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Background: In the absence of evidence from randomised controlled trials, observational data can be used to emulate clinical trials and guide clinical decisions. Observational studies are, however, susceptible to confounding and bias. Among the used techniques to reduce indication bias are propensity score matching and marginal structural models. Objective: To use the comparative effectiveness of fingolimod vs natalizumab to compare the results obtained with propensity score matching and marginal structural models. Methods: Patients with clinically isolated syndrome or relapsing remitting MS who were treated with either fingolimod or natalizumab were identified in the MSBase registry. Patients were propensity score matched, and inverse probability of treatment weighted at six monthly intervals, using the following variables: age, sex, disability, MS duration, MS course, prior relapses, and prior therapies. Studied outcomes were cumulative hazard of relapse, disability accumulation, and disability improvement. Results: 4608 patients (1659 natalizumab, 2949 fingolimod) fulfilled inclusion criteria, and were propensity score matched or repeatedly reweighed with marginal structural models. Natalizumab treatment was associated with a lower probability of relapse (PS matching: HR 0.67 [95% CI 0.62-0.80]; marginal structural model: 0.71 [0.62-0.80]), and higher probability of disability improvement (PS matching: 1.21 [1.02 -1.43]; marginal structural model 1.43 1.19 -1.72]). There was no evidence of a difference in the magnitude of effect between the two methods. Conclusions: The relative effectiveness of two therapies can be efficiently compared by either marginal structural models or propensity score matching when applied in clearly defined clinical contexts and in sufficiently powered cohorts.

Background and purpose: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS).Methods: We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow -up >= 1 year, and Expanded Disability Status Scale (EDSS) score >= 3, with >= 1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12 -month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics.Results: Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45- 0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41- 0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09- 1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity.Conclusions: DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age. This study was financially supported by the National Health and Medical Research Council of Australia (1129189, 1140766, 1080518) We thank the patients and their carers who have agreed to participate in the global MSBase cohort study. The MSBase Foundation is a not-for-profit organization that receives support from Roche, Merck, Biogen, Novartis, Bayer-Schering, Sanofi-Genzyme, and Teva. The study was conducted separately and apart from the guidance of the sponsors. Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australian University Librarians.

Summary Background Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells, have been proposed as a promising therapeutic option for people with multiple sclerosis on the basis of their immunomodulatory and neuroprotective properties. The MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) study was devised to evaluate the safety, tolerability, and activity of autologous MSCs derived from bone marrow and infused intravenously in patients with active multiple sclerosis. Methods MESEMS is a randomised phase 2 trial done at 15 sites in nine countries. Patients (aged 18–50 years) with active relapsing-remitting or progressive multiple sclerosis were included if they had a disease duration of 2–15 years since onset of multiple sclerosis and an Expanded Disability Status Scale score of 2·5–6·5. Patients were randomly assigned (1:1), according to a crossover design, to receive a single intravenous dose of autologous bone marrow-derived MSCs followed by placebo at week 24, or to receive placebo followed by autologous MSCs at week 24, with a follow-up visit at week 48. Primary objectives were to test safety and activity of MSC treatment. The primary safety endpoint was to assess the number and severity of adverse events within each treatment arm. The primary efficacy endpoint was the number of gadolinium-enhancing lesions (GELs) counted over week 4, 12, and 24 compared between treatment groups. The primary efficacy endpoint was assessed in the full analyis set, after all participants completed the week 24 visit. Efficacy endpoints were evaluated using a predefined statistical testing procedure. Safety was monitored throughout the study by recording vital signs and adverse events at each visit. Findings From July 16, 2012, until July 31, 2019, 144 patients were randomly assigned to first receive early intravenous infusion of autologous bone marrow-derived MSCs (n=69) or placebo (n=75). MSC treatment did not meet the primary endpoint of efficacy on the total number of GELs accumulated from baseline to week 24 (rate ratio [RR] 0·94, 95% CI 0·58–1·50; p=0·78). 213 adverse events were recorded, similarly distributed between groups (93 cases recorded in 35 [51%] of 69 patients treated first with MSCs vs 120 cases in 42 [56%] of 75 patients infused first with placebo). The most frequent adverse events reported were infection and infestations, with a total of 54 (25%) of 213 adverse events (18 [19%] of 93 in the early-MSC group and 36 [30%] of 120 in the delayed-MSC group). Nine serious adverse events were reported in seven patients treated with placebo versus none in the MSC group. All serious adverse events were considered to be unrelated to the treatment infusion. No deaths were reported during the study. Interpretation Bone marrow-derived MSC treatment was safe and well tolerated but did not show an effect on GELs, an MRI surrogate marker of acute inflammation, in patients with active forms of multiple sclerosis, at week 24. Thus, this study does not support the use of bone marrow-derived MSCs to treat active multiple sclerosis. Further studies should address the effect of MSCs on parameters related to tissue repair. Funding Fondazione Italiana Sclerosi Multipla (FISM), the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), and the Multiple Sclerosis International Federation (MSIF) for centralised activities. Individual trials participating in the MESEMS network are funded by the following agencies: FISM and Compagnia di San Paolo (Italy); The Danish Multiple Sclerosis Society, The Toyota Foundation, and Danish Blood Donors’ Research Foundation (Denmark); the Spanish Health Research Institute Carlos 3 and the Andalusian Public Foundation Progreso y Salud (Spain); the Royan Institute for Stem Cell Biology and Technology (Iran); the Spinal Cord Injury and Tissue Regeneration Centre Salzburg, Paracelsus Medical University, and Salzburg (Austria); the Fondation pour l’aide a la recherche sur la sclerose en plaques (ARSEP), French Muscular Dystrophy Association (AFM)-Telethon (France); the UK Multiple Sclerosis Society and the UK Stem Cell Foundation (UK); and the Multiple Sclerosis Society of Canada and The Multiple Sclerosis Scientific Research Foundation and Research Manitoba (Canada).

Since the early 1980s, Epstein-Barr virus (EBV) infection has been described as one of the main risk factors for developing multiple sclerosis (MS), and recently, new epidemiological evidence has reinforced this premise. EBV seroconversion precedes almost 99% of the new cases of MS and likely predates the first clinical symptoms. The molecular mechanisms of this association are complex and may involve different immunological routes, perhaps all running in parallel (i.e., molecular mimicry, the bystander damage theory, abnormal cytokine networks, and coinfection of EBV with retroviruses, among others). However, despite the large amount of evidence available on these topics, the ultimate role of EBV in the pathogenesis of MS is not fully understood. For instance, it is unclear why after EBV infection some individuals develop MS while others evolve to lymphoproliferative disorders or systemic autoimmune diseases. In this regard, recent studies suggest that the virus may exert epigenetic control over MS susceptibility genes by means of specific virulence factors. Such genetic manipulation has been described in virally-infected memory B cells from patients with MS and are thought to be the main source of autoreactive immune responses. Yet, the role of EBV infection in the natural history of MS and in the initiation of neurodegeneration is even less clear. In this narrative review, we will discuss the available evidence on these topics and the possibility of harnessing such immunological alterations to uncover predictive biomarkers for the onset of MS and perhaps facilitate prognostication of the clinical course.

Background: Disease-modifying therapies (DMTs) used to treat multiple sclerosis (MS) alter the immune system and therefore increase the risk of infection. There is growing concern about the impact of COVID-19 on patients with MS (pwMS), especially those treated with DMTs. Methods: This is a single-center prospective observational study based on data from the Esclerosis Múltiple y COVID-19 (EMCOVID-19) study. Demographic characteristics, MS history, laboratory data and SARS-CoV-2 serology, and symptoms of COVID-19 in pwMS treated with any DTM were extracted. The relationship among demographics, MS status, DMT, and COVID-19 was evaluated. Results: A total of 259 pwMS were included. The administration of interferon was significantly associated with the presence of SARS-CoV-2 antibodies (26.4% vs. 10.7%, p = 0.006). Although patients taking interferon were significantly older (49.1 vs. 43.5, p= 0.003), the association of interferon with the presence of SARS-CoV-2 antibodies was still significant in the multivariate analysis (OR 2.99 (1.38; 6.36), p= 0.006). Conclusions: According to our data, pwMS present a higher risk of COVID-19 infection compared with results obtained from the general population. There is no evidence of a worse COVID-19 outcome in pwMS. DMTs did not significantly change the frequency of COVID-19, except for interferon; however, these findings must be interpreted with caution given the small sample of pwMS taking each DMT.

Metilprednisolona; Esclerosi múltiple; Recaiguda Metilprednisolona; Esclerosis múltiple; Recaída Methylprednisolone; Multiple sclerosis; Relapse Minimizing the risk of relapse is essential in multiple sclerosis (MS). As none of the treatments currently available are capable of completely preventing relapses, treatment of these episodes remains a cornerstone of MS care. The objective of this manuscript is to reduce uncertainty and improve quality of care of this neurological process. This article addresses definitions of key concepts, recommendations for clinical examination, classification criteria, magnetic resonance imaging, biomarkers, and specific therapeutic counsels including special populations such as pregnant and breastfeeding women, and children. An algorithm for treating MS relapses is also provided. This research was funded by NOVARTIS FARMACÉUTICA, SA, for the two expert panel meetings held and the recording and transcription of the content of the first meeting performed by the contract research organization, Dynamic.

Natalizumab is a monoclonal antibody that binds CD49d. Although it is one of the most effective treatments for Relapsing-Remitting Multiple Sclerosis (RRMS), a dosing regimen has not been optimized for safety and efficacy in individual patients. We aimed to identify biomarkers to monitor Natalizumab treatment and to establish a personalized dose utilizing an ongoing longitudinal study in 29 RRMS patients under Natalizumab with standard interval dose (SD) of 300 mg/4wks or extended interval dose (EID) of 300 mg/6wks. Blood samples were analyzed by flow cytometry to determine CD49d saturation and expression in several T and B lymphocytes subpopulations. Each patient was analyzed at two different timepoints separated by 3 Natalizumab administrations. Natalizumab and sVCAM-1 levels in serum were also analyzed using ELISA. To determine the reproducibility of various markers, two different timepoints were compared and no significant differences were observed for CD49d expression nor for saturation; SD patients had higher saturation levels (~80%) than EID patients (~60%). A positive correlation exists between CD49d saturation and Natalizumab serum levels. CD49d expression and saturation are stable parameters that could be used as biomarkers in the immunomonitoring of Natalizumab treatment. Moreover, Natalizumab and sVCAM-1 serum levels could be used to optimize an individual’s dosing schedule.

Autologous antigen-specific therapies based on tolerogenic dendritic cells (tolDC) offer the possibility to treat autoimmune diseases by restoring homeostasis and targeting specifically autoreactive responses. Here, we explore the hypothesis that systemic inflammation occurring in autoimmune diseases, such as multiple sclerosis (MS), can generate a disease-specific environment able to alter the functionality of tolDC. In this context in fact, a combined therapy of tolDC with an immunomodulatory treatment could potentiate the beneficial effect of this antigen-specific cell therapy. For this purpose, we analyzed the efficacy of a combined therapy based on the use of vitamin D3 (VitD3)-tolDC plus interferon beta (IFN-beta) in MS. VitD3-tolDC were generated from healthy donors and MS patients and co-cultured with allogeneic peripheral blood mononuclear cells, in the presence or absence of IFN-beta. In vitro, VitD3-tolDC treatment reduced the percentage of activated T cells and allogeneic proliferation, whereas VitD3-tolDC+IFN-beta treatment enhanced the suppressive ability of VitD3-tolDC and, additionally, induced a shift towards a Th2 profile. To determine the clinical benefit of the combined therapy, C57BL/6-experimental autoimmune encephalomyelitis (EAE)-induced mice were treated with antigen-specific VitD3-tolDC and/or IFN-beta. Treatment of EAE mice with combined therapy ameliorated the disease course compared to each monotherapy. These results suggest that a combined therapy based on antigen-specific VitD3-tolDC and IFN-beta may represent a promising strategy for MS patients.

This Special Issue, entitled “Personalized Diagnosis and Therapy for Multiple Sclerosis” encompasses eight publications that we consider relevant, because their reading will help the clinician working regularly with people who suffer from multiple sclerosis (MS) [...]

The use of autologous tolerogenic dendritic cells (tolDC) has become a promising alternative for the treatment of autoimmune diseases. Among the different strategies available, the use of vitamin D3 for the generation of tolDC (vitD3-tolDC) constitutes one of the most robust approaches due to their immune regulatory properties, which are currently being tested in clinical trials. However, the mechanisms that vitD3-tolDC trigger for the induction of tolerance remain elusive. For this reason, we performed a full phenotypical, functional, and transcriptomic characterization of T cells upon their interaction with autologous, antigen-specific vitD3-tolDC. We observed a strong antigen-specific reduction of T cell proliferation, combined with a decrease in the relative prevalence of TH1 subpopulations and IFN-γ production. The analysis of the transcriptomic profile of T CD4+ cells evidenced a significant down-modulation of genes involved in cell cycle and cell response to mainly pro-inflammatory immune-related stimuli, highlighting the role of JUNB gene as a potential biomarker of these processes. Consequently, our results show the induction of a strong antigen-specific hyporesponsiveness combined with a reduction on the TH1 immune profile of T cells upon their interaction with vitD3-tolDC, which manifests the regulatory properties of these cells and, therefore, their therapeutic potential in the clinic.

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.

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

Background and purpose Oral or intravenous methylprednisolone (≥500 mg/day for 5 days) is recommended for multiple sclerosis (MS) relapses. Nonetheless, the optimal dose remains uncertain. We compared clinical and radiological effectiveness, safety and quality of life (QoL) of oral methylprednisolone [1250 mg/day (standard high dose)] versus 625 mg/day (lesser high dose), both for 3 days] in MS relapses. Methods A total of 49 patients with moderate to severe MS relapse within the previous 15 days were randomized in a pilot, double-blind, multicentre, non-inferiority trial (ClinicalTrial.gov, NCT01986998). The primary endpoint was non-inferiority of the lesser high dose by Expanded Disability Status Scale (EDSS) score improvement on day 30 (non-inferiority margin, 1 point). The secondary endpoints were EDSS score change on days 7 and 90, changes in T1 gadolinium-enhanced and new/enlarged T2 lesions on days 7 and 30, and safety and QoL results. Results The primary outcome was achieved [mean (95% confidence interval) EDSS score difference, -0.26 (-0.7 to 0.18) at 30 days (P = 0.246)]. The standard high dose yielded a superior EDSS score improvement on day 7 (P = 0.028). No differences were observed in EDSS score on day 90 (P = 0.352) or in the number of T1 gadolinium-enhanced or new/enlarged T2 lesions on day 7 (P = 0.401, 0.347) or day 30 (P = 0.349, 0.529). Safety and QoL were good at both doses. Conclusions A lesser high-dose oral methylprednisolone regimen may not be inferior to the standard high dose in terms of clinical and radiological response.

Summary Background No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator, on disability progression in patients with SPMS. Methods This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144. Findings 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups. Interpretation Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS. Funding Novartis Pharma AG.

BACKGROUND AND OBJECTIVES: Research in Multiple Sclerosis (MS) has recently focused on extracting knowledge from real-world clinical data sources. This type of data is more abundant than data produced during clinical trials and potentially more informative about real-world clinical practice. However, this comes at the cost of less curated and controlled data sets. In this work we aim to predict disability progression by optimally extracting information from longitudinal patient data in the real-world setting, with a special focus on the sporadic sampling problem. METHODS: We use machine learning methods suited for patient trajectories modeling, such as recurrent neural networks and tensor factorization. A subset of 6682 patients from the MSBase registry is used. RESULTS: We can predict disability progression of patients in a two-year horizon with an ROC-AUC of 0.85, which represents a 32% decrease in the ranking pair error (1-AUC) compared to reference methods using static clinical features. CONCLUSIONS: Compared to the models available in the literature, this work uses the most complete patient history for MS disease progression prediction and represents a step forward towards AI-assisted precision medicine in MS. ispartof: COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE vol:208 ispartof: location:Ireland status: published

Background In natalizumab-treated relapsing-remitting MS (RRMS) patients, various extended interval dosing strategies are under evaluation to minimize severe treatment-associated side effects, mainly progressive multifocal leukoencephalopathy development. Up to now, it has not been presented any approach, even in form of assay design, to determine the optimal percentage of CD49d receptor occupancy (RO) associated with a favorable clinical, radiological, and immunological response. Methods A multiparametric quantitative flow cytometry method was settled to measure CD49d RO on peripheral blood lymphocytes. The analytical protocol was tested in a 6-month follow-up from 19 RRMS patients treated with the natalizumab standard dosing of every 4 weeks or an extended-interval dosing of every 6 weeks. Results Extended natalizumab dose schedule promoted an increase of CD49d molecules per cell surface and a reduction of CD49d RO levels. The reduction observed on CD49d RO was not only depending on dose schedule but also on individual parameters such as body mass. Interestingly, individual clinical outcome was apparently the same between the different dose schedules or even better with the extended interval dosing. Conclusions Following up CD49d RO levels with a well-regulated monitoring work scheme is crucial to further identify over-/under-treated patients and to define a safe, personalized natalizumab regimen. © 2017 International Clinical Cytometry Society

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.

Aim Dimethyl fumarate (DMF) is one of the most promising therapies for relapsing‐remitting multiple sclerosis (RRMS) patients since it has shown immunomodulatory and neuroprotective effects. However, a percentage of RRMS patients do not exhibit an optimal response to DMF. The objective of this study was to identify early biomarkers of treatment response by analyzing changes in peripheral leukocyte subpopulations directly in whole blood samples. Methods A longitudinal and prospective study analyzing peripheral blood leukocyte subpopulations in 22 RRMS patients before initiating DMF treatment (baseline) and at 1, 3, 6, and 12 months of follow‐up was performed. Differences between no evidence of disease activity (NEDA) and ongoing disease activity (ODA) patients were analyzed. Results The beneficial effect of DMF was associated with a specific depletion of memory CD4+ and CD8+ T lymphocytes and B cells. Importantly, only NEDA patients showed (a) a shift from a pro‐ to an antiinflammatory profile, with an increase of Th2 cells and a decrease of Th1‐like Th17 lymphocytes; and (b) an increase of regulatory CD56bright NK cells. Conclusion The optimal response to DMF is mediated by a shift to antiinflammatory and immunoregulatory profile, which puts forward Th1‐like Th17 lymphocytes as a potential early biomarker of treatment response.

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

Resumen: Introducción: Un primer brote de mielitis puede ocurrir en el contexto de enfermedades desmielinizantes, inflamatorias sistémicas o infecciosas. Nuestro objetivo fue analizar las diferencias entre mielitis asociadas a esclerosis múltiple (EM) y mielitis por otras etiologías. Métodos: Análisis retrospectivo, unicéntrico, de pacientes con primer brote de mielitis (2000-2013). Se analizaron variables demográficas, etiológicas, clínicas, radiológicas y pronósticas, y se compararon entre mielitis por EM y mielitis por otras etiologías. Resultados: Se incluyó un total de 91 pacientes. Tiempo medio de seguimiento: 7 años. Diagnósticos: EM 57 (63%), mielitis transversa idiopática 22 (24%), asociada a enfermedades sistémicas 6 (7%), otros diagnósticos (6%). Mielitis por EM: menor edad de inicio (35 ± 11 vs .41 ± 13; p = 0,02), mayor afectación esfinteriana (40,4 vs. 27,3%; p = 0,05), mayor afectación multifocal en la RM medular (77,2 vs. 26,5%; p = 0,001), menor extensión de la lesión (segmentos vertebrales 2,4 vs. 1,4; p = 0,001), localización cervical (82,5 vs. 64,7%; p = 0,05) y localización posterior (89,5 vs. 41,2%; p = 0,001). Mielitis por otras etiologías: mayor localización anterior (47,1 vs. 24,6%; p = 0,02) y centromedular (47,1 vs. 14,1%; p = 0,001) y mejor recuperación al año (EDSS 2,0 vs. 1,5; p = 0,01). Análisis multivariante: la afectación multifocal medular (OR 9,38; IC 95%: 2,04-43,1) y del cordón posterior (OR 2,16; IC 95%: 2,04-2,67) se asociaron de forma independiente al diagnóstico de EM. Conclusiones: Un alto porcentaje de pacientes con un primer brote de mielitis serán diagnosticados de EM. La presencia de lesiones medulares multifocales y en el cordón posterior se asocian de forma significativa a este diagnóstico. Abstract: Background: Myelitis can appear as an initial symptom in the context of demyelinating diseases, systemic inflammatory diseases, and infectious diseases. We aim to analyse the differences between myelitis associated with multiple sclerosis (MS) and myelitis resulting from other aetiologies. Methods: Single-centre, retrospective analysis of patients with initial myelitis (2000-2013). Demographic, aetiological, clinical, radiological and prognostic variables were analysed and compared between patients with myelitis from MS and those with myelitis due to other aetiologies. Results: We included 91 patients; mean follow-up was 7 years. Diagnoses were as follows: MS 57 (63%), idiopathic transverse myelitis 22 (24%), associated systemic diseases 6 (7%), and other diagnoses (6%). Myelitis due to MS was associated with younger age of onset (35 ± 11 vs. 41 ± 13; P = .02), more pronounced sphincter involvement (40.4 vs. 27.3%; P=.05), greater multifocal involvement in spinal MRI (77.2 vs. 26.5%; P=.001), shorter lesion extension (2.4 vs. 1.4 vertebral segments; P=.001), cervical location (82.5 vs. 64.7%; P=.05) and posterior location (89.5 vs. 41.2%; P=.001). Myelitis due to other aetiologies more frequently showed anterior location (47.1 vs. 24.6%; P=.02), and central cord involvement (47.1 vs. 14.1%; P=.001), with better recovery at one year of follow up (EDSS 2.0 vs. 1.5; P=.01). Multivariate analysis showed that multifocal spinal cord involvement (OR 9.38, 95% CI: 2.04-43.1) and posterior cord involvement (OR 2.16, 95% CI: 2.04-2.67) were independently associated with the diagnosis of MS. Conclusions: A high percentage of patients with an initial myelitis event will be diagnosed with MS. The presence of multifocal and posterior spinal cord lesions was significantly associated with the diagnosis of MS. Palabras clave: Mielitis, Esclerosis múltiple, Mielitis idiopáticas, Enfermedades sistémicas, Keywords: Myelitis, Multiple sclerosis, Idiopathic myelitis, Systemic diseases

Background: Myelitis can appear as an initial symptom in the context of demyelinating diseases, systemic inflammatory diseases, and infectious diseases. We aim to analyse the differences between myelitis associated with multiple sclerosis (MS) and myelitis resulting from other aetiologies. Methods: Single-centre, retrospective analysis of patients with initial myelitis (2000-2013). Demographic, aetiological, clinical, radiological and prognostic variables were analysed and compared between patients with myelitis from MS and those with myelitis due to other aetiologies. Results: We included 91 patients; mean follow-up was 7 years. Diagnoses were as follows: MS 57 (63%), idiopathic transverse myelitis 22 (24%), associated systemic diseases 6 (7%), and other diagnoses (6%). Myelitis due to MS was associated with younger age of onset (35 ± 11 vs 41 ± 13; P = .02), more pronounced sphincter involvement (40.4% vs 27.3%; P = .05), greater multifocal involvement in spinal MRI (77.2% vs 26.5%; P = .001), shorter lesion extension (2.4 vs. 1.4 vertebral segments; P = .001), cervical location (82.5% vs 64.7%; P = .05) and posterior location (89.5% vs 41.2%; P = .001). Myelitis due to other aetiologies more frequently showed anterior location (47.1% vs 24.6%; P = .02), and central cord involvement (47.1% vs 14.1%; P = .001), with better recovery at one year of follow up (EDSS 2.0 vs 1.5; P = .01). Multivariate analysis showed that multifocal spinal cord involvement (OR 9.38, 95% CI: 2.04-43.1) and posterior cord involvement (OR 2.16, 95% CI: 2.04-2.67) were independently associated with the diagnosis of MS. Conclusions: A high percentage of patients with an initial myelitis event will be diagnosed with MS. The presence of multifocal and posterior spinal cord lesions was significantly associated with the diagnosis of MS. Resumen: Introducción: Un primer brote de mielitis puede ocurrir en el contexto de enfermedades desmielinizantes, inflamatorias sistémicas o infecciosas. Nuestro objetivo fue analizar las diferencias entre mielitis asociadas a esclerosis múltiple (EM) y mielitis por otras etiologías. Métodos: Análisis retrospectivo, unicéntrico, de pacientes con primer brote de mielitis (2000-2013). Se analizaron variables demográficas, etiológicas, clínicas, radiológicas y pronósticas, y se compararon entre mielitis por EM y mielitis por otras etiologías. Resultados: Se incluyó un total de 91 pacientes. Tiempo medio de seguimiento: 7 años. Diagnósticos: EM 57 (63%), mielitis transversa idiopática 22 (24%), asociada a enfermedades sistémicas 6 (7%), otros diagnósticos (6%). Mielitis por EM: menor edad de inicio (35 ± 11 vs .41 ± 13; p = 0,02), mayor afectación esfinteriana (40,4 vs 27,3%; p = 0,05), mayor afectación multifocal en la RM medular (77,2 vs 26,5%; p = 0,001), menor extensión de la lesión (segmentos vertebrales 2,4 vs 1,4; p = 0,001), localización cervical (82,5 vs 64,7%; p = 0,05) y localización posterior (89,5 vs 41,2%; p = 0,001). Mielitis por otras etiologías: mayor localización anterior (47,1 vs 24,6%; p = 0,02) y centromedular (47,1 vs 14,1%; p = 0,001) y mejor recuperación al año (EDSS 2,0 vs 1,5; p = 0,01). Análisis multivariante: la afectación multifocal medular (OR 9,38; IC 95%: 2,04-43,1) y del cordón posterior (OR 2,16; IC 95%: 2,04-2,67) se asociaron de forma independiente al diagnóstico de EM. Conclusiones: Un alto porcentaje de pacientes con un primer brote de mielitis serán diagnosticados de EM. La presencia de lesiones medulares multifocales y en el cordón posterior se asocian de forma significativa a este diagnóstico. Keywords: Myelitis, Multiple sclerosis, Idiopathic myelitis, Systemic diseases, Palabras clave: Mielitis, Esclerosis múltiple, Mielitis idiopáticas, Enfermedades sistémicas

Peripheral blood biomarkers able to predict disease activity in multiple sclerosis (MS) patients have not been identified yet. Here, we analyzed the immune phenotype of T lymphocyte subpopulations in peripheral blood samples from 66 RRMS patients under DMF (n = 22) or fingolimod (n = 44) treatment, by flow cytometry. A correlation study between the percentage and absolute cell number of each lymphocyte subpopulation with the presence of relapses or new MRI lesions during 12-month follow-up was performed. Patients who had undergone relapses showed at baseline higher percentage of Th1CM cells (relapsed: 11.60 ± 4.17%vs. nonrelapsed: 9.25 ± 3.17%, p < 0.05) and Th1Th17CM cells (relapsed: 15.65 ± 6.15%vs. nonrelapsed: 10.14 ± 4.05%, p < 0.01) before initiating DMF or fingolimod treatment. Kaplan-Meier analysis revealed that patients with Th1Th17CM (CD4+CCR7+CD45RA−CCR6+CXCR3+) cells > 11.48% had a 50% relapse-free survival compared to patients with Th1Th17CMcells < 11.48% whose relapse-free survival was 88% (p = 0.013, log-rank test). Additionally, a high percentage of Th1Th17CM cells was also found in patients with MRI activity (MRI activity: 14.02 ± 5.87%vs. no MRI activity: 9.82 ± 4.06%, p < 0.01). Our results suggest that the percentage of Th1Th17CM lymphocytes at baseline is a predictive biomarker of activity during the first 12 months of treatment, regardless of the treatment.

Tolerogenic dendritic cell (tolDC)-based therapies have become a promising approach for the treatment of autoimmune diseases by their potential ability to restore immune tolerance in an antigen-specific manner. However, the broad variety of protocols used to generate tolDC in vitro and their functional and phenotypical heterogeneity are evidencing the need to find robust biomarkers as a key point towards their translation into the clinic, as well as better understanding the mechanisms involved in the induction of immune tolerance. With that aim, in this study we have compared the transcriptomic profile of tolDC induced with either vitamin D3 (vitD3-tolDC), dexamethasone (dexa-tolDC) or rapamycin (rapa-tolDC) through a microarray analysis in 5 healthy donors. The results evidenced that common differentially expressed genes could not be found for the three different tolDC protocols. However, individually, CYP24A1, MUCL1 and MAP7 for vitD3-tolDC; CD163, CCL18, C1QB and C1QC for dexa-tolDC; and CNGA1 and CYP7B1 for rapa-tolDC, constituted good candidate biomarkers for each respective cellular product. In addition, a further gene set enrichment analysis of the data revealed that dexa-tolDC and vitD3-tolDC share several immune regulatory and anti-inflammatory pathways, while rapa-tolDC seem to be playing a totally different role towards tolerance induction through a strong immunosuppression of their cellular processes.

Aims Fingolimod, an orally active immunomodulatory drug for relapsing-remitting multiple sclerosis (RRMS), sequesters T cells in lymph nodes through functional antagonism of the sphingosine-1-phosphate receptor, reducing the number of potential autoreactive cells that migrate to the central nervous system. However, not all RRMS patients respond to this therapy. Our aim was to test the hypothesis that by immune-monitoring RRMS patient's leukocyte subpopulations it is possible to find biomarkers associated with clinical response to fingolimod. Methods Results Prospective study. Analysis of peripheral blood mononuclear cell subpopulations by multiparametric flow cytometry, at baseline and +1, +3, +6, +12 months of follow-up in 40 RRMS patients starting fingolimod therapy. Fingolimod treatment induced a severe lymphopenia affecting mainly T and B cells. A relative increase in T-reg (memory T-reg: 3.8 +/- 1.0% baseline vs 8.8 +/- 4.4% month +1; activated T-reg: 1.5 +/- 0.7% baseline vs 3.7 +/- 2.1% month +1, P < 0.001) as well as transitional B cells (10.5 +/- 12.3% baseline vs 18.7 +/- 14.6% month +1, P < 0.001) was observed. Interestingly, lymphocyte subpopulations were already at baseline significantly different in responder patients. The percentage of recent thymic emigrants (RTE) used to stratify fingolimod responder, and no responder patients was the best biomarker (4.0 +/- 1.4% vs 7.4 +/- 1.9%, respectively [P < 0.001]). Conclusion The results support that immune-monitoring of lymphocyte subpopulations in peripheral blood is a promising tool to select RRMS candidate for fingolimod treatment.

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: Population-based studies on neuromyelitis optica spectrum disorders (NMOSD) are limited, and it is unclear whether the rates have changed with the implementation of the new 2015 criteria. Objectives: To estimate the incidence and prevalence of NMOSD in Catalonia (Spain), using both the 2006 and the 2015 criteria. Methods: In this clinic-based retrospective study, patients diagnosed with NMOSD between 2006 and 2015 were identified using multiple sources, including direct contact to all Catalan hospitals, identification of cases through the Catalan Health Surveillance System, and registry of antibodies to aquaporin-4 (AQP4-IgG) and myelin oligodendrocyte glycoprotein (MOG-IgG) in a reference laboratory. The incidence rate was calculated for the period 1 January 2006–1 January 2016 and prevalence for the date 1 January 2016. Results: We identified 74 patients (by the 2015 criteria). Most patients were Caucasian (81%), and female (76%) with a median age at disease onset of 42 years (range, 10–76 years). In total, 54 (73%) patients were positive for AQP4-IgG, 11 (15%) double-seronegative, and 9 (12%) MOG-IgG-positive. Rates of incidence and prevalence (0.63/1,000,000 person-years and 0.89/100,000, respectively) were 1.5-fold higher than those reported by the 2006 criteria. Lowest rates were seen in children and elder people and highest in women and middle-aged people (40–59 years). The female predominance was lost in incident AQP4-IgG-seronegative children and AQP4-IgG-positive elder people. MOG-IgG and double-seronegativity contributed similarly but did not influence the long-term outcome. Conclusion: The new criteria increase the estimates, but NMOSD remains as a rare disease. The differences in age- and sex-specific estimates highlight the importance of the serologic classification.

A risk for developing progressive multifocal leukoencephalopathy is a major barrier to natalizumab use. Extended dosing intervals have been proposed as a way to maintain therapeutic efficacy and reduce progressive multifocal leukoencephalopathy incidence. This is the first reported case of progressive multifocal leukoencephalopathy in a patient using an extended dosing regimen (300 mg/6 weeks). A close clinical and imaging monitoring allowed early detection, which is a major prognostic factor. A favorable outcome was seen with a therapy comprising plasma exchange therapy, mirtazapine, mefloquine and cidofovir. Further studies will be needed to assess the potential role of extended dosing intervals to improve prognosis in patients receiving natalizumab and also to measure its impact clinically and/or radiologically.

Background: To date, there are no available factors to predict the outcome after multiple sclerosis relapse. Aim: To investigate factors that may be useful for predicting response to methylprednisolone treatment, following a relapse of multiple sclerosis (MS). Methods: The study included 48 MS patients enrolled in a double-blind multicenter trial to receive intravenous versus oral high-dose methylprednisolone treatment. Associations were sought between the disability status prior to relapse and the relapse severity, determined by changes in the Expanded Disability Status Scale (EDSS) score, as well as the improvements after treatment. We also analyzed the relationships between the number of magnetic resonance imaging (MRI) gadolinium-enhancing lesions (Gd+) and improvement. Results: A higher EDSS score before relapse was associated with more severe relapses ( p = 0.04) and less marked improvement (odds ratio (OR) 1.8; 95% CI (1.2–2.2); p = 0.05) after methylprednisolone treatment. Relapse severity ( p = 0.29) and the number of Gd+ lesions at relapse ( p = 0.41) were not related with improvement. Conclusions: Clinical baseline status prior to MS relapse is a predictor of response to methylprednisolone treatment.

Advances in the understanding of pathogenic mechanisms of diseases have led to the defining of new biomarkers for diagnosis, prognosis, and therapy response. In this context, flow cytometry has been positioned as one of the most useful technologies for monitoring immune-mediated diseases, such as multiple sclerosis (MS), allowing a detailed analysis of lymphocyte subpopulations in peripheral blood. The autoimmune inflammatory response in MS results in changes in lymphocyte subpopulations that might be useful as surrogate markers for the evaluation of disease activity, progression, and monitoring of therapy response. This chapter discusses the role of T-lymphocyte and B-lymphocyte subpopulations in MS pathogenesis, the effect of MS treatments on these subsets, and their potential usefulness as biomarkers of treatment response.