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Introduction: Multiple sclerosis (MS) is a highly symptomatic disease, with a wide range of disabilities affecting many bodily functions, even in younger persons with a short disease history. The availability of a cannabinoid oromucosal spray (Sativex) for the management of treatment-resistant MS spasticity has provided a new opportunity for many patients. Objective: Our study aimed to assess the cost effectiveness of Sativex in Italian patients with treatment-resistant MS spasticity. The analysis was based on the real-world data of a large registry of Italian patients. Methods: A cost-utility analysis was conducted using data collected prospectively from an electronic registry of all patients who began to use Sativex for MS-resistant spasticity between January 2014 and February 2015 in 30 specialized MS units across Italy and were followed up for ≤ 6months. Data on drug consumption and spasticity/utility were used to estimate the incremental cost-effectiveness ratio (ICER) of Sativex, as compared with no intervention. No costs or spasticity/utility changes were assumed for no treatment intervention. The ICER was expressed as quality-adjusted life-years (QALYs) gained, using the Italian NHS perspective and a 6-month time horizon. Results: Sativex effectiveness and consumption was estimated analyzing data of 1350 patients from the registry. These patients reported a mean (SD) utility increment of 0.087 (0.069) after 1month of treatment, 0.118 (0.073) after 3months’ treatment and 0.127 (0.080) after 6months’ treatment. The 6-month cost of treating the entire population with Sativex was €1,361,266, with a €1008 cost and 0.0284 QALYs gained per patient. The estimated ICER was €35,516 per QALY gained, with little variability around the central estimate of cost-effectiveness, as shown by the cost-effectiveness acceptability curve. Conclusion: The use of Sativex could improve the quality of life of patients with a reasonable incremental cost resulting as a cost-effective option for patients with MS-resistant spasticity. These results could help clinicians and decision makers to develop improved management strategies for spasticity in patients with MS, optimizing the use of available resources.

Objective. The aim of this prospective observational multicenter postmarketing study was to evaluate fingolimod efficacy in a real world clinical setting.Methods. One hundred forty-two subjects with relapsing-remitting multiple sclerosis (RRMS) were enrolled in three multiple sclerosis centers throughout Central and Southern Italy between January 2011 and September 2013. After enrollment, regular visits and EDSS assessment were scheduled every 3 months, and MRI scan was obtained every 12 months. Patients were followed up from 1 to 33 months (mean 14.95 ± 9.15 months). The main efficacy endpoints included the proportion of patients free from clinical relapses, from disability progression, from magnetic resonance imaging activity, and from any disease activity.Results. Out of 142 patients enrolled in the study, 88.1% were free from clinical relapse and 69.0% were free from disability progression; 68.5% of patients remained free from new or newly enlarging T2 lesions and 81.7% of patients were free from gadolinium enhancing lesions. Overall the proportion of patients free from any disease activity was 41.9%.Conclusions. Our data in a real world cohort are consistent with previous findings that yield convincing evidence for the efficacy of fingolimod in patients with RRMS.

Rituximab (RTX) efficacy in NMO is suggested by several case series. No consensus exists on optimal dosing strategies. At present the treatment schedules more frequently used are 375 mg/m2/week iv for 4 weeks (RTX-A) and 1000 mg iv twice, 2 weeks apart (RTX-B). Aim of this study is to confirm RTX efficacy and safety in the treatment of NMO and to evaluate whether a most favourable dosage regimen exists. Data on RTX-treated NMO patients were collected from 13 Italian Hospitals. 73 patients (64 F), were enlisted. RTX-A was administered in 42/73 patients, RTX-B in 31/73. Median follow-up was 27 months (range 7-106). Mean relapse rate in the previous year before RTX start was 2.2 +/- 1.3 for RTX-A and 2.3 +/- 1.2 for RTX-B. ARR in the first year of treatment was 0.8 +/- 0.9 for RTX-A and 0.2 +/- 0.4 for RTX-B, in the second year of treatment was 0.9 +/- 1.5 for RTX-A and 0.4 +/- 0.8 for RTX-B patients (p = 0.001 for the first year, ns (0.09) for the second year). RTX-B was more effective in delaying the occurrence of a relapse (HR 2.2 (95 % IC 1.08-4.53) p = 0.02). Adverse events were described in 19/73 patients (mainly urinary tract and respiratory infections, and infusion reactions). Two deaths were reported in severely disabled patients. Though with the limitations of an observational study, our data support RTX efficacy in NMO and suggest that high dose pulses might be more effective than a more fractioned dose.

Background The approval of 9-δ-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex) for the management of treatment-resistant multiple sclerosis (MS) spasticity opened a new opportunity for many patients. The aim of our study was to describe Sativex effectiveness and adverse events profile in a large population of Italian patients with MS in the daily practice setting. Methods We collected data of all patients starting Sativex between January 2014 and February 2015 from the mandatory Italian medicines agency (AIFA) e-registry. Spasticity assessment by the 0–10 numerical rating scale (NRS) scale is available at baseline, after 1 month of treatment (trial period), and at 3 and 6 months. Results A total of 1615 patients were recruited from 30 MS centres across Italy. After one treatment month (trial period), we found 70.5% of patients reaching a ≥20% improvement (initial response, IR) and 28.2% who had already reached a ≥30% improvement (clinically relevant response, CRR), with a mean NRS score reduction of 22.6% (from 7.5 to 5.8). After a multivariate analysis, we found an increased probability to reach IR at the first month among patients with primary and secondary progressive MS, (n=1169, OR 1.4 95% CI 1.04 to 1.9, p=0.025) and among patients with >8 NRS score at baseline (OR 1.8 95% CI 1.3–2.4 p

Background: There are a few and conflicting results from randomised controlled trials (RCTs) pertaining to the influence of gender in response to currently used disease modifying drugs in Multiple Sclerosis (MS). Observational studies may be especially valuable for answering effectiveness questions in subgroups not studied in RCTs. Objective: To conduct a post-marketing analysis aimed to evaluate the gender effect on Interferon beta (IFN beta) treatment response in a cohort of relapsing (RR) MS patients. Methods: A cohort of 2570 IFN beta-treated RRMS was prospectively followed for Lip to 7 years in 15 Italian MS Centers. Cox proportional hazards regression models were used to assess gender differences for risk of reaching 1st relapse and risk of progression by I point on Expanded Disability Status Scale (EDSS) score. Gender effects were also explored by a propensity score (PS) matching algorithm, and a tree-growing technique. Results: The multivariate Cox Regression analyses showed that male patients had a significant (p = 0.0097) lower risk for 1st relapse and a trend (p = 0.0897) for a higher risk to reach I point EDSS progression than females. The PS matched multivariate Cox Regression confirmed these results. The RECPAM analysis showed that male sex conferred a significant reduction in the risk for 1st relapse (HR = 0.86; 95% Cl = 0.76-0.98; p = 0.0226) in the subgroup with a low pre-treatment number of bouts, and a significant increase in the risk for I point EDSS progression (HR = 1.33; 95% Cl: 1.00-1.76; p

OBJECTIVE: Recent findings support greater efficacy of early vs. delayed interferon beta (IFNbeta) treatment in patients with a first clinical event suggestive of multiple sclerosis (MS). We aimed to evaluate the effectiveness of early IFNbeta treatment in definite relapsing-remitting MS (RRMS) and to assess the optimal time to initiate IFNbeta treatment with regard to the greatest benefits on disability progression. METHODS: A cohort of 2,570 IFNbeta-treated RRMS patients was prospectively followed for up to 7 years in 15 Italian MS Centers. A Cox proportional hazards regression model adjusted for propensity score (PS) quintiles was used to assess differences between groups of patients with early vs. delayed IFNbeta treatment on risk of reaching a 1-point progression in the Expanded Disability Status Scale (EDSS) score, and the EDSS 4.0 and 6.0 milestones. A set of PS-adjusted Cox hazards regression models were calculated according to different times of treatment initiation (within 1 year up to within 5 years from disease onset). A sensitivity analysis was performed to assess the robustness of findings. RESULTS: The lowest hazard ratios (HRs) for the three PS quintiles-adjusted models were obtained by a cutoff of treatment initiation within 1 year from disease onset. Early treatment significantly reduced the risk of reaching a 1-point progression in EDSS score (HR = 0.63; 95% CI = 0.48-0.85; p < 0.002), and the EDSS 4.0 milestone (HR = 0.56; 95% CI = 0.36-0.90; p = 0.015). Sensitivity analysis showed the bound of significance for unmeasured confounders. INTERPRETATION: Greater benefits on disability progression may be obtained by an early IFNbeta treatment in RRMS.

We evaluated the risk of worsening according to the length of exposure to interferon beta (IFNβ)ina large cohort of 2090 multiple sclerosis patients collected by the Italian MS Database Network. Overall 44-140 patient-visits with a follow-up of 22-143 patient-years were evaluated. Forty-one per cent of patients were exposed to IFNβ for up to 2 years, 39% for 2- 4 years and 20% for more than 4 years. A Cox regression model was used to analyse two clinical outcomes: disability progression and worsening of relapse rate. The technique of propensity score was applied to reduce bias in the comparison of non-randomized groups. The risks of disability progression (HR=0.23; 95% CI: 0.17 - 0.30) and worsening of relapse rate (HR=0.19; 95% CI: 0.14 - 0.27) were reduced by about 4- 5- fold in patients exposed to IFNβ for more than four years, compared with patients exposed for up to two years. The propensity score technique confirmed the findings. The proportion of days covered by IFNβ treatment was lower ( P

Objective: Recent findings support greater efficacy of early vs. delayed interferon beta (IFN) treatment in patients with a first clinical event suggestive of multiple sclerosis (MS). We aimed to evaluate the effectiveness of early IFN treatment in definite relapsing-remitting MS (RRMS) and to assess the optimal time to initiate IFN treatment with regard to the greatest benefits on disability progression. Methods: A cohort of 2,570 IFN-treated RRMS patients was prospectively followed for up to 7 years in 15 Italian MS Centers. A Cox proportional hazards regression model adjusted for propensity score (PS) quintiles was used to assess differences between groups of patients with early vs. delayed IFN treatment on risk of reaching a 1-point progression in the Expanded Disability Status Scale (EDSS) score, and the EDSS 4.0 and 6.0 milestones. A set of PS-adjusted Cox hazards regression models were calculated according to different times of treatment initiation (within 1 year up to within 5 years from disease onset). A sensitivity analysis was performed to assess the robustness of findings. Results: The lowest hazard ratios (HRs) for the three PS quintiles–adjusted models were obtained by a cutoff of treatment initiation within 1 year from disease onset. Early treatment significantly reduced the risk of reaching a 1-point progression in EDSS score (HR 0.63; 95% CI 0.48 – 0.85; p 0.002), and the EDSS 4.0 milestone (HR 0.56; 95% CI 0.36 – 0.90; p 0.015). Sensitivity analysis showed the bound of significance for unmeasured confounders. Interpretation: Greater benefits on disability progression may be obtained by an early IFN treatment in RRMS. Ann Neurol 2009;66:513–520

none 39 no Articolo con dati scientifici originali pubblicato nella sezione "Editorial" della rivista We evaluated efficacy of natalizumab in relapsing-remitting multiple sclerosis patients in a clinical practice setting. We report data on the first consecutive 343 patients receiving natalizumab in 12 multiple sclerosis (MS) Italian centers enrolled between April 2007 and November 2010. The main efficacy endpoints were the proportion of patients free from relapses, disease progression, combined clinical activity, defined as presence of relapse or disease progression, from MRI activity, and from any disease activity defined as the absence of any single or combined activity. At the end of follow-up, the cumulative proportion of patients free from relapses was 68%; the proportion of patients free from Expanded Disability Status Scale (EDSS) progression was 93%; the proportion of patients free from combined clinical activity was 65%; the proportion of patients free from MRI activity was 77%; and the proportion of patients free from any disease activity was 53%. Natalizumab was effective in reducing clinical and neuroradiological disease activity. Its effectiveness in clinical practice is higher than that reported in pivotal trials and was maintained over time. none Totaro R; Lugaresi A; Bellantonio P; Danni M; Costantino G; Gasperini C; Florio C; Pucci E; Maddestra M; Spitaleri D; Lus G; Ardito B; Farina D; Rossi M; Di Carmine C; Altobelli E; Maccarone B; Casalena A; De Luca G; Travaglini D; Di Ioia M; Di Tommaso V; Fantozzi R; Ruggieri S; Provinciali L; De Riso S; Mundi C; Fuiani A; Galgani S; Ruggieri S; Maniscalco GT; Giuliani G; Cartechini E; Petretta V; Fratta M; Alfieri G; Gatto M; Carolei A; Natalizumab Long-Term Treatment Study group Totaro R; Lugaresi A; Bellantonio P; Danni M; Costantino G; Gasperini C; Florio C; Pucci E; Maddestra M; Spitaleri D; Lus G; Ardito B; Farina D; Rossi M; Di Carmine C; Altobelli E; Maccarone B; Casalena A; De Luca G; Travaglini D; Di Ioia M; Di Tommaso V; Fantozzi R; Ruggieri S; Provinciali L; De Riso S; Mundi C; Fuiani A; Galgani S; Ruggieri S; Maniscalco GT; Giuliani G; Cartechini E; Petretta V; Fratta M; Alfieri G; Gatto M; Carolei A; Natalizumab Long-Term Treatment Study group

Objective To investigate the impact of interferon-beta (IFNβ) on disease progression in relapsing-remitting multiple sclerosis patients. Methods A cohort of 1,504 relapsing-remitting multiple sclerosis (1,103 IFNβ–treated and 401 untreated) patients was followed for up to 7 years. Cox proportional hazards regression adjusted for propensity score inverse weighting was used to assess the differences between the two groups for three different clinical end points: secondary progression (SP) and irreversible Expanded Disability Status Scale (EDSS) scores 4 and 6. Times from first visit and from date of birth were used as survival time variables. Results The IFNβ–treated group showed a highly significant reduction in the incidence of SP (hazard ratio [HR], 0.38, 95% confidence interval [CI], 0.24–0.58 for time from 1st visit; HR, 0.36, 95% CI, 0.23–0.56 for time from date of birth; p < 0.0001), EDSS score of 4 (HR, 0.70, 95% CI, 0.53–0.94 for time from first visit; HR, 0.69, 95% CI, 0.52–0.93 for time from date of birth; p < 0.02), and EDSS score of 6 (HR, 0.60, 95% CI, 0.38–0.95 for time from first visit; HR, 0.54, 95% CI, 0.34–0.86 for time from date of birth; p ≤ 0.03) when compared with untreated patients. SP and EDSS scores of 4 and 6 were reached with significant delays estimated by times from first visit (3.8, 1.7, and 2.2 years) and from date of birth (8.7, 4.6, and 11.7 years) in favor of treated patients. Sensitivity analysis confirmed findings. Interpretation IFN-β slows progression in relapsing-remitting multiple sclerosis patients. Ann Neurol 2007;61:300–306

Objective: The aim of this study was to compare the efficacy of natalizumab and fingolimod in relapsing-remitting multiple sclerosis patients in real-world clinical setting. Methods: We enrolled 391 patients starting either natalizumab or fingolimod for relapsing-remitting multiple sclerosis, referred to four multiple sclerosis centers between March 2007 and July 2013. Cumulative proportion of patients free from any disease activity, as defined by freedom from relapse, Expanded Disability Status Scale (EDSS) progression, new or newly enlarging T2 lesions, and gadolinium enhancing lesions at magnetic resonance imaging (MRI) was assessed at 12-month follow-up. Results: Out of 391 patients, 197 were treated with natalizumab and 194 with fingolimod. The cumulative proportion of patients free from any disease activity was 72.0% in the natalizumab and 59.1% in the fingolimod group (P=0.014). This proportion was lower in fingolimod patients with prior natalizumab exposure compared to those without (51.7% vs. 61.8%; P=0.008). Moreover, the cumulative proportion of patients free from new MRI lesions was 87.5% in the natalizumab vs. 70.0% in the fingolimod group (P

Aim: We propose a simple tool for early prediction of unfavorable long-term evolution of multiple sclerosis (MS). Methods: A Bayesian model allowed us to calculate, within the first year of disease and for each patient, the Bayesian Risk Estimate for MS (BREMS) score that represents the risk of reaching secondary progression (SP). Results: The median BREMS were higher in 158 patients who reached SP within 10 years in comparison with 1087 progression-free patients (0.69 vs. 0.30, p

The randomized controlled trial (RCT) is considered to be the "gold standard" for providing evidence on drug efficacy. However, particularly for answering long-term questions in chronic diseases such as multiple sclerosis (MS), RCTs are often not feasible because of their size, duration, ethical constraints and costs. Data derived from observational studies complement information provided by RCTs. A major issue is that observational studies are more exposed and prone to biases, which can partly be addressed through rigorous study design or statistical analysis. Propensity score (PS) techniques are the most frequently used. PS is the probability that an individual would receive a certain treatment based on his/her pretreatment characteristics. This score is being widely used in many therapeutic areas and also in MS to adjust for the uncontrolled assignment of treatment in observational studies. However, since PS cannot adjust for unmeasured or unknown confounders, the conclusions from an observational study may not be considered as strong as those from RCTs.

The Multiple Sclerosis Database Network (MSDN) is the first Italian multiple sclerosis (MS) registry. The preliminary results on the MSDN cohort demonstrated that the risk of disability progression, in a sample of 2090 MS patients, was reduced by about four- to five-fold in patients exposed to IFNbeta for more than 4 years compared with patients exposed for up to 2 years. More recent results showed, in a subset of 1170 relapsing-remitting MS patients, of whom 918 were treated with IFNbeta and 252 were untreated, that IFNbeta-treated patients had a differential reduction in EDSS score change of -0.055 for each year of follow-up in comparison with the untreated group. These results provide significant information on the effectiveness of IFNbeta treatment on long-term disability progression in MS.

This independent, population-based surveillance study monitored, in clinical practice, the efficacy of interferon beta (IFNbeta) products in 1173 patients with multiple sclerosis (MS) from the Department of Neurological and Psychiatric Sciences, University of Bari, Italy. Relapses and Expanded Disability Status Scale (EDSS) scores were evaluated for up to 6 years for Avonex, Betaferon and Rebif 22 groups, and for up to 3 years for the Rebif 44 group. IFNbeta products produced significant reductions from baseline in relapse rates at 2, 4 and >4 years (p

There is evidence that inflammatory processes in multiple sclerosis (MS) are age-dependent. In this study we evaluated the impact of aging on gadolinium (Gd) enhancement of brain magnetic resonance imaging (MRI) lesions in MS patients. Pre- and post-contrast MRI scans, acquired using a standardized procedure by the same MRI scanner, at least 1 month far from clinical relapse or steroid treatment, were examined in 200 disease-modifying treatment free MS patients. Seventy-three patients (36.5%) showed at least one enhancing lesion. Age at MRI examination (p=0.0001), disease duration (p=0.002) and EDSS score were significantly (p=0.02) lower, whereas relapse rate in the preceding 2 years was higher (p=0.003) in patients with enhancing lesions than in patients with unenhancing scans. Multivariate logistic analysis showed that current age was the variable better predicting Gd enhancement (p=0.004). The odds ratios were 0.95 (CI: 0.92-0.98) for each year of patient's age and 0.64 (CI: 0.48-0.87) for each age decade. The main changes in enhancement risk occurred after 35 years of age. Multivariate Poisson regression model showed that relapse rate in the preceding 2 years (p0.0001) and current age (p=0.0003) were the best predictors of the number of enhancing lesions. This information can be used to increase the statistical power of clinical trials using Gd-enhancing lesions as an outcome measure.

Multiple sclerosis (MS) patients complain with the first symptoms of the disease in a range period which varies from childhood to adult life. The extent to which clinical presentation, disease course and demographic features may differ between childhood and adult onset has been the object of investigation. This paper aims to demonstrate that the different clinical phenotypes in young and old patients might simply reflect different phases of a same pathological process.

In a multicenter cross-sectional study, the authors assessed pain in patients with multiple sclerosis (MS) using a symptom-oriented approach. Out of 2,077 questionnaires, we used 1,672 for data analysis. Pain and frequencies included trigeminal neuralgia 2%, Lhermitte's sign 9%, dysesthetic pain 18.1%, back pain 16.4%, and painful tonic spasms 11%. Comparison between different groups showed significant differences for age, Expanded Disability Status Scale, disease duration, and disease course, but not for sex. This study underlines the relevance of pain in the clinical history of MS.

This independent, population-based surveillance study monitored the efficacy and safety of interferon beta (IFNb) products in 1033 patients with relapsing -remitting multiple sclerosis (RRMS) from 15 centres in Italy. Relapses, Expanded Disability Status Scale (EDSS) scores, and adverse events were evaluated for up to 24 months. Data of patients with a baseline EDSS score 5-3.5 are reported. The proportions of relapse-free patients were similar among the groups at 12 and 24 months (P =0.10). IFNb products produced significant reductio ns from baseline in relapse rates at 12 and 24 months (P B-0.001), with no differences among treatments (P =0.2). There were no significant differences in mean EDSS change among groups at 12 or 24 months. The IFNb-1b group showed a higher incidence of adverse events during the first year of treatment (P B-0.05) than IFNb-1a groups, and more withdrawals (10%) compared with Avonex (5%) at 24 months. IFNb products are equally effective in low disability RRMS, but IFNb-1a may have a more favorable efficacy/tolerability ratio.