Seasonal variations of 25-OH vitamin D serum levels are associated with clinical disease activity in multiple sclerosis patients

doi:10.1016/j.jns.2017.01.059

Journal of the Neurological Sciences

Volume 375, 15 April 2017, Pages 160-164

https://doi.org/10.1016/j.jns.2017.01.059 Get rights and content

Highlights

•
25-(OH)-D serum concentrations showed seasonal variations in patients with multiple sclerosis.
•
the nadir of vitamin D serum concentrations in winter preceded the peak in prevalence of relapses in spring by two months.
•
an increment of 10 ng/ml 25-(OH)-D resulted in 20% reduction in the prevalence of relapse at visit.

Abstract

Low 25-hydroxy vitamin D (25-[OH]-D) serum concentrations have been associated with higher disease activity in multiple sclerosis (MS) patients. In a large cross-sectional study we assessed the vitamin D status in MS patients in relation to seasonality and relapse rate. 415 MS-patients (355 relapsing-remitting MS and 60 secondary-progressive, 282 female, mean age 39.1 years) of whom 25-(OH)-D serum concentrations were determined at visits between 2010 and 2013 were included in the study. All clinical data including relapse at visit and expanded disability status scale were recorded in a standardized manner by an experienced neurologist. Seasonal variations of 25-(OH)-D serum concentrations were modelled by sinusoidal regression and seasonal variability in the prevalence of relapse by cubic regression. The mean 25-(OH)-D serum concentration was 24.8 ng/ml (range 8.3–140 ng/ml) with peak levels of 32.2 ng/ml in July/August and nadir in January/February (17.2 ng/ml). The lowest modelled prevalence of relapse was in September/October (28%) and the highest modelled prevalence in March/April (47%). The nadir of 25-(OH)-D serum concentrations preceded the peak in prevalence of relapses by two months. In summary, seasonal variation of 25-(OH)-D serum levels were inversely associated with clinical disease activity in MS patients. Future studies should investigate whether vitamin D supplementation in MS patients may decrease the seasonal risk for MS relapses.

Introduction

During recent years there is increasing evidence that vitamin D may contribute to the pathogenesis of multiple sclerosis (MS) and influences the disease course and activity [1], [2], [3], [4]. Several studies reported an association of low serum 25-hydroxy vitamin D (25-[OH]-D) concentrations with the occurrence of MS relapses as well as disease activity on magnetic resonance imaging (MRI) [5], [6], [7], [8], [9], [10], [11], [12].

Vitamin D synthesis depends on sunlight exposure and vitamin D serum concentrations show seasonal variations especially in northern latitudes where UVB radiation is low during autumn and winter [13], [14]. In Germany up to 62% of the adult population with permanent residence in Germany have been reported to have suboptimal vitamin D serum levels especially during winter and spring: 4308 of the 6995 study participants showed vitamin D deficiency below 20 ng/ml (after conversion of the study results to ng/ml) [15]. Early studies on seasonal variations of relapse onset probability in MS showed conflicting results, however a meta-analysis in 2000 identified a clear association of relapse onset and season with a spring peak and a winter trough [16]. This could be recently confirmed by a multinational study from Australia which revealed latitude dependent seasonal variations of relapse rates [17]. In addition seasonal variability of disease activity on MRI in MS patients was reported in an earlier study where the highest prevalence of active – gadolinium enhancing - MS lesions on cerebral MRI was observed in spring/early summer and the lowest in autumn [18]. So far there is no systematic investigation on vitamin D serum concentrations in relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) patients in Germany in relation to seasonal variability.

The aim of this study was to assess 25-(OH)-D serum concentrations and possible seasonal variations as well as their association with clinical disease activity in a large cross sectional, single centre study of MS patients in Germany.

Section snippets

Patients

All patients were seen at our outpatient clinic at the Institute of Clinical Neuroimmunology which is a tertiary hospital in Munich specialized on the treatment of patients with MS. Visits of MS patients are triggered by the following indications: to establish and/or confirm the diagnosis of MS, to initiate or recommend disease modifying therapies (DMTs), to monitor the therapeutic effects and side-effects of DMT's and to confirm and treat MS relapses. During the visits clinical data such as

Statistical analysis

Descriptive and inductive statistics were performed with the statistical software R (R 3.1.0). The seasonal variation in the 25-(OH)-D serum concentrations was modelled by sinusoidal regression by month at measurement in accordance with previous publications [2], [5], [8], [21], [22]. In order to obtain sufficient and balanced numbers in each time category we coded the calendar-months the serum sample was taken into bimonthly intervals. Seasonal variability in the prevalence of relapses was

Clinical characteristics of patients

A total of 415 MS-patients were included, 355 with RRMS and 60 with SPMS. The proportions of patients visiting the outpatient clinic in winter (206) and summer (209) was almost identical. The mean age (± SD) was 39.6 (± 11.3) years. 212 of the 415 patients (51%) received a disease modifying therapy (DMT). A total of 158 patients had a relapse at visit (38%). All clinical characteristics are displayed in Table 1.

Distribution of 25-(OH)-D serum concentrations

The mean 25-(OH)-D serum concentrations of all patients were 24.8 ng/ml (range:

Discussion and conclusion

As commonly observed in the general population, a 25-(OH)-D deficiency was also evident in MS patients, and 25-(OH)-D serum concentrations showed a clear seasonal variation with a peak in end of summer/beginning of autumn and a nadir in end of winter/beginning of spring [23]. The prevalence of relapse at visit also showed seasonal variations and was inversely associated with 25-(OH)-D serum concentrations. The trough and peak of the seasonal changes in 25 (OH) D serum levels preceded the

Author contribution

Patient care and management: T. Kümpfel, L.A. Gerdes.

Study design, acquisition and analysis of data: Ch. Hartl, V. Obermeier, T. Kümpfel, M. Brügel.

Drafting a significant portion of the manuscript or figures: T. Kümpfel, Ch. Hartl, V. Obermeier, R v. Kries critical revision of the manuscript for intellectual content: T. Kümpfel, L.A. Gerdes, R v. Kries, M. Brügel.

Conflict of interest

There is no conflict of interest and all authors have nothing to disclose.

Funding

This study was supported by the German Federal Ministry of Education and Research, Multiple Sclerosis Disease-Related Competence Network (“Klinisches Kompetenznetz Multiple Sklerose”, MS cohort study 01GI0914) and “Verein zur Therapieforschung für MS Kranke”.

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Vitamin D status, proinflammatory cytokines and bone mineral density in Mexican people with multiple sclerosis
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Citation Excerpt :
Additionally, diverse clinical signs have been linked to VD insufficiency in people with MS such as osteoporosis, cognitive impairment, fatigue, disability, exacerbation of relapses and progression of disease (Darwish et al., 2017; Pilutti and Motl, 2019; Sintzel et al., 2018; Zamzam et al., 2019). Despite deficient concentrations of VD (< 20 ng/mL) have been widely reported in different populations with MS (> 90% of prevalence) there is scarce information in Latin-America (LA); since latitudes between 40 ° North and South are considered as regions with sufficient annual UVB sun exposure, VD sufficiency has been assumed, however, recent evidence suggests that this may have been underestimated (Barnes et al., 2007; Hartl et al., 2017; Holick, 2015; Kępczyńska et al., 2016; Kirbas et al., 2013; Mendes et al., 2018). In México (32 ° 43′ N, 14 ° 32′ S), although MS is considered a rare disease, recent studies reported an increase of prevalence, from 1.6 cases per 100,000 inhabitants in the decade of 1970 to nearly 15 cases per 100,000 inhabitants nowadays.
Vitamin D (VD) has been classically associated with calcium homeostasis and bone mineral density since it has a key role on mineralization and resorption. Immunomodulatory effects have been attributable to VD; low concentrations of VD have been associated with elevation of inflammatory markers. Inflammatory autoimmune diseases, such as multiple sclerosis (MS), a chronic neurodegenerative suffering, whose etiology is still unknown, is directly related to an increase in pro-inflammatory cytokines such as interleukin 17 and interleukin 1β who play an important role in this physiopathology. Nowadays, even though additional studies have linked MS's clinical signs with low VD concentration, there is scarce information of this association in people from regions with sufficient sun exposure. The aim of this study was to evaluate serum VD and cytokine concentrations, and bone density, in Mexican people with MS.
Vitamin D (25OHD), interleukin 1β, interleukin 6 and interleukin 17 concentrations of twenty-five volunteers with MS were determined by enzyme-linked immunosorbent assay. Bone mineral density and body composition assessment was performed by dual energy X-Ray absorptiometry.
A mean concentration of 17.3 ± 4.6 ng/ml of 25OHD was obtained, in a range of 5.15 to 25.71 ng/ml; when international advisory bodies thresholds were applied 76% of the participants exhibited some degree of VD inadequacy. Pro-inflammatory markers were detectable among the participants: interleukin 1β in 100%, interleukin 6 in 64%, whereas interleukin 17 was found in 24% of the volunteers. Bone mineral density below the expected for the age was found in 8% of the participants, with lumbar spine as the most affected anatomic region. Non-significant correlations were found between VD and bone mineral density (Z-score) or pro-inflammatory markers.
Although non-significant correlations were found between VD and bone mineral density or cytokines, it is important to highlight that an important percentage of our participants exhibited some degree of VD inadequacy, an unknown fact for them, since these are not included in routine clinical evaluations. The low concentrations of VD among this sample regardless of annual UVB sun exposure may suggest the involvement of endogenous and not environmental factors. Further works are needed in order to deepen the physiological causes and effects of VD deficiency in people with MS.
Seasonal fluctuations in serum levels of vitamin D in Japanese patients with multiple sclerosis
2021, Journal of Neuroimmunology
Citation Excerpt :
However, 25(OH)D is the only form of vitamin D that is used to identify vitamin D deficiency, sufficiency, or intoxication (Holick, 2009) because it has a longer circulating half-life (approximately 2–3 weeks vs. only 4–6 h) and higher circulating levels than 1,25(OH)2D (Holick, 2009). Therefore, 25(OH)D status, but not 1,25(OH)2D status, has been measured in many studies on MS patients (Munger et al., 2006; Mowry et al., 2010; Runia et al., 2012; Hartl et al., 2017; Biström et al., 2019; Ostkamp et al., 2021). Our previous analysis of correlation between EDSS or MSSS and serum levels of 1,25(OH)2D or 25(OH)D measured only between June and August in patients with MS in Hokkaido revealed negative correlations between 25(OH)D and EDSS/MSSS but not between 1,25(OH) 2D and EDSS/MSSS (Niino et al., 2013).
We explored the presence of seasonal fluctuations in serum vitamin D levels and potential relationship between vitamin D levels and disease severity or prognosis in patients with multiple sclerosis (MS) in northern Japan. Serum levels of 25(OH)D in spring were significantly lower than in summer and autumn, whereas no differences in 1,25(OH)₂D levels were demonstrated among four seasons. Seasonal fluctuations in 25(OH)D were demonstrated in patients with EDSS ≤3.5, but not in those with EDSS≥4.0. Negative correlations between 25(OH)D and EDSS or MSSS were found in each season. Seasonal fluctuations in 25(OH)D levels may be affected by physical disabilities.
Daily and seasonal mitochondrial protection: Unraveling common possible mechanisms involving vitamin D and melatonin
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Multiple sclerosis, a demyelinating inflammatory disease, has been the cornerstone for establishing relationships between melatonin and vitamin D. Ghareghani and colleagues recently published a review summarizing and proposing common mechanisms between sunlight, vitamin D, bacterial infection, and melatonin production in the pathophysiology of multiple sclerosis [3]. A variety of epidemiological and experimental evidence proposes that high circulating levels of vitamin D are linked with a lower risk of multiple sclerosis [4–6], and the supplementation of the vitamin might reduce the relapses [7]. Insufficient sunshine exposure and hypovitaminosis D are widespread in temperate countries, which present the highest incidence for multiple sclerosis [8].
From an evolutionary point of view, vitamin D and melatonin appeared very early and share functions related to defense mechanisms. In the current clinical setting, vitamin D is exclusively associated with phosphocalcic metabolism. Meanwhile, melatonin has chronobiological effects and influences the sleep-wake cycle. Scientific evidence, however, has identified new actions of both molecules in different physiological and pathological settings. The biosynthetic pathways of vitamin D and melatonin are inversely related relative to sun exposure. A deficiency of these molecules has been associated with the pathogenesis of cardiovascular diseases, including arterial hypertension, neurodegenerative diseases, sleep disorders, kidney diseases, cancer, psychiatric disorders, bone diseases, metabolic syndrome, and diabetes, among others. During aging, the intake and cutaneous synthesis of vitamin D, as well as the endogenous synthesis of melatonin are remarkably depleted, therefore, producing a state characterized by an increase of oxidative stress, inflammation, and mitochondrial dysfunction. Both molecules are involved in the homeostatic functioning of the mitochondria. Given the presence of specific receptors in the organelle, the antagonism of the renin-angiotensin-aldosterone system (RAAS), the decrease of reactive species of oxygen (ROS), in conjunction with modifications in autophagy and apoptosis, anti-inflammatory properties inter alia, mitochondria emerge as the final common target for melatonin and vitamin D. The primary purpose of this review is to elucidate the common molecular mechanisms by which vitamin D and melatonin might share a synergistic effect in the protection of proper mitochondrial functioning.
Nutrition and autoimmune diseases
2020, Present Knowledge in Nutrition: Clinical and Applied Topics in Nutrition
Autoimmune diseases are a host of diseases characterized by abnormal immune response against normal tissues of the body. There are about 100 autoimmune diseases, and they are estimated to affect at least 3%–5% of population. While the etiology is still unclear, both genetic and environmental factors are recognized to play key roles in the disease development. Pharmaceutical therapies have substantially improved the disease control and prognosis. However, the adverse effects and high cost of the drugs limit their use. There has been an increasing interest in alternative and complementary means to improve the outcomes of conventional therapies in many autoimmune diseases. Diet as a modifiable factor has the potential to improve clinical outcomes for several major autoimmune diseases. This chapter provides a summary and analysis of both observational and experimental studies as well as perspectives on the role of nutrition in prevention and treatment of some of the most prominent autoimmune diseases.
Seasonal Changes in Serum Metabolites in Multiple Sclerosis Relapse
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¹: These authors contributed equally.

View full text

Seasonal variations of 25-OH vitamin D serum levels are associated with clinical disease activity in multiple sclerosis patients

Highlights

Abstract

Introduction

Section snippets

Patients

Statistical analysis

Clinical characteristics of patients

Distribution of 25-(OH)-D serum concentrations

Discussion and conclusion

Author contribution

Conflict of interest

Funding

J. Steroid Biochem. Mol. Biol.

J. Neurol. Sci.

Mayo Clin. Proc.

Am. J. Med.

J. Neuroimmunol.

Eur. J. Cell Biol.

J. Neurol. Sci.

J. Neuroimmunol.

Contemp. Clin. Trials

J. Neurol. Sci.

A longitudinal study of serum 25-hydroxyvitamin D and intact parathyroid hormone levels indicate the importance of vitamin D and calcium homeostasis regulation in multiple sclerosis

J. Neurol. Neurosurg. Psychiatry

Immunomodulatory effects of vitamin D in multiple sclerosis

Brain

Vitamin D is associated with degree of disability in patients with fully ambulatory relapsing-remitting multiple sclerosis

Eur. J. Neurol.

Low 25-hydroxyvitamin D, but not the bioavailable fraction of 25-hydroxyvitamin D, is a risk factor for multiple sclerosis

Eur. J. Neurol.

Lower serum vitamin D levels are associated with a higher relapse risk in multiple sclerosis

Neurology

Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis

Ann. Neurol.

Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis

Mult. Scler.

Vitamin D as an early predictor of multiple sclerosis activity and progression

JAMA Neurol.

Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis

Ann. Neurol.

25-Hydroxyvitamin D levels in serum at the onset of multiple sclerosis

Mult. Scler.

Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis

Ann. Neurol.

Seasonal prevalence of MS disease activity

Neurology

Vitamin D: a candidate for the environmental effect in multiple sclerosis - observations from Norway

Neuroepidemiology

Vitamin D status among adults in Germany-results from the German Health Interview and Examination Survey for adults (DEGS1)

BMC Public Health

Seasonal variation of relapse rate in multiple sclerosis is latitude dependent

Ann. Neurol.