no differences were seen between switchers and stayers in self-reported disability status. Conclusions MS registry participants who switched to an oral DMT from injectable showed no significant differences in QoL or self-reported disability status compared to those remaining on injectable DMT continuously in the same time period.

Background Fingolimod, an oral drug, has been reported to reduce relapse rate in multiple sclerosis (MS). However disease progression may still occur in spite of control of inflammation. Functional imbalances within and between cerebral networks associated with disruption of structural and functional network integrity, have been reported in MS. An effective therapy is expected to stabilize such functional network integrity. Objective The purpose of this study was to investigate changes in structural and resting-state functional connectivity of motor and cognitive networks, and associated changes in neurologic scores in MS, during 2 years of fingolimod therapy. Methods Twenty five subjects with MS were recruited for this study. Subjects were scanned with diffusion tensor imaging (DTI) and resting-state functional connectivity MRI (fcMRI) scan protocol at 3 T with 6-month interval over a period of 2 years. Neurologic performance scores of motor and cognitive performances were also obtained. Results DTI measures worsened during the 1st year and then stabilized; any trend of stabilization of fcMRI was delayed until the 2nd year. While motor performance did not change, cognitive performance showed improvement. Several baseline DTI measures correlated with relevant neurologic scores. Conclusion Initial worsening of motor and cognitive network was reported after 1 year of treatment, but seems DTI and fcMRI measures seem to stabilize after around one year fingolimod therapy.

To evaluate the cost-effectiveness of fingolimod versus interferon (IFN)-β1a at a dose of 30 μg per week for the treatment of relapsing pediatric-onset multiple sclerosis (POMS) in Canada. A discrete-time Markov model was developed to compare fingolimod with IFN β-1a over a time horizon of two years representing patients followed up to mean age of 18 years from a Canadian health care system perspective. Twenty-one health states based on the Expanded Disability Status Scale (EDSS) were considered: EDSS 0‒9 for relapsing multiple sclerosis (MS), EDSS 0‒9 for secondary progressive MS, and “Death.” Relative treatment efficacy for fingolimod versus IFN-β1a was estimated from the PARADIGMS study. Costs and resource use were obtained from published literature and Canadian sources. Utilities were estimated by mapping the Pediatric Quality of Life inventory data onto the Child Health Utility Index-9 Dimension using a published mapping algorithm. Future costs and benefits were discounted at 1.5% per annum. Compared with IFN β-1a, fingolimod led to an increase in quality-adjusted life-years (QALYs) (0.125) with incremental costs (Canadian dollars [CAD] 2,977) and to an incremental cost-effectiveness ratio (ICER) of CAD 23,886/QALY over a time horizon of two years representing patients followed up to mean age of 18 years. The monetary benefits of fingolimod treatment versus IFN β-1a at a willingness-to-pay (WTP) threshold of CAD 50,000 per QALY gained were higher than the costs. One-way sensitivity analysis and probabilistic sensitivity analysis (PSA) both confirmed the robustness of the results. The main limitations of this analysis primarily stem from the limited data availability in POMS. Fingolimod is cost effective compared with IFN β-1a for the treatment of POMS over a time horizon of two years representing patients followed up to a mean age of 18 years in Canada.

Background Oral fingolimod is convenient to use than injectable disease modifying agents (DMAs) in patients with multiple sclerosis (MS). However, the existing literature regarding the comparative adherence trajectories between oral fingolimod and injectable DMAs is limited. Objective To compare the adherence trajectories between oral DMA, fingolimod, and injectable DMAs in patients with MS. Methods A retrospective longitudinal study was conducted using adults (≥18 years) with MS (ICD-9-CM: 340 and a DMA prescription) from the IBM MarketScan Commercial Claims and Encounters Database between 2010 and 2012. Patients were grouped into oral fingolimod or injectable DMA users based on the index DMA among patients with MS. The annual DMA adherence trajectories, based on the proportion of days covered (PDC), were examined using group-based trajectory modeling (GBTM) during the one-year follow-up period after treatment initiation. Multivariable multinomial logistic regression using stabilized inverse probability treatment weights (IPTW) was performed to assess the association between the DMA route of administration (Oral vs Injectable) and the adherence trajectory groups. The balance of covariates between oral and injectable DMAs before and after IPTW was checked against a standardized difference threshold of 0.25. Results The study cohort consisted of 1,700 MS patients who were initiated with oral (15.8%) or injectable (84.2%) DMAs between 2010 and 2012. The adherence rates (PDC≥0.8) in oral fingolimod and injectable DMA users were found to be 64.7% and 50.8%, respectively. The GBTM grouped individuals in the study cohort into three adherence trajectories - rapid discontinuers (23.5%), complete adherers (49.9%), and slow decliners (26.6%). The multinomial logistic regression model with stabilized IPTW revealed that oral fingolimod users had higher odds to be a complete adherer (adjusted odds ratio [AOR]: 2.78, 95% CI: 1.85-4.16) or a slow discontinuer (AOR: 2.62, 95% CI: 1.70-4.05) than injectable DMA users. Conclusions Oral DMA fingolimod was associated with better adherence than injectable DMAs across group-based trajectories. Further research is warranted to evaluate the adherence trajectories with newer oral DMAs introduced in the last decade for MS.

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.

Macular oedema is a rare complication of fingolimod treatment. It usually presents within 3–4 months, but occasionally presents later. It can resolve without treatment despite continuation of fingolimod treatment. Herein we report a case of very late onset macular oedema in a 49-year-old woman with multiple sclerosis treated with fingolimod for 7 years. The patient presented with blurred vision in both eyes with visual acuities of 20/32 in her right eye and 20/25 in her left eye. She had macular oedema, that without discontinuing fingolimod treatment, resolved after 1 month.

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

Background: Tumefactive multiple sclerosis (TMS) is a rare multiple sclerosis (MS) form that usually manifests as the initial presentation or in the early stages of MS. Objective: The aim of this study is to evaluate reports of TMS associated with fingolimod use. Methods: The Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database and the medical literature were searched for cases of TMS occurring during or after fingolimod treatment. Results: We identified 29 TMS cases, 19 following fingolimod initiation and 10 following fingolimod discontinuation. In these cases, a TMS diagnosis occurred at a median of 7 years after MS diagnosis, and a median of 7 and 3 months following initiation and discontinuation of fingolimod, respectively. Twenty-two cases were assessed as possible and seven as probable from a causal association perspective. A much larger crude number of TMS reports was observed for fingolimod compared to other disease-modifying therapies. Conclusion: TMS should be considered when a severe or atypical MS relapse occurs shortly after fingolimod initiation or discontinuation, and should prompt imaging evaluation and appropriate treatment initiation. Prescribers’ awareness of the association between TMS and fingolimod may avoid unnecessary diagnostic procedures. In light of our findings, fingolimod (Gilenya) prescribing information was amended to include TMS in the Warnings and Precautions section.

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.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.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 (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.

Most disease-modifying drugs (DMDs) are contraindicated in pregnancy. Management of MS is especially challenging for pregnant patients, as withdrawal of DMDs leave the patient at risk of increased disease activity. We, a group of experts in MS care from countries in the Arab Gulf, present our consensus recommendations on the management of MS in these patients. Where possible, a patient planning pregnancy can be switched to a DMD considered safe in this setting. Interferon β now can be used during pregnancy, where there is a clinical need to maintain treatment, in addition to glatiramer acetate. Natalizumab (usually to 30 weeks’ gestation for patients with high disease activity at high risk of relapse and disability progression) may also be continued into pregnancy. Cladribine tablets and alemtuzumab have been hypothesised to act as immune reconstitution therapies (IRTs). These drugs provide a period of prolonged freedom from relapses for many patients, but the patient must be prepared to wait for up to 20 months from initiation of therapy before becoming pregnant. If a patient becomes pregnant while taking fingolimod, and requires continued DMD treatment, a switch to interferon β or natalizumab after a variable washout period may be prescribed, depending on the level of disease activity. Women who wish to breastfeed should be encouraged to do so, and interferon β may also be used during breastfeeding. There is a lack of data regarding the safety of using other DMDs during breastfeeding.

Patient safety during pregnancy is an important concern. This article presents a method of using an industry safety database to access prospective pregnancy cases. This method, termed here 'PRegnancy outcomes Intensive Monitoring' (PRIM) was developed for fingolimod (Gilenya ™), a treatment option for multiple sclerosis (MS), due to slow enrollment in the company pregnancy registry. The aim of PRIM was to enhance the process of pregnancy data collection and improve data quality, and in particular to enable estimation of the proportion of major congenital malformation and other pregnancy outcomes. To do this, the spontaneous reports of maternal exposure to fingolimod in pregnancy or in the eight weeks immediately before the last menstrual period of patients not enrolled in the pregnancy registry were identified. Follow up checklists were sent at four time points: initial pregnancy report, end of pregnancy, infant attained 3 and 12 months of age. These focused on core data required for derivation of programmed analyses. From 01 Mar 2014 to 28 Feb 2018, a total of 831 prospective maternal exposures with 843 infants were reported, with fetal outcomes reported in 459/843 (54.4 %) of those infants. This enabled the calculation of proportions of pregnancy cases with the main pregnancy outcomes and of fetal cases with malformation. The number of reported pregnancies was significantly higher in PRIM than in the registry, showing that structured use of pharmacovigilance data enables speedier assessment of risks of maternal drug exposure.

Neurologists managing women with Multiple Sclerosis (MS) need information about the safety of disease modifying drugs (DMDs) during pregnancy. However, this knowledge is limited. The present study aims to summarize previous studies by performing a systematic review and meta-analyses. The terms “multiple sclerosis” combined with DMDs of interest and a broad profile for pregnancy terms were used to search Embase and Medline databases to identify relevant studies published from January 2000 to July 2019.1260 studies were identified and ten studies met our inclusion criteria. Pooled risk ratios (RR) of pregnancy and birth outcomes in pregnancies exposed to DMDs compared to those not exposed were calculated using a random effects model. For spontaneous abortion RR = 1.14, 95% CI 0.99–1.32, for preterm births RR = 0.93, 95% CI 0.72–1.21 and for major congenital malformations RR = 0.86, 95% CI 0.47–1.56. The most common major congenital malformations reported in MS patients exposed to MS drugs were atrial septal defect (ASD) (N = 4), polydactyly (N = 4) and club foot (N = 3), which are among the most prevalent birth defects observed in the general population. In conclusion, interferons, glatiramer acetate or natalizumab, do not appear to increase the risk for spontaneous abortions, pre-term birth or major congenital malformations. There were very few patients included that were exposed to fingolimod, azathioprine and rituximab; therefore, these results cannot be generalized across drugs. Future studies including internal comparators are needed to enable treating physicians and their patients to decide on the best treatment options.

Background: Clinical and real-world studies have shown significant reductions in multiple sclerosis (MS) relapses with fingolimod versus injectable disease-modifying therapies (DMTs). Multiple sclerosis relapse rate and incidence were compared in patients switching from an injectable DMT to fingolimod and those cycling from one injectable DMT to another or remaining on their original injectable DMT. Methods: Retrospective analysis was performed using Commercial and Medicare Supplemental claims data (July 1, 2010, to June 30, 2016) of adults with MS receiving ≥1 injectable DMT. Relapses were identified from MS-related hospitalization, outpatient emergency department or office visit, and corticosteroid administration. Annualized relapse rate ratio was estimated. Results: Of 16,352 patients, 1110 were switchers to fingolimod, 908 were injectable DMT cyclers, and 14,334 were nonswitchers. At baseline, rate and incidence of MS relapses were higher in switchers and injectable DMT cyclers versus nonswitchers (P < .001); mean ± SD relapse rates declined from 0.4 ± 0.7, 0.4 ± 0.7, and 0.2 ± 0.5 at baseline to 0.2 ± 0.5, 0.3 ± 0.6, and 0.1 ± 0.4 after follow-up in switchers, injectable DMT cyclers, and nonswitchers, respectively. Relapse incidence declined in each cohort. The highest reductions in relapse rate and incidence were in switchers to fingolimod, where relapse risk was significantly reduced versus injectable DMT cyclers (22%, P = .0433) and nonswitchers (47%, P < .001). Conclusions: This study provides evidence that patients switching from an injectable DMT to fingolimod have the highest reductions in annualized rate and incidence of MS relapses and significantly reduced risk of relapse versus injectable DMT cyclers and nonswitchers.

The majority of disease-modifying drugs (DMDs) available for the management of active relapsing–remitting multiple sclerosis (RMS) depend on continuous drug intake for maintained efficacy, with escalation to a more active drug when an unacceptable level of disease activity returns. Among continuously applied regimens, interferons and glatiramer acetate act as immunomodulators, while dimethyl fumarate, fingolimod, ocrelizumab, natalizumab and teriflunomide are associated with continuous immunosuppression. By contrast, immune reconstitution therapy (IRT) provides efficacy that outlasts a short course of treatment. Autologous hemopoietic stem cell transplantation is perhaps the classic example of IRT, but this invasive and intensive therapy has challenging side-effects. A short treatment course of a pharmacologic agent hypothesized to act as an IRT, such as Cladribine Tablets 3.5 mg/kg or alemtuzumab, can provide long-term suppression of MS disease activity, without need for continuous treatment (the anti-CD20 mechanism of ocrelizumab has the potential to act as an IRT, but is administered continuously, at 6-monthly intervals). Cladribine Tablets 3.5 mg/kg shows some selectivity in targeting adaptive immunity with a lesser effect on innate immunity. The introduction of IRT-like disease-modifying drugs (DMDs) challenges the traditional maintenance/escalation mode of treatment and raises new questions about how disease activity is measured. In this review, we consider a modern classification of DMDs for MS and its implications for the care of patients in the IRT era.

Objective: Clinical studies in childhood multiple sclerosis (MS) are very limited compared with adults. Although first-line injection therapies are well tolerated in this patient group, there are difficulties in the long-term treatment of patients due to the difficulty and adverse effects of injections for children. Oral therapies are better tolerated for use and adverse effects compared with injection therapies. This study aimed to evaluate the clinical features and treatment outcomes of patients aged under 18 years with relapsing-remitting MS (RRMS) who received fingolimod treatment. Materials and Methods: In this study, the clinical records of 22 patients with RRMS who received fingolimod treatment were examined. The patients were prospectively followed up between February 2015 and December 2018. The patients were evaluated in terms of relapse rate, Expanded Disability Status Scale (EDSS) scores, brain and cervical magnetic resonance imaging, and adverse effects before and after fingolimod treatment. Results: The median age of 13 (59%) female and 9 (41%) male patients was 18 (range: 10-21) years. The median fingolimod treatment duration was 2.5 (range: 1.3-3.9) years. The median age of disease onset was 13 (range: 8-17) years. Fifteen patients (68%) received a first-line treatment prior to fingolimod. The reason for switching to fingolimod was inefficacy in 33%, adverse effects in 40%, and both in %27 of patients. In 32% of patients, fingolimod was started as a first-line treatment. A total of three patients had recurrent relapses under treatment with fingolimod. The median annualized relapse rate (ARR) before fingolimod was 1.9 (range: 0.3-8.0), and the ARR with fingolimod was 0 (range: 0-2.0) (Wilcoxon’s signed-rank test; p

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.