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.