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This is a protocol for a Cochrane Review (intervention). The objectives are as follows: The objectives of the review are to estimate the benefits and harms of: azathioprine (AZA) compared with placebo or other disease ‐modifying treatments (DMTs) as first‐choice treatment for relapsing forms of multiple sclerosis (MS); AZA compared with placebo or other DMTs for relapsing forms of MS when switching from another DMT; AZA compared with placebo or other DMTs as first‐choice treatment for progressive forms of MS; and AZA compared with placebo or other DMTs for progressive forms of MS when switching from another DMT.

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

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.

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.

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.

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

OBJECTIVE: Previous studies assessing seasonal variation of relapse onset in multiple sclerosis have had conflicting results. Small relapse numbers, differing diagnostic criteria, and single region studies limit the generalizability of prior results. The aim of this study was to determine whether there is a temporal variation in onset of relapses in both hemispheres and to determine whether seasonal peak relapse probability varies with latitude. METHODS: The international MSBase Registry was utilized to analyze seasonal relapse onset distribution by hemisphere and latitudinal location. All analyses were weighted for the patient number contributed by each center. A sine regression model was used to model relapse onset and ultraviolet radiation (UVR) seasonality. Linear regression was used to investigate associations of latitude and lag between UVR trough and subsequent relapse peak. RESULTS: A total of 32,762 relapses from 9,811 patients across 30 countries were analyzed. Relapse onset followed an annual cyclical sinusoidal pattern with peaks in early spring and troughs in autumn in both hemispheres. Every 10° of latitude away from the equator was associated with a mean decrease in UVR trough to subsequent relapse peak lag of 28.5 days (95% confidence interval = 3.29-53.71, p = 0.028). INTERPRETATION: We demonstrate for the first time that there is a latitude-dependent relationship between seasonal UVR trough and relapse onset probability peak independent of location-specific UVR levels, with more distal latitude associated with shorter gaps. We confirm prior meta-analyses showing a strong seasonal relapse onset probability variation in the northern hemisphere, and extend this observation to the southern hemisphere.

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

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.

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).

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

Clinical Trial; Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; OBJECTIVES To compare treatment persistence between two dosages of interferon β-1a in a large observational multiple sclerosis registry and assess disease outcomes of first line MS treatment at these dosages using propensity scoring to adjust for baseline imbalance in disease characteristics. METHODS Treatment discontinuations were evaluated in all patients within the MSBase registry who commenced interferon β-1a SC thrice weekly (n = 4678). Furthermore, we assessed 2-year clinical outcomes in 1220 patients treated with interferon β-1a in either dosage (22 µg or 44 µg) as their first disease modifying agent, matched on propensity score calculated from pre-treatment demographic and clinical variables. A subgroup analysis was performed on 456 matched patients who also had baseline MRI variables recorded. RESULTS Overall, 4054 treatment discontinuations were recorded in 3059 patients. The patients receiving the lower interferon dosage were more likely to discontinue treatment than those with the higher dosage (25% vs. 20% annual probability of discontinuation, respectively). This was seen in discontinuations with reasons recorded as "lack of efficacy" (3.3% vs. 1.7%), "scheduled stop" (2.2% vs. 1.3%) or without the reason recorded (16.7% vs. 13.3% annual discontinuation rate, 22 µg vs. 44 µg dosage, respectively). Propensity score was determined by treating centre and disability (score without MRI parameters) or centre, sex and number of contrast-enhancing lesions (score including MRI parameters). No differences in clinical outcomes at two years (relapse rate, time relapse-free and disability) were observed between the matched patients treated with either of the interferon dosages. CONCLUSIONS Treatment discontinuations were more common in interferon β-1a 22 µg SC thrice weekly. However, 2-year clinical outcomes did not differ between patients receiving the different dosages, thus replicating in a registry dataset derived from "real-world" database the results of the pivotal randomised trial. Propensity score matching effectively minimised baseline covariate imbalance between two directly compared sub-populations from a large observational registry. This study was funded by MSBase Foundation, a not-for-profit organisation. The MSBase Foundation receives financial support from Merck Serono, Biogen Idec, Novartis Pharma, Bayer Schering and Sanofi Aventis. The study was also funded by Multiple Sclerosis Research Australia and MSAngels. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Yes

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.

Objective: We investigated the effect of glatiramer acetate (GA) on the modulation of immune cell subpopulations and serum levels of multiple immune/metabolic markers in patients with relapsing-remitting multiple sclerosis (RRMS) to understand whether the treatment with GA could induce a specific change in the immunometabolic asset of patients with RRMS. Material and methods: We performed an extensive peripheral blood immunophenotyping and measured serum levels of several parameters involved in the pathogenesis of RRMS and also relevant in the pathogenesis of metabolic syndrome and obesity such as leptin, soluble leptin-receptor (sLep-R), myeloperoxidase (MPO), soluble CD40 ligand (sCD40-L), soluble tumor necrosis factor-receptor (sTNF-R), monocyte chemoattractant protein 1 (MCP-1), soluble Inter-Cellular Adhesion Molecule-1 (sICAM-1) and osteoprotegerin (OPG), in 20 naïve-to-treatment RRMS patients and 20 healthy controls. We repeated these analyses over time at 6 and 12. months after starting GA treatment. Results: Our analysis showed that naïve-to-treatment RRMS patients had a lower number of CD16+CD56+ NK cells, CD19+ B cells, CD4+ T cells co-expressing the MHC class II activation marker HLA-DR (CD4+DR+) and naïve CD4+CD45RA+ T cells in basal conditions. GA treatment induced a specific and significant decrease of circulating CD19+ B cells. Naïve-to-treatment RRMS patients also showed a significantly higher number of CD4+ T cells with a memory phenotype (CD4+CD45RO+) whose peripheral frequency was not affected by GA treatment. These changes over time associated with a higher serum concentration of leptin and lower levels of MPO. GA treatment also reduced significantly the circulating levels of sCD40-L and sTNF-R overtime. Conclusions: Our data suggest that the clinical outcome of GA treatment is associated with changes in immune cell subpopulations and modulation of specific immunometabolic markers. These data add substantial evidence of the immune modulating effect of GA during RRMS and could be of relevance in understanding the pathogenesis of disease and its follow-up.

Background: The results of head-to-head comparisons of injectable immunomodulators (interferon β, glatiramer acetate) have been inconclusive and a comprehensive analysis of their effectiveness is needed. Objective: We aimed to compare, in a real-world setting, relapse and disability outcomes among patients with multiple sclerosis (MS) treated with injectable immunomodulators. Methods: Pairwise analysis of the international MSBase registry data was conducted using propensity-score matching. The four injectable immunomodulators were compared in six head-to-head analyses of relapse and disability outcomes using paired mixed models or frailty proportional hazards models adjusted for magnetic resonance imaging variables. Sensitivity and power analyses were conducted. Results: Of the 3326 included patients, 345–1199 patients per therapy were matched (median pairwise-censored follow-up was 3.7 years). Propensity matching eliminated >95% of the identified indication bias. Slightly lower relapse incidence was found among patients treated with glatiramer acetate or subcutaneous interferon β-1a relative to intramuscular interferon β-1a and interferon β-1b ( p≤0.001). No differences in 12-month confirmed progression of disability were observed. Conclusion: Small but statistically significant differences in relapse outcomes exist among the injectable immunomodulators. MSBase is sufficiently powered to identify these differences and reflects practice in tertiary MS centres. While the present study controlled indication, selection and attrition bias, centre-dependent variance in data quality was likely.

Background: Several studies have shown that pregnancy reduces multiple sclerosis (MS) relapses, which increase in the early postpartum period. Postpartum relapse risk has been predicted by pre-pregnancy disease activity in some studies. Objective: To re-examine effect of pregnancy on relapses using the large international MSBase Registry, examining predictors of early postpartum relapse. Methods: An observational case–control study was performed including pregnancies post-MS onset. Annualised relapse rate (ARR) and median Expanded Disability Status Scale (EDSS) scores were compared for the 24 months pre-conception, pregnancy and 24 months postpartum periods. Clustered logistic regression was used to investigate predictors of early postpartum relapses. Results: The study included 893 pregnancies in 674 females with MS. ARR (standard error) pre-pregnancy was 0.32 (0.02), which fell to 0.13 (0.03) in the third trimester and rose to 0.61 (0.06) in the first three months postpartum. Median EDSS remained unchanged. Pre-conception ARR and disease-modifying treatment (DMT) predicted early postpartum relapse in a multivariable model. Conclusion: Results confirm a favourable effect on relapses as pregnancy proceeds, and an early postpartum peak. Pre-conception DMT exposure and low ARR were independently protective against postpartum relapse. This novel finding could provide clinicians with a strategy to minimise postpartum relapse risk in women with MS planning pregnancy.

Limited data suggest that multiple sclerosis (MS) in Latin America (LA) could be less severe than in the rest of the world. The objective was to compare the course of MS between LA and other regions. Methods Centers from 18 countries with >20 cases enrolled in the MSBase Registry participated. Patients with MS with a disease duration of >1 year and Results A total of 9610 patients were included. Patients were from: Europe, 6290 (65.6%); North America, 1609 (16.7%); Australia, 1119 (11.6%); and LA, 592 (6.1%). The mean MSSS in patients from LA was 4.47 ± 2.8, 4.53 ± 2.8 in North America, 4.51 ± 2.8 in Europe and 4.49 ± 2.7 in Australia. Mean MSSS in the northern hemisphere was 4.51 ± 1.6 compared to 4.48 ± 1.9 in the southern hemisphere. No differences were found for MSSS among hemispheres ( p = 0.68), regions ( p = 0.96) or countries ( p = 0.50). Conclusions Our analyses did not discover any difference in mean MSSS among patients from different regions, hemispheres or countries.

Previous papers show discordant patterns of monthly and seasonal differences in the frequency of multiple sclerosis relapses. Attacks are more often reported in spring and summer, but there are many variations, mainly as to summer peaks. This paper, an MSBase collaboration substudy, reports multiple series of relapses from 1980 to 2010, comparing ultradecennal trends of seasonal frequency of attacks in different countries. The MSBase international database was searched for relapses in series recording patient histories from 1980 up to 2010. The number of relapses by month was stratified by decade (1981-1990, 1991-2000, 2001-2010). Positive spring versus summer peaks were compared by odds ratios; different series were compared by weighted odds ratio (Peto OR). Decade comparison of the 1990s versus 2000s shows inversion of spring-summer peak (2000s = March; 1990s = July), significant in the whole group (Peto odds ratio = 1.31, CI = 1.10-1.56, p = 0.003) and in Salerno series (OR = 1.97, CI = 1.14-1.40). The global significance persisted also excluding Salerno series (Peto odds ratio = 1.25, CI = 1.04-1.50, p = 0.002). Multicentric data confirm a summer peak of relapses in the 1991-2000 decade, significantly different from the spring peak of 2001-2010. Seasonal frequency of relapses shows long-term variations, so that other factors such as viral epidemics might have more relevance than ultraviolet exposure.

none 50 si studio multicentrico The aim of this work was to evaluate sex differences in the incidence of multiple sclerosis relapses; assess the relationship between sex and primary progressive disease course; and compare effects of age and disease duration on relapse incidence. Annualized relapse rates were calculated using the MSBase registry. Patients with incomplete data or

OBJECTIVE: To analyze time-trends in age at disability milestones among MS patients who were enrolled into the MSBase International Registry during 1996-2010 period.METHODS: We used linear regression to describe the relationship between mean age at major EDSS benchmarks and calendar time. We then assessed time-trend in age at initial EDSS rating with a three level linear growth model specifying that patients were nested within each of 20 participating countries. The model estimated the average of time-trends in mean age at initial clinical assessment within each country while controlling for patients' EDSS and sex in each country. Analyses were repeated in subsamples of patients diagnosed according to Poser or McDonald criteria.RESULTS: The MSBase Registry contained data on 11,108 MS patients enrolled between 1996 and 2010 who fulfilled our inclusion criteria. During the 1996-2010 period, enrollment age for patients with EDSS 4/4.5 increased by 7.9 years, from 43 to 51 years (pCONCLUSIONS: The more recent MSBase enrollees in each of the mild-to-moderate disability strata were significantly older than earlier enrollees. Possible explanations for this phenomenon are discussed.

Previous papers show different patterns of seasonal distribution of multiple sclerosis attacks. This paper compares long-time modifications. Salerno MS registry (Southern Italy), was reviewed, including 189 patients, age onset 12–51 years (mean = 29.88, SD = 8.4), disease duration mean = 6.94 years (1–29), attacks mean = 4.5 (2–25, SD = 3.41). Data were stratified by decades. Number of events/month was analyzed by odds ratios and forecast modeling (ARIMA); means by ANOVA and post hoc tests, and correlations by multiple regression. We found 869 relapses: J = 72, F = 48, M = 122, A = 75, M = 68, Jn = 59, Jl = 81, A = 74, S = 63, O = 70, N = 72, D = 65. In 2001–2008 there was one significant peak (March); in 1991–2000 many (greatest = July), and in 1984–1990, one positive (June), one negative (April). Differences between 1990s and 2000s are significant. It is the first study addressing ultradecennal trends, and finding that the season distribution of MS attacks is significantly different: the study confirms frequency peaks in early spring and summer, but they are different in different decades. This significant ultra-decade difference might support hypotheses more linked to infections or toxic substances than to sunlight, UV, or similar.

BACKGROUND Azathioprine is the most widely used immunosuppressive treatment in multiple sclerosis (MS). It is an alternative to interferon beta for treating MS also because it is less expensive. Concerns about its safety, mainly a possible increased risk of malignancy, has limited its use. This systematic review aimed to determine the trade off between the benefits and risks of azathioprine in multiple sclerosis. OBJECTIVES To compare azathioprine versus placebo. To determine the effect of azathioprine on major clinical outcomes, i.e., disability progression and relapses in patients with multiple sclerosis. SEARCH STRATEGY The Multiple Sclerosis Group's Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL- Issue 4, 2006), Cochrane Database of Systematic Reviews (CDSR - Issue 4, 2006), Database of Abstracts of Reviews of Effectiveness (DARE - searched 28.12.06) MEDLINE (PubMed) (1966 to December 2006), EMBASE (1980 to December 2006). Journals and reference lists were hand searched for relevant articles both to benefit and adverse effects. Regulatory agencies were additional sources of information for adverse effects. SELECTION CRITERIA All parallel group randomised controlled trials (RCTs) comparing azathioprine treatment of a least one year duration with placebo for patients with multiple sclerosis. Cohorts, case controls, case series and case reports were also used to assess adverse effects. DATA COLLECTION AND ANALYSIS Potentially relevant references were evaluated and all data extracted by two independent authors. MAIN RESULTS The five trials that met our criteria included 698 randomised patients: data from 499 (71.5%) were available for analysis of relapse frequency in patients at one year's, from 488 (70%) at two years' and from 415 (59.5%) at three years' follow-up. Azathioprine reduced the number of patients who had relapses during the first year of treatment (relative risk reduction [RRR] =20%; 95% CI = 5% to 33%), at two years' (RRR =23%; 95% CI = 12% to 33%) and three years' (RRR =18%; 95% CI = 7% to 27%) follow-up. These results were consistent in sensitivity analysis. There was no heterogeneity among the studies. Data from only three small trials with a total of 87 patients were available to calculate the number of patients who progressed during the first two to three years. There was a statistically significant benefit (RRR = 42%; 95% CI = 7% to 64%) of azathioprine therapy at three years' follow-up; this result was robust after sensitivity analyses and there was no heterogeneity among the trials. Gastrointestinal disturbances, bone marrow suppression and hepatic toxicity were greater in the azathioprine group rather than in the placebo group; they were anticipated, and, by monitoring and dosage adjustment, were easily managed. Withdrawals due to adverse effects were few, occurring mostly during the first year of azathioprine treatment and mainly due to gastrointestinal intolerance (5%). Data from the trials and from cohort and case controls studies available in the literature did not show an increase in risk of malignancy from azathioprine. A possible long-term risk of cancer from azathioprine may be related to a treatment duration above ten years and cumulative doses above 600 g. AUTHORS' CONCLUSIONS Azathioprine is an appropriate maintenance treatment for patients with multiple sclerosis who frequently relapse and require steroids. Cumulative doses of 600 g should not be exceeded in relation to a possible increased risk of malignancy. Considering the trade off between the benefits and harms, azathioprine is a fair alternative to interferon beta for treating multiple sclerosis. A logical next step for future trials would seem the direct comparison of azathioprine and interferon beta. In fact the direct comparison between these two widely used treatments in multiple sclerosis has not been made.

Background: Relapse is a relatively sudden worsening of neurological status in multiple sclerosis patients. The aim of this paper is to describe the frequency and timing of the subsequent clinical remission, and factors linked to a possible lack of recovery. Methods: Two hundred and twenty-three relapses in 62 multiple sclerosis patients were examined retrospectively. Kurtzke’s Expanded Disability Status Scale (EDSS) scores were calculated every 3 months from 1 year before to 1 year after. Remission was defined as improvement vs. the EDSS as scored during the relapse. Recovery was defined as return to the EDSS as scored before the relapse. Results: The frequency of improvement was 78% at 3 months, 86% at 6, and lower in males (65 vs. 81%). The frequency of recovery was 55% at 3 months, 71% at 6. Kaplan-Meier curves showed stabilization after 6 months, with improvement in 90% of patients, 100% without further relapses. Relapses without recovery were only 30%; 15% excluding short-term relapses. Conclusions: Incomplete remissions do not appear to be linked to the evolution of the relapse, but to further relapses in the following months; in other words, to the short-term relapse rate.

Jokubaitis, Vilija G./0000-0002-3942-4340; Oreja-Guevara, Celia/0000-0002-9221-5716; Lugaresi, Alessandra/0000-0003-2902-5589; Slee, Mark/0000-0003-4323-2453; Horakova, Dana/0000-0003-1915-0036; Havrdova, Eva Kubala/0000-0002-9543-4359; Sanchez Menoyo, Jose Luis/0000-0003-2634-8294; Prat, Alexandre/0000-0001-6188-0580; Kalincik, Tomas/0000-0003-3778-1376; Butzkueven, Helmut/0000-0003-3940-8727; pucci, eugenio/0000-0001-7606-7330; van Pesch, Vincent/0000-0003-2885-9004; Trojano, Maria/0000-0002-6329-8946 WOS: 000365135700024 PubMed: 26359291 Prevention of irreversible disability is currently the most important goal of disease modifying therapy for multiple sclerosis. The disability outcomes used in most clinical trials rely on progression of Expanded Disability Status Scale score confirmed over 3 or 6 months. However, sensitivity and stability of this metric has not been extensively evaluated. Using the global MSBase cohort study, we evaluated 48 criteria of disability progression, testing three definitions of baseline disability, two definitions of progression magnitude, two definitions of long-term irreversibility and four definitions of event confirmation period. The study outcomes comprised the rates of detected progression events per 10 years and the proportions of the recorded events persistent at later time points. To evaluate the ratio of progression frequency and stability for each criterion, we calculated the proportion of events persistent over the five subsequent years once progression was achieved. Finally, we evaluated the clinical and demographic determinants characterising progression events and, for those that regressed back to baseline, determinants of their subsequent regression. The study population consisted of 16 636 patients with the minimum of three recorded disability scores, totalling 112 584 patient-years. The progression rates varied between 0.41 and 1.14 events per 10 years, with the length of required confirmation interval as the most important determinant of the observed variance. The concordance among all tested progression criteria was only 17.3%. Regression of disability occurred in 11-34% of the progression events over the five subsequent years. The most important determinant of progression stability was the length of the confirmation period. For the most accurate set of the progression criteria, the proportions of 3-, 6-, 12- or 24-month confirmed events persistent over 5 years reached 70%, 74%, 80% and 89%, respectively. Regression post progression was more common in younger patients, relapsing-remitting disease course, and after a smaller change in disability, and was inflated by higher visit frequency. These results suggest that the disability outcomes based on 3-6-month confirmed disability progression overestimate the accumulation of permanent disability by up to 30%. This could lead to spurious results in short-term clinical trials, and the issue may be magnified further in cohorts consisting predominantly of younger patients and patients with relapsing-remitting disease. Extension of the required confirmation period increases the persistence of progression events. NHMRC Early Career FellowshipNational Health and Medical Research Council of Australia [1071124]; NHMRC Practitioner FellowshipNational Health and Medical Research Council of Australia [1080518]; NHMRCNational Health and Medical Research Council of Australia [1083539, 1032484]; NHMRC Centre for Research ExcellenceNational Health and Medical Research Council of Australia [1001216]; MSBase Foundation; Merck SeronoMerck SeronoMerck & Company; BiogenBiogen; Novartis Pharma; Bayer-ScheringBayer AG; Sanofi-AventisSanofi-Aventis; BioCSL The work was supported by the NHMRC Early Career Fellowship (1071124), NHMRC Practitioner Fellowship (1080518), NHMRC Project Grants (1083539 and 1032484), NHMRC Centre for Research Excellence (Grant ID 1001216) and 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.