Alessia Manni

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

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

Long-Term Data of Efficacy, Safety, and Tolerability in a Real-Life Setting of THC/CBD Oromucosal Spray-Treated Multiple Sclerosis Patients

Delta‐9‐tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray was approved as add‐on therapy for spasticity in patients with multiple sclerosis (MS). We show our 40‐week postmarketing experience regarding efficacy and safety of THC/CBD spray in an Italian cohort of 102 MS patients. Patients were evaluated using the Expanded Disability Status Scale (EDSS) score, the Numerical Rating Scale (NRS) for spasticity, the Ambulation Index (AI), and Timed 25‐Foot Walk (T25‐FW) at the beginning of treatment and then every 3 months. After 4 weeks, if a clinically significant improvement in spasticity (at least 20% of baseline NRS score) was not seen, administration of the drug was stopped. In our cohort, patients received an average of 6.5 ± 1.6 sprays each day. The mean reduction to the NRS spasticity score was 2.5 ± 1.2 points (P < .0001). Thirty‐seven patients (36.2%) discontinued the treatment. The incidence of adverse events (AEs) was 40.2%. Fifty‐eight patients (56.9%) were also assessed using the NRS for pain, and 46 patients (45.1%) with bladder dysfunction were assessed for the IPSS (International Prostatic Symptoms Score) score, showing a significant improvement in these scales (P = .011 and P = .001, respectively). In conclusion, treatment with THC/CBD spray appears to be a valid answer to some of the unmet needs in MS patients, such as spasticity and other refractory‐to‐treatment symptoms.

Lymphocyte subsets as biomarkers of therapeutic response in Fingolimod treated Relapsing Multiple Sclerosis patients

We investigated, lymphocyte count (LC) and lymphocyte subpopulations (LS) in a real life setting of Fingolimod (FTY) treated Relapsing MS (RMS) patients. Peripheral blood counts with LS, relapses and MRI scans were recorded in a cohort of 119 FTY patients, during one year of treatment. Simple and multivariate logistic regression models, were performed. ROC analysis identified cut-off values of LS predicting a higher risk of relapses and of Gd+ lesions. We demonstrated a FTY-induced re-modulation of the immune system, suggesting that LS in RMS FTY treated patients can predict the clinical response to the drug.

The Cost of Relapsing-Remitting Multiple Sclerosis Patients Who Develop Neutralizing Antibodies during Interferon Beta Therapy

Background Relapsing Remitting Multiple Sclerosis (RRMS) patients treated with interferon beta (IFN beta) can develop neutralizing antibodies (NAbs) that reduce treatment efficacy. Several clinical studies explored the association of NAb+ status with increased disease activity. Objective The aim of this study was to estimate the cost of RRMS patients who develop NAbs while treated with IFN beta by the Italian National Healthcare Service (NHS) and the Italian Society perspectives. Methods The clinical data derived from a published observational study on 567 RRMS Italian patients treated with IFN beta. The management cost data derived from the published literature. Cost data were inflated to Euro 2014. Results The annual direct cost to treat a patient was estimated in €15,428 in the NAb+ cohort and €14,317 in the NAb- cohort. The annual societal cost was estimated in €33,890 and €30,790 in NAb+ and NAb- patients, respectively. The cost increase related to the NAb+ status was €3,100 in the Italian societal perspective and €1,111 in the Italian NHS perspective. Conclusion The results of this economic evaluation suggest the presence of an association between NAb+ status and increased costs for the management of RRMS in Italy. Further pharmacoeconomic research will be needed to confirm this first result.

A pipeline backprojector for on-line 3-D PET

A hardware architecture for on-line three dimensional backprojection is considered for positron emission tomography (PET). The architecture is based on processing elements that work in pipeline on a flowing data stream using an event by event approach. The architecture is suitable for backprojection filtering reconstruction where reconstruction requires backprojection first and a subsequent three-dimensional filtering. Although the main target of the architectural design is a VLSI implementation, the modularity of the approach also makes it suitable for an implementation on off the shelf processors. The work takes as reference the complexity requirements of a PET scanner endowed of 24 rings and 784 detectors per ring and a volume of interest subdivided into 128*128*47 voxels. The design of the building blocks of the architecture are described together with their operating mode.

An architecture for on-line 3-D PET data reconstruction

The paper presents a pipeline architecture for on-line 3-D Positron Emission Tomography backprojection using an event by event algorithm that projects the single coincidence line on the three-dimensional Region of Interest. The operating mode of processors is Single Instruction stream Multiple Data stream. Real-time reconstruction requirements in terms of processing power of single processors are evaluated.

Neutralizing Antibodies and Multiple Sclerosis in the Era of Disease Modifying Treatments

Abstract During an era of rapid changes in Multiple Sclerosis (MS), the early identification of nonresponder patients to therapies is crucial in order to provide them an alternative treatment strategy. The need to identify biomarkers of therapeutic response is a challenge in MS. Biopharmaceutical products approved for MS, such as interferon beta (IFNβ), glatiramer acetate (GA), and natalizumab (NTZ), can lead to the development of antidrug antibodies (ADA), with detrimental effects on their efficacy. In this chapter the evidences of the impact of neutralizing antibodies (NAbs) during IFNβ, GA, and NTZ treatment on clinical and MRI outcomes will be reported. The use of NAbs testing in clinical practice remains a powerful tool in the management of MS therapy.

Gender differences in safety issues during Fingolimod therapy: Evidence from a real-life Relapsing Multiple Sclerosis cohort

Benefits and risks of new therapies in Multiple Sclerosis (MS) must be balanced carefully and tailored to patients. We aimed to describe our experience with Fingolimod (FTY), correlating demographics, clinical and hematological features of the Relapsing MS (RMS) cohort with the occurring Adverse Events (AEs).