Risk of multiple sclerosis relapses when switching from fingolimod to cell-depleting agents: the role of washout duration.

BACKGROUND: Fingolimod (FTY) induces sequestration of lymphocytes in secondary lymphoid organs and the average lymphocyte recovery following discontinuation takes 1-2 months. It has been hypothesized that the therapeutic effects of subsequent cell-depleting agents may be compromised if initiated before lymphocyte recovery has occurred. OBJECTIVE: To assess the risk of relapses following FTY discontinuation and the initiation of a B/T cell-depleting agent in relation to washout duration using data from the Italian MS Register. METHODS: The risk of relapses was assessed in relation to different washout durations (< 6, 6-11, 12-17 and > / = 18 weeks) in patients starting alemtuzumab, rituximab, ocrelizumab or cladribine following FTY discontinuation. RESULTS: We included 329 patients in the analysis (226F, 103 M; mean age 41 ± 10 years). During the cell-depleting treatment, the incidence rate ratio for a relapse was significantly greater in patients with a washout period of 12-17 and > / = 18 weeks compared to the reference period (< 6 weeks). The risk of a relapse was significantly influenced by the occurrence of relapses during FTY treatment and by washout length, with hazard ratios markedly increasing with the washout duration. CONCLUSION: The risk of relapses increases with the washout duration when switching from FTY to lymphocyte-depleting agents.

A multicenter survey on access to care in Multiple Sclerosis-related trigeminal neuralgia.

The prevalence of trigeminal neuralgia (TN) in patients with Multiple Sclerosis (MS) is higher than in the general population and its management can be particularly challenging due to a number of reasons including high recurrence rates, lack of MS-specific treatment guidelines and uncertainties about pain pathophysiology. Aim of this cross-sectional, multicentre survey was to gather information on the current treatment modalities and options of MS-related TN across 23 Italian MS centres. Initial medical management (carbamazepine or oxcarbazepine) of MS-related TN was fairly homogeneous throughout Italian centres. The most commonly available surgical procedure was microvascular decompression, but the frequency and types of surgical procedures available locally differed considerably throughout MS centers, and were unavailable in one quarter of them. This survey reveals some of the issues that could hamper an optimal patient management and underlines the need for a consensus on MS-related TN to support health-care professionals in their approach to this challenging condition and to facilitate the development of local guidelines aimed at ensuring equity in access to care and treatment optimization.

Informing MS patients on treatment options: a consensus on the process of consent taking.

In the last years, change in multiple sclerosis (MS) therapeutic scenario has highlighted the need for an improved doctor-patient communication in advance of treatment initiation in order to allow patient's empowerment in the decision-making process. AIMS: The aims of our project were to review the strategies used by Italian MS specialists to inform patients about treatment options and to design a multicentre shared document that homogenizes the information about disease-modifying treatment (DMTs) and the procedure of taking informed consent in clinical practice. RESULTS: The new resource, obtained by consensus among 31 neurologists from 27 MS Centres in Italy with the supervision of a medico-legal advisor, received the aegis of Italian Neurological Society (SIN) and constitutes a step toward a standardized decision process around DMTs in MS.

A multicenter, observational, prospective study of self- and parent-reported quality of life in adolescent multiple sclerosis patients self-administering interferon-ß1a using RebiSmart™-the FUTURE study.

Besides the impact of disease per se, the use of immunomodulatory therapies in adolescents with relapsing-remitting multiple sclerosis (RRMS) may have an effect on quality of life (QL). The FUTURE (Quality of liFe in adolescent sUbjecTs affected by mUltiple sclerosis treated with immunomodulatoRy agEnt using self-injecting device) study was designed to evaluate the changes in QL of Italian adolescents with RRMS receiving treatment with IFN-ß1a (Rebif; 22 µg), administered subcutaneously three times weekly using the RebiSmart™ electronic autoinjection device over a 52-week period. Fifty adolescents with RRMS were enrolled and 40 completed the study. Changes from baseline to end of treatment (EoT) in adolescent self-reported and parent-reported QL were assessed using the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (PedsQL), which has been validated for use in pediatric MS and for which an Italian version is available. The adolescent self-reported total PedsQL4.0 score and all of its subscales tended to increase from baseline to EoT, the only exception being "Emotional functioning." In parent-reported measures, the total PedsQL4.0 score increased significantly from baseline to EoT (+ 5.27 points, p = 0.041). Significant increases were also evident for parent-reported "Psychosocial health summary score" (+ 5.90 points; p = 0.015) and "School functioning" (+ 7.84 points; p = 0.029). Our results indicate that adolescents with RRMS using the electronic injection device RebiSmart™ for self-administration of Rebif® can experience long-term improvements in QL.

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.

Clinical and magnetic resonance imaging predictors of disease progression in multiple sclerosis: a nine-year follow-up study.

OBJECTIVE: The objective of this paper is to identify clinical or magnetic resonance imaging (MRI) predictors of long-term clinical progression in a large cohort of multiple sclerosis (MS) patients. METHODS: A total of 241 relapsing-remitting (RR) MS patients were included in a nine-year follow-up (FU) study. The reference MRIs were acquired at baseline (BL) as part of a multicenter, cross-sectional, clinical-MRI study. Volumetric MRI metrics were measured by a fully automated, operator-independent, multi-parametric segmentation method. Clinical progression was evaluated as defined by: conversion from RR to secondary progressive (SP) disease course; progression of Expanded Disability Status Scale (EDSS); achievement and time to reach EDSS 4. RESULTS: We concluded that conversion from RR to SP (OR 0.79; CI 0.7-0.9), progression of EDSS (OR 0.85; CI 0.77-0.93), achievement of EDSS 4 (OR 0.8; CI 0.7-0.9), and time to reach EDSS 4 (HR 0.88; CI 0.82-0.94) were all predicted by BL gray matter (GM) volume and, except for progression of EDSS, by BL EDSS (respectively: (OR 2.88; CI 1.9-4.36), (OR 2.7; CI 1.7-4.2), (HR 3.86; CI 1.94-7.70)). CONCLUSIONS: BL GM volume and EDSS are the best long-term predictors of disease progression in RRMS patients with a relatively long and mild disease.

The impact of neutralizing antibodies on the risk of disease worsening in interferon ß-treated relapsing multiple sclerosis: a 5 year post-marketing study.

The impact of neutralizing antibodies (NAbs) on interferon ß (IFNß) efficacy in MS patients is still an object of controversy. To evaluate the clinical response to IFNß during NAb-positive (NAb+) and NAb-negative (NAb-) statuses on a large population of relapsing remitting (RR) MS patients were followed up to 5 years. Sera from 567 RR MS patients treated with IFNß for 2-5 years were collected every 6-12 months and evaluated for NAb presence by a cytopathic effect assay. The relapse rate and expanded disability status scale (EDSS) score were assessed at baseline and every 6 months for each patient. A NAb+ status was defined after two consecutive positive titers of NAbs >/= 20 neutralizing units (NU)/mL. Multivariate models were used to analyze the relapse rate, the time to first relapse, the time to confirmed EDSS score 4 during NAb+ and NAb- statuses. A propensity score (PS) matching analysis was performed to assess the robustness of the multivariate models. Fourteen percent of patients became NAb+ during the follow-up. A significant increase of the relapse rate (IRR = 1.38; p = 0.0247) and decrease of the time to 1st relapse (IRR = 1.51; p = 0.0111) were found during NAb+ periods. The PS matching analysis, in a selected cohort of patients, demonstrated a negative trend of NAbs on the time to reach the milestone EDSS 4 (IRR = 2.94; p = 0.0879). This long-term post-marketing observational study further confirms that the occurrence of NAbs significantly affects the risk of disease worsening in IFNß- treated RRMS.

Breastfeeding is not related to postpartum relapses in multiple sclerosis.

OBJECTIVE: To assess the relationship between breastfeeding and risk of puerperal relapses in a large cohort of patients with multiple sclerosis (MS). METHODS: We prospectively followed-up pregnancies occurring between 2002 and 2008 in women with MS, recruited from 21 Italian MS centers, and gathered data on breastfeeding through a standardized interview. The risk of relapses after delivery was assessed using the Cox regression analysis. RESULTS: A total of 302 out of 423 pregnancies in 298 women resulted in full-term deliveries. Patients were followed up for at least 1 year after delivery. The time-dependent profile of the relapse rate before, during, and after pregnancy did not differ between patients who breastfed and patients who did not. In the multivariate analysis, adjusting for age at onset, age at pregnancy, disease duration, disability level, and relapses in the year prior to pregnancy and during pregnancy, treatment with disease-modifying drugs (DMDs), and exposure to toxics, the only significant predictors of postpartum relapses were relapses in the year before pregnancy (hazard ratio [HR] = 1.5; 95%confidence interval [CI] 1.3-1.9; p < 0.001) and during pregnancy (HR = 2.2; 95% CI 1.5-3.3; p < 0.001). CONCLUSIONS: In our sample, postpartum relapses were predicted only by relapses before and during pregnancy. Therefore, the reported association between breastfeeding and a lower risk of postpartum relapses may simply reflect different patient behavior, biased by the disease activity. Our results can assist neurologists facing the breastfeeding issue in mother counseling and shared decision-making. Especially, among patients with high risk of postpartum relapses, breastfeeding may not be feasible and early postpartum treatment should be an option.

Multiple sclerosis in Italy: cost-of-illness study.

This study estimates the direct costs of multiple sclerosis (MS) in Italy from the perspective of the National Health System. Patients diagnosed with MS for ≥1 year prior to study entry were included in the analysis; neurological disability was assessed using the Expanded Disability Status Scale (EDSS). Cost variables were analyzed according to: MS phenotype, disease course over the previous year and EDSS rating. A total of 510 patients were included in the analysis. Overall costs were significantly higher for relapsing-remitting MS and secondary progressive MS than for primary progressive MS (P < 0.05). Costs were higher for EDSS scores 0.0-3.5 and 4.0-6.0 than for scores > 6.0 (P < 0.05). The extrapolated data gave an estimated annual direct cost of MS per patient of 18,030. In conclusion, relapsing-remitting MS or secondary progressive MS phenotypes and lower estimated EDSS scores appear to be associated with higher costs.

Pregnancy and fetal outcomes after interferon-ß exposure in multiple sclerosis.

OBJECTIVE: To assess pregnancy and fetal outcomes after in utero exposure to interferon-ß (IFNß) in all pregnancies occurring in women with multiple sclerosis (MS) during the study period, with a specific focus on the risk of spontaneous abortion. METHODS: In this cohort study, data were gathered through a standardized, semi-structured interview. Patients who discontinued IFNß less than 4 weeks from conception (exposed) were compared with those who had discontinued the drug at least 4 weeks from conception or who were never treated (not exposed). Possible confounders were handled through multivariate analyses adjusted for propensity score (PS). RESULTS: We collected data on 396 pregnancies in 388 women, 88 classified as exposed (mean exposure 4.6 ± 5.8 weeks). IFNß exposure was not associated with an increased risk of spontaneous abortion (PS-adjusted odds ratio [OR] 1.08, 95% confidence interval [CI] 0.4 to 2.9, p = 0.88), although it was associated with both lower baby weight (PS-adjusted ß -113.8, p < 0.0001) and length (PS-adjusted ß -1.102, p < 0.0001). Proportion of spontaneous abortion in exposed patients fell within the range expected for the Italian population in the same period. IFNß exposure (PS-adjusted OR 2.11, 95% CI 1.18 to 3.78, p = 0.012) and cesarean delivery were the only predictors of preterm delivery. In the exposed group, we did not observe any significant fetal complications, malformations, or developmental abnormalities over a median follow-up of 2.1 years. CONCLUSIONS: Our findings point to the relative safety of IFNß exposure times of up to 4 weeks and can assist neurologists facing therapeutic decisions in women with MS with a pregnancy plan.

observational studies: propensity score analysis of non-randomized data.

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.

Real-life impact of early interferon beta therapy in relapsing multiple sclerosis.

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.

Post-marketing of disease modifying drugs in multiple sclerosis: an exploratory analysis of gender effect in interferon beta treatment.

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 (IFNbeta) treatment response in a cohort of relapsing (RR) MS patients. METHODS: A cohort of 2570 IFNbeta-treated RRMS was prospectively followed for up 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 1 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 1 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% CI=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 1 point EDSS progression (HR=1.33; 95% CI: 1.00-1.76; p<0.05) in the subgroup with a delayed treatment, but a still young age at the start of treatment. CONCLUSION: The results of this exploratory analysis seem to suggest that male patients do not respond to IFNbeta treatment in the same way of females.

Variations of the perforin gene in patients with multiple sclerosis.

Perforin is involved in cell-mediated cytotoxicity and mutations of its gene (PRF1) cause familial hemophagocytic lymphohistiocytosis (FLH2). PRF1 sequencing in 190 patients with multiple sclerosis and 268 controls detected two FLH2-associated variations (A91V, N252S) in both groups and six novel mutations (C999T, G1065A, G1428A, A1620G, G719A, C1069T) in patients. All together, carriers of these variations were more frequent in patients than in controls (phenotype frequency: 17 vs 9%, P=0.0166; odds ratio (OR)=2.06, 95% confidence interval (CI): 1.13-3.77). Although A91V was the most frequent variation and displayed a trend of association with multiple sclerosis (MS) in the first population of patients and controls (frequency of the 91V allele: 0.076 vs 0.043, P=0.044), we used it as a marker to confirm PRF1 involvement in MS and assessed its frequency in a second population of 966 patients and 1520 controls. Frequency of the 91V allele was significantly higher in patients than in controls also in the second population (0.075 vs 0.058%, P=0.019). In the combined cohorts of 1156 patients and 1788 controls, presence of the 91V allele in single or double dose conferred an OR=1.38 (95% CI=1.10-1.74). These data suggest that A91V and possibly other perforin variations indicate susceptibility to MS.

Italian Multiple Sclerosis Database Network.

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.

The IFNbeta treatment of multiple sclerosis (MS) in clinical practice: the experience at the MS Center of Bari, Italy.

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<0.0001), with no differences among treatments (p=0.2). A modest significant (p<0.05) increase of EDSS was observed in all treatment groups from baseline to 48 months, followed thereafter by a plateau. The IFNbeta-1b group showed more withdrawals (19%) compared with Avonex (6%) and Rebif (7%) at 6 years.

Atypical forms of multiple sclerosis or different phases of a same disease?

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.

The transition from relapsing-remitting MS to irreversible disability: clinical evaluation.

The development of a progressive course is by far the most deleterious event in the case of a multiple sclerosis (MS) patient. It occurs in about 90% of relapsing remitting patients by 20-25 years from onset. The clinical transition to secondary progressive MS is phenotypically distinctive and both patients and physicians acknowledge that a fundamental shift in the degree of responsiveness to anti-inflammatory therapies has occurred. This review discusses the clinical studies that provided important findings relating to our understanding on different mechanisms that may contribute to irreversible disability in MS.

Adhesion molecules and matrix metalloproteinases in Multiple Sclerosis: effects induced by Interferon-beta.

In Multiple Sclerosis (MS) pathology, early inflammation involves leukocyte migration across the blood-brain barrier (BBB) within the central nervous system. In this process, adhesion molecules (AMs), both membrane-bound and soluble-circulating forms, and matrix metalloproteinases (MMPs) certainly play a regulatory role. In MS, recombinant Interferon-beta (rIFNbeta) is effective in reducing gadolinium contrast-enhancing lesions on magnetic resonance imaging and this suggests that it may reduce BBB damage or even restore its integrity by different mechanisms that include interference with both AM and MMP pathways. This review will highlight the effects induced by rIFNbeta, both in vitro and in vivo, on cell-bound and soluble forms of AMs and on MMPs.

The differential diagnosis of multiple sclerosis: classification and clinical features of relapsing and progressive neurological syndromes.

In the absence of pathognomonic clinical features or a definitive laboratory test, multiple sclerosis (MS) remains ultimately a diagnosis of exclusion. Accurate diagnosis is increasingly important with available disease modifying therapy. Unfortunately the rate of misdiagnosis remains around 5%-10%, indicating that 1 in 20 patients thought to have MS has, instead, a condition resembling MS. In this review we describe conditions that may be confused with MS because they can present as lesions disseminated in time, space, or both. Conditions often confused with MS may be inflammatory (systemic lupus erythematosus, Sjögren's syndrome, vasculitis, sarcoidosis, Behçet's disease), infectious (Lyme disease, syphilis, progressive multifocal leukoencephalopathy, HTLV-1 infection, herpes zoster), genetic (lysosomal disorders, adrenoleukodystrophy, mitochondrial disorders, CADASIL), metabolic (vitamin B12 deficiency), neoplastic (CNS lymphoma) and spinal (degenerative and vascular malformations) diseases. The key to the accurate diagnosis of MS is vigilance for atypical features, suggesting the possibility of an alternative diagnosis.