Numerous observational studies have suggested that there is a correlation between the level of serum vitamin D and MS risk and disease activity. To explore this hypothesis, a literature search of large, prospective, observation studies, epidemiological studies, and studies using new approaches such as Mendelian randomization was conducted. Available data and ongoing research included in this review suggest that the level of serum vitamin D affects the risk of developing MS and also modifies disease activity in MS patients. Newer Mendelian randomization analyses suggest there is a causal relationship between low vitamin D level and the risk of MS. Post-hoc evaluations from two phase 3 studies, BENEFIT and BEYOND, support the findings of observational trials. Study limitations identified in this review recognize the need for larger controlled clinical trials to establish vitamin D supplementation as the standard of care for MS patients. Though there is increasing evidence indicating that lower vitamin D levels are associated with increased risk of MS and with greater clinical and brain MRI activity in established MS, the impact of vitamin D supplementation on MS activity remains inadequately investigated.

ObjectivesCompared with controls, multiple sclerosis (MS) patients die, on average, 7–14 years prematurely. Previously, we reported that, 21 years after their participation in the pivotal randomised, controlled trial (RCT) of interferon β-1b, mortality was reduced by 46–47% in the two groups who received active therapy during the RCT. To determine whether the excessive deaths observed in placebo-treated patients was due to MS-related causes, we analysed the causes-of-death (CODs) in these three, randomised, patient cohorts.DesignLong-term follow-up (LTF) of the pivotal RCT of interferon β-1b.SettingEleven North American MS-centres participated.ParticipantsIn the original RCT, 372 patients participated, of whom 366 (98.4%) were identified after a median of 21.1 years from RCT enrolment.InterventionsUsing multiple information sources, we attempted to establish COD and its relationship to MS in deceased patients.Primary outcomeAn independent adjudication committee, masked to treatment assignment and using prespecified criteria, determined the likely CODs and their MS relationships.ResultsAmong the 366 MS patients included in this LTF study, 81 deaths were recorded. Mean age-at-death was 51.7 (±8.7) years. COD, MS relationship, or both were determined for 88% of deaths (71/81). Patients were assigned to one of nine COD categories: cardiovascular disease/stroke; cancer; pulmonary infections; sepsis; accidents; suicide; death due to MS; other known CODs; and unknown COD. Of the 69 patients for whom information on the relationship of death to MS was available, 78.3% (54/69) were adjudicated to be MS related. Patients randomised to receive placebo during the RCT (compared with patients receiving active treatment) experienced an excessive number of MS-related deaths.ConclusionsIn this long-term, randomised, cohort study, MS patients receiving placebo during the RCT experienced greater all-cause mortality compared to those on active treatment. The excessive mortality in the original placebo group was largely from MS-related causes, especially, MS-related pulmonary infections.

Objective: To examine the effects of interferon beta (IFN␤)-1b on all-cause mortality over 21 years in the cohort of 372 patients who participated in the pivotal randomized clinical trial (RCT), retaining (in the analysis) the original randomized treatment-assignments. Methods:For this randomized long-term cohort study, the primary outcome, defined before data collection, was the comparison of all-cause mortality between the IFN␤-1b 250 g and placebo groups from the time of randomization through the entire 21-year follow-up interval (intention-totreat, log-rank test for Kaplan-Meier survival curves). All other survival outcomes were secondary.Results: After a median of 21.1 years from RCT enrollment, 98.4% (366 of 372) of patients were identified, and, of these, 81 deaths were recorded (22.1% [81 of 366]). Patients originally randomly assigned to IFN␤-1b 250 g showed a significant reduction in all-cause mortality over the 21-year period compared with placebo (p ϭ 0.0173), with a hazard ratio of 0.532 (95% confidence interval 0.314-0.902). The hazard rate of death at long-term follow-up by Kaplan-Meier estimates was reduced by 46.8% among IFN␤-1b 250 g-treated patients (46.0% among IFN␤-1b 50 g-treated patients) compared with placebo. Baseline variables did not influence the observed treatment effect. Conclusions:There was a significant survival advantage in this cohort of patients receiving early IFN␤-1b treatment at either dose compared with placebo. Near-complete ascertainment, together with confirmatory findings from both active treatment groups, strengthens the evidence for an IFN␤-1b benefit on all-cause mortality. Classification of Evidence:This study provides Class III evidence that early treatment with IFN␤-1b is associated with prolonged survival in initially treatment-naive patients with relapsingremitting multiple sclerosis. Neurology Multiple sclerosis (MS) is a chronic, inflammatory disease of the CNS with a lifelong course, necessitating outcome assessments over both the short term and long term.1 However, randomized clinical trials (RCTs) have typically focused only on short-term outcomes such as clinical measures of relapse and physical disability, as well as MRI measures of disease activity and severity.2-8 Although survival is the ultimate long-term outcome, to date mortality in patients with MS treated with disease-modifying therapy (DMT) has not been well-studied, largely because of the length and completeness of observation needed. 9 *These authors contributed equally to this work.

ObjectiveWomen with multiple sclerosis are often diagnosed and treated during their reproductive years. Limited data are available on the safety of treatment during pregnancy. The Betaseron Pregnancy Registry prospectively monitored women exposed to interferon β-1b (IFNβ-1b) during pregnancy to estimate the rates of birth defects, spontaneous abortions (SABs) and other negative outcomes in this population.DesignFrom 2006 to 2011, this observational registry enrolled women exposed prior to conception or during pregnancy (but prior to or without abnormalities on prenatal screening). Follow-up continued from enrolment through the 4-month paediatric visit.SettingPatients in the USA who met these criteria were enrolled in the registry.ResultsThe registry enrolled 99 pregnant women; 3 were lost to follow-up. The earliest exposure to IFNβ-1b occurred during the first trimester for 95 pregnancies and in the third trimester for 1 pregnancy. There were 99 birth outcomes (3 twins), including 86 (86.9%) live births, 11 (11.1%) SABs and 2 (2%) stillbirths. Birth defects were reported in five (5.1%) cases. Rates of birth defects and SAB were not significantly different from population comparators. No developmental concerns were identified at the 4-month paediatric visit.ConclusionsThe small sample size limits the ability to draw definitive conclusions; however, there was no pattern to suggest increased negative outcomes with IFNβ-1b.Clinical trials registration numberNCT00317564.

IntroductionPatients with multiple sclerosis (MS) generally undergo long-term treatment with disease-modifying therapies (DMTs). In the US, patients taking glatiramer acetate, interferon beta-1a, or interferon beta-1b, typically use a mechanical autoinjector. Recent survey results have shown that using an electronic autoinjector, such as BETACONNECT™ (Bayer Pharma AG) for interferon beta-1b/Betaseron® (Bayer Pharma AG) may reduce injection discomfort and increase patient satisfaction with treatment. The aim of the current survey was to assess patient perceptions of BETACONNECT compared with mechanical autoinjectors using a survey integrated with demonstrations and simulated injections with BETACONNECT.MethodsPatients with MS currently using mechanical autoinjectors for glatiramer acetate/Copaxone® (Teva Pharmaceuticals USA, Inc.), interferon beta-1a/Rebif® (EMD Serono Inc.), or interferon beta-1b/Extavia® (Novartis Pharmaceuticals Corp.), participated in a 60-min in-person interview. Patients rated the importance of 18 ideal autoinjector attributes, and the performance of their current autoinjectors across these attributes. BETACONNECT was demonstrated and patients performed simulated injections with BETACONNECT before rating it across the same attributes. Patient overall autoinjector preference was assessed.ResultsNinety patients completed the survey: 63 were using autoinjectors for Copaxone, 25 for Rebif, and 2 for Extavia. BETACONNECT scored higher than mechanical autoinjectors across all 18 attributes. The top attributes of an ideal autoinjector were the injection process is easy overall, easy to push the button to start the injection, and autoinjector is comfortable to hold during injections. Unique BETACONNECT features most valued by patients were the built-in dwell time, self-check function, greater ability to customize injections, adjustment of injection speed, low injection noise, and automatic needle retraction. Overall, 75 out of 90 patients (83%) expressed a preference for BETACONNECT over their current autoinjector.ConclusionBETACONNECT attributes and features were highly rated by patients, compared with both an ideal autoinjector and their current mechanical autoinjectors. These findings suggest that the use of BETACONNECT may increase patient satisfaction and potentially increase overall medication adherence.FundingBayer HealthCare Pharmaceuticals.Electronic supplementary materialThe online version of this article (doi:10.1007/s40120-016-0047-3) contains supplementary material, which is available to authorized users.

IntroductionMultiple sclerosis (MS) typically requires life-long management with disease-modifying therapies (DMTs). Many DMTs require regular self-injection, and can be associated with injection site reactions, pain, and needle/injection phobia—but these can be addressed by improvements in autoinjector design. The aim of this study was to investigate patient satisfaction and preference for BETACONNECT™ (Bayer Pharma AG), a novel interferon beta-1b autoinjector.MethodsPatients in Germany performing self-injections using BETACONNECT took part in the study. Data were collected through an online 15-min structured survey. Participants rated their experience with BETACONNECT on a 6-point scale and those satisfied with BETACONNECT were asked to describe the reason using a free-text box.ResultsOne-hundred and eighteen patients with MS completed the survey. Ninety percent preferred BETACONNECT to their previous injection method (only 4% previously used manual injections, so most had previously used other autoinjectors). Ninety-two percent were very confident/confident in their ability to perform an injection using BETACONNECT. The most common free-text responses to “Why are you satisfied with the BETACONNECT™ autoinjector?” were ease of use (46%), less irritation/pain at the injection site (33%), and smoother injections (24%). Features considered most useful were automated injections (98%), adjustable injection speed (98%), and adjustable injection depth (98%). Ninety-seven percent thought it was easy to know when an injection was complete and 95% agreed/strongly agreed it was easy to learn to use the autoinjector. Seventy-three percent agreed that the quietness and effortlessness of the BETACONNECT reduced their level of injection anxiety, 92% that its size and shape makes it easy to handle during injections, and 67% that it decreases injection site pain. Eighty percent of those using the reminder function thought they were less likely to miss an injection.ConclusionPatients with MS self-injecting interferon beta-1b expressed a high level of satisfaction and preference for BETACONNECT. Thus, BETACONNECT represents a valid option to improve patients’ overall injection experience.FundingBayer HealthCare Pharmaceuticals.Electronic supplementary materialThe online version of this article (doi:10.1007/s40120-015-0036-y) contains supplementary material, which is available to authorized users.

BackgroundInformation on causes of death (CODs) for patients with multiple sclerosis (MS) in the United States is sparse and limited by standard categorizations of underlying and immediate CODs on death certificates. Prior research indicated that excess mortality among MS patients was largely due to greater mortality from infectious, cardiovascular, or pulmonary causes.ObjectiveTo analyze disease categories in order to gain insight to pathways, which lead directly to death in MS patients.MethodsCommercially insured MS patients enrolled in the OptumInsight Research database between 1996 and 2009 were matched to non-MS comparators on age/residence at index year and sex. The cause most-directly leading to death from the death certificate, referred to as the “principal” COD, was determined using an algorithm to minimize the selection of either MS or cardiac/pulmonary arrest as the COD. Principal CODs were categorized into MS, cancer, cardiovascular, infectious, suicide, accidental, pulmonary, other, or unknown. Infectious, cardiovascular, and pulmonary CODs were further subcategorized.Results30,402 MS patients were matched to 89,818 controls, with mortality rates of 899 and 446 deaths/100,000 person-years, respectively. Excluding MS, differences in mortality rate between MS patients and non-MS comparators were largely attributable to infections, cardiovascular causes, and pulmonary problems. Of the 95 excessive deaths (per 100,000 person-years) related to infectious causes, 41 (43.2%) were due to pulmonary infections and 45 (47.4%) were attributed to sepsis. Of the 46 excessive deaths (per 100,000 person-years) related to pulmonary causes, 27 (58.7%) were due to aspiration. No single diagnostic entity predominated for the 60 excessive deaths (per 100,000 person-years) attributable to cardiac CODs.ConclusionsThe principal COD algorithm improved on other methods of determining COD in MS patients from death certificates. A greater awareness of the common CODs in MS patients will allow physicians to anticipate potential problems and, thereby, improve the care that they provide.

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