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High-dose vitamin D3 supplementation in relapsing-remitting multiple sclerosis: a randomised clinical trial.
Cassard, SD, Fitzgerald, KC, Qian, P, Emrich, SA, Azevedo, CJ, Goodman, AD, Sugar, EA, Pelletier, D, Waubant, E, Mowry, EM
EClinicalMedicine. 2023;:101957
Abstract
BACKGROUND Vitamin D insufficiency is associated with risk of multiple sclerosis (MS) relapse; whether supplementation influences prognosis is unknown. The Vitamin D to Ameliorate MS (VIDAMS) trial aimed to determine if high dose (5000 International Units (IU)/day) versus low dose (600 IU/day) vitamin D3, added to daily glatiramer acetate (GA), reduced the risk of clinical relapse in people with established relapsing remitting MS (RRMS) over 96 weeks. METHODS VIDAMS is a randomised, phase 3, double-blind, multi-centre, controlled trial conducted at sixteen neurology clinics in the United States. Participants with MAGNIMS 2010 RRMS, aged 18-50 years, with recent disease activity were eligible to enroll if they had an Expanded Disability Status Scale score ≤4.0; minimum serum 25-hydroxyvitamin D level of 15 ng/ml within 30 days of screening; and average ≤ 1000 IU supplemental vitamin D3 daily in the 90 days prior to screening. Of 203 screened, 183 were eligible for the 30-day run-in to assess GA adherence, after which 172 were randomised 1:1 to low dose vitamin D3 (LDVD) or high dose vitamin D3 (HDVD), and were followed every 12 weeks for 96 weeks. The primary outcome was the proportion that experienced a confirmed relapse and analyses used Kaplan Meier and Cox proportional hazards models. 165 participants returned for ≥1 follow-up visit and were included in the primary and safety analyses; 140 completed a week 96 visit. This study was registered with ClinicalTrials.gov, NCT01490502. FINDINGS Between March 22, 2012 and March 8, 2019, 172 participants were enrolled and randomised (83 LDVD, 89 HDVD) and differed at baseline only in gender and race: more males received HDVD (31%) than LDVD (16%), and fewer Black participants received HDVD (12%) than LDVD (22%). Among 165 participants with at least one follow-up visit, the proportion experiencing confirmed relapse did not differ between LDVD and HDVD [at 96 weeks: 32% vs. 34%, p = 0.60; hazard ratio (HR): 1.17 (0.67, 2.05), p = 0.57]. There was no hypercalcaemia. Three participants developed nephrolithiasis or ureterolithiasis (1 in the LDVD and 2 in the HDVD group). Two were possibly related to study drug; and one was presumed related to concomitant treatment with topiramate for migraine. INTERPRETATION VIDAMS provides evidence that HDVD supplementation, added to GA, does not reduce the risk of clinical relapse in people with RRMS. Taken together with the null findings of previous trials, these results suggest that prescribing higher doses of vitamin D for purposes of modifying the RRMS course may not be beneficial. FUNDING This investigation was supported by a grant from the National Multiple Sclerosis Society (RG 4407A2/1). Teva Neuroscience, Inc. provided Copaxone (GA) for the duration of the trial.
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Association of Vitamin D Polygenic Risk Scores and Disease Outcome in People With Multiple Sclerosis.
Vasileiou, ES, Hu, C, Bernstein, CN, Lublin, F, Wolinsky, JS, Cutter, GR, Sotirchos, ES, Kowalec, K, Salter, A, Saidha, S, et al
Neurology(R) neuroimmunology & neuroinflammation. 2023;(1)
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Abstract
BACKGROUND AND OBJECTIVES Observational studies suggest low levels of 25-hydroxyvitamin D (25[OH]D) may be associated with increased disease activity in people with multiple sclerosis (PwMS). Large-scale genome-wide association studies (GWAS) suggest 25(OH)D levels are partly genetically determined. The resultant polygenic scores (PGSs) could serve as a proxy for 25(OH)D levels, minimizing potential confounding and reverse causation in analyses with outcomes. Herein, we assess the association of genetically determined 25(OH)D and disease outcomes in MS. METHODS We generated 25(OH)D PGS for 1,924 PwMS with available genotyping data pooled from 3 studies: the CombiRx trial (n = 575), Johns Hopkins MS Center (n = 1,152), and Immune-Mediated Inflammatory Diseases study (n = 197). 25(OH)D-PGS were derived using summary statistics (p < 5 × 10-8) from a large GWAS including 485,762 individuals with circulating 25(OH)D levels measured. We included clinical and imaging outcomes: Expanded disability status scale (EDSS), timed 25-foot walk (T25FW), nine-hole peg test (9HPT), radiologic activity, and optical coherence tomography-derived ganglion cell inner plexiform layer (GCIPL) thickness. A subset (n = 935) had measured circulating 25(OH)D levels. We fitted multivariable models based on the outcome of interest and pooled results across studies using random effects meta-analysis. Sensitivity analyses included a modified p value threshold for inclusion in the PGS (5 × 10-5) and applying Mendelian randomization (MR) rather than using PGS. RESULTS Initial analyses demonstrated a positive association between generated 25(OH)D-PGS and circulating 25(OH)D levels (per 1SD increase in 25[OH]D PGS 3.08%, 95% CI: 1.77%, 4.42%; p = 4.33e-06; R2 = 2.24%). In analyses with outcomes, we did not observe an association between 25(OH)D-PGS and relapse rate (per 1SD increase in 25[OH]D-PGS: 0.98; 95% CI: 0.87-1.10), EDSS worsening (per 1SD: 1.05; 95% CI: 0.87-1.28), change in T25FW (per 1SD: 0.07%; 95% CI: -0.34 to 0.49), or change in 9HPT (per 1SD: 0.09%; 95% CI: -0.15 to 0.33). 25(OH)D-PGS was not associated with new lesion accrual, lesion volume or other imaging-based outcomes (whole brain, gray, white matter volume loss or GCIPL thinning). The results were similarly null in analyses using other p value thresholds or those applying MR. DISCUSSION Genetically determined lower 25(OH)D levels were not associated with worse disease outcomes in PwMS and raises questions about the plausibility of a treatment effect of vitamin D in established MS.
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Intermittent calorie restriction alters T cell subsets and metabolic markers in people with multiple sclerosis.
Fitzgerald, KC, Bhargava, P, Smith, MD, Vizthum, D, Henry-Barron, B, Kornberg, MD, Cassard, SD, Kapogiannis, D, Sullivan, P, Baer, DJ, et al
EBioMedicine. 2022;:104124
Abstract
BACKGROUND Intermittent fasting or calorie restriction (CR) diets provide anti-inflammatory and neuroprotective advantages in models of multiple sclerosis (MS); data in humans are sparse. METHODS We conducted a randomised-controlled feeding study of different CR diets in 36 people with MS over 8 weeks. Participants were randomised to 1 of 3 diets: 1) a control diet, in which the participant received 100% of his or her calorie needs 7 days per week, 2) a daily CR diet, in which the participant received 78% of his or her calorie needs 7 days per week, or 3) an intermittent CR diet, in which the participant received 100% of his or her calorie needs on 5 days per week and 25% of his or her calorie needs 2 days per week (i.e., a "5:2" style diet). Untargeted metabolomics was performed on plasma samples at weeks 0, 4 and 8 at Metabolon Inc (Durham, NC). Flow cytometry of cryopreserved peripheral blood mononuclear cells at weeks 0 and 8 were used to identify CD3+;CD4+ (CD4+) and CD3+;CD4- (as a proxy for CD8+) T cell subsets including effector memory, central memory, and naïve cells. FINDINGS 31 (86%) completed the trial. Over time, individuals randomised to intermittent CR had significant reductions in effector memory (for CD4-EM: -3.82%; 95%CI: -7.44, -0.21; for CD4-: -6.96%; 95%CI: -11.96, -1.97) and Th1 subsets (-4.26%; 95% CI: -7.11, -1.40) and proportional increases in naïve subsets (for CD4-: 10.11%; 95%CI: 3.30, 16.92%). No changes were observed for daily CR or weight-stable diets. Larger within-person changes in lysophospholipid and lysoplasmalogen metabolites in intermittent CR were associated with larger reductions in memory T cell subsets and larger increases in naïve T cell subsets. INTERPRETATION In people with MS, an intermittent CR diet was associated with reduction in memory T cell subsets and certain biologically-relevant lipid markers. FUNDING National MS Society, NIH, Johns Hopkins Catalyst Award.
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Safety and feasibility of various fasting-mimicking diets among people with multiple sclerosis.
Roman, SN, Fitzgerald, KC, Beier, M, Mowry, EM
Multiple sclerosis and related disorders. 2020;:102149
Abstract
BACKGROUND Fasting-mimicking diets have shown promise in experimental autoimmune encephalitis and are currently being investigated among people with multiple sclerosis (MS). Ensuring adherence to diet changes is critical to determining the efficacy of such interventions. OBJECTIVE Our primary aim was to evaluate the safety and feasibility of several fasting-mimicking diets and investigate whether various levels of clinical support improve diet adherence among people with MS. Secondarily, this study evaluated the impact of fasting-mimicking diets on weight and patient-reported outcomes (PROs). METHODS We conducted three pilot studies (two randomized controlled for 6 months; one randomized with transition to single arm) restricting either the amount or timing of calorie intake over 24 or 48 weeks. Interventions included calorie restriction (daily or intermittently) or time-restricted feeding. Adherence measures varied across studies but were collected at study visits along with weight and PRO data. RESULTS A total of 90 participants enrolled; 70 completed the studies, with no serious adverse events reported. Overall adherence to the calorie restriction diets was poor. When participants were tasked with maintaining a diet in a pragmatic setting, neither previously completed intense clinical support and education, nor weekly electronic communication throughout the diet period appeared to improve diet adherence. Participants who were able to adhere to a calorie restriction diet predictably lost weight. In contrast to calorie restriction, adherence to a time-restricted feeding (TRF) diet was relatively good. No statistically significant changes in PROs were observed in an intention-to-treat analysis. CONCLUSION The role diet may play in clinical outcomes in MS remains unknown, as class I evidence is lacking. Diet adherence remains a primary barrier to the feasible conduct of large, randomized controlled diet trials. Strict adherence to a TRF dietary change may be more feasible than calorie restriction and should be considered in future fasting-mimicking diet trials. ClinicalTrials.gov Registry:A Pilot Study of Intermittent Calorie Restriction in Multiple Sclerosis - NCT02647502. A Pragmatic Trial of Dietary Programs in People with Multiple Sclerosis (MS) - NCT02846558.
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Conducting dietary intervention trials in people with multiple sclerosis: Lessons learned and a path forward.
Fitzgerald, KC, Sand, IK, Senders, A, Spain, R, Giesser, B, Sullivan, P, Baer, DJ, LaRocca, N, Zackowski, K, Mowry, EM
Multiple sclerosis and related disorders. 2020;:101478
Abstract
Disease course in people with multiple sclerosis (MS) is heterogeneous. The impact of dietary and nutritional factors on MS prognosis is of interest to both patients and clinicians; differences in diet are hypothesized to contribute to disease evolution over time. However, studying diet, especially in people with MS, introduces methodologic complexity that should be recognized. In this review, we focus on methodological aspects relevant to the conduct of dietary interventions in people with MS, given our experience in leading such studies and the challenges we encountered in the realization of this work. We summarize key aspects of study design and important considerations, regardless of the specifics of the actual study (e.g. the particular diet of interest, target MS population, etc.). We discuss strategies for the design of the intervention as well as the selection of appropriate study endpoints. Finally, we provide an overview of strategies to improve the rigor of conducting dietary studies in people with MS.
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Effect of intermittent vs. daily calorie restriction on changes in weight and patient-reported outcomes in people with multiple sclerosis.
Fitzgerald, KC, Vizthum, D, Henry-Barron, B, Schweitzer, A, Cassard, SD, Kossoff, E, Hartman, AL, Kapogiannis, D, Sullivan, P, Baer, DJ, et al
Multiple sclerosis and related disorders. 2018;23:33-39
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Plain language summary
Multiple sclerosis (MS) is a disease of the central nervous system. Dietary modification is emerging as a safe intervention to potentially modify disease course. The main aim of this study was to assess the safety and feasibility of an intermittent fasting diet in people with MS. Secondary outcomes explored the effects of calorie restriction (CR) diets on body weight and anthropometric characteristics as well as on patient-reported outcomes including fatigue, sleep and mood. The study is a pilot randomised controlled feeding study of three different types of diets. Each participant (n=36) was randomized to 1 of 3 diets: a control diet (placebo), a daily CR diet and intermittent CR diet. Results indicate that daily CR diet was associated with marginally greater weight loss than the intermittent CR diet. Both CR diets were associated with trends toward improvements in cardiometabolic outcomes. Furthermore, CR diets were associated with in improvements in emotional well-being. Authors conclude that CR and weight loss represent interventions for clinically relevant symptoms due to MS, such as emotional well-being, without adding meaningful risks or adverse outcomes.
Abstract
An intermittent fasting or calorie restriction diet has favorable effects in the mouse forms of multiple sclerosis (MS) and may provide additional anti-inflammatory and neuroprotective advantages beyond benefits obtained from weight loss alone. We conducted a pilot randomized controlled feeding study in 36 people with MS to assess safety and feasibility of different types of calorie restriction (CR) diets and assess their effects on weight and patient reported outcomes in people with MS. Patients were randomized to receive 1 of 3 diets for 8 weeks: daily CR diet (22% daily reduction in energy needs), intermittent CR diet (75% reduction in energy needs, 2 days/week; 0% reduction, 5 days/week), or a weight-stable diet (0% reduction in energy needs, 7 days/week). Of the 36 patients enrolled, 31 (86%) completed the trial; no significant adverse events occurred. Participants randomized to CR diets lost a median 3.4 kg (interquartile range [IQR]: -2.4, -4.0). Changes in weight did not differ significantly by type of CR diet, although participants randomized to daily CR tended to have greater weight loss (daily CR: -3.6 kg [IQR: -3.0, -4.1] vs. intermittent CR: -3.0 kg [IQR: -1.95, -4.1]; P = 0.15). Adherence to study diets differed significantly between intermittent CR vs. daily CR, with lesser adherence observed for intermittent CR (P = 0.002). Randomization to either CR diet was associated with significant improvements in emotional well-being/depression scores relative to control, with an average 8-week increase of 1.69 points (95% CI: 0.72, 2.66). CR diets are a safe/feasible way to achieve weight loss in people with MS and may be associated with improved emotional health.
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Metabolic alterations in multiple sclerosis and the impact of vitamin D supplementation.
Bhargava, P, Fitzgerald, KC, Calabresi, PA, Mowry, EM
JCI insight. 2017;(19)
Abstract
BACKGROUND Our goal was to identify changes in the metabolome in multiple sclerosis (MS) and how vitamin D supplementation alters metabolic profiles in MS patients and healthy controls. METHODS We applied global untargeted metabolomics to plasma from a cross-sectional cohort of age- and sex-matched MS patients and controls and a second longitudinal cohort of MS patients and healthy controls who received 5,000 IU cholecalciferol daily for 90 days. We applied partial least squares discriminant analysis, weighted correlation network analysis (WGCNA), and pathway analysis to the metabolomics data. Generalized estimating equations models were used to assess change in WGCNA-identified module scores or metabolite pathways with vitamin D supplementation. RESULTS Utilizing multiple analytical techniques, we identified metabolic alterations in oxidative stress (γ-glutamyl amino acid, glutathione) and xenobiotic metabolism (benzoate, caffeine) in MS patients compared with healthy controls in the first cohort. In the vitamin D supplementation cohort, we identified two sets of metabolites altered differentially between MS patients and healthy controls with vitamin D supplementation. The first included markers of oxidative stress and protein oxidation (P = 0.006), while the second contained lysolipids and fatty acids (P = 0.03). CONCLUSIONS Using metabolomics, we identified alterations in oxidative stress and xenobiotic metabolism in MS patients and subsequently demonstrated a reduction of oxidative stress markers with vitamin D supplementation in healthy controls but not in MS patients. We demonstrate the utility of metabolomics in identifying aberrant metabolic processes and in monitoring the ability of therapeutic interventions to correct these abnormalities. TRIAL REGISTRATION ClinicalTrials.gov NCT01667796. FUNDING This study was supported by NIH grant K23 NS067055, grants from the Race to Erase MS, the National Multiple Sclerosis Society, the American Academy of Neurology, and North American Research Committee on Multiple Sclerosis.
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Sodium intake and multiple sclerosis activity and progression in BENEFIT.
Fitzgerald, KC, Munger, KL, Hartung, HP, Freedman, MS, Montalbán, X, Edan, G, Wicklein, EM, Radue, EW, Kappos, L, Pohl, C, et al
Annals of neurology. 2017;(1):20-29
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Abstract
OBJECTIVE To assess whether a high-salt diet, as measured by urinary sodium concentration, is associated with faster conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and MS activity and disability. METHODS BENEFIT was a randomized clinical trial comparing early versus delayed interferon beta-1b treatment in 465 patients with a CIS. Each patient provided a median of 14 (interquartile range = 13-16) spot urine samples throughout the 5-year follow-up. We estimated 24-hour urine sodium excretion level at each time point using the Tanaka equations, and assessed whether sodium levels estimated from the cumulative average of the repeated measures were associated with clinical (conversion to MS, Expanded Disability Status Scale [EDSS]) and magnetic resonance imaging (MRI) outcomes. RESULTS Average 24-hour urine sodium levels were not associated with conversion to clinically definite MS over the 5-year follow-up (hazard ratio [HR] = 0.91, 95% confidence interval [CI] = 0.67-1.24 per 1g increase in estimated daily sodium intake), nor were they associated with clinical or MRI outcomes (new active lesions after 6 months: HR = 1.05, 95% CI = 0.97-1.13; relative change in T2 lesion volume: -0.11, 95% CI = -0.25 to 0.04; change in EDSS -0.01, 95% CI = -0.09 to 0.08; relapse rate: HR = 0.78, 95% CI = 0.56-1.07). Results were similar in categorical analyses using quintiles. INTERPRETATION Our results, based on multiple assessments of urine sodium excretion over 5 years and standardized clinical and MRI follow-up, suggest that salt intake does not influence MS disease course or activity. Ann Neurol 2017;82:20-29.
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Hormone therapy use and physical quality of life in postmenopausal women with multiple sclerosis.
Bove, R, White, CC, Fitzgerald, KC, Chitnis, T, Chibnik, L, Ascherio, A, Munger, KL
Neurology. 2016;(14):1457-1463
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Abstract
OBJECTIVE To determine the association between hormone therapy (HT) and physical quality of life (QOL) in postmenopausal women with multiple sclerosis (MS). METHODS We included female participants from the prospective Nurses' Health Study, with a diagnosis of definite or probable MS, who had completed a physical functioning assessment (PF10; subscale of the 36-Item Short-Form Health Survey QOL survey) at a time point between 3 and 10 years after their final menstrual period (early postmenopause). We assessed the association between HT use at this time point (never vs at least 12 months of systemic estrogen with/without progestin) and both PF10 and the 36-Item Short-Form Health Survey Physical Component Scale. We used a linear regression model adjusting for age, MS duration, menopause type and duration, and further for additional covariates (only ancestry was significant). RESULTS Among 95 participants meeting all inclusion criteria at their first postmenopausal assessment, 61 reported HT use and 34 reported none. HT users differed from non-HT users in MS duration (p = 0.02) and menopause type (p = 0.01) but no other clinical or demographic characteristics. HT users had average PF10 scores that were 23 points higher than non-HT users (adjusted p = 0.004) and average Physical Component Scale scores that were 9.1 points higher in the 59 women with these available (adjusted p = 0.02). Longer duration of HT use was also associated with higher PF10 scores (p = 0.02, adjusted p = 0.06). CONCLUSIONS Systemic HT use was associated with better physical QOL in postmenopausal women with MS in this observational study. Further studies are necessary to investigate causality.
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Association of Vitamin D Levels With Multiple Sclerosis Activity and Progression in Patients Receiving Interferon Beta-1b.
Fitzgerald, KC, Munger, KL, Köchert, K, Arnason, BG, Comi, G, Cook, S, Goodin, DS, Filippi, M, Hartung, HP, Jeffery, DR, et al
JAMA neurology. 2015;(12):1458-65
Abstract
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.