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Vitamin D supplementation reduces relapse rate in relapsing-remitting multiple sclerosis patients treated with natalizumab
Multiple Sclerosis and Related Disorders, November 2016, Pages 169 - 173
Vitamin D insufficiency is common among multiple sclerosis patients, and hypovitaminosis D has been associated with multiple sclerosis (MS) risk and disease activity.
To investigate how recommendations on vitamin D3 supplements affect 25-hydroxyvitamin D (25(OH)D) levels in patients with relapsing-remitting MS (RRMS) and to examine the clinical effects associated with changes in 25(OH)D levels.
In this prospective cohort study, baseline blood samples were collected from 170 natalizumab-treated RRMS patients during winter 2009–2010 and were repeated the following winter. Vitamin D supplements were recommended according to standard clinical practice in our clinic to patients with serum 25(OH)D<50 nmol/l at baseline. Information was obtained on annualized relapse-rate (ARR) the year prior to baseline and the following year.
We found that recommending vitamin D supplements in patients with vitamin D insufficiency was associated with a significant increase in serum 25(OH)D concentrations (p=5.1×10−10), which was significantly related with decreases in ARR; for each nmol/l increase in Δ25(OH)D a −0.014 (95% CI −0.026 to −0.003) decrease in ΔARR was observed, p=0.02.
Correction of hypovitaminosis D in clinical practice by recommending oral D3 supplements resulted in increases in 25(OH)D levels in serum, which were associated with decreases in ARR in RRMS.
- Recommending vitamin D3 supplements in vitamin D insufficient, relapsing-remitting MS patients is associated with increased 25-hydroxyvitamin D (25(OH)D) levels.
- Increased 25(OH)D levels in these patients are associated with decreases in the annualized relapse rate (ARR).
- No association was found between changes in 25(OH)D and changes in gene expression of molecules representing the immune system. This reflects how complex vitamin D research is.
Keywords: Multiple sclerosis, 25-hydroxyvitamin D, Vitamin D3 supplement, Annualized relapse-rate, Immunomodulation.
Low serum levels of 25-hydroxyvitamin D (25(OH)D), low intake of dietary vitamin D and lack of sun exposure have been suggested as environmental risk factors for multiple sclerosis (MS), indicating a potential role of vitamin D in the pathogenesis of MS (Munger et al, 2006, Munger et al, 2004, Salzer et al, 2012, and Islam et al, 2007). MS patients in general have lower serum levels of 25(OH)D than do healthy controls, supporting pathogenetic effects of vitamin D insufficiency in MS (Soilu-Hanninen et al., 2005). Moreover, protective effects of higher vitamin D levels have been suggested during the disease course of MS (Simpson et al, 2010, Pierrot-Deseilligny et al, 2012, Mowry et al, 2012, Scott et al, 2013, Runia et al, 2012, and Soilu-Hanninen et al, 2012a). Low serum levels of 25(OH)D in patients with clinically isolated syndromes (CIS) have been associated with increased risk of developing clinically definite MS (Martinelli et al., 2013). This is supported by a study reporting that 25(OH)D is not only associated with the risk of conversion from CIS to clinically definite MS, but is also associated with disease activity and disability over a five year period (Ascherio et al., 2014). Based on these findings it has been suggested that serum 25(OH)D levels at disease onset could predict the disease course in MS. The exact mechanisms by which vitamin D affects the pathogenesis of MS are uncertain, but it is well established that the active vitamin D metabolite, 1, 25-dihydroxyvitamin D (1, 25(OH)2D) has immunomodulatory effects that could be beneficial in autoimmune diseases (reviewed by Prietl and collegues (Prietl et al., 2013)). In studies of experimental autoimmune encephalomyelitis (EAE), the rodent model of MS, and in vitro a vitamin D-induced induction of indoleamine 2, 3-dioxygenase (IDO) expression, leading to the induction of CD4+CD25+FoxP3+ regulatory T cells and an increase in interleukin-10 expression has been proposed as part of the immunomodulatory potential of vitamin D (Correale et al, 2009 and Farias et al, 2013).
Interestingly, a recent study comparing vitamin D- and interferon-induced genes associated with disease activity on magnetic resonance imaging (MRI) in CIS showed a significant overlap between the genes (Munger, 2013). Synergistic effects of vitamin D and interferon-beta (IFN-β) have been suggested previously. In EAE, disease protection by IFN-β monotherapy is significantly ameliorated by adding a vitamin D analogue to the IFN-β treatment (van et al., 2007). This finding is supported by clinical studies, which have shown that the effects of 25(OH)D and IFN-β might potentiate each other in MS (Stewart et al, 2012 and Soilu-Hanninen et al, 2012b). Furthermore, previous studies from our group suggest that endogenous type 1 IFNs and IFN-β show overlapping, protective effects in MS.
Recently, attention has been paid to a novel immunoregulatory T-cell subset, FoxA1+Treg cells, which express programmed cell death 1 ligand 1 (PD-L1 or CD274) and may be crucially involved in mediating immunoregulatory effects of IFN-β (Liu et al., 2014). The effects of vitamin D on this cell type and potential interactions with endogenous type 1 IFN activity is unknown.
We hypothesized that in an outpatient clinic setting a substantial proportion of MS patients would have low serum 25(OH)D levels (25(OH)D <50 nmol/l), and studied the effects of a simply recommendation on vitamin D supplements in these patients on 25(OH)D levels and the annualized relapse rate (ARR) in a one year prospective study. We selected to study a group MS patients treated with natalizumab, because they are in close contact with the MS clinic, coming for infusion every month, assuring that all relapses are carefully evaluated.
2. Participants and methods
Of 233 ethnically Danish natalizumab-treated RRMS patients attending the Danish Multiple Sclerosis Center in 2009 written informed consent for study participation was obtained from 210 patients.
All patients were diagnosed with MS according to the 2005 revised McDonald criteria and were classified as “highly active MS patients” defined as either two relapses in one year or three relapses in two years prior to natalizumab initiation in spite of first-line treatment or as patients with extraordinary disease activity at time of diagnosis (Polman et al, 2005 and Sorensen et al, 2014). The patients had blood samples collected from December 2009 to March 2010 (baseline) and from December 2010 to March 2011 (follow up). Patients with 25(OH)D below 50 nmol/l at baseline were recommended vitamin D3 supplies according to local guidelines (Table 1). Patients were recommended rechecks of the 25(OH)D levels at their general practitioner in the period between baseline and follow up, but we did not follow up on this, since it was not of relevance for the study outcome. This study was performed as an observational study in real life setting to examine how a simple recommendation on vitamin D supplements to vitamin D insufficient RRMS patients could affect the 25(OH)D level without doing any further interventions.
Recommendations on tablet vitamin D3 according to National guidelines.
|Serum 25 (OH)D level in nmol/l||Recommended supplement (oral vitamin D3)|
|50>25(OH)D≥25||50 µga daily|
|25>25(OH)D≥12.5||75 µg daily|
|<12.5||100 µg daily|
a1 μg equals to 40 IU
During follow up 40 patients were excluded because they discontinued natalizumab treatment due to either pregnancy (5 patients), development of secondary progressive MS (2 patients), cancer (1 patient), development of anti-natalizumab antibodies (2 patients), moving to other parts of Denmark (2 patients) or other reasons such as fear of PML or low compliance to the clinical visits (28 patients), leaving 170 patients eligible for the study.
Of the 170 included patients, 134 had complete clinical information and were eligible for the study. The inclusion criteria were natalizumab treatment for at least 1 year prior to enrolment. Patient characteristics are shown in Table 2.
Baseline characteristics of the patients from the clinical substudy.
|Patient characteristics||Patients with 25 (OH)D<50 nmol/l, n=43||Patients with 25 (OH)D between 50 and 74 nmol/l, n=56||Patients with 25 (OH)D≥75 nmol/l, n=35||All patients in the clinical substudy, n=134|
|Age, years, mean (range)||40.0 (25–55)||40.8 (23–63)||43.6 (25–59)||41.3 (23–63)|
|Sex, male/female, n (%)||15/28 (35/65)||15/41 (27/73)||9/26 (26/74)||39/95 (29/71)|
|Duration of MS, years, mean (range)||11.6 (3–27)||11.5 (2–29)||11.6 (3–25)||11.6 (2–29)|
|EDSS, mean (range)||3.5 (0–6)||3.5 (0–6)||3.5 (1–6)||3.5 (0–6)|
|Baseline 25(OH)D, mean (range)||34 (10–48)||60.7 (50–74)||94.4 (75–138)||61 (10–138)|
|Baseline ARR, mean (range)||0.7 (0–5)||0.7 (0–3)||0.4 (0–3)||0.6 (0–5)|
EDSS=Expanded Disability Status Scale, ARR=Annualized relapse rate.
The study was approved by the local Ethics Committee (KF-01 314009).
2.1. Study design and clinical data
In this prospective cohort study all patients were followed prospectively and examined by a neurologist at 6 monthly intervals with registration of relapses and expanded disability status scores (EDSS). Clinical data on the patients including disease duration at baseline and ARR in the year prior baseline and from baseline to follow up were ascertained by review of all medical histories including both nurses’ charts and neurologists’ by one medical doctor (the corresponding author). Importantly this was done before the author knew about the patients 25(OH)D status. We defined a relapse as new neurological symptoms or exacerbation of existing symptoms for at least 24 h, in the absence of infection or fever or other neurologic conditions that could explain the symptoms.
2.2. Measurement of 25(OH)D
Plasma samples collected at baseline and at follow up were stored at −80 °C until analyzed. 25(OH)D was measured using a competitive electrochemiluminescent immunoassay on a Modular E-module analyzer (Roche, Mannheim, Germany). Assay precision was tested daily whereas assay accuracy was tested four times a year using an external quality control program (DEQAS). For control material at ~50 nmol/l and ~100 nmol/l the interassay coefficient of variance was 10% and 5%, respectively, and the lower measuring limit was 10 nmol/l. Vitamin D sufficiency was defined as 25(OH)D≥50 nmol/l, vitamin D insufficiency as 25(OH)D between 25 and 49 nmol/l, vitamin D deficiency as 25(OH)D between 13 and 24 nmol/l, and severe deficiency as 25(OH)D <12 nmol/l (Mosekilde, 2008).
Primary outcome measure was the effect of vitamin D recommendation on mean serum 25(OH)D and annualized relapse rate (ARR) in patients with baseline vitamin D insufficiency or deficiency. Additionally, we performed post-hoc analyses in patients with baseline 25(OH)D between 50–74 nmol/l and ≥75 nmol/l, which in many places is defined as the lower limit of vitamin D sufficiency in relation to extraskeletal effects of this vitamin (Holick, 2010). Changes in 25(OH)D and in ARR in the year prior to baseline as well as from baseline to follow up were analyzed by a paired samples t-test. A regression model was used to assess the association between the absolute changes in 25(OH)D (Δ25(OH)D) and changes in ARR (ΔARR). Potential confounders were included (disease duration, sex and age at baseline) in a multivariable regression analysis.
Statistical significance was set at p<0.05. Statistical analysis was performed using SPSS (version19).
Among all included patients in the clinical sub-study (n=134) 25(OH)D was <50 nmol/l in 43. Mean 25(OH)D at baseline in this vitamin D insufficient group was 34nmol/l, and Δ25(OH)D was 32.6 (95%CI 24.4–40.8, p=5.1×10−10); thus a significant increase in 25(OH)D was observed from baseline to follow up. See Table 3. Moreover, a significant and inverse relationship was observed between Δ25(OH)D and ΔARR in these patients both in a univariable analysis (p=0.02) and in a multivariable analysis adjusted for disease duration, sex and age, which did not change the result; for each nmol/l increase in Δ25(OH)D a −0.014 (95% CI −0.026 to −0.003) decrease in ΔARR was observed, p=0.02, Table 4. To exclude an effect of natalizumab treatment itself we did a post hoc analysis in which we stratified the 43 patients with baseline 25(OH)D<50 nM according to natalizumab treatment duration and this did not change the results. Mean duration of natalizumab treatment in this group at baseline was 24 months (range 14–38 months), results not shown.
Baseline 25(OH)D levels and changes in 25(OH)D (Δ25(OH)D) from baseline to follow up in the patient subgroups.
|N||Baseline mean 25 (OH)D, nmol/l||Δ25 (OH)D, nmol/l, (95%CI)||p-value|
|Patients with baseline 25(OH)D <50 nmol/la||43||34||32.6 24.4–40.8)||5.1×10−10|
|Patients with baseline 25(OH)D between 50–74 nmol/l||56||61||5.4 0.9–10.0)||0.02|
|Patients with baseline 25(OH)D≥75 nmol/l||35||94||2.4 (−7.1 to 11.9)||0.6|
|All patients included in the clinical part||134||61||13.4 (8.8–18.0)||5.3×10−8|
aTo whom D3 supplements were recommended.
Association between Δ25(OH)D and ΔARR.
|Effect size, B (95%CI)||P-value|
|Patients with baseline 25(OH)D<50 nmol/l, n=43|
|Δ25(OH)D on ΔARR||−0.014 (−0.026 to −0.003)||0.02|
|Patients with baseline 25(OH)D between 50–74 nmol/l, n=56|
|Δ25(OH)D on ΔARR||−0.004 (−0.02 to 0.1)||0.7|
|Patients with baseline 25(OH)D≥75 nmol/l, n=35|
|Δ25(OH)D on ΔARR||0.3× 10-4 (−0.01 to 0.01)||0.96|
|All patients included in the clinical sub-study, n=134|
|Δ25(OH)D on ΔARR||−0.005 (−0.011 to 0.001)||0.07|
Association between Δ25(OH)D and the dependent variable ΔARR in the patients in the multivariable regression analysis adjusted for disease duration, sex and age. The effect size B is measured as relapses per year, and 95% confidence intervals for B are included. For each nM increase in 25(OH)D level in the patients with baseline 25(OH)D<50 nM a 0.014 decrease in ARR was observed.
In the patients with 25(OH)D between 50–74 n mol/l at baseline (n=56), who were not specifically recommended vitamin D supplies, a significant increase in 25(OH)D was still observed; Δ25(OH)D=5.4 (95%CI 0.9–10.0), p=0.02 (Table 3). There was, however, no significant relationship between ΔARR and Δ25(OH)D in this subgroup (Table 4).
Finally, in the patients with 25(OH)D≥75 nmol/l (n=35) to whom vitamin D supplementation was neither recommended, there was no significant change in 25(OH)D: Δ25(OH)D=2.4nmol/l (95%CI −7.1 to11.9, p=0.6). Table 3. Neither was there any significant relationship between ΔARR and Δ25(OH)D in this patient subgroup (Table 4).
In this prospective cohort study examining the clinical effects of 25(OH)D in natalizumab-treated patients with RRMS from an outpatient clinic, we found that recommending vitamin D supplements in patients with vitamin D insufficiency or deficiency was associated with a significant increase in serum 25(OH)D concentrations. Furthermore, increases in 25(OH)D levels were significantly related with decreases in ARR.
Some studies have demonstrated favourable effects of 25(OH)D on the disease course in MS (Simpson et al., 2010; Pierrot-Deseilligny et al., 2012; Mowry et al., 2012; Scott et al., 2013; Runia et al., 2012; Soilu-Hanninen et al., 2012a), however, the overall evidence for this beneficial effect remains inconclusive (James et al, 2013 and Pozuelo-Moyano et al, 2013). In the present study recommendation on vitamin D supplies to patients with serum 25(OH)D<50 nmol/l had a significant and favourable effect on the ARR. Importantly, this was only observed for patients with baseline 25(OH)D levels below 50 nmol/l, who were recommended vitamin D supplies, since a post-hoc analysis of all patients with baseline levels below 75 nmol/l (data not shown) weakened the relationship, and when including all 134 patients in the analysis, the relationship was no longer statistically significant (Table 4).
We did not find a relationship between ΔARR and Δ25(OH)D in either patients with baseline 25(OH)D between 50–74 nmol/l or 25(OH)D ≥75 nmol/l. A possible explanation for this is that the increase in 25(OH)D in these groups was too small to affect clinical outcome. Indeed, vitamin D supplements were only recommended to vitamin D insufficient or deficient patients at baseline. However, it is also possible that it may be sufficient to achieve 25(OH)D concentrations above 50nmol/l to affect clinical outcome in patients with RRMS. The possibility of negative effects of administration of high doses of vitamin D3, although this is still an unsettled question, favours supplement of small doses of D3 since these have not previously been associated with any serious adverse events. This does not, however, exclude that additional effects may be seen if higher, non-physiological concentrations are achieved by vitamin D supplements in pharmacological doses. Ongoing randomized, double-blind, placebo-controlled studies may reveal additional effects of supraphysiological concentrations of 25(OH)D (Smolders et al, 2011 and Dorr et al, 2012).
The strength of our study was that blood samples were collected only at wintertime to avoid the influence of the seasonal variation in 25(OH)D. In addition, only patients of Danish origin were included, thereby reducing the risk of confounding by racial variations in the genetic regulation of vitamin D bioavailability and the effects mediated by vitamin D (Powe et al., 2013). Importantly, mean 25(OH)D at baseline in the 134 patients was higher than 50 nmol/l, the lower limit of vitamin D sufficiency in Denmark (Table 2), which could reduce the power to detect clinical effects of changes in 25(OH)D since an effect of 25(OH)D on disease activity may already have existed at baseline in all patients with 25(OH)D>50 nmol/l. This was supported by our primary result of an inverse and significant relationship between ΔARR and Δ25(OH)D in patients with baseline 25(OH)D<50 nmol/l, who experienced a significant increase in Δ25(OH)D in response to recommendation on vitamin D supplies from baseline to follow up. Since natalizumab-treated patients in our clinic are followed closely with monthly treatments and registrations, frequent blood analyses, and semi-annual clinical examinations by a neurologist, they may be a more well-informed group of patients regarding their disease, and many of them may already have used vitamin D supplements compared to other MS patients. Accordingly, a selection bias may be the reason for the relatively high mean baseline 25(OH)D in the 134 patients.
The main limitation in this study is the lack of a control group, and the natural course of the disease may therefore influence the results as well as increasing the risk of an effect by regression to the mean. Moreover, we only had one 25(OH)D measurement per year per patient, which may not correctly reflect the annualized vitamin D status in the patients. A prospective collection of serum samples every third month would have been preferable during the two year period from which we obtained information on the ARR. However, it has been suggested that a single measurement of 25(OH)D is a good indicator of the 25(OH)D level the preceding three years (Platz et al., 2004). Moreover, blood samples were only collected during winter time, which is considered as the most representative season for measuring the 25(OH)D status (Saltyte et al., 2012).
It is also important to notice that the mean disease duration in this study was 11 years. It has been suggested that vitamin D may favourably affect the disease course in MS, but only in patients with a disease duration ≤5 years (Smolders et al., 2008). In this study, nevertheless, mean disease duration in the subgroups did not differ from the overall high mean disease duration, and when adjusting for disease duration in the multivariable analysis it did not change the results. In this way we can exclude that a shorter disease duration in the group of patients with baseline vitamin D insufficiency could be the reason for a significant association between 25(OH)D and ARR. Finally, it would have been preferable to have a second clinical endpoint such as disease activity on magnetic resonance imaging (MRI), which could strengthen the results.
We conclude that simple recommendation of vitamin D supplements (50–100 µg/day) to RRMS patients with 25(OH)D<50 nmol/l was associated with a significant increase in mean 25(OH)D, and that this increase was inversely associated with ΔARR.
Conflict of interest
Julie Hejgaard Laursen has received honoraria for lecturing from Merck Serono and has had travel expenses reimbursed by Teva, Almirall and Merck Serono. Helle Bach Soendergaard has nothing to disclose. Per Soelberg Sorensen has received personal compensation from Biogen Idec, Merck Serono, Novartis, Genmab, TEVA, Elan, GSK, Bayer Schering and Sanofi-aventis, Genzyme as member of scientific advisory boards, steering committees or independent data monitoring boards in clinical trials, or as speaker at meetings. His research unit has received research support from Biogen Idec, Bayer Schering, Merck Serono, Sanofi-Aventis and Novartis. Finn Sellebjerg has served on scientific advisory boards for Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis and Teva, has been on the steering committee of a clinical trial sponsored by Merck Serono, and served as consultant for Biogen Idec and Novo Nordisk; has received support for congress participation from Biogen Idec, Novartis, Sanofi Aventis and Teva; has received speaker honoraria from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis and Schering-Plough. His laboratory has received research support from Biogen Idec, Bayer Schering, Merck Serono, Sanofi-Aventis and Novartis. Annette Oturai has served on scientific advisory boards for Novartis, and served as consultant for Biogen Idec; has received support for congress participation from Biogen Idec, Novartis, Sanofi Aventis and Teva; has received speaker honoraria from, Biogen Idec, Novartis, and Sanofi-Aventis. Her laboratory has received research support from Biogen Idec and Novartis.
We are grateful to the Danish Multiple Sclerosis Society (R367-Rp29216) for financial support.
Great thanks to the technical staff of the Laboratory of Neuroimmunology, Danish Multiple Sclerosis Center: Joy Mendel-Hartvig, Freja Melissa Bekner, Michael Kolbjørn Jensen and Rikke Larsen.
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Rigshospitalet, Copenhagen University Hospital, Danish Multiple Sclerosis Center, Department of Neurology, Blegdamsvej 9, 2100 Copenhagen, Denmark
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