Gustavo Suarez

Association of Vitamin D Levels With Multiple Sclerosis Activity and Progression in Patients Receiving Interferon Beta-1b

IMPORTANCE Low serum 25-hydroxyvitamin D (25[OH]D) levels are associated with an increased risk of multiple sclerosis (MS) as well as with increased disease activity and rate of progression in clinically isolated syndromes and early MS. OBJECTIVE To assess the association between 25(OH)D and disease course and prognosis in patients with relapsing-remitting MS treated with interferon beta-1b. DESIGN, SETTING, AND PARTICIPANTS We conducted a prospective cohort study assessing 25(OH)D levels and subsequent MS disease course and progression characterized by magnetic resonance imaging (MRI) and clinical end points. The study took place between November 2003 and June 2005; data analysis was performed between June 2013 and December 2014. The study was conducted among participants in the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) study, a large, phase 3, prospective, multicenter, blinded, randomized clinical trial. Patients were monitored for at least 2 years. Clinic visits were scheduled every 3 months, and MRI was performed at baseline and annually thereafter. Eligible patients included 1482 participants randomized to receive 250 μg or 500 μg of interferon-1b with at least 2 measurements of 25(OH)D obtained 6 months apart. EXPOSURES Serum 25(OH)D measurements were performed at baseline, 6 months, and 12 months. MAIN OUTCOMES AND MEASURES Main outcomes included cumulative number of new active lesions (T2 lesions and gadolinium acetate-enhancing lesions), change in normalized brain volume, relapse rate, and progression determined by the Expanded Disability Status Scale (EDSS). Statistical analyses were adjusted for age, sex, randomized treatment, region, disease duration, and baseline EDSS score. RESULTS Overall, average 25(OH)D levels in 1482 patients were significantly inversely correlated with the cumulative number of new active lesions between baseline and the last MRI, with a 50.0-nmol/L increase in serum 25(OH)D levels associated with a 31% lower rate of new lesions (relative rate [RR], 0.69; 95% CI, 0.55-0.86; P = .001). The lowest rate of new lesions was observed among patients with 25(OH)D levels greater than 100.0 nmol/L (RR, 0.53; 95% CI, 0.37-0.78; P = .002). No significant associations were found between 25(OH)D levels and change in brain volume, relapse rates, or EDSS scores. Results were consistent following adjustment for HLA-DRB1*15 or vitamin D-binding protein status. CONCLUSIONS AND RELEVANCE Among patients with MS treated with interferon beta-1b, higher 25(OH)D levels were associated with lower rates of MS activity observed on MRI. Results for brain atrophy and clinical progression were more equivocal.

No association of multiple sclerosis activity and progression with EBV or tobacco use in BENEFIT

Objective: To evaluate whether Epstein-Barr virus (EBV) immunoglobulin G (IgG) antibody levels or tobacco use were associated with conversion to multiple sclerosis (MS) or MS progression/activity in patients presenting with clinically isolated syndrome (CIS). Methods: In this prospective, longitudinal study, we measured EBV IgG antibody and cotinine (biomarker of tobacco use) levels at up to 4 time points (baseline, months 6, 12, and 24) among 468 participants with CIS enrolled in the BENEFIT (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment) clinical trial. Outcomes included time to conversion to clinically definite or McDonald MS, number of relapses, Expanded Disability Status Scale (EDSS) changes, brain and T2 lesion volume changes, and number of new active lesions over 5 years. Analyses were adjusted for age, sex, treatment allocation, baseline serum 25-hydroxyvitamin D level, number of T2 lesions, body mass index, EDSS, steroid treatment, and CIS onset type. Results: We found no associations between any EBV IgG antibody or cotinine levels with conversion from CIS to MS or MS progression as measured by EDSS or activity clinically or on MRI. The relative risk of conversion from CIS to clinically definite MS was 1.14 (95% confidence interval 0.76–1.72) for the highest vs the lowest quintile of EBNA-1 IgG levels, and 0.96 (95% confidence interval 0.71–1.31) for cotinine levels >25 ng/mL vs <10. Conclusions: Neither increased levels of EBV IgG antibodies, including against EBNA-1, nor elevated cotinine levels indicative of tobacco use, were associated with an increased risk of CIS conversion to MS, or MS activity or progression over a 5-year follow-up.

Causes of death among persons with multiple sclerosis

BACKGROUND Multiple Sclerosis (MS) is a leading cause of disability among young Americans. Reports suggest that life expectancy (i.e., average age at death) remains reduced as compared to the general population, but underlying causes of death (UCOD) are less well-characterized. OBJECTIVE To describe the cause-specific mortality among participants enrolled in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry and to compare the profile of these causes by age, sex, race and disability status at entry into NARCOMS, with U.S. mortality data. METHODS The underlying cause of death (UCOD), any mention cause of death and proportionate mortality were compared among U.S. NARCOMS participants by age, sex, race and disability status. RESULTS Of the 32,445 participants to be considered for this study, 2,927 had died. Compared to survivors, decedents were older at enrollment and MS diagnosis, more likely to be male, and had less education. UCOD differed markedly by age group. In both sexes, MS as the UCOD was proportionately lower by 20% or more in those aged 25-39 compared to those aged 75 or older. Cancer and cardiovascular causes were more frequent as causes of death with increasing age, but were less than expected at older ages. The effect of disability on mortality was roughly equivalent to the effect of aging on mortality. CONCLUSIONS Among NARCOMS participants older age at enrollment, male sex and greater disability were associated with increased mortality risk. This cohort of MS subjects had a lower proportionate mortality from cardiovascular disease and cancer compared to the U.S. population.

Survey of US Patients with Multiple Sclerosis: Comparison of the New Electronic Interferon Beta-1b Autoinjector (BETACONNECT™) With Mechanical Autoinjectors

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.

Treatment of Multiple Sclerosis - Relationship between Vitamin D and Interferon β-1b

There are many reports suggesting an association between vitamin D status and both the development of multiple sclerosis (MS) and its course. This relationship and the effects of vitamin D and interferon β-1b (IFNβ-1b) in the treatment of patients are reviewed in the BEtaferon/ Betaseron in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) and the Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose in multiple sclerosis (BEYOND) studies. In the BENEFIT study the average serum 25-hydroxyvitamin D (25[OH]D) levels strongly predicted MS disease activity and progression. The probability of clinically definite MS (CDMS) and magnetic resonance imaging (MRI) activity was lower in these clinically isolated syndrome (CIS) patients with 25(OH)D levels ≥50 nmol/L and in those starting with IFNβ -1b. Furthermore, there was a beneficial effect on relapse rate, occurrence of new active MRI lesions and disease progression for a 50 nmol/L increase in 25(OH)D levels. Similarly, in relapsing-remitting (RR) MS patients from the BEYOND study serum 25(OH)D levels were inversely associated with MRI markers of MS activity. Genetic analysis of patients from these studies indicated that there may be a benefit in monitoring and managing vitamin D levels in early MS patients treated with IFNβ-1b and a cumulative number of risk alleles predict lower 25(OH)D levels in CIS and RRMS patients. Further studies have suggested that some of the IFNβ-1b therapeutic effects on relapse could be mediated through modulation of vitamin D metabolism. Thus, there seems to be a benefit on clinical and MRI measures if patients are treated with both vitamin D and IFNβ-1b. There is a need to further evaluate this effect in clinical trials. The relationship between vitamin D and MS disease activity along with the effects of vitamin D and IFNβ-1b in the treatment of MS patients is reviewed.

Vitamin D Deficiency and Possible Role in Multiple Sclerosis

TOUCH MEDICAL MEDIA • Despite a lack of consensus, vitamin D deficiency and insufficiency have been defined as a serum level of 25-hydroxyvitamin D (25[OH]D) <50 nmol/L or 52.5–72.5 nmol/L respectively. • Vitamin D deficiency is widespread. • Vitamin D is probably involved in the prevention of numerous disease states. • Most primary care clinicians are unaware of the recommended dose for vitamin D supplementation or the optimum serum level in multiple sclerosis (MS) patients. • In the general population management of vitamin D deficiency in children and adults can be effectively achieved by administering 50,000 IU vitamin D2 or vitamin D3 once a week for 6 or 8 weeks respectively: – In the general population 600–1,000 IU/d is effective to prevent recurrence in children and 50,000 IU vitamin D3 or vitamin D2 every 2 weeks (equivalent to approximately 3,600 IU daily) in adults. This strategy maintains blood levels of 25(OH)D at approximately 100–150 nmol/L for up to 6 years with no evidence of toxicity. – In pregnant women supplementation with 2,000 and 4,000 IU/d during pregnancy improve maternal/ neonatal vitamin D status. • Considerable evidence exists for the protective effects of vitamin D in MS, with higher sun exposure and vitamin D intake associated with a lower risk of MS. • Improvement in 25(OH)D status appears to additively enhance the beneficial effects of interferon-beta. To date, this effect has not as yet been observed with glatiramer acetate. • Results from the Betaferon/Betaseron in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) study showed that patients with vitamin D levels (25[OH]D) <50 nmol/L had more prominent clinical and MRI disease activity.

No association of multiple sclerosis activity and progression with EBV or tobacco use in BENEFITAuthor Response

We read with interest the article by Munger et al.1 The authors were incorrect that “(only) one study among patients with multiple sclerosis (MS) has found no association between smoking and progression, …”1 In a study of 205 women with MS of 5-year mean duration, we also found no association between smoking and progression.2 Nevertheless, this work suggested that APOE …