Fingolimod Therapy Research Articles

HSV-2-related hemophagocytic lymphohistiocytosis in a fingolimod-treated patient with MS.

Fingolimod is an oral, disease-modifying therapy used to treat multiple sclerosis (MS).1 However, severe viral infections, including disseminated varicella-zoster virus infection,1 herpes simplex encephalitis,1,2 varicella-zoster virus encephalitis and vasculopathy,3 or progressive multifocal leukoencephalopathy,4 have been reported during fingolimod therapy. Hemophagocytic lymphohistiocytosis (HLH), often triggered by certain viral infections, is a fatal disease characterized by fever, pancytopenia, elevated liver enzymes, hyperferritinemia, hepatosplenomegaly, and hemophagocytosis.5 A triggering infection causes persistent activation of lymphocytes and histiocytes, resulting in exaggerated immune responses and hemophagocytosis. We describe an autopsied case of disseminated herpes simplex virus type 2 (HSV-2) infection presenting with HLH, following 0.5 mg fingolimod and corticosteroid therapies. Acknowledgment: The authors thank the patient and his family for their cooperation regarding this report. This case report was approved by the ethical committee of Anjo Kosei Hospital. The authors obtained written informed consent from the patient's family for this publication.

Mobitz type I and II atrioventricular blocks during fingolimod therapy.

We investigated patients who showed a second-degree atrioventricular block (S-AVB) after the first fingolimod administration. We observed six patients with S-AVB, three Mobitz type I, and three type II. Monitoring continued on the second day for all patients. Three patients showed persistence of the S-AVB, with resolution on the second or third day. One patient had a persistent S-AVB up to the fourth day when fingolimod was discontinued. We conclude that Mobitz type II S-AVB is possible during fingolimod therapy. Patients with S-AVB could be monitored until resolution of the S-AVBs, as these may persist several days after the first fingolimod administration.

Commentary: Acute Hemorrhagic Leukoencephalitis (Weston-Hurst Syndrome) in a Patient with Relapse-Remitting Multiple Sclerosis.

Recently, Yildiz et al. reported the occurrence of acute hemorrhagic leukoencephalitis (AHLE) in a patient with pluriannual relapse-remitting multiple sclerosis (MS) after 1 month of high-dose interferon-β-1a treatment. The authors raised the question whether this case may be a hyperacute form of acute disseminated encephalomyelitis (ADEM) or a rare hemorrhagic evolution of tumefactive demyelination (TD), both unusual in the course of MS (1). They concluded that AHLE occurrence was unrelated to the underlying MS since hemorrhage has not been found in neuropathological patterns of both MS and TD. Although two published case reports of TD with hemorrhage in the course of fingolimod and natalizumab therapies (brain biopsy was not performed) have been mentioned in the paper, the potential predisposing effect of interferon-β therapy on the AHLE development has not been hypothesized.

Fingolimod-associated PML in a patient with prior immunosuppression

Fingolimod, a sphingosine-1-phosphate receptor modulator, was the first oral disease-modifying drug approved for relapsing-remitting multiple sclerosis (RRMS).1 Fingolimod decreases multiple sclerosis disease activity through a presumed mechanism of sequestration of lymphocytes in lymph nodes, thereby reducing circulating lymphocytes available for entry into the CNS. Its lymphopenic effect has raised concern for predisposition to opportunistic infections.2 Recently, the US Food and Drug Administration (FDA) issued a new warning on labeling for fingolimod following reports of 2 cases of progressive multifocal leukoencephalopathy (PML) associated with fingolimod therapy.3

Lymphocyte Dynamics During and After Fingolimod Therapy: Long-Term Data from the INFORMS Trial (P5.294)

Lymphocyte Dynamics During and After Fingolimod Therapy: Long-Term Data from the INFORMS Trial (P5.294)

Real-World Durability of Long-Term Relapse Rates Among Patients with Multiple Sclerosis Receiving Fingolimod Therapy: A Retrospective US Claims Database Analysis (P3.074)

Real-World Durability of Long-Term Relapse Rates Among Patients with Multiple Sclerosis Receiving Fingolimod Therapy: A Retrospective US Claims Database Analysis (P3.074)

Fingolimod therapy modulates circulating B cell composition, increases B regulatory subsets and production of IL-10 and TGFβ in patients with Multiple Sclerosis

Fingolimod, an oral therapeutic agent approved for patients with relapsing-remitting Multiple Sclerosis (MS), has been shown to prevent lymphocyte egress from secondary lymphoid tissues; however the specific drug effect on B cells in fingolimod-treated patients remains to be fully elucidated. We present here a comprehensive analysis on the proportions of B cell subsets in the periphery, and the levels of activation, functional surface markers and cytokine profile of B cells in MS patients, following initiation of fingolimod therapy, using flow cytometry and cytokine bead array. Fingolimod therapy increased the ratio of naïve to memory cells, elevated the percentage of plasma cells and highly increased the proportion of transitional B cells as well as additional regulatory subsets, including: IL10+, CD25+ and CD5+ B cells. The percentage of activated CD69+ cells was highly elevated in the remaining circulating B cells, which produced increased levels of IL10, TGFβ, IL6, IL4, LTα, TNFα and IFNγ cytokines, with an overall increased ratio of TGFβ to pro-inflammatory cytokines. Furthermore, fingolimod therapy reduced ICAM-1+ cells, suggesting a possible reduction in antigen-presenting capacity. Phosphorylated-fingolimod was shown in vitro to reduce S1PR1 RNA and protein, to slightly increase viability and to activate anti-apoptotic Bcl2 in transformed B cells of patients with MS. In conclusion, fingolimod therapy modulates significantly the composition of circulating B cells, promoting regulatory subsets and an anti-inflammatory cytokine repertoire.

Glioblastoma following treatment with fingolimod for relapsing-remitting multiple sclerosis

Glioblastoma is an uncommon and aggressive primary brain tumor with incidence of 3 per 100,000 annually. We report a 50-year-old woman diagnosed with glioblastoma within threeyears of induction of fingolimod therapy for relapsing-remitting multiple sclerosis. Fingolimod, an immunomodulating agent used in the treatment of relapsing-remitting multiple sclerosis, has also been suggested to impart a cardioprotective role in heart failure and arrhythmia via activation of P21-activated kinase-1 (Pak1). In the brain, Pak1 activation has been shown to correlate with decreased survival time amongst patients with glioblastoma. A molecular mechanism underlying a link between fingolimod use and glioblastoma development may involve activation of Pak1. To our knowledge, this is the first report of a potential association between fingolimod use and glioblastoma development.

Progressive Multifocal Leukoencephalopathy in a Multiple Sclerosis Patient Diagnosed after Switching from Natalizumab to Fingolimod.

Background. Natalizumab- (NTZ-) associated progressive multifocal leukoencephalopathy (PML) is a severe and often disabling infectious central nervous system disease that can become evident in multiple sclerosis (MS) patients after NTZ discontinuation. Recently, novel diagnostic biomarkers for the assessment of PML risk in NTZ treated MS patients such as the anti-JC virus antibody index have been reported, and the clinical relevance of milky-way lesions detectable by MRI has been discussed. Case Presentation and Conclusion. We report a MS patient in whom PML was highly suspected solely based on MRI findings after switching from NTZ to fingolimod despite repeatedly negative (ultrasensitive) polymerase chain reaction (PCR) testing for JC virus DNA in cerebrospinal fluid. The PML diagnosis was histopathologically confirmed by brain biopsy. The occurrence of an immune reconstitution inflammatory syndrome (IRIS) during fingolimod therapy, elevated measures of JCV antibody indices, and the relevance of milky-way-like lesions detectable by (7 T) MRI are discussed.

Disseminated cryptococcosis in a patient with multiple sclerosis treated with fingolimod

Multiple sclerosis (MS), a leading nontraumatic cause of neurologic disability,1 is an inflammatory disorder involving autoreactive T cells attacking myelin sheaths in the CNS, resulting in demyelination and axonal loss. The development of disease-modifying therapies (DMTs) for MS has been remarkable in recent years. Many approved DMTs for MS are parenteral. Oral fingolimod2,3 (Gilenya, Novartis, Basel, Switzerland) was approved by the US Food and Drug Administration (FDA) in 2010. Immunomodulation including sequestration of lymphocytes in the secondary lymphoid organs is the main proposed mechanism of action. In a phase 3 trial, rare but fatal viral infections were observed.2 One patient with MS developed disseminated primary varicella-zoster virus infection. Another patient had herpes simplex encephalitis. Both patients received fingolimod 1.25 mg once daily, a dose that is higher than the currently FDA-approved dose. Although fingolimod at 0.5 mg once daily did not show increased infection incidence in individual trials that led to FDA approval, a recent analysis of pooled trial data demonstrated a relatively higher rate of varicella-zoster virus infections in patients treated with fingolimod 0.5 mg daily than in placebo recipients.4 Disseminated cryptococcosis is a rare opportunistic infection reported in immunocompromised individuals such as patients with AIDS.5 In this report, we describe a patient with MS who received fingolimod therapy and subsequently developed disseminated cryptococcal infection. Acknowledgment: The author thanks Dr. F. Yan for collecting histology, MRI data, and editing.

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

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

Effects of Three Months Fingolimod Therapy on Heart Rate.

Fingolimod is a novel disease-modifying drug for relapsing-remitting multiple sclerosis (RRMS). Fingolimod initiation associates with a decrease in heart rate (HR). However, the long-term effects of fingolimod on HR are not known. The aim of this study was prospectively investigate the effect of 3-month fingolimod therapy on HR. Twenty-seven RRMS patients underwent 24-h ambulatory electrocardiogram recording 20 ± 16 days before (baseline) and at the day of fingolimod initiation (1 day). Twenty-four patients completed 3 months follow-up (3 months). The average HR over 24-h and the average HR for daytime and nighttime were assessed at baseline, 1 day and 3 months. Fingolimod initiation resulted in slowing of HR from 82 ± 11 1/min at baseline to 63 ± 9.5 1/min at 5 h after the initiation of the therapy. The average HR during 24-h was lower at 1d (66 ± 7.8 1/min;p < 0.001) and also at 3 months (69 ± 8.3 1/min;p < 0.001) as compared to baseline (74 ± 10 1/min). The average daytime HR at 1 day (68 ± 8.4 1/min) was lower as compared to baseline (78 ± 11 1/min, p < 0.001), whereas no difference was found between the average daytime HR at baseline and at 3 months (79 ± 10 1/min). The average nighttime HR at 1 day (59 ± 8.8 1/min;p < 0.001) and at 3 months (60 ± 9.2 1/min;p < 0.05) both were lower than at baseline (64 ± 9.9 1/min). In conclusion, fingolimod resulted in HR decrease reaching the nadir at 5 h after the first dose. HR remained lower after 3 months fingolimod treatment as compared to baseline. Particularly, HR at daytime recovered whereas the nighttime HR showed not recovery as compared to the day of fingolimod initiation.

Peripheral blood T cell dynamics predict relapse in multiple sclerosis patients on fingolimod.

BackgroundFingolimod efficiently reduces multiple sclerosis (MS) relapse by inhibiting lymphocyte egress from lymph nodes through down-modulation of sphingosine 1-phosphate (S1P) receptors. We aimed to clarify the alterations in peripheral blood T cell subsets associated with MS relapse on fingolimod.Methods/Principal FindingsBlood samples successively collected from 23 relapsing-remitting MS patients before and during fingolimod therapy (0.5 mg/day) for 12 months and 18 healthy controls (HCs) were analysed for T cell subsets by flow cytometry. In MS patients, the percentages of central memory T (CCR7+CD45RO+) cells (TCM) and naïve T (CCR7+CD45RO-) cells decreased significantly, while those of effector memory T (CCR7-CD45RA-) and suppressor precursor T (CD28-) cells increased in both CD4+T and CD8+T cells from 2 weeks to 12 months during fingolimod therapy. The percentages of regulatory T (CD4+CD25highCD127low) cells in CD4+T cells and CCR7-CD45RA+T cells in CD8+T cells also increased significantly. Eight relapsed patients demonstrated greater percentages of CD4+TCM than 15 non-relapsed patients at 3 and 6 months (p=0.0051 and p=0.0088, respectively). The IL17-, IL9-, and IL4-producing CD4+T cell percentages were significantly higher at pre-treatment in MS patients compared with HCs (p<0.01 for all), while the IL17-producing CD4+T cell percentages tended to show a transient increase at 2 weeks of fingolimod therapy (pcorr=0.0834).ConclusionsThe CD4+TCM percentages at 2 weeks to 12 months during fingolimod therapy are related to relapse.

Fingolimod first-dose effects in patients with relapsing multiple sclerosis concomitantly receiving selective serotonin-reuptake inhibitors

Selective serotonin-reuptake inhibitors (SSRIs), commonly administered for depression and anxiety in patients with multiple sclerosis, are associated with QT interval prolongation. Fingolimod (FTY720; Gilenya®, Novartis Pharma AG) is a first-in-class sphingosine 1-phosphate receptor modulator approved for relapsing forms of multiple sclerosis. Fingolimod first-dose administration is associated with a transient, generally asymptomatic, slowing of heart rate, which may also prolong QT interval. This posthoc analysis compared cardiac outcomes in over 3300 patients with relapsing multiple sclerosis who were or were not receiving SSRIs during fingolimod treatment initiation, including a subset of patients receiving citalopram or escitalopram. Vital signs were recorded hourly for 6h, and electrocardiograms were obtained pre-dose and 6h post-dose. Changes in mean hourly heart rate from baseline (pre-dose) to 6h post-dose were similar among patients not receiving SSRIs (fingolimod 0.5mg, –7.5bpm; placebo, 0.0bpm) and those receiving SSRIs (fingolimod 0.5mg, –6.6bpm; placebo, 0.3bpm). In patients treated with fingolimod 0.5mg, the mean change in corrected QT interval from baseline to 6h after treatment initiation was under 10ms, and few patients had absolute corrected QT intervals of over 450ms (men) or 470ms (women), calculated according to Bazett׳s or Fridericia׳s correction methods, irrespective of whether or not they were receiving an SSRI; similar findings were reported in the placebo group. Co-administration of SSRIs and fingolimod was not associated with an increased incidence of any electrocardiogram findings compared with fingolimod therapy alone, and the majority of patients receiving fingolimod (83–86%) were discharged from first-dose monitoring at 6h irrespective of whether they were also receiving SSRIs. These analyses provide reassurance that concomitant use of SSRIs does not affect cardiac outcomes associated with fingolimod treatment initiation.

Effect of Fingolimod on Platelet Count Among Multiple Sclerosis Patients.

Background:While many studies have previously focused on fingolimod's effect on immune cells, the effect it has on circulating and local central nervous system platelets (Plts) has not yet been investigated. This study will elucidate what effects fingolimod treatment has on multiple sclerosis (MS) patients’ plasma Plt levels. In addition, it will propose possible reasoning for these effects and suggest further investigation into this topic.Methods:This quasi-experimental study used patients from the Isfahan Multiple Sclerosis Society to produce a subject pool of 80 patients, including 14 patients who ceased fingolimod use due to complications. The patients had their blood analyzed to determine Plt levels both 1-month prior to fingolimod treatment and 1-month after fingolimod treatment had been started.Results:The mean level of Plts before initiation of fingolimod therapy (Plt1) among these MS patients was 256.53 ± 66.26. After 1-month of fingolimod treatment, the Plt level yielded an average of 229.96 ± 49.67 (Plt2). This number is significantly lower than the average Plt count before treatment (P < 0.01).Conclusions:MS patients taking oral fingolimod treatment may be at risk for side-effects caused by low Plt levels. This may not be a factor for patients with higher or normal Plt levels. However, a patient with naturally low Plt levels may experience a drop below the normal level and be at risk for excessive bleeding. In addition to these possible harmful side-effects, the decreased Plt population may pose positive effects for MS patients.

Newly produced T and B lymphocytes and T-cell receptor repertoire diversity are reduced in peripheral blood of fingolimod-treated multiple sclerosis patients

Background: Fingolimod inhibits lymphocyte egress from lymphoid tissues, thus altering the composition of the peripheral lymphocyte pool of multiple sclerosis patients. Objective: The objective of this paper is to evaluate whether fingolimod determines a decrease of newly produced T- and B-lymphocytes in the blood and a reduction in the T-cell receptor repertoire diversity that may affect immune surveillance. Methods: Blood samples were obtained from multiple sclerosis patients before fingolimod therapy initiation and then after six and 12 months. Newly produced T and B lymphocytes were measured by quantifying T-cell receptor excision circles and K-deleting recombination excision circles by real-time PCR, while recent thymic emigrants, naive CD8+ lymphocytes, immature and naive B cells were determined by immune phenotyping. T-cell receptor repertoire was analyzed by complementarity determining region 3 spectratyping. Results: Newly produced T and B lymphocytes were significantly reduced in peripheral blood of fingolimod-treated patients. The decrease was particularly evident in the T-cell compartment. T-cell repertoire restrictions, already present before therapy, significantly increased after 12 months of treatment. Conclusions: These results do not have direct clinical implications but they may be useful for further understanding the mode of action of this immunotherapy for multiple sclerosis patients.

Relapses in patients treated with fingolimod after previous exposure to natalizumab

In post hoc analyses of an open-label, phase 3b study (FIRST), relapse rates during 4 months of fingolimod therapy were compared in patients with and without previous natalizumab exposure. Reductions in the proportion of patients experiencing relapses and annualized relapse rates (ARRs) from years 1 and 1–2 pre-study were evident between months 1 and 2 of fingolimod treatment, and were most pronounced in natalizumab-naïve patients and those who discontinued natalizumab >6 months pre-study. Patients who discontinued natalizumab 3–6 months pre-study had a peak ARR during month 1 of fingolimod treatment, followed by a decrease during months 2–4. These data indicate that fingolimod has the potential to reduce disease reactivation but that timing of treatment initiation may be critical for achieving an optimal effect.

Tumefactive demyelination and a malignant course in an MS patient during and following fingolimod therapy

Finglimod, a sphingosine 1-phosphate receptor modulator, is the first orally administered therapy approved for prophylaxis in multiple sclerosis (MS). Several reports in the last two years suggested that it might be associated with severe augmentation of disease activity upon initiation or discontinuation of therapy. We present an MS patient who developed a giant cavitating brain lesion under fingolimod and in whom cessation of therapy was associated with a very active course. Brain biopsy revealed the lesion to be due to an active demyelinating inflammatory process. With the current wave of immunosuppressive treatments for MS, there is a need to be vigilant to side effects and risks not identified in large multicenter trials, collect the data and set guidelines and precautions for present and future medications.

Efficacy of Fingolimod Therapy Does Not Dependent on the Individual Body Mass Index in Patients with MS (P7.223)

Efficacy of Fingolimod Therapy Does Not Dependent on the Individual Body Mass Index in Patients with MS (P7.223)

Switching From Natalizumab to Fingolimod in Multiple Sclerosis

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