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.

Detection of disability worsening in relapsing-remitting multiple sclerosis patients: a real-world roving Expanded Disability Status Scale reference analysis from the Italian Multiple Sclerosis Register.

BACKGROUND AND PURPOSE: In relapsing-remitting multiple sclerosis patients (RRMS) disability progressively accumulates over time. To compare the cumulative probability of 6-month confirmed disability-worsening events using a fixed baseline or a roving Expanded Disability Status Scale (EDSS) reference, in a real-world setting. METHODS: A cohort of 7964 RRMS patients followed for 2 or more years, with EDSS scores recorded every 6 months, was selected from the Italian Multiple Sclerosis Register. The overall probability of confirmed disability-worsening events and of confirmed disability-worsening events unrelated to relapse was evaluated using as reference a fixed baseline EDSS score or a roving EDSS score in which the increase had to be separated from the last EDSS assessment by at least 6 or 12 months. RESULTS: Using a fixed baseline EDSS reference, the cumulative probability of 6-year overall confirmed disability-worsening events was 33.2%, and that of events unrelated to relapse was 10.9% (33% of overall confirmed disability-worsening events). Using a roving EDSS, the proportions were respectively 35.2% and 21.3% (61% of overall confirmed disability-worsening events). CONCLUSIONS: In a real-world setting, roving EDSS reference scores appear to be more sensitive for detecting confirmed disability-worsening events unrelated to relapse in RRMS patients.

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 role of neutralizing antibodies to interferon-ß as a biomarker of persistent MRI activity in multiple sclerosis: a 7-year observational study.

PURPOSE: During interferon-ß (IFN-ß) therapy, up to 45 % of patients may develop neutralizing antibodies (NAbs), associated with a decreased efficacy of the drug. We investigated in a real-life setting the impact of NAbs on magnetic resonance imaging (MRI) outcomes in a population of 567 IFN-ß-treated relapsing-remitting (RR) multiple sclerosis (MS) patients up to 7 years. We also evaluated NAbs' role as a biomarker of the persistence of MRI disease activity. METHODS: Patients' sera were tested for NAbs' presence by cytopathic effect (CPE) assay every 6-12 months. MRI scans were performed every 12 months. Generalized hierarchical linear models accounting for within-patient correlation were used to analyze T1 gadolinium-enhancing and new T2 lesions. Moreover, further tests were carried out to assess the overall outcome difference from year 1 to year 7 according to NAb status and the possible interaction between NAb status and time of follow-up. RESULTS: Seventy-five patients (13.2 %) became NAb positive (NAb+) during the follow-up. Considering T1 gadolinium-enhancing (GD+) lesions, we observed a significantly higher incidence in NAb+ patients (52 %, p = 0.0091). Also for new T2 lesions, we found a higher incidence in NAb+ patients (50 %, p = 0.0075). The negative impact of NAbs on the MRI outcomes considered did not change during the follow-up. CONCLUSIONS: Our 7-year results show the negative effect of NAbs on MRI measures of disease activity and confirm their role as a surrogate marker of IFN-ß treatment efficacy.

Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study.

BACKGROUND AND OBJECTIVE: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. METHODS: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. RESULTS: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. CONCLUSIONS: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.

Anxiety state affects information processing speed in patients with multiple sclerosis.

The aim of this study was to investigate the impact of anxiety on the cognitive performance of a clinical sample of relapsing-remitting (RR) MS patients. One hundred ninety patients (140 females) were included in the study and assessed through the beck depression inventory, the state-trait anxiety inventory and the Rao's brief repeatable battery which assesses cognitive domains most frequently impaired in MS. As for neuropsychological performance, a total of 76 (40%) subjects fulfilled our criterion for cognitive impairment. Tests most frequently failed by cognitive impairment (CI) patients were those assessing complex attention and information processing speed [Simbol Digit Modalities Test (SDMT), Paced Auditory Serial Auditory Test (PASAT) 3 and 2] and verbal memory. In the univariate analysis, state anxiety was related to failure on the SDMT (p = 0.042), and marginally, to failure on the PASAT-3 (p = 0.068), and to the presence of CI (p = 0.082). Moderate/severe depression was detected in 38 (20%) patients and fatigue in 109 (57%). Higher depression scores were related to impairment on the ST (OR = 1.05; 95% CI 1.01-1.10; p = 0.029).

Computer-assisted rehabilitation of attention in patients with multiple sclerosis: results of a randomized, double-blind trial.

BACKGROUND: There is controversial information on the efficacy of cognitive rehabilitation in multiple sclerosis (MS). OBJECTIVE: The objective of this paper is to test a home-based computerized program for retraining attention dysfunction in MS. METHODS: Relapsing-remitting patients who failed > 2 tests of attention on an extensive neuropsychological battery were randomized to specific or nonspecific computerized training (ST, n-ST), in one-hour sessions, twice a week for three months. Outcome measures included neuropsychological assessment, depression, fatigue, everyday activities and a visual analogue scale assessing attentive performance (VAS). Assessments were repeated after the interventions and after a further three months. Statistical analysis included the analysis of variance (ANOVA) for repeated measures. RESULTS: Eighty-eight out of 102 randomized patients completed the study (69 women, age 40.9 ± 11.5 years, disease duration 13.0 ± 8.7 years, Expanded Disability Status Scale score 2.7 ± 1.5). Fifty-five patients were randomized to ST, 33 to n-ST. A benefit of the ST was observed on the Paced Auditory Serial Addition Test (p < 0.002). However, patient self-report did not reveal differences between ST and n-ST patient groups. CONCLUSION: Although our program trained different attention components, we could detect some improvements exclusively on tasks of sustained attention. Moreover, patient self-perceived results may be independent of the training program.

Verbal fluency deficits in clinically isolated syndrome suggestive of multiple sclerosis.

BACKGROUND: Little is known about relationships between Cognitive Impairment (CI) and verbal fluency measures in patients with a Clinically Isolated Syndrome (CIS) suggestive of Multiple Sclerosis. The aim of this study was to assess the extent of verbal fluency deficits and their predictive value for the presence of a CI in a population of CIS patients. METHODS: CI was detected by the Rao's Brief Repeatable Battery (BRB) and the Stroop Test (ST) in 100 CIS patients. The BRB includes the Word List Generation (WLG) test for semantic verbal fluency. The FAS test was used to investigate phonemic verbal fluency. CI was defined as the failure in at least 3 tests on BRB (without WLG to exclude criterion contamination bias) and ST. RESULTS: Eleven patients failed in at least 3 of the BRB tests and were classified as cognitively impaired. The comparison of Receiver Operating Characteristic curves showed that the Area Under the Curve (AUC) of the WLG was not significantly different from the AUC of the FAS (0.787 vs 0.755; p=N.S.). A cut-off <17 words for the WLG achieved 64% of sensitivity and a 79% of specificity, and a cut-off <28 words achieved 82% of sensitivity and a 66% of specificity in discriminating patients with CI. CONCLUSIONS: Verbal fluency deficits occur early in the disease course and may predict the presence of CI in CIS patients.

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.

Load-dependent dysfunction of the putamen during attentional processing in patients with clinically isolated syndrome suggestive of multiple sclerosis.

BACKGROUND: Load-related functional magnetic resonance imaging (fMRI) abnormalities of brain activity during performance of attention tasks have been described in definite multiple sclerosis (MS). No data are available in clinically isolated syndrome (CIS) suggestive of MS. OBJECTIVES: The objective of this research is to evaluate in CIS patients the fMRI pattern of brain activation during an attention task and to explore the effect of increasing task load demand on neurofunctional modifications. METHODS: Twenty-seven untreated CIS patients and 32 age- and sex-matched healthy controls (HCs) underwent fMRI while performing the Variable Attentional Control (VAC) task, a cognitive paradigm requiring increasing levels of attentional control processing. Random-effects models were used for statistical analyses of fMRI data. RESULTS: CIS patients had reduced accuracy and greater reaction time at the VAC task compared with HCs (p=0.007). On blood oxygenation level-dependent (BOLD)-fMRI, CIS patients had greater activity in the right parietal cortex (p=0.0004) compared with HCs. Furthermore, CIS patients had greater activity at the lower (p=0.05) and reduced activity at the greater (p=0.04) level of attentional control demand in the left putamen, compared with HCs. CONCLUSIONS: This study demonstrates the failure of attentional control processing in CIS. The load-related fMRI dysfunction of the putamen supports the role of basal ganglia in the failure of attention observed at the earliest stage of MS.

Serum and CSF N-acetyl aspartate levels differ in multiple sclerosis and neuromyelitis optica.

BACKGROUND: The identification of biomarkers able to improve the differential diagnosis between multiple sclerosis (MS) and neuromyelitis optica (NMO) is challenging because of a different prognosis and response to treatment. Growing evidence indicates that brain and CSF N-acetyl aspartate (NAA) concentration is a useful marker for characterising different phases of axonal pathology in demyelinating diseases, and preliminary studies suggest that increased serum NAA levels may be a telltale sign of acute neuronal damage or defective NAA metabolism in oligodendrocytes. OBJECTIVE: To evaluate whether serum and CSF NAA concentration differs in patients with MS and NMO. DESIGN: Observational, multicentre, prospective, cross sectional study. METHODS: Serum samples were collected from 48 relapsing-remitting MS, 32 NMO and 76 age matched healthy controls. Coeval CSF samples were available for all MS and for 8/32 NMO patients. NAA was measured in serum and CSF by liquid chromatography-mass spectrometry. RESULTS: MS patients showed higher serum and CSF NAA levels than NMO patients, and higher serum NAA levels than healthy controls (p<0.001). High serum NAA values, exceeding the 95th percentile of serum NAA values in healthy controls, were found in 100% of patients with MS and in no patient with NMO. No differences in serum NAA levels were found between NMO and healthy controls. In MS, serum and CSF NAA levels correlated with disability score. CONCLUSIONS: Determination of serum and CSF NAA levels may represent a suitable tool in the diagnostic laboratory workup to differentiate MS and NMO.

Safety profile of Tysabri: international risk management plan.

Therapeutic monoclonal antibodies are potent new tools for a molecular targeted approach to modify the course of multiple sclerosis (MS). Natalizumab is a monoclonal antibody targeted against alpha-4 integrin that has proved to be very effective in the treatment of MS. It is well tolerated, although severe side effects have been reported that have conditioned its use as a second-line drug for the treatment of MS. The clinical benefit of natalizumab should be weighed carefully against the potential risk of serious adverse events. Therefore, risk management plans have already been developed in order to prevent or minimise risks relating to natalizumab. Data so far obtained from these observational programs confirm the already demonstrated risk-benefit profile of natalizumab in clinical trials.

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.