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Background: Recent progress in multiple sclerosis (MS) management has contributed to a greater life expectancy in persons with MS. Ageing with MS comes with unique challenges and bears the potential to greatly affect quality of life and socioeconomic burden. Objectives: To compare frailty in ageing persons with multiple sclerosis (pwMS) and controls; to correlate frailty with MS clinical characteristics. Methods: PwMS and controls over 50 years old were recruited in a cross-sectional study. Two validated frailty measures were assessed: the frailty index and the Fried’s phenotype. Several multiple linear regressions accounting for demographic and clinical characteristics were performed. Results: Eighty pwMS (57 females, mean age 58.5 ± 6 years old) and 37 controls (24 females, mean age 61 ± 6.5 years old) were recruited. Multivariable analysis identified significantly higher frailty index in pwMS (0.21 ± 0.12 vs 0.11 ± 0.08, p Conclusion: Our results suggest that frailty can be routinely assessed in pwMS. Increased frailty in MS patients suggests that, along with MS therapeutics, a tailored multidisciplinary approach of ageing pwMS is needed.

Background: Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening. Methods: By re-analyzing original published results from MSBase, France, and Denmark using uniform meth-odologies, we aimed at identifying the effects of differences in methodology, in the MS-populations, and at re-evaluating the differences in effectiveness between the two drugs. We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/ exclusion criteria and statistical methods with Inverse Probability Treatment Weighting. Results: The pooled analyses comprised 968 natalizumab-and 1479 fingolimod treated patients. The on-treatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod. Conclusion: The results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed. BiogenBiogen; NovartisNovartis; MerckMerck & Company; RocheRoche Holding; Teva; Sanofi GenzymeSanofi-AventisGenzyme Corporation; NHMRCNational Health and Medical Research Council of Australia [1140766,1129789, 1157717]; French State; Agence Nationale de la Recherche-French National Research Agency (ANR)European Commission [ANR-10-COHO-002]; Eugene Devic EDMUS Foundation; ARSEP Foundation

International audience; Objective: To explore the associations of patient and disease characteristics with the duration of therapeutic lag for relapses and disability progression.Background: Therapeutic lag represents the delay from initiation of therapy to attainment of full treatment effect. Understanding the determinants of therapeutic lag provides valuable information for personalised choice of therapy in multiple sclerosis (MS).Design/Methods: Data from MSBase, a multinational MS registry, and OFSEP, the French national registry, were used. Patients diagnosed with MS, minimum 1-year exposure to MS treatment, minimum 3-year pre-treatment follow up and yearly review were included in the analysis. By studying incidence of relapses and 6-month confirmed disability progression, the duration of therapeutic lag was calculated by identifying the first local minimum of the first derivative after treatment start in subgroups stratified by patient and disease characteristics. Pairwise analyses of univariate predictors were performed. Combinations of determinants that consistently drove differences in therapeutic lag in pair by pair analyses were included in the final model.Results: Baseline EDSS, ARR and sex were associated with duration of therapeutic lag on disability progression in univariate and pairwise bivariable analyses. In the final model, therapeutic lag was 27.8 weeks shorter in females with ARR6 compared to those with EDSS>=6 (26.6, 18.2–34.9 vs 54.3, 47.2–61.5). Baseline EDSS, ARR, sex and MS phenotype were associated with duration of therapeutic lag on relapses in univariate analyses. Pairwise bivariable analyses of the pairs of determinants suggested ependently associated with therapeutic lag. In the final model, therapeutic lag was shortest in those with RRMS and EDSS

Objectives Pro‐ and anti‐inflammatory properties have been attributed to interleukin‐27 (IL‐27). Nevertheless, the impact of this cytokine on chronic inflammatory diseases such as multiple sclerosis (MS) remains ill‐defined. We investigated the biology of IL‐27 and its specific receptor IL‐27Rα in MS patients. Methods Levels of IL‐27 and its natural antagonist (IL‐27‐Rα) were measured by ELISA in biological fluids. CD4+ and CD8+ T lymphocytes were isolated from untreated relapsing–remitting MS patients and healthy donors. Transcriptome‐wide analysis compared T‐cell subsets stimulated or not with IL‐27. Expression of the IL‐27Rα, key immune factors, STAT phosphorylation and cytokine production was assessed by flow cytometry. Results We observed elevated levels of IL‐27 in the serum and cerebrospinal fluid of MS patients compared with controls. Moreover, we show that specific IL‐27‐mediated effects on T lymphocytes are reduced in MS patients including the induction of PD‐L1. IL‐27‐triggered STAT3 signalling pathway is enhanced in CD4+ and CD8+ T lymphocytes from MS patients. Elevated IL‐27Rα levels in serum from MS patients are sufficient to impair the capacity of IL‐27 to act on immune cells. We demonstrate that shedding of IL‐27Rα by activated CD4+ T lymphocytes from MS patients contributes to the increased IL‐27Rα peripheral levels and consequently can dampen the IL‐27 responsiveness. Conclusion Our work identifies several mechanisms that are altered in the IL‐27/IL‐27R axis in MS patients, especially in T lymphocytes. Our results underline the importance of characterising the biology of cytokines in human patients prior to design new therapeutics., T lymphocytes play a central role in the pathobiology of chronic inflammatory diseases including multiple sclerosis (MS). We identified perturbations in the IL‐27/IL‐27R pathway in MS patients; IL‐27 triggers higher STAT3p response in T lymphocytes from MS vs. controls and induces PD‐L1 less efficiently on T cells from MS patients. Moreover, elevated IL‐27Rα levels in serum from MS patients, shed from activated CD4 T lymphocytes, are sufficient to impair the capacity of IL‐27 to act on immune cells.

Introduction: Natalizumab has proved to be more effective than fingolimod in reducing disease activity in relapsing-remitting multiple sclerosis (RRMS). Whether this association is universal for all patient groups remains to be determined. Objective: The aim of this study was to compare the relative effectiveness of natalizumab and fingolimod in RRMS subgroups defined by the baseline demographic and clinical characteristics of interest. Methods: Patients with RRMS who were given natalizumab or fingolimod were identified in a merged cohort from three international registries. Efficacy outcomes were compared across subgroups based on patients’ sex, age, disease duration, Expanded Disability Status Scale (EDSS) score, and disease and magnetic resonance imaging (MRI) activity 12 months prior to treatment initiation. Study endpoints were number of relapses (analyzed withweighted negative binomial generalized linear model) and 6-month confirmed disability worsening and improvement events (weighted Cox proportional hazards model), recorded during study therapy. Each patient was weighted using inverse probability of treatment weighting based on propensity score. Results: A total of 5148 patients (natalizumab 1989; fingolimod 3159) were included, with a mean ± standard deviation age at baseline of 38 ± 10 years, and the majority (72%) were women. The median on-treatment follow-up was 25 (quartiles 15–41) months. Natalizumab was associated with fewer relapses than fingolimod (incidence rate ratio [IRR]; 95% confidence interval [CI]) in women (0.76; 0.65–0.88); in those aged ≤38 years (0.64; 0.54–0.76); in those withdisease duration ≤7 years (0.63; 0.53–0.76); in those with EDSS score 38 years (1.34; 1.04–1.73); those with disease duration >7 years (1.33; 1.01–1.74); those with EDSS score

Background:Cerebellar and brainstem symptoms are common in early stages of multiple sclerosis (MS) yet their prognostic values remain unclear.Objective:The aim of this study was to investigate long-term disability outcomes in patients with early cerebellar and brainstem symptoms.Methods:This study used data from MSBase registry. Patients with early cerebellar/brainstem presentations were identified as those with cerebellar/brainstem relapse(s) or functional system score ⩾ 2 in the initial 2 years. Early pyramidal presentation was chosen as a comparator. Andersen-Gill models were used to compare cumulative hazards of (1) disability progression events and (2) relapses between patients with and without early cerebellar/brainstem symptoms. Mixed effect models were used to estimate the associations between early cerebellar/brainstem presentations and expanded disability status scale (EDSS) scores.Results:The study cohort consisted of 10,513 eligible patients, including 2723 and 3915 patients with early cerebellar and brainstem symptoms, respectively. Early cerebellar presentation was associated with greater hazard of progression events (HR = 1.37, p Conclusion:Early cerebellar presentation is associated with unfavourable outcomes, while early brainstem presentation is associated with favourable prognosis. These presentations may be used as MS prognostic markers and guide therapeutic approach.

Background: High-efficacy therapies in multiple sclerosis are traditionally used after unsuccessful treatment with first-line disease modifying therapies. We hypothesised that early commencement of high-efficacy therapy would be associated with reduced long-term disability. We therefore aimed to compare long-term disability outcomes between patients who started high-efficacy therapies within 2 years of disease onset with those who started 4–6 years after disease onset. Methods: In this retrospective international observational study, we obtained data from the MSBase registry and the Swedish MS registry, which prospectively collect patient data that are specific to multiple sclerosis as part of routine clinical care. We identified adult patients (aged ≥18 years) with relapsing-remitting multiple sclerosis, with at least 6 years of follow-up since disease onset, and who started the high-efficacy therapy (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) either 0–2 years (early) or 4–6 years (late) after clinical disease onset. We matched patients in the early and late groups using propensity scores calculated on the basis of their baseline clinical and demographic data. The primary outcome was disability, measured with the Expanded Disability Status Score (EDSS; an ordinal scale of 0–10, with higher scores indicating increased disability), at 6–10 years after disease onset, assessed with a linear mixed-effects model. Findings: We identified 6149 patients in the MSBase registry who had been given high-efficacy therapy, with data collected between Jan 1, 1975, and April 13, 2017, and 2626 patients in the Swedish MS Registry, with data collected between Dec 10, 1997, and Sept 16, 2019. Of whom, 308 in the MSBase registry and 236 in the Swedish MS registry were eligible for inclusion. 277 (51%) of 544 patients commenced therapy early and 267 (49%) commenced therapy late. For the primary analysis, we matched 213 patients in the early treatment group with 253 in the late treatment group. At baseline, the mean EDSS score was 2·2 (SD 1·2) in the early group and 2·1 (SD 1·2) in the late group. Median follow-up time for matched patients was 7·8 years (IQR 6·7–8·9). In the sixth year after disease onset, the mean EDSS score was 2·2 (SD 1·6) in the early group compared with 2·9 (SD 1·8) in the late group (p

none 24 si Importance: It is unclear whether relapses and disease-modifying therapies are associated with the rate of disability accumulation in patients with secondary progressive multiple sclerosis (SPMS). Objective: To examine the association of relapses with the rate of disability accumulation in patients with SPMS and to assess whether treatment before or during the secondary progressive phase can slow the progression of disability accumulation. Design, Setting, and Participants: In this observational cohort study, patient data were prospectively collected from the MSBase international registry between January 1, 1995, and February 1, 2018. Among 53680 patients in the MSBase registry, 4997 patients with SPMS (using the Lorscheider definition) were identified. Of those, 1621 patients were eligible for study inclusion based on sufficient follow-up before and after the onset of SPMS. Data were analyzed from November 15, 2017, to January 13, 2020. Exposures: The association between disability accumulation and several clinical and demographic variables, including relapses and exposure to immunotherapy, was evaluated. Main Outcomes and Measures: Two outcomes were analyzed as measures of disability accumulation during SPMS: The rate of disability accumulation during the secondary progressive phase (change relative to the reference population of patients with MS and absolute change) and the risk of becoming wheelchair dependent. A third outcome, the cumulative risk of experiencing confirmed disability progression events, was used for a secondary analysis. Outcomes were evaluated using multivariable mixed models (ie, linear and Cox models). Results: Of 1621 patients eligible for inclusion, 1103 patients (68.0%) were female, with a mean (SD) age at MS onset of 33.9 (10.6) years. A total of 661 patients (40.8%) experienced superimposed relapses during SPMS. Therapy receipt and relapses during early relapsing-remitting MS were not associated with disability accumulation during the secondary progressive phase. Higher relapse rates during the secondary progressive disease stage were associated with an increased risk of becoming wheelchair dependent (hazard ratio [HR], 1.87; 95% CI, 1.17-3.00; P =.009). Among patients who experienced superimposed relapses during SPMS, greater receipt of disease-modifying therapies was significantly associated with a reduced rate of disability progression and a lower risk of becoming wheelchair dependent. Conclusions and Relevance: In this study, the rate of disability progression after the onset of SPMS was not associated with the early disease course and treatment decisions. Relapses during SPMS were associated with accelerated disability progression and represent an accessible treatment target. Disease-modifying therapy was associated with improvements in disability outcomes among patients with active relapses during SPMS. The study's results suggest that inflammatory disease activity remains a substantial yet modifiable component of SPMS. open Lizak N.; Malpas C.B.; Sharmin S.; Havrdova E.K.; Horakova D.; Izquierdo G.; Eichau S.; Lugaresi A.; Duquette P.; Girard M.; Prat A.; Larochelle C.; Trojano M.; Grand'maison F.; Grammond P.; Sola P.; Ferraro D.; Hupperts R.; Bergamaschi R.; Boz C.; Van Pesch V.; Spitaleri D.; Terzi M.; Kalincik T. Lizak N.; Malpas C.B.; Sharmin S.; Havrdova E.K.; Horakova D.; Izquierdo G.; Eichau S.; Lugaresi A.; Duquette P.; Girard M.; Prat A.; Larochelle C.; Trojano M.; Grand'maison F.; Grammond P.; Sola P.; Ferraro D.; Hupperts R.; Bergamaschi R.; Boz C.; Van Pesch V.; Spitaleri D.; Terzi M.; Kalincik T.

Background: There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort. Methods: SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18-65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5-6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29). Findings: From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15-27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 [95% CI 0·81-2·26]). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (

Patients with the 'aggressive' form of multiple sclerosis accrue disability at an accelerated rate, typically reaching Expanded Disability Status Score (EDSS) ≥ 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive multiple sclerosis, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive multiple sclerosis is essential to optimize treatment in this multiple sclerosis subtype. We evaluated whether patients who will develop aggressive multiple sclerosis can be identified based on early clinical markers. We then replicated this analysis in an independent cohort. Patient data were obtained from the MSBase observational study. Inclusion criteria were (i) first recorded disability score (EDSS) within 12 months of symptom onset; (ii) at least two recorded EDSS scores; and (iii) at least 10 years of observation time, based on time of last recorded EDSS score. Patients were classified as having 'aggressive multiple sclerosis' if all of the following criteria were met: (i) EDSS ≥ 6 reached within 10 years of symptom onset; (ii) EDSS ≥ 6 confirmed and sustained over ≥6 months; and (iii) EDSS ≥ 6 sustained until the end of follow-up. Clinical predictors included patient variables (sex, age at onset, baseline EDSS, disease duration at first visit) and recorded relapses in the first 12 months since disease onset (count, pyramidal signs, bowel-bladder symptoms, cerebellar signs, incomplete relapse recovery, steroid administration, hospitalization). Predictors were evaluated using Bayesian model averaging. Independent validation was performed using data from the Swedish Multiple Sclerosis Registry. Of the 2403 patients identified, 145 were classified as having aggressive multiple sclerosis (6%). Bayesian model averaging identified three statistical predictors: age > 35 at symptom onset, EDSS ≥ 3 in the first year, and the presence of pyramidal signs in the first year. This model significantly predicted aggressive multiple sclerosis [area under the curve (AUC) = 0.80, 95% confidence intervals (CIs): 0.75, 0.84, positive predictive value = 0.15, negative predictive value = 0.98]. The presence of all three signs was strongly predictive, with 32% of such patients meeting aggressive disease criteria. The absence of all three signs was associated with a 1.4% risk. Of the 556 eligible patients in the Swedish Multiple Sclerosis Registry cohort, 34 (6%) met criteria for aggressive multiple sclerosis. The combination of all three signs was also predictive in this cohort (AUC = 0.75, 95% CIs: 0.66, 0.84, positive predictive value = 0.15, negative predictive value = 0.97). Taken together, these findings suggest that older age at symptom onset, greater disability during the first year, and pyramidal signs in the first year are early indicators of aggressive multiple sclerosis., National Health and Medical Research Council of Australia; Roche; Merck; Biogen; Novartis; Bayer Schering; Sanofi Genzyme; Teva

Turkoglu, Recai/0000-0001-9724-851X; Ferraro, Diana/0000-0003-4818-3806; McCombe, Pamela/0000-0003-2704-8517; Altintas, Ayse/0000-0002-8524-5087; Jokubaitis, Vilija G./0000-0002-3942-4340; Slee, Mark/0000-0003-4323-2453; Lugaresi, Alessandra/0000-0003-2902-5589; van Pesch, Vincent/0000-0003-2885-9004; Vucic, Steve/0000-0002-8323-873X WOS: 000481049900001 PubMed: 31397221 Background: The risk factors for conversion from relapsing-remitting to secondary progressive multiple sclerosis remain highly contested. Objective: The aim of this study was to determine the demographic, clinical and paraclinical features that influence the risk of conversion to secondary progressive multiple sclerosis. Methods: Patients with adult-onset relapsing-remitting multiple sclerosis and at least four recorded disability scores were selected from MSBase, a global observational cohort. The risk of conversion to objectively defined secondary progressive multiple sclerosis was evaluated at multiple time points per patient using multivariable marginal Cox regression models. Sensitivity analyses were performed. Results: A total of 15,717 patients were included in the primary analysis. Older age (hazard ratio (HR) = 1.02, p < 0.001), longer disease duration (HR = 1.01, p = 0.038), a higher Expanded Disability Status Scale score (HR = 1.30, p < 0.001), more rapid disability trajectory (HR = 2.82, p < 0.001) and greater number of relapses in the previous year (HR = 1.07, p = 0.010) were independently associated with an increased risk of secondary progressive multiple sclerosis. Improving disability (HR = 0.62, p = 0.039) and disease-modifying therapy exposure (HR = 0.71, p = 0.007) were associated with a lower risk. Recent cerebral magnetic resonance imaging activity, evidence of spinal cord lesions and oligoclonal bands in the cerebrospinal fluid were not associated with the risk of conversion. Conclusion: Risk of secondary progressive multiple sclerosis increases with age, duration of illness and worsening disability and decreases with improving disability. Therapy may delay the onset of secondary progression. National Health and Medical Research Council of AustraliaNational Health and Medical Research Council of Australia [1083539, 1129189, 1140766]; BiogenBiogen; RocheRoche Holding; Bayer ScheringBayer AG; Sanofi Genzyme; Teva; MerckMerck & Company; NovartisNovartis The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was financially supported by National Health and Medical Research Council of Australia (project grants 1083539 and 1129189 and fellowship 1140766). The MSBase Foundation is a not-for-profit organisation that receives support from Merck, Biogen, Roche, Novartis, Bayer Schering, Sanofi Genzyme and Teva. The study was conducted separately and apart from the guidance of the sponsors.

ObjectiveTo determine the safety and efficacy of balloon vs sham venoplasty of narrowing of the extracranial jugular and azygos veins in multiple sclerosis (MS).MethodsPatients with relapsing or progressive MS were screened using clinical and ultrasound criteria. After confirmation of >50% narrowing by venography, participants were randomized 1:1 to receive balloon or sham venoplasty of all stenoses and were followed for 48 weeks. Participants and research staff were blinded to intervention allocation. The primary safety outcome was the number of adverse events (AEs) during 48 weeks. The primary efficacy outcome was the change from baseline to week 48 in the patient-reported outcome MS Quality of Life–54 (MSQOL-54) questionnaire. Standardized clinical and MRI outcomes were also evaluated.ResultsOne hundred four participants were randomized (55 sham; 49 venoplasty) and 103 completed 48 weeks of follow-up. Twenty-three sham and 21 venoplasty participants reported at least 1 AE; one sham (2%) and 5 (10%) venoplasty participants had a serious AE. The mean improvement in MSQOL-54 physical score was +1.3 (sham) and +1.4 (venoplasty) (p = 0.95); MSQOL-54 mental score was +1.2 (sham) and −0.8 (venoplasty) (p = 0.55).ConclusionsOur data do not support the continued use of venoplasty of extracranial jugular and/or azygous venous narrowing to improve patient-reported outcomes, chronic MS symptoms, or the disease course of MS.ClinicalTrials.gov identifierNCT01864941.Classification of evidenceThis study provides Class I evidence that for patients with MS, balloon venoplasty of extracranial jugular and azygous veins is not beneficial in improving patient-reported, standardized clinical, or MRI outcomes.

none 39 si OBJECTIVE: To compare the effectiveness of glatiramer acetate (GA) vs intramuscular interferon beta-1a (IFN-β-1a), we applied a previously published statistical method aimed at identifying patients' profiles associated with efficacy of treatments. METHODS: Data from 2 independent multiple sclerosis datasets, a randomized study (the Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis [CombiRx] trial, evaluating GA vs IFN-β-1a) and an observational cohort extracted from MSBase, were used to build and validate a treatment response score, regressing annualized relapse rates (ARRs) on a set of baseline predictors. RESULTS: The overall ARR ratio of GA to IFN-β-1a in the CombiRx trial was 0.72. The response score (made up of a linear combination of age, sex, relapses in the previous year, disease duration, and Expanded Disability Status Scale score) detected differential response of GA vs IFN-β-1a: in the trial, patients with the largest benefit from GA vs IFN-β-1a (lower score quartile) had an ARR ratio of 0.40 (95% confidence interval [CI] 0.25-0.63), those in the 2 middle quartiles of 0.90 (95% CI 0.61-1.34), and those in the upper quartile of 1.14 (95% CI 0.59-2.18) (heterogeneity p = 0.012); this result was validated on MSBase, with the corresponding ARR ratios of 0.58 (95% CI 0.46-0.72), 0.92 (95% CI 0.77-1.09,) and 1.29 (95% CI 0.97-1.71); heterogeneity p < 0.0001). CONCLUSIONS: We demonstrate the possibility of a criterion, based on patients' characteristics, to choose whether to treat with GA or IFN-β-1a. This result, replicated on an independent real-life cohort, may have implications for clinical decisions in everyday clinical practice. open Bovis F.; Kalincik T.; Lublin F.; Cutter G.; Malpas C.; Horakova D.; Havrdova E.K.; Trojano M.; Prat A.; Girard M.; Duquette P.; Onofrj M.; Lugaresi A.; Izquierdo G.; Eichau S.; Patti F.; Terzi M.; Grammond P.; Bergamaschi R.; Sola P.; Ferraro D.; Ozakbas S.; Iuliano G.; Boz C.; Hupperts R.; Grand'Maison F.; Oreja-Guevara C.; van Pesch V.; Cartechini E.; Petersen T.; Altintas A.; Soysal A.; Ramo-Tello C.; McCombe P.; Turkoglu R.; Butzkueven H.; Wolinsky J.S.; Solaro C.; Sormani M.P. Bovis F.; Kalincik T.; Lublin F.; Cutter G.; Malpas C.; Horakova D.; Havrdova E.K.; Trojano M.; Prat A.; Girard M.; Duquette P.; Onofrj M.; Lugaresi A.; Izquierdo G.; Eichau S.; Patti F.; Terzi M.; Grammond P.; Bergamaschi R.; Sola P.; Ferraro D.; Ozakbas S.; Iuliano G.; Boz C.; Hupperts R.; Grand'Maison F.; Oreja-Guevara C.; van Pesch V.; Cartechini E.; Petersen T.; Altintas A.; Soysal A.; Ramo-Tello C.; McCombe P.; Turkoglu R.; Butzkueven H.; Wolinsky J.S.; Solaro C.; Sormani M.P.

ObjectiveWhether immunotherapy improves long-term disability in multiple sclerosis has not been satisfactorily demonstrated. This study examined the effect of immunotherapy on long-term disability outcomes in relapsing-remitting multiple sclerosis.MethodsWe studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year and exposed to a multiple sclerosis therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the hazard of 12-month confirmed increase and decrease in disability, EDSS step 6 and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously re-adjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability and MRI activity.Results14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval 0.43–0.82, p=0.0016), worsening of disability (0.56, 0.38-0.82, p=0.0026) and progress to EDSS step 6 (0.33, 0.19-0.59, p=0.00019). Among 1085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50–0.70, p=10-9) and worsening of disability (0.81, 0.67-0.99, p=0.043).ConclusionsContinued treatment with multiple sclerosis immunotherapies reduces disability accrual (by 19-44%), the risk of need of a walking aid by 67% and the frequency of relapses (by 40-41%) over 15 years. A proof of long-term effect of immunomodulation on disability outcomes is the key to establishing its disease modifying properties.

Patients with the ‘aggressive’ form of MS accrue disability at an accelerated rate, typically reaching EDSS >= 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive MS, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive MS is essential to optimise treatment in this MS subtype. We evaluated whether patients who will develop aggressive MS can be identified based on early clinical markers, and to replicate this analysis in an independent cohort. Patient data were obtained from MSBase. Inclusion criteria were (a) first recorded disability score (EDSS) within 12 months of symptom onset, (b) at least 2 recorded EDSS scores, and (c) at least 10 years of observation time. Patients were classified as having ‘aggressive MS’ if they: (a) reached EDSS >= 6 within 10 years of symptom onset, (b) EDSS >=6 was confirmed and sustained over >=6 months, and (c) EDSS >=6 was sustained until the end of follow-up. Clinical predictors included patient variables (sex, age at onset, baseline EDSS, disease duration at first visit) and recorded relapses in the first 12 months since disease onset (count, pyramidal signs, bowel-bladder symptoms, cerebellar signs, incomplete relapse recovery, steroid administration, hospitalisation). Predictors were evaluated using Bayesian Model Averaging (BMA). Independent validation was performed using data from the Swedish MS Registry. Of the 2,403 patients identified, 145 were classified as having aggressive MS (6%). BMA identified three statistical predictors: age > 35 at symptom onset, EDSS >= 3 in the first year, and the presence of pyramidal signs in the first year. This model significantly predicted aggressive MS (AUC = .80, 95% CIs = .75, .84). The presence of all three signs was strongly predictive, with 32% of such patients meeting aggressive disease criteria. The absence of all three signs was associated with a 1.4% risk. Of the 556 eligible patients in the Swedish MS Registry cohort, 34 (6%) met criteria for aggressive MS. The combination of all three signs was also predictive in this cohort (AUC = .75, 95% CIs = .66, .84). Taken together, these findings suggest that older age at symptom onset, greater disability during the first year, and pyramidal signs in the first year are early indicators of aggressive MS.

Turkoglu, Recai/0000-0001-9724-851X; McCombe, Pamela/0000-0003-2704-8517; Jokubaitis, Vilija G./0000-0002-3942-4340; Oreja-Guevara, Celia/0000-0002-9221-5716; Ramo-Tello, Cristina/0000-0001-8643-5053; Vucic, Steve/0000-0002-8323-873X; Nguyen, Ai-Lan/0000-0003-0378-6005; Kalincik, Tomas/0000-0003-3778-1376; van Pesch, Vincent/0000-0003-2885-9004; Skibina, Olga/0000-0002-6275-8138; Lugaresi, Alessandra/0000-0003-2902-5589; Slee, Mark/0000-0003-4323-2453 WOS: 000459833100045 PubMed: 30623864 Background: Exposure to disease-modifying therapy (DMT) during early pregnancy in women with relapsing-remitting MS (RAMS) may be increasing. Objective: To retrospectively determine incidence of pregnancy, DMT exposure and pregnancy outcomes in women with RAMS. Methods: We identified all women with RAMS aged 15-45 years in the MSBase Registry between 2005-2016. Annualised pregnancy incidence rates were calculated using Poisson regression models. DMT exposures and pregnancy outcomes were assessed. Results: Of 9,098 women meeting inclusion criteria, 1,178 (13%) women recorded 1,521 pregnancies. The annualised incidence rate of pregnancy was 0.042 (95% CI 0.040, 0.045). A total of 635 (42%) reported pregnancies were conceived on DMT, increasing from 27% in 2006 to 62% in 2016. The median duration of DMT exposure during pregnancy was 30 days (IQR: 9, 50). There were a higher number of induced abortions on FDA pregnancy class C/D drugs compared with pregnancy class B and no DMT (p = 0.010); but no differences in spontaneous abortions, term or preterm births. Conclusions: We report low pregnancy incidence rates, with increasing number of pregnancies conceived on DMT over the past 12-years. The median duration of DMT exposure in pregnancy was relatively short at one month. National Health and Medical Research Council of Australia centre for research excellence grant [1001216]; BiogenBiogen; MerckMerck & Company; NovartisNovartis; RocheRoche Holding; Sanofi-Genzyme This study was financially supported by a National Health and Medical Research Council of Australia centre for research excellence grant [1001216]. The MSBase Foundation is a not-for-profit organisation that receives support from Biogen, Merck, Novartis, Roche and Sanofi-Genzyme. The study was conducted separately and apart from the guidance of the sponsors.

Turkoglu, Recai/0000-0001-9724-851X; Ferraro, Diana/0000-0003-4818-3806; Jokubaitis, Vilija G./0000-0002-3942-4340; McCombe, Pamela/0000-0003-2704-8517; Lugaresi, Alessandra/0000-0003-2902-5589; Slee, Mark/0000-0003-4323-2453; Kalincik, Tomas/0000-0003-3778-1376; Vucic, Steve/0000-0002-8323-873X; Ramo-Tello, Cristina/0000-0001-8643-5053 WOS: 000471115600018 PubMed: 30636699 Objective Oral immunotherapies have become a standard treatment in relapsing-remitting multiple sclerosis. Direct comparison of their effect on relapse and disability is needed. Methods We identified all patients with relapsing-remitting multiple sclerosis treated with teriflunomide, dimethyl fumarate or fingolimod, with minimum 3-month treatment persistence and disability follow-up in the global MSBase cohort study. Patients were matched using propensity scores. Three pairwise analyses compared annualised relapse rates and hazards of disability accumulation, disability improvement and treatment discontinuation (analysed with negative binomial models and weighted conditional survival models, with pairwise censoring). Results The eligible cohorts consisted of 614 (teriflunomide), 782 (dimethyl fumarate) or 2332 (fingolimod) patients, followed over the median of 2.5 years. Annualised relapse rates were lower on fingolimod compared with teriflunomide (0.18 vs 0.24; p=0.05) and dimethyl fumarate (0.20 vs 0.26; p=0.01) and similar on dimethyl fumarate and teriflunomide (0.19 vs 0.22; p=0.55). No differences in disability accumulation (p >= 0.59) or improvement (p >= 0.14) were found between the therapies. In patients with >= 3-month treatment persistence, subsequent discontinuations were less likely on fingolimod than teriflunomide and dimethyl fumarate (p

Objective: This study evaluated the effect of relapse phenotype on disability accumulation in multiple sclerosis. Methods: Analysis of prospectively collected data was conducted in 19,504 patients with relapse-onset multiple sclerosis and minimum 1-year prospective follow-up from the MSBase cohort study. Multivariable linear regression models assessed associations between relapse incidence, phenotype and changes in disability (quantified with Expanded Disability Status Scale and its Functional System scores). Sensitivity analyses were conducted. Results: In 34,858 relapses recorded during 136,462 patient-years (median follow-up 5.9 years), higher relapse incidence was associated with greater disability accumulation (β = 0.16, p Conclusion: Relapses are associated with accumulation of neurological disability. Relapses in pyramidal, cerebellar and bowel/bladder systems have the greatest association with disability change. Therefore, prevention of these relapses is an important objective of disease-modifying therapy. The differential impact of relapse phenotypes on disability outcomes could influence management of treatment failure in multiple sclerosis.

Objective To identify predictors of 10-year Expanded Disability Status Scale (EDSS) change after treatment initiation in patients with relapse-onset multiple sclerosis. Methods Using data obtained from MSBase, we defined baseline as the date of first injectable therapy initiation. Patients need only have remained on injectable therapy for 1 day and were monitored on any approved disease-modifying therapy, or no therapy thereafter. Median EDSS score changes over a 10-year period were determined. Predictors of EDSS change were then assessed using median quantile regression analysis. Sensitivity analyses were further performed. Results We identified 2,466 patients followed up for at least 10 years reporting post-baseline disability scores. Patients were treated an average 83% of their follow-up time. EDSS scores increased by a median 1 point (interquartile range = 0–2) at 10 years post-baseline. Annualized relapse rate was highly predictive of increases in median EDSS over 10 years (coeff = 1.14, p = 1.9 × 10−22). On-therapy relapses carried greater burden than off-therapy relapses. Cumulative treatment exposure was independently associated with lower EDSS at 10 years (coeff = −0.86, p = 1.3 × 10−9). Furthermore, pregnancies were also independently associated with lower EDSS scores over the 10-year observation period (coeff = −0.36, p = 0.009). Interpretation We provide evidence of long-term treatment benefit in a large registry cohort, and provide evidence of long-term protective effects of pregnancy against disability accrual. We demonstrate that high annualized relapse rate, particularly on-treatment relapse, is an indicator of poor prognosis. Ann Neurol 2016;80:89–100

ObjectiveWe posit that interleukin-15 (IL-15) is a relevant contributor to MS pathobiology as this cytokine is elevated in the CNS and periphery of patients with MS. We aim to investigate (1) the impact of IL-15 on T lymphocytes from patients with MS and (2) the in vivo role of IL-15 using the experimental autoimmune encephalomyelitis (EAE) mouse model.MethodsWe compared the impact of IL-15 on T lymphocytes obtained from untreated patients with MS (relapsing-remitting, secondary progressive, and primary progressive) to cells from age/sex-matched healthy controls (HCs) using multiparametric flow cytometry and in vitro assays. We tested the effects of peripheral IL-15 administration after EAE disease onset in C57BL/6 mice.ResultsIL-15 triggered STAT5 signaling in an elevated proportion of T cells from patients with MS compared with HCs. This cytokine also enhanced the production of key proinflammatory cytokines (interferon γ, granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-17, and tumor necrosis factor) by T cells from both MS and controls, but these effects were more robust for the production of IL-17 and GM-CSF in T-cell subsets from patients with MS. At the peak of EAE disease, the proportion of CD4+ and CD8+ T cells expressing CD122+, the key signaling IL-15 receptor chain, was enriched in the CNS compared with the spleen. Finally, peripheral administration of IL-15 into EAE mice after disease onset significantly aggravated clinical scores and increased the number of inflammatory CNS-infiltrating T cells long term after stopping IL-15 administration.ConclusionsOur results underscore that IL-15 contributes to the amplification of T-cell inflammatory properties after disease onset in both MS and EAE.

Introduction Balo’s concentric sclerosis (BCS) is a rare CNS disorder characterized by alternating bands of demyelination on MRI. One of the main issues is its relationship with multiple sclerosis (MS). Objectives To describe 6 BCS patients. To review the risk of developing MS in BCS patients. Methods We retrospectively recorded clinical and radiological findings of 6 BCS patients and performed a review of the literature. Results Six patients (5 women) with a mean age of 25 years old were included. Main symptoms were hemiparesis/hemihypoesthesia. On MRI, two patients had a single BCS lesion and four had additional MS-like lesions. Alternating bands were usually more visible on DWI. A patient had reduced central perfusion and SWI hypointensity suggestive of a central vein. Oligoclonal bands were identified in 5/6 patients. After 7 years of follow-up, all patients achieved MS criteria with mild disability (mean EDSS 1.75; 0–4). Our literature review included 65 BCS patients from 30 studies: although CSF oligoclonal bands and the presence of additional MS lesions were associated with subsequent relapses, this was not significant. Discussion/conclusion Our series allows a detailed MRI description in BCS and gives a new insight into BCS evolution and its strong relationship with MS.

For over three decades the desire to better control the output of marine seismic sources and concerns over the environmental impact of impulsive sources have driven the development of alternative source designs. Previous advances in Marine Vibrator designs for both geophysical and military use coupled with the significantly increased efficiencies in land vibrator operations have led to a resurgence of interest in the use of marine vibrators. The Marine Vibrator Joint Industry Project (MV JIP), sponsored by ExxonMobil, Shell, and Total started in 2011 and has supported the development of three separate Marine Vibrator technologies. This presentation discusses the testing and characterization of one of these designs, the Applied Physical Sciences (APS) Integrated projector Node (MV-IPN).

Imaging in the Terahertz (THz) and millimeter-wave (mm-wave) bands offer advantages over doing do in other conventional bands, such as the visible, infrared (IR). The THz band ranges from 300 GHz to 3 THz or in wavelength, 1 mm to 100 μm. These longer wavelengths allows THz radiation to pass unobscured through some materials allowing for imaging hidden threats or defects within such materials. Going further, millimeter-waves cover the spectral band of 30 – 300 GHz, or 10 cm to 1 mm. In addition to passing through denser materials, they also have much less atmospheric absorption, thus are ideal for imaging in adverse weather conditions. In the THz/mm-wave, the greatest challenge to real-time active imaging was previously the lack of compact sensor arrays. INO has overcome this by optimizing its microbolometer focal plane array (originally developed for the infrared) for the longer wavelengths, covering both the THz and mm-wave bands. The remaining challenge for active imaging is how to obtain useful imagery using coherent sources. INO has been working on improving the quality of the illumination beam over the past few years, as well as designing high quality fast imaging optics. This paper will focus on the different techniques that have been tested across the THz and into the mm-wave bands in both transmission and reflection imaging modes. The impact on image quality will be demonstrated, and their implications to developing useful systems for different applications will be discussed.

Subwavelength imaging has recently seen increased interest in multiple fields. There are various applications and distinct contexts for performing subwavelength imaging. The technological ways to proceed as well as the benefits obtained are as various as the applications foreseen. To benefit from subwavelength imaging a way around standard imaging procedure is often required. INO is also involved in this activity mainly for the infrared and the THz wavebands. In the infrared band a detector with 17 um pixel pitch, larger than the pixel, was used in conjunction with a microscanning device to oversample the image at a pitch much smaller than the wavelength. In this case the pixel size is in the order of the wavelength but the sampling is at subwavelength level. In the THz band a 35 um pixel pitch is used at wavelength ranging from 70 um to 1,063 mm to perform imaging through various objects. In this case, the pixel itself is smaller than the wavelength. Subwavelength imaging is not without its challenges, though. For instance, while the use of ultra-fast optics provides better definition, their design becomes more challenging as the models used are at their very limits. Questions about information content of images can be raised as well. New research avenues are being investigated to help address the challenges of subwavelength imaging with the goal of achieving higher imaging system performance. This paper discusses aspects to be considered, review some results obtained and identify some of the key issues to be further addressed.

Jokubaitis, Vilija G./0000-0002-3942-4340; Lugaresi, Alessandra/0000-0003-2902-5589; McCombe, Pamela/0000-0003-2704-8517; Kermode, Allan/0000-0002-4476-4016; Slee, Mark/0000-0003-4323-2453; Kalincik, Tomas/0000-0003-3778-1376; Pedrini, Marzena/0000-0002-2614-8607; Butzkueven, Helmut/0000-0003-3940-8727; Trojano, Maria/0000-0002-6329-8946 WOS: 000447789100014 PubMed: 28857680 Objective: This propensity score-matched analysis from MSBase compared the effectiveness of cladribine with interferon , fingolimod or natalizumab. Methods: We identified all patients with relapse-onset multiple sclerosis, exposure to the study therapies and 1-year on-treatment follow-up from MSBase. Three pairwise propensity score-matched analyses compared treatment outcomes over 1year. The outcomes were hazards of first relapse, disability accumulation and disability improvement events. Sensitivity analyses were completed. Results: The cohorts consisted of 37 (cladribine), 1940 (interferon), 1892 (fingolimod) and 1410 patients (natalizumab). The probability of experiencing a relapse on cladribine was lower than on interferon (p=0.05), similar to fingolimod (p=0.31) and higher than on natalizumab (p=0.042). The probability of disability accumulation on cladribine was similar to interferon (p=0.37) and fingolimod (p=0.089) but greater than natalizumab (p=0.021). The probability of disability improvement was higher on cladribine than interferon (p=0.00017), fingolimod (p=0.0025) or natalizumab (p=0.00099). Sensitivity analyses largely confirmed the above results. Conclusion: Cladribine is an effective therapy for relapse-onset multiple sclerosis. Its effect on relapses is comparable to fingolimod and its effect on disability accrual is comparable to interferon and fingolimod. Cladribine may potentially associate with superior recovery from disability relative to interferon, fingolimod and natalizumab. National Health and Medical Research Council of AustraliaNational Health and Medical Research Council of Australia [1129189, 1083539, 1080518]; MerckMerck & Company; BiogenBiogen; NovartisNovartis; RocheRoche Holding; Bayer ScheringBayer AG; Sanofi Genzyme; Teva The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This study was financially supported by National Health and Medical Research Council of Australia (project grants 1129189 and 1083539 and practitioner fellowship 1080518). The MSBase Foundation is a not-for-profit organisation that receives support from Merck, Biogen, Novartis, Roche, Bayer Schering, Sanofi Genzyme and Teva.

Ferraro, Diana/0000-0003-4818-3806; Jokubaitis, Vilija G./0000-0002-3942-4340; Lugaresi, Alessandra/0000-0003-2902-5589; van Pesch, Vincent/0000-0003-2885-9004; Ramo-Tello, Cristina/0000-0001-8643-5053; Kalincik, Tomas/0000-0003-3778-1376; Slee, Mark/0000-0003-4323-2453 WOS: 000449955900014 PubMed: 30083762 IMPORTANCE The role of inflammatory disease activity as a determinant of disability in progressive-onset multiple sclerosis (MS) remains contested. OBJECTIVE To examine the association of superimposed relapses in progressive-onset MS on disease outcomes. DESIGN, SETTING, AND PARTiCIPANTS Observational cohort study from MSBase, a prospectively collected, international database. Data were collected between January 1995 and February 2017. Analyses began in February 2017. From 44 449 patients at time of extraction, 1419 eligible patients (31.9%) were identified for analysis. Inclusion criteria consisted of primary progressive MS (PPMS) or progressive-relapsing MS (PRMS), adult-onset disease, and minimum data set (including >= 3 visits with disability recorded, >= 3 months between second and last visit). Data were analyzed using multivariable regression models (Andersen-Gill) with mixed effects. Two sensitivity analyses to exclude both relapse-related disability progression and bout-onset progressive MS were performed. EXPOSURES Grouped according to presence or absence of relapse, defined as an acute episode of clinical worsening. Quantifiable disability change or correlation on imaging was not required to confirm relapse. MAIN OUTCOMES AND MEASURES Cumulative hazard of disability progression. RESULTS Patients with PRMS were younger than those with PPMS (mean [SD] age, 46 [15] vs 51 [10] years, Cohen d =0.40) and demonstrated a mean lower Expanded Disability Status Scale score (mean [SD] score, 4.0 [3] vs 4.5 [2.5], Cohen d=0.28) at inclusion. The ratio of men to women was similar in the PRMS and PPMS groups (252:301 vs 394:472). The overall mean (SD) age was 48 (11) years for men and 50 (10) years for women. Likelihood of confirmed disability progression was lower in patients with superimposed relapses (hazard ratio [HR], 0.83; 95% CI, 0.74-0.94; P = .003). Proportion of follow-up time spent on disease-modifying therapy significantly reduced the hazard of confirmed disability progression in the cohort with relapse (HR, 0.96; 95% CI, 0.94-0.99; P = .01) but not in those without relapse (HR, 1.02; 95% CI, 0.99-1.05; P = .26). When accounting for relapse-related progression, the association of disease-modifying therapy in the cohort with superimposed relapse was no longer observed (HR, 1.10; 95% CI, 0.96-1.24; P = .16). CONCLUSIONS AND RELEVANCE In progressive-onset MS, superimposed relapses are associated with a lower risk of confirmed disability progression. This is most likely attributed to the association of disease-modifying therapy with the prevention of relapse-related disability accrual in patients with superimposed relapse. These findings suggest that inflammatory relapses are an important and modifiable determinant of disability accrual in progressive-onset disease. BayerBayer AG; BiogenBiogen; Merck Co.Merck & Company; NovartisNovartis; Sanofi; Teva Pharmaceutical Industries; Fondazione Italiana Sclerosi MultiplaFondazione Italiana Sclerosi Multipla (FISM); Canadian Institutes of Health ResearchCanadian Institutes of Health Research (CIHR); EMD; GenzymeGenzyme Corporation; Teva Medical Cente; Beer Yaakov, Israel; Mater Dei Hospital, Balzan, Malta; University of Western Australia, Perth, Australia; Austin Health, Melbourne, Australia; Universitary Hospital Ghent, Ghent, Belgium; MS Clinic, Hopital Tenon, Paris, France; University of Debrecen, Debrecen, Hungary; Bombay Hospital Institute of Medical Sciences, Mumbai, India; PGIMER, Chandigarh, India; Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; Royal Hospital, Muscat, Oman; Central Military Emergency University Hospital, Bucharest, Romania; MSBase Administrations Dr Jokubaitis received conference travel support from Teva Pharmaceutical Industries, Novartis, and Biogen and speaker honoraria from Biogen and Novartis. Dr Lugaresi is an advisory board member at Bayer, Biogen, Genzyme, and Merck & Co; received travel grants and honoraria from Bayer, Biogen, Merck & Co, Novartis, Sanofi, Teva Pharmaceutical Industries, and Fondazione Italiana Sclerosi Multipla; and her institution received research grants from Bayer, Biogen, Merck & Co, Novartis, Sanofi, Teva Pharmaceutical Industries, and Fondazione Italiana Sclerosi Multipla. Dr Hupperts received honoraria as a consultant on scientific advisory boards from Merck & Co, Biogen, Sanofi Genzyme, and Teva Pharmaceutical Industries; research funding from Merck & Co and Biogen; and speaker honoraria from Sanofi Genzyme and Novartis. Dr Izquierdo received speaking honoraria from Biogen, Novartis, Sanofi, Merck & Co, and Teva Pharmaceutical Industries. Dr Girard received consulting fees from Teva Pharmaceutical Industries-Canada Innovation, Biogen, Novartis, and Sanofi Genzyme; lecture payments from Teva Pharmaceutical Industries-Canada Innovation, Novartis, and EMD; and has received a research grant from Canadian Institutes of Health Research. Dr Duquette served on editorial boards and has been supported to attend meetings by EMD, Biogen, Novartis, Genzyme, and Teva Medical Cente, Beer Yaakov, Israel: Shlomo Flechter, MD; Mater Dei Hospital, Balzan, Malta: Norbert Vella, MD; University ofWestern Australia, Perth, Australia: Allan Kermode, PhD, Marzena Fabis-Pedrini, MSc; Austin Health, Melbourne, Australia: Richard Macdonell, PhD; Universitary Hospital Ghent, Ghent, Belgium: Guy Laureys, MD; MS Clinic, Hopital Tenon, Paris, France: Etienne Roullet, MD; University of Debrecen, Debrecen, Hungary: Tunde Csepany, MD; Bombay Hospital Institute of Medical Sciences, Mumbai, India: Bhim Singhal, MD; PGIMER, Chandigarh, India: Dheeraj Khurana, MD; Hospital Kuala Lumpur, Kuala Lumpur, Malaysia: Joyce Pauline Joseph, MD; Royal Hospital, Muscat, Oman: Jabir Alkhaboori, MD; Central Military Emergency University Hospital, Bucharest, Romania: Carmen-Adella Sirbu, MD (data acquisition); and MSBase Administrations: Charlotte Sartori, Sabah Quddus, and Eloise Hinson (administrative and technical support).

Background: The current best practice suggests yearly magnetic resonance imaging (MRI) to monitor treatment response in multiple sclerosis (MS) patients. Objective: To evaluate the current practice of clinicians changing MS treatment based on subclinical new MRI lesions alone. Methods: Using MSBase, an international MS patient registry with MRI data, we analysed the probability of treatment change among patients with clinically silent new MRI lesions. Results: A total of 8311 MRI brain scans of 4232 patients were identified. Around 26.9% (336/1247) MRIs with one new T2 lesion were followed by disease-modifying therapy (DMT) change, increasing to 50.2% (129/257) with six new T2 lesions. DMT change was twice as likely with new T1 contrast enhancing compared to new T2 lesions odds ratio (OR): 2.43, 95% confidence interval (CI): 2.00–2.96 vs OR: 1.26 (95% CI: 1.22–1.29). DMT change with new MRI lesions occurred most frequently with ‘injectable’ DMTs. The probability of switching therapy was greater only after high-efficacy therapies became available in 2007 (after, OR: 1.43, 95% CI: 1.28–1.59 vs before, OR: 0.98, 95% CI: 0.520–1.88). Conclusion: MS clinicians rely increasingly on MRI alone in their treatment decisions, utilizing low thresholds (1 new T2 lesion) for optimizing MS therapy. This signals a shift towards no evidence of disease activity (NEDA)-3 since high-efficacy therapies became available.

Background and purpose Treatment options in primary progressive multiple sclerosis (PPMS) are scarce and, with the exception of ocrelizumab, anti-inflammatory agents have failed to show efficacy in ameliorating disability progression. The aim of this study was to investigate a potential effect of anti-inflammatory disease-modifying treatment on disability outcomes in PPMS. Methods Using MSBase, a large, international, observational database, we identified patients with PPMS who were either never treated or treated with a disease-modifying agent. Propensity score matching was used to select subpopulations with similar baseline characteristics. Expanded Disability Status Scale (EDSS) outcomes were compared with an intention-to-treat and an as-treated approach in paired, pairwise-censored analyses. Results Of the 1284 included patients, 533 were matched (treated, n = 195; untreated n = 338). Median on-study pairwise-censored follow-up was 3.4 years (quartiles 1.2-5.5). No difference in the hazard of experiencing 3-month confirmed EDSS progression events was observed between the groups [hazard ratio (HR), 1.0; 95% confidence interval (CI), 0.6-1.7, P = 0.87]. We did not find significant differences in the hazards of confirmed EDSS improvement (HR, 1.0; 95% CI, 0.6-1.6, P = 0.91) or reaching a confirmed EDSS step ≥7 (HR, 1.1; 95% CI, 0.7-1.6, P = 0.69). Conclusion Our pooled analysis of disease-modifying agents suggests that these therapies have no substantial effect on short- to medium-term disability outcomes in PPMS.

Background: A definitive diagnosis of multiple sclerosis (MS), as distinct from a clinically isolated syndrome, requires one of two conditions: a second clinical attack or particular magnetic resonance imaging (MRI) findings as defined by the McDonald criteria. MRI is also important after a diagnosis is made as a means of monitoring subclinical disease activity. While a standardized protocol for diagnostic and follow-up MRI has been developed by the Consortium of Multiple Sclerosis Centres, acceptance and implementation in Canada have been suboptimal. Methods: To improve diagnosis, monitoring, and management of a clinically isolated syndrome and MS, a Canadian expert panel created consensus recommendations about the appropriate application of the 2010 McDonald criteria in routine practice, strategies to improve adherence to the standardized Consortium of Multiple Sclerosis Centres MRI protocol, and methods for ensuring effective communication among health care practitioners, in particular referring physicians, neurologists, and radiologists. Results: This article presents eight consensus statements developed by the expert panel, along with the rationale underlying the recommendations and commentaries on how to prioritize resource use within the Canadian healthcare system. Conclusions: The expert panel calls on neurologists and radiologists in Canada to incorporate the McDonald criteria, the Consortium of Multiple Sclerosis Centres MRI protocol, and other guidance given in this consensus presentation into their practices. By improving communication and general awareness of best practices for MRI use in MS diagnosis and monitoring, we can improve patient care across Canada by providing timely diagnosis, informed management decisions, and better continuity of care.

Objective In patients suffering multiple sclerosis activity despite treatment with interferon β or glatiramer acetate, clinicians often switch therapy to either natalizumab or fingolimod. However, no studies have directly compared the outcomes of switching to either of these agents. Methods Using MSBase, a large international, observational, prospectively acquired cohort study, we identified patients with relapsing–remitting multiple sclerosis experiencing relapses or disability progression within the 6 months immediately preceding switch to either natalizumab or fingolimod. Quasi-randomization with propensity score–based matching was used to select subpopulations with comparable baseline characteristics. Relapse and disability outcomes were compared in paired, pairwise-censored analyses. Results Of the 792 included patients, 578 patients were matched (natalizumab, n = 407; fingolimod, n = 171). Mean on-study follow-up was 12 months. The annualized relapse rates decreased from 1.5 to 0.2 on natalizumab and from 1.3 to 0.4 on fingolimod, with 50% relative postswitch difference in relapse hazard (p = 0.002). A 2.8 times higher rate of sustained disability regression was observed after the switch to natalizumab in comparison to fingolimod (p

Signori, Alessio/0000-0001-6289-9144; Sajedi, Seyed Aidin/0000-0002-6704-9787; Jokubaitis, Vilija G./0000-0002-3942-4340; Shaygannejad, Vahid/0000-0002-6226-0161; Oreja-Guevara, Celia/0000-0002-9221-5716; amato, Maria Pia/0000-0003-3325-3760; Lugaresi, Alessandra/0000-0003-2902-5589; Majdinasab, Nastaran/0000-0001-5163-7210; Kalincik, Tomas/0000-0003-3778-1376; Butzkueven, Helmut/0000-0003-3940-8727; van Pesch, Vincent/0000-0003-2885-9004; pucci, eugenio/0000-0001-7606-7330; Petersen, Thor/0000-0001-5633-2600; Prat, Alexandre/0000-0001-6188-0580; Sanchez Menoyo, Jose Luis/0000-0003-2634-8294; Slee, Mark/0000-0003-4323-2453; SORMANI, MARIA PIA/0000-0001-6892-104X; Trojano, Maria/0000-0002-6329-8946 WOS: 000432098100013 PubMed: 28382837 Background: Several natural history studies on primary progressive multiple sclerosis (PPMS) patients detected a consistent heterogeneity in the rate of disability accumulation. Objectives: To identify subgroups of PPMS patients with similar longitudinal trajectories of Expanded Disability Status Scale (EDSS) over time. Methods: All PPMS patients collected within the MSBase registry, who had their first EDSS assessment within 5 years from onset, were included in the analysis. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM), using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups showing similar characteristics. Results: A total of 853 PPMS (51.7% females) from 24 countries with a mean age at onset of 42.4 years (standard deviation (SD): 10.8 years), a median baseline EDSS of 4 (interquartile range (IQR): 2.5-5.5), and 2.4 years of disease duration (SD: 1.5 years) were included. LCMM detected three different subgroups of patients with a mild (n = 143; 16.8%), moderate (n = 378; 44.3%), or severe (n = 332; 38.9%) disability trajectory. The probability of reaching EDSS 6 at 10 years was 0%, 46.4%, and 81.9% respectively. Conclusion: Applying an LCMM modeling approach to long-term EDSS data, it is possible to identify groups of PPMS patients with different prognosis. MSBase Foundation; Merck SeronoMerck SeronoMerck & Company; BiogenBiogen; Novartis Pharma; Bayer ScheringBayer AG; Sanofi-AventisSanofi-Aventis; BioCSL The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by the MSBase Foundation. The MSBase Foundation is a not-for-profit organization that receives support from Merck Serono, Biogen, Novartis Pharma, Bayer Schering, Sanofi-Aventis and BioCSL. The study was conducted separately and apart from the guidance of the sponsors.

Objective To evaluate variability and predictability of disability trajectories in moderately advanced and advanced multiple sclerosis (MS), and their modifiability with immunomodulatory therapy. Methods The epochs between Expanded Disability Status Scale (EDSS) steps 3-6, 4-6 and 6-6.5 were analysed. Patients with relapse-onset MS and having reached 6-month confirmed baseline EDSS step (3/4/6) were identified in MSBase, a global observational MS cohort study. We used multivariable survival models to examine the impact of disease-modifying therapy, clinical and demographic factors on progression to the outcome EDSS step (6/6.5). Sensitivity analyses with varying outcome definitions and inclusion criteria were conducted. Results For the EDSS 3-6, 4-6 and 6-6.5 epochs, 1560, 1504 and 1231 patients were identified, respectively. Disability trajectories showed large coefficients of variance prebaseline (0.92-1.11) and postbaseline (2.15-2.50), with no significant correlations. The probability of reaching the outcome step was not associated with prebaseline variables, but was increased by higher relapse rates during each epoch (HRs 1.58-3.07; p

none 47 si Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (480%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2-4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to secondary progressive disease and treatment discontinuation. We conclude that demographic, clinical and paraclinical information helps predict individual response to disease-modifying therapies at the time of their commencement. none Kalincik, Tomas; Manouchehrinia, Ali; Sobisek, Lukas; Jokubaitis, Vilija; Spelman, Tim; Horakova, Dana; Havrdova, Eva; Trojano, Maria; Izquierdo, Guillermo; Lugaresi, Alessandra; Girard, Marc; Prat, Alexandre; Duquette, Pierre; Grammond, Pierre; Sola, Patrizia; Hupperts, Raymond; Grand'Maison, Francois; Pucci, Eugenio; Boz, Cavit; Alroughani, Raed; Van Pesch, Vincent; Lechner-scott, Jeannette; Terzi, Murat; Bergamaschi, Roberto; Iuliano, Gerardo; Granella, Franco; Spitaleri, Daniele; Shaygannejad, Vahid; Oreja-guevara, Celia; Slee, Mark; Ampapa, Radek; Verheul, Freek; Mccombe, Pamela; Olascoaga, Javier; Amato, Maria Pia; Vucic, Steve; Hodgkinson, Suzanne; Ramo-tello, Cristina; Flechter, Shlomo; Cristiano, Edgardo; Rozsa, Csilla; Moore, Fraser; Sanchez-menoyo, Jose Luis; Saladino, Maria Laura; Barnett, Michael; Hillert, Jan; Butzkueven, Helmut Kalincik, Tomas; Manouchehrinia, Ali; Sobisek, Lukas; Jokubaitis, Vilija; Spelman, Tim; Horakova, Dana; Havrdova, Eva; Trojano, Maria; Izquierdo, Guillermo; Lugaresi, Alessandra; Girard, Marc; Prat, Alexandre; Duquette, Pierre; Grammond, Pierre; Sola, Patrizia; Hupperts, Raymond; Grand'Maison, Francois; Pucci, Eugenio; Boz, Cavit; Alroughani, Raed; Van Pesch, Vincent; Lechner-scott, Jeannette; Terzi, Murat; Bergamaschi, Roberto; Iuliano, Gerardo; Granella, Franco; Spitaleri, Daniele; Shaygannejad, Vahid; Oreja-guevara, Celia; Slee, Mark; Ampapa, Radek; Verheul, Freek; Mccombe, Pamela; Olascoaga, Javier; Amato, Maria Pia; Vucic, Steve; Hodgkinson, Suzanne; Ramo-tello, Cristina; Flechter, Shlomo; Cristiano, Edgardo; Rozsa, Csilla; Moore, Fraser; Sanchez-menoyo, Jose Luis; Saladino, Maria Laura; Barnett, Michael; Hillert, Jan; Butzkueven, Helmut

Kermode, Allan/0000-0002-4476-4016; Ferraro, Diana/0000-0003-4818-3806; Lugaresi, Alessandra/0000-0003-2902-5589; Jokubaitis, Vilija G./0000-0002-3942-4340; McCombe, Pamela/0000-0003-2704-8517; Ramo-Tello, Cristina M/0000-0001-8643-5053; Oreja-Guevara, Celia/0000-0002-9221-5716; Havrdova, Eva Kubala/0000-0002-9543-4359; Vucic, Steve/0000-0002-8323-873X; Kalincik, Tomas/0000-0003-3778-1376; Slee, Mark/0000-0003-4323-2453; Prat, Alexandre/0000-0001-6188-0580; Sanchez Menoyo, Jose Luis/0000-0003-2634-8294; van Pesch, Vincent/0000-0003-2885-9004; Trojano, Maria/0000-0002-6329-8946; Butzkueven, Helmut/0000-0003-3940-8727; Lorscheider, Johannes/0000-0003-1100-2506; pucci, eugenio/0000-0001-7606-7330; Petersen, Thor/0000-0001-5633-2600 WOS: 000409172500017 PubMed: 28794248 Objective: To investigate the effect of disease-modifying treatment on short-term disability outcomes in secondary progressive multiple sclerosis (SPMS). Methods: Using MSBase, an international cohort study, we previously validated a highly accurate definition of SPMS. Here, we identified patients in MSBase who were either untreated or treated with a disease-modifying drug when meeting this definition. Propensity score matching was used to select subpopulations with comparable baseline characteristics. Disability outcomes were compared in paired, pairwise-censored analyses adjusted for treatment persistence, visit density, and relapse rates. Results: Of the 2,381 included patients, 1,378 patients were matchable (treated n=689, untreated n=689). Median pairwise-censored follow-up was 2.1 years (quartiles 1.2-3.8 years). No difference in the risk of 6-month sustained disability progression was observed between the groups (hazard ratio [HR] 0.9, 95% confidence interval [CI] 0.7-1.1, p=0.27). We also did not find differences in any of the secondary endpoints: risk of reaching Expanded Disability Status Scale (EDSS) score $ 7 (HR 0.6, 95% CI 0.4-1.1, p=0.10), sustained disability reduction (HR 1.0, 95% CI 0.8-1.3, p=0.79), or change in disability burden (area under the EDSS-time curve, beta=20.05, p=0.09). Secondary and sensitivity analyses confirmed the results. Conclusions: Our pooled analysis of the currently available disease-modifying agents used after conversion to SPMS suggests that, on average, these therapies have no substantial effect on relapse-unrelated disability outcomes measured by the EDSS up to 4 years. Classification of evidence: This study provides Class IV evidence that for patients with SPMS, disease-modifying treatment has no beneficial effect on short-term disability progression. BiogenBiogen; National Health and Medical Research CouncilNational Health and Medical Research Council of Australia; University of MelbourneUniversity of Melbourne; MerckMerck & Company; NovartisNovartis; BayerBayer AG; GenzymeGenzyme Corporation; Teva; Sanofi-AventisSanofi-Aventis This study was financially supported by Biogen (Fellowship in MS Registries Research), the National Health and Medical Research Council (practitioner fellowship 1,080,518; project grants 1,083,539 and 1,129,189; and Centre for Research Excellence 1,001,216), and the University of Melbourne (Faculty of Medicine, Dentistry and Health Sciences research fellowship). The MSBase Foundation is a not-for-profit organization that receives support from Merck, Biogen, Novartis, Bayer, Genzyme, Teva, and Sanofi-Aventis. The study was conducted separately and apart from the guidance of the sponsors.

Lugaresi, Alessandra/0000-0003-2902-5589; McCombe, Pamela/0000-0003-2704-8517; Jokubaitis, Vilija G./0000-0002-3942-4340; Ziemssen, Tjalf/0000-0001-8799-8202; Slee, Mark/0000-0003-4323-2453; Havrdova, Eva Kubala/0000-0002-9543-4359; Horakova, Dana/0000-0003-1915-0036; van Pesch, Vincent/0000-0003-2885-9004; pucci, eugenio/0000-0001-7606-7330; Trojano, Maria/0000-0002-6329-8946; Sanchez Menoyo, Jose Luis/0000-0003-2634-8294; Brown, William/0000-0002-7737-5834; Rice, Claire/0000-0002-9851-4426; Scolding, Neil/0000-0001-9177-1043; Kalincik, Tomas/0000-0003-3778-1376; Butzkueven, Helmut/0000-0003-3940-8727; Vucic, Steve/0000-0002-8323-873X WOS: 000396336600016 PubMed: 28209331 Background Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years. Methods In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) score 6.5 or lower, and no more than 10 years since the first multiple sclerosis symptom. The primary endpoint was annualised relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events. We compared relapse rates with negative binomial models, and estimated cumulative hazards with conditional proportional hazards models. Findings Patients were treated between Aug 1, 1994, and June 30, 2016. The cohorts consisted of 189 patients given alemtuzumab, 2155 patients given interferon beta, 828 patients given fingolimod, and 1160 patients given natalizumab. Alemtuzumab was associated with a lower annualised relapse rate than interferon beta (0.19 [95% CI 0.14-0.23] vs 0.53 [0.46-0.61], p

Objectives: The aim was to analyse risk of relapse phenotype recurrence in multiple sclerosis and to characterise the effect of demographic and clinical features on this phenotype. Methods: Information about relapses was collected using MSBase, an international observational registry. Associations between relapse phenotypes and history of similar relapses or patient characteristics were tested with multivariable logistic regression models. Tendency of relapse phenotypes to recur sequentially was assessed with principal component analysis. Results: Among 14,969 eligible patients (89,949 patient-years), 49,279 phenotypically characterised relapses were recorded. Visual and brainstem relapses occurred more frequently in early disease and in younger patients. Sensory relapses were more frequent in early or non-progressive disease. Pyramidal, sphincter and cerebellar relapses were more common in older patients and in progressive disease. Women presented more often with sensory or visual symptoms. Men were more prone to pyramidal, brainstem and cerebellar relapses. Importantly, relapse phenotype was predicted by the phenotypes of previous relapses. (OR = 1.8–5, p = 10-14). Sensory, visual and brainstem relapses showed better recovery than other relapse phenotypes. Relapse severity increased and the ability to recover decreased with age or more advanced disease. Conclusion: Relapse phenotype was associated with demographic and clinical characteristics, with phenotypic recurrence significantly more common than expected by chance.

Objective: To determine early risk of relapse after switch from natalizumab to fingolimod; to compare the switch experience to that in patients switching from interferon-b/glatiramer acetate (IFN-b/GA) and those previously treatment naive; and to determine predictors of time to first relapse on fingolimod. Methods: Data were obtained from the MSBase Registry. Relapse rates (RRs) for each patient group were compared using adjusted negative binomial regression. Survival analyses coupled with adjusted Cox regression were used to model predictors of time to first relapse on fingolimod. Results: A total of 536 patients (natalizumab-fingolimod [n 5 89]; IFN-b/GA-fingolimod [n 5 350]; naive-fingolimod [n 5 97]) were followed up for a median 10 months. In the natalizumab-fingolimod group, there was a small increase in RR on fingolimod (annualized RR [ARR] 0.38) relative to natalizumab (ARR 0.26; p 5 0.002). RRs were generally low across all patient groups in the first 9 months on fingolimod (RR 0.001–0.13). However, 30% of patients with disease activity on natalizumab relapsed within the first 6 months on fingolimod. Independent predictors of time to first relapse on fingolimod were the number of relapses in the prior 6 months (hazard ratio [HR] 1.59 per relapse; p 5 0.002) and a gap in treatment of 2–4 months compared to no gap (HR 2.10; p 5 0.041). Conclusions: RRs after switch to fingolimod were lowin all patient groups. The strongest predictor of relapse on fingolimod was prior relapse activity. Based on our data, we recommend a maximum 2-month treatment gap for switches to fingolimod to decrease the hazard of relapse. Classification of evidence: This study provides Class IV evidence that RRs are not higher in patients with multiple sclerosis switching to fingolimod from natalizumab compared to those patients switching to fingolimod from other therapies. Neurology® 2014;82:1–8

Havrdova, Eva Kubala/0000-0002-9543-4359; Horakova, Dana/0000-0003-1915-0036; Lugaresi, Alessandra/0000-0003-2902-5589; amato, Maria Pia/0000-0003-3325-3760; pietrolongo, erika/0000-0002-6311-5994; Shaygannejad, Vahid/0000-0002-6226-0161; McCombe, Pamela/0000-0003-2704-8517; Jokubaitis, Vilija G./0000-0002-3942-4340; Oreja-Guevara, Celia/0000-0002-9221-5716; pucci, eugenio/0000-0001-7606-7330; Sanchez Menoyo, Jose Luis/0000-0003-2634-8294; Trojano, Maria/0000-0002-6329-8946; Shaygannejad, Vahid/0000-0002-9732-4153; Skibina, Olga/0000-0002-6275-8138; Vucic, Steve/0000-0002-8323-873X; Kalincik, Tomas/0000-0003-3778-1376; Sirbu, Carmen Adella/0000-0002-1982-1066; van Pesch, Vincent/0000-0003-2885-9004; Slee, Mark/0000-0003-4323-2453; Butzkueven, Helmut/0000-0003-3940-8727; Hodgkinson, Suzanne/0000-0002-9029-6663; Petersen, Thor/0000-0001-5633-2600 WOS: 000354353900008 PubMed: 25665031 IMPORTANCE After multiple sclerosis (MS) relapse while a patient is receiving an injectable disease-modifying drug, many physicians advocate therapy switch, but the relative effectiveness of different switch decisions is often uncertain. OBJECTIVE To compare the effect of the oral immunomodulator fingolimod with that of all injectable immunomodulators (interferons or glatiramer acetate) on relapse rate, disability, and treatment persistence in patients with active MS. DESIGN, SETTING, AND PARTICIPANTS Matched retrospective analysis of data collected prospectively from MSBase, an international, observational cohort study. The MSBase cohort represents a population of patients with MS monitored at large MS centers. The analyzed data were collected between July 1996 and April 2014. Participants included patients with relapsing-remitting MS who were switching therapy to fingolimod or injectable immunomodulators up to 12 months after on-treatment clinical disease activity (relapse or progression of disability), matched on demographic and clinical variables. Median follow-up duration was 13.1 months (range, 3-80). Indication and attrition bias were controlled with propensity score matching and pairwise censoring, respectively. Head-to-head analyses of relapse and disability outcomes used paired, weighted, negative binomial models or frailty proportional hazards models adjusted for magnetic resonance imaging variables. Sensitivity analyses were conducted. EXPOSURES Patients had received fingolimod, interferon beta, or glatiramer acetate for a minimum of 3 months following a switch of immunomodulatory therapy. MAIN OUTCOMES AND MEASURES Annualized relapse rate and proportion of relapse-free patients, as well as the proportion of patients without sustained disability progression. RESULTS Overall, 379 patients in the injectable group were matched to 148 patients in the fingolimod group. The fingolimod group had a lower mean annualized relapse rate (0.31 vs 0.42; 95% CI, 0.02-0.19; P = .009), lower hazard of first on-treatment relapse (hazard ratio [HR], 0.74; 95% CI, 0.56-0.98; P = .04), lower hazard of disability progression (HR, 0.53; 95% CI, 0.31-0.91; P = .02), higher rate of disability regression (HR, 2.0; 95% CI, 1.2-3.3; P = .005), and lower hazard of treatment discontinuation (HR, 0.55; P = .04) compared with the injectable group. CONCLUSIONS AND RELEVANCE Switching from injectable immunomodulators to fingolimod is associated with fewer relapses, more favorable disability outcomes, and greater treatment persistence compared with switching to another injectable preparation following on-treatment activity of MS. Novartis Pharma; Multiple Sclerosis Research Australia [11-054]; National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [628856, 1071124, 1032484]; Centre For Research Excellence grant [1001216]; MSBase Foundation; Biogen IdecBiogen; Sanofi; Merck SeronoMerck SeronoMerck & Company; Bayer ScheringBayer AG This investigator-initiated analysis was financially supported by Novartis Pharma, Multiple Sclerosis Research Australia (fellowship 11-054), National Health and Medical Research Council (fellowships 628856 and 1071124, grant 1032484, and Centre For Research Excellence grant 1001216), and MSBase Foundation (a not-for-profit organization that receives support from Bayer Schering, Biogen Idec, Merck Serono, Novartis Pharma, and Sanofi).

This paper reports the NETD values of various uncooled bolometers fabricated at INO. They are measured using an external readout circuit that emulates the readout scheme of a commercial ROIC. The measured NETD values range between 6 and 75 mK, depending on the pixel pitch and response time. Pixel pitches of 12, 17 and 35 μm are considered. The figure of merit of the characterized detectors is below 350 mK*ms.

none 49 si studio multicentrico Background: Age at onset (AAO) in multiple sclerosis (MS) is an important marker of disease severity and may have prognostic significance. Understanding what factors can influence AAO may shed light on the aetiology of this complex disease, and have applications in the diagnostic process. Methods: The study cohort of 22 162 eligible patients from 21 countries was extracted from the MSBase registry. Only patients with MS aged ≥16 years were included. To reduce heterogeneity, only centres of largely European descent were included for analysis. AAO was defined as the year of the first symptom suggestive of inflammatory central nervous system demyelination. Predictors of AAO were evaluated by linear regression. Results: Compared with those living in lower latitudes (19.0-39.9°), onset of symptoms was 1.9 years earlier for those at higher latitudes (50.0-56.0°) (p=3.83×10-23). A reciprocal relationship was seen for ambient ultraviolet radiation (UVR), with a significantly increasing AAO for patients with MS per each quartile increment of ambient UVR (p=1.56×10-17). We found that the AAO of female patients was ∼5 months earlier than male patients (p=0.002). AAO of progressive-onset patients with MS were ∼9 years later than relapsing-onset patients (p=1.40×10-265). Conclusions: An earlier AAO in higher latitude regions was found in this worldwide European-descent cohort and correlated inversely with variation in latitudinal UVR. These results suggest that environmental factors which act at the population level may significantly influence disease severity characteristics in genetically susceptible populations. open Tao, Chunrong; Simpson, Steve; Van Der Mei, Ingrid; Blizzard, Leigh; Havrdova, Eva; Horakova, Dana; Shaygannejad, Vahid; Lugaresi, Alessandra; Izquierdo, Guillermo; Trojano, Maria; Duquette, Pierre; Girard, Marc; Grand'Maison, Franois; Grammond, Pierre; Alroughani, Raed; Terzi, Murat; Oreja-Guevara, Celia; Sajedi, Seyed Aidin; Iuliano, Gerardo; Sola, Patrizia; Lechner-Scott, Jeannette; Van Pesch, Vincent; Pucci, Eugenio; Bergamaschi, Roberto; Barnett, Michael; Ramo, Cristina; Singhal, Bhim; Spitaleri, Daniele L. A.; Slee, Mark; Verheul, Freek; Fernández Bolaños, Ricardo; Amato, Maria Pia; Cristiano, Edgardo; Granella, Franco; Hodgkinson, Suzanne; Fiol, Marcela; Gray, Orla; Mccombe, Pamela; Saladino, Maria Laura; Sánchez Menoyo, José Luis; Shuey, Neil; Vucic, Steve; Shaw, Cameron; Deri, Norma; Arruda, Walter Oleschko; Butzkueven, Helmut; Spelman, Tim; Taylor, Bruce V; MSBase Study Group Tao, Chunrong; Simpson, Steve; Van Der Mei, Ingrid; Blizzard, Leigh; Havrdova, Eva; Horakova, Dana; Shaygannejad, Vahid; Lugaresi, Alessandra; Izquierdo, Guillermo; Trojano, Maria; Duquette, Pierre; Girard, Marc; Grand'Maison, Franois; Grammond, Pierre; Alroughani, Raed; Terzi, Murat; Oreja-Guevara, Celia; Sajedi, Seyed Aidin; Iuliano, Gerardo; Sola, Patrizia; Lechner-Scott, Jeannette; Van Pesch, Vincent; Pucci, Eugenio; Bergamaschi, Roberto; Barnett, Michael; Ramo, Cristina; Singhal, Bhim; Spitaleri, Daniele L. A.; Slee, Mark; Verheul, Freek; Fernández Bolaños, Ricardo; Amato, Maria Pia; Cristiano, Edgardo; Granella, Franco; Hodgkinson, Suzanne; Fiol, Marcela; Gray, Orla; Mccombe, Pamela; Saladino, Maria Laura; Sánchez Menoyo, José Luis; Shuey, Neil; Vucic, Steve; Shaw, Cameron; Deri, Norma; Arruda, Walter Oleschko; Butzkueven, Helmut; Spelman, Tim; Taylor, Bruce V; MSBase Study Group

Background: With the advent of MRI scanning, the value of lumbar puncture to assess oligoclonal band (OCB) statusfor the diagnosis of multiple sclerosis (MS) is increasingly uncertain. One major issue is that the reported frequency of cerebrospinal fluid (CSF)-restricted oligoclonal banding for the diagnosis of MS varies considerably in different studies. In addition, the relationship between OCB positivity and disease outcome remains uncertain, as reported studies are generally too small to assess comparative disability outcomes with sufficient power. Methods: In order to further investigate variation of OCB positivity in patients with MS, we utilized MSBase, a longitudinal, Web-based collaborative MS outcomes registry following clinical cohorts in several continents and latitudes. We also assessed whether OCB positivity affects long-term disability outcome. Results: A total of 13,242 patient records were obtained from 37 MS specialist centres in 19 different countries. OCB status was documented in 4481 (34%) patients and 80% of these were OCB positive. The presence of OCB was associated with degree of latitude ( p = 0.02). Furthermore, the outcome of patients negative for CSF-specific OCB was significantly better in comparison to the OCB positive patients, as assessed by Expanded Disability Status Scale change ( p < 0.001). Conclusions: The results of this study indicate that latitude could explain some of the inconsistencies in OCB status reported in different populations. The study confirms that OCB positivity in MS is associated with a worse long-term prognosis.

Objectives The objective of this study was to evaluate the quality of medication information available in medical charts before and after the implementation of a medication reconciliation form. Patients and methods This study is a retrospective chart review of patients under 18 years who were taking two medications or more at home and were admitted to a paediatric hospital for more than 24 hours and discharged from a general paediatrics, infectious disease, gastroenterology or pneumology ward over two 20-week periods (pre- and postimplementation). Each week, 10 medical records were randomly chosen and reviewed. The quality of the medication information was measured on admission (dose, route of administration and frequency) and on discharge (dose, route of administration, frequency and duration of treatment). The proportion of medications that fully met these criteria was compared between the groups using the chi-squared test. Results Information was analysed for a total of 3275 medications in the preimplementation group, vs. 3240 medications in the post-implementation group. Baseline characteristics were similar in both groups. On admission, the quality of medication information was comparable between the pre- and post-implementation groups (29.1 vs. 29.3%, respectively; P = 0.86). However, on discharge, an improvement in the quality of information was observed in the post-implementation group (51.7 vs. 65.2%; P < 0.001). Conclusion Our study demonstrated that the forms used in the reconciliation process, in particular the discharge prescription, could increase the quality of the information related to drug use in medical charts. We believe that medication reconciliation forms should be widely used by all the health care professional teams involved in the drug history or prescription process.

From swine to humans : the A (H1N1) 2009 influenza pandemic. On April 25th 2009, Mexico notified the WHO of an outbreak of an influenza-like disease. The pathogen responsible was rapidly identified as an influenza virus of swine origin, the A(H1N1) 2009 influenza virus. The virus quickly spread worldwide, leading the WHO to announce a phase 6 pandemic alert on June 11th 2009. The majority of cases were mild, but 2 to 10 % of cases required hospitalization for respiratory distress, especially in children under 5, pregnant women, and patients with cardiovascular and respiratory diseases, diabetes or immunosuppression. By April 11th 2010, 17,798 deaths were officially notified to the WHO, a very low number compared to the usual death toll of seasonal influenza. This low death rate is due to the presence of immune resistance in the population over 60, a most likely consequence of sequence homologies between the 1918 and 2009 H1N1 pandemic viruses. Several anti-A (H1N1) 2009 vaccines were prepared in 2009, with and without adjuvants, and all were proven safe and immunogenic in Phase I/ II studies carried out in volunteers. However, the vaccination campaign met little enthusiasm, for reasons which will be reported. Swine appear once more as an important potential reservoir for influenza virus strains pathogenic for man, an observation which pleads for enhanced virological surveillance in this species., Le 25 avril 2009, le Mexique notifiait l’OMS de l’apparition d’un foyer de maladie de type grippal. Le virus fut identifié peu de temps après comme un virus influenza d’origine porcine, le virus influenza A (H1N1) 2009. Celui-ci diffusa ensuite très rapidement dans le monde entier, conduisant l’OMS à déclarer dès le 11 juin 2009 le niveau 6 de pandémie. Bien que la majorité des cas cliniques aient été bénins, deux à 10% ont nécessité une hospitalisation pour détresse respiratoire, notamment chez les enfants de moins de 5 ans, les femmes enceintes et les personnes souffrant de troubles cardiovasculaires ou pulmonaires, de diabète, ou d’immunodépression. Le nombre de décès dus à la grippe A (H1N1) 2009 officiellement notifiées à l’OMS au 11 avril 2010 ne s’élevait qu’à 17 798, un chiffre étonnamment bas par rapport aux chiffres habituels de mortalité de la grippe saisonnière. Cette faible mortalité reflète l’existence d’une résistance immunitaire chez les personnes âgées de plus de 60 ans, apparemment due à des homologies de séquences entre le virus pandémique de 2009 et celui de 1918. De nombreux vaccins anti-A (H1N1) 2009 ont été préparés courant 2009, avec ou sans adjuvant et tous ont fait la preuve de leur innocuité et de leur immunogénicité dans des études de Phase I/ II chez des volontaires. La campagne de vaccination, lancée en octobre 2009, ne devait cependant connaître qu’un succès mitigé, pour des raisons qui seront exposées. Le porc apparaît une fois de plus comme un réservoir potentiel important de souches de virus grippal pathogènes pour l’homme, ce qui implique de renforcer la surveillance virologique chez cette espèce., Girard Marc. Du porc à l'homme: la pandémie de grippe A (H1N1) 2009. In: Bulletin de l'Académie Vétérinaire de France tome 163 n°2, 2010. pp. 109-117.

In October 2007, a joint ANRS-NIH workshop was held on "Mucosal immunity and HIV/AIDS vaccines" in Veyrier-du-Lac, France. Goal of the meeting was to discuss recent developments in the understanding of viral entry and dissemination at mucosal surfaces, rationale for designing vaccines to elicit mucosal immune responses by various routes of immunization, and the types of immune responses elicited. Lessons were drawn from existing vaccines against viral mucosal infections, from the recent failure of the Merck Ad5/HIV vaccine and from attempts at mucosal immunization against SIV. This report summarizes the main concepts and conclusions that came out of the meeting.

Objective To assess demographic, clinical, magnetic resonance imaging, and treatment exposure predictors of time to 3 or 12-month confirmed disability worsening in clinically isolated syndrome (CIS) and early multiple sclerosis (MS). Methods We utilized the MSBase Incident Study (MSBasis), a prospective cohort study of outcome after CIS. Predictors of time to first 3 and 12-month confirmed expanded disability status scale worsening were analyzed using Cox proportional hazards regression. Results About 1989 patients were analyzed, the largest seen-from-onset cohort reported to-date. A total of 391 patients had a first 3-month confirmed disability worsening event, of which 307 were sustained for 12 months. Older age at CIS onset (adjusted hazard ratio: aHR 1.17, 95% 1.06, 1.30), pyramidal (aHR 1.45, 95% CI 1.13, 1.89) and ambulation (HR 1.60, 95% CI 1.09, 2.34) system dysfunction, annualized relapse rate (aHR 1.20, 95% CI 1.18, 1.22), and lower proportion of observation time on treatment were associated with 3-month confirmed worsening. Predictors of time to 12-month sustained worsening included pyramidal system dysfunction (Hazard ratio: aHR 1.38, 95% CI 1.05, 1.83), and older age at CIS onset (aHR 1.17, 95% CI 1.04, 1.31). Greater proportion of follow-up time exposed to treatment was associated with greater reductions in the rate of worsening. Interpretation This study provides class IV evidence for a strong protective effect of disease-modifying treatment to reduce disability worsening events in patients with CIS and early MS, and confirms age and pyramidal dysfunction at onset as risk factors.