xo++
03-07-2009, 11:56 AM
A few interesting Vitamin D studies in this year's batch of abstracts.
First, women with MS appear to benefit more from Vitamin D than men.
Secondly a small trial of Vitamin D3 found high-doses of D3 to be safe and to alter the immunological profile of patients in a manner thought to be beneficial in MS.
Third, a study found that the lower levels of Vitamin D are associated with disease severity in MS.
Finally, an Australian study found relapses higher in the northern hemisphere in spring and southern hemisphere in autumn (which could be explained by lower levels of Vitamin D in these seasons).
[S39.004] Gender Differences in Immunomodulatory Effects of 1,25 Dihydroxyvitamin D3 in Multiple Sclerosis
Jorge Correale, María C. Ysrraelit, María I. Gaitán, Buenos Aires, Argentina
OBJECTIVE: To study gender differences in the immunomodulatory effects of Vitamin D in MS.
BACKGROUND: Vitamin D has a protective effect against MS development, supported by reduced disease risk associated with sun exposure and Vitamin D supplement use. Elevated Vitamin D blood levels have also been associated with lower risk of MS. However, Vitamin D inhibits EAE in female but not in male mice. DESIGN/
METHODS: Serum 25(OH)D3 and 1,25(OH)2D3 levels were measured using ELISA in 58 relapsing remitting MS (RRMS) patients during remission, 34 RRMS patients during relapse, 40 primary progressive MS (PPMS) subjects and 60 healthy controls. Cell proliferation was measured using [3H]-thymidine incorporation assays. Vitamin D receptor, CYP27B1, CYP24A1, and Vitamin-D binding protein (DBP) expression was measured by RT-PCR, while cytokine production was evaluated using ELISA. CD4+CD25+ regulatory T cells were studied using flow cytometry.
RESULTS: Female and male patients showed similar levels of 25(OH)D3 and 1,25(OH)2D3 in all groups studied. However, inhibition of proliferation of MBP-specific T cells, as well as secretion of Interferon- and IL-17 by 1,25(OH)2D3 were significantly stronger in females compared to males (p< 0.01). Likewise, enhancement of IL-10 secretion, and increased number of CD4+CD25+ regulatory T cells induced by Vitamin D was higher in female MS patients compared to males (p < 0.001). Female MS patients had significantly lower levels of CYP24A1 mRNA, encoding the inactivating 24-OHase enzyme, and increased amounts of DBP compared to males, indicating gender differences in Vitamin D metabolism. Finally, treatment of MBP-specific T cells with 17beta-estradiol significantly reduced CYP24A1 mRNA expression and increased DBP expression favoring Vitamin D uptake.
CONCLUSIONS/RELEVANCE: Gender differences in the metabolism of Vitamin D suggest a higher protective effect of Vitamin D-based therapeutic strategies in women. Supported by: Institute for Neurological Research Dr. Raul Carrea, FLENI
_____________
[P01.110] Immunological Analysis of a Phase I/II Dose-Escalation Trial of Oral Vitamin D3 with Calcium Supplementation in Patients with Multiple Sclerosis
Jodie M. Burton, Samantha Kimball, Amit Bar-Or, Hans-Michael Dosch, Donald Gagne, Roy Cheung, Cheryl D'Souza, Melanie Ursell, Reinhold Vieth, Paul O'Connor, Montreal, QC, Canada, Etobicoke, ON, Canada, Toronto, ON, Canada
OBJECTIVE: To characterize the safety and immunological profile of high-dose oral vitamin D3 (VD3) in multiple sclerosis (MS).
BACKGROUND: Low UV radiation and 25-hydroxyvitamin D (25(OH)D) are associated with increasing risk and prevalence of MS. We have recently established that high-dose oral VD3 is safe in MS with apparent clinical benefit. This is presumably mediated through immune-regulation and a hypothesized shift away from the pro-inflammatory state believed to be key in MS.
DESIGN/METHODS: A prospective controlled 52-week trial matched MS patients for demographic and disease characteristics, with randomization to treatment and control groups. Treatment patients started VD3 at 4,000 IU/d and escalated over 28 weeks to 40,000 IU/d, at which they spent 6 weeks. This was followed by maintenance with 10,000 IU/d for 12 weeks, 4,000 IU/d for 8 weeks and a 4-week wash-out (roughly 14,000 IU/d over 52 weeks). Calcium (1,200 mg/d) was given throughout the trial. T-scores (a measure of T-cell reactivity to test antigens) were measured at the first and last visit. MMP-9/TIMP-1 values and cytokines profiles were measured at visits 1 (0 IU/d), 4 (10,000 IU/d), 7 (40,000 IU/d) and 11 (0 IU/d). Statistical methods included sign rank, Mann-Whitney U, McNemar, Chi-square and repeated measures modeling.
RESULTS: Forty-nine patients were enrolled (25 treatment, 24 control). Despite a maximum mean 25(OH)D of 413nmol/L (66-729), no adverse events, including calcium abnormalities, occurred. T-scores (TCS) dropped significantly over 52 weeks in treatment patients (p=0.002), but not in controls. The proportion of patients with a TCS below the pre-determined threshold was also greater in treatment patients (p=0.032). Reduction in TCS was significantly greater in patients with an end of trial 25(OH)D => 100nmol/L (p=0.032). MMP-9/TIMP-1 and cytokine analyses will be presented.
CONCLUSIONS/RELEVANCE: High-dose VD3 (10,000 IU/d, possibly higher) in MS is safe and tolerable with immunodulatory effects. Such effects may explain clinical improvement in treated patients. Supported by: Direct-MS and the Multiple Sclerosis Society of Canada.
_______________
[P04.142] Serum Vitamin D Levels Are Associated with Multiple Sclerosis Disease Severity
Bijal K. Mehta, Allison S. Drake, Barbara E. Teter, Murali Ramanathan, Nupur Batra, Nitin Agarwal, Robert Zivadinov, Bianca Weinstock-Guttman, Buffalo, NY
OBJECTIVE: To evaluate whether 25-hydroxyvitamin D (25(OH)D) levels are associated with disease severity in patients with multiple sclerosis (MS).
BACKGROUND: Vitamin D deficiency has been implicated as a risk factor for MS. Higher circulating levels of 25(OH)D are associated with a decreased risk of developing MS. In vivo studies have demonstrated that 25(OH)D inhibits EAE induction in mice and also prevents disease progression. However, the association between 25(OH)D and MS disease severity in humans has yet to be elucidated.
DESIGN/METHODS: Clinical, demographic and 25(OH)D data from 228 MS patients enrolled in the New York State Multiple Sclerosis Consortium (NYSMSC) were analyzed (mean age 50.59.5yrs). The Expanded Disability Status Scale (EDSS) was used to measure MS disease severity (median 3.0); serum 25(OH)D level results were obtained from the same commercial laboratory. Serum 25(OH)D levels <32ng/mL were considered less than sufficient. Ordinal regression was performed to assess the impact of several factors on EDSS score.
RESULTS: Mean serum 25(OH)D level was 29.8ng/mL, with 63.4% of patients considered 25(OH)D deficient/insufficient. The ordinal regression model contained the following variables: sex, age, age at symptom onset, season and 25(OH)D level (Chi-square = 49.9, p < 0.001). Correcting for sex, season, age and age of onset, 25(OH)D levels were found to be significantly predictive of EDSS scores (Wald parameter = 4.9, p<0.05).
CONCLUSIONS/RELEVANCE: The results of this study indicate that 25(OH)D levels are significantly associated with MS disease severity. While further studies regarding the role of 25(OH)D in MS are warranted, these results support a potential disease modifying effect of high levels of 25(OH)D.
_____________
[P08.027] Temporal Variation of Onset of Relapses in Multiple Sclerosis: Results from the Northern and Southern Hemispheres in the MSBase Registry
Orla Mary Gray, Damien Jolley, et. al.
OBJECTIVE: To determine if there is a temporal variation in onset of relapses using the MSBase registry, a large, multi-centre cohort study of MS outcomes. To compare the time of onset of relapses in the northern and southern hemispheres.
BACKGROUND: Previous studies into time of onset of relapses have suggested that relapses are seasonal, with more relapses in spring and fewest in winter. The proposed mechanism is that reduced vitamin D levels at spring onset precipitate relapses. However small numbers, differing diagnostic criteria and the involvement of single regions limited these studies.
DESIGN/METHODS: Data was extracted on 16th July 2008. The dataset comprised 7,860 cases with all forms of MS from 33 centres in 16 countries, including 25,784 documented relapses. Relapses with 1st January recorded as day of onset were excluded, leaving 22,684 in total including 5,542 first demyelinating events. Relapses were stratified by hemisphere of residence and compared by season, quartile and month of onset. Statistical analysis was performed using chi-squared test.
RESULTS: 22,684 relapses (19,775 northern, 2,909 southern) were included. Relapses were significantly more common in spring in the northern hemisphere (P<0.0001) and autumn in the southern hemisphere (P<0.0001). June had the highest number of relapses than any other month in either hemisphere (P<0.0001). These results were replicated with analysis of the 5,542 first demyelinating event in MS cases (4,801 northern, 741 southern).
CONCLUSIONS/RELEVANCE: A highly significant temporal variation in onset of relapses is present in both northern and southern hemispheres. However, peak relapse incidence does not occur in the same season in the northern and southern hemispheres.
First, women with MS appear to benefit more from Vitamin D than men.
Secondly a small trial of Vitamin D3 found high-doses of D3 to be safe and to alter the immunological profile of patients in a manner thought to be beneficial in MS.
Third, a study found that the lower levels of Vitamin D are associated with disease severity in MS.
Finally, an Australian study found relapses higher in the northern hemisphere in spring and southern hemisphere in autumn (which could be explained by lower levels of Vitamin D in these seasons).
[S39.004] Gender Differences in Immunomodulatory Effects of 1,25 Dihydroxyvitamin D3 in Multiple Sclerosis
Jorge Correale, María C. Ysrraelit, María I. Gaitán, Buenos Aires, Argentina
OBJECTIVE: To study gender differences in the immunomodulatory effects of Vitamin D in MS.
BACKGROUND: Vitamin D has a protective effect against MS development, supported by reduced disease risk associated with sun exposure and Vitamin D supplement use. Elevated Vitamin D blood levels have also been associated with lower risk of MS. However, Vitamin D inhibits EAE in female but not in male mice. DESIGN/
METHODS: Serum 25(OH)D3 and 1,25(OH)2D3 levels were measured using ELISA in 58 relapsing remitting MS (RRMS) patients during remission, 34 RRMS patients during relapse, 40 primary progressive MS (PPMS) subjects and 60 healthy controls. Cell proliferation was measured using [3H]-thymidine incorporation assays. Vitamin D receptor, CYP27B1, CYP24A1, and Vitamin-D binding protein (DBP) expression was measured by RT-PCR, while cytokine production was evaluated using ELISA. CD4+CD25+ regulatory T cells were studied using flow cytometry.
RESULTS: Female and male patients showed similar levels of 25(OH)D3 and 1,25(OH)2D3 in all groups studied. However, inhibition of proliferation of MBP-specific T cells, as well as secretion of Interferon- and IL-17 by 1,25(OH)2D3 were significantly stronger in females compared to males (p< 0.01). Likewise, enhancement of IL-10 secretion, and increased number of CD4+CD25+ regulatory T cells induced by Vitamin D was higher in female MS patients compared to males (p < 0.001). Female MS patients had significantly lower levels of CYP24A1 mRNA, encoding the inactivating 24-OHase enzyme, and increased amounts of DBP compared to males, indicating gender differences in Vitamin D metabolism. Finally, treatment of MBP-specific T cells with 17beta-estradiol significantly reduced CYP24A1 mRNA expression and increased DBP expression favoring Vitamin D uptake.
CONCLUSIONS/RELEVANCE: Gender differences in the metabolism of Vitamin D suggest a higher protective effect of Vitamin D-based therapeutic strategies in women. Supported by: Institute for Neurological Research Dr. Raul Carrea, FLENI
_____________
[P01.110] Immunological Analysis of a Phase I/II Dose-Escalation Trial of Oral Vitamin D3 with Calcium Supplementation in Patients with Multiple Sclerosis
Jodie M. Burton, Samantha Kimball, Amit Bar-Or, Hans-Michael Dosch, Donald Gagne, Roy Cheung, Cheryl D'Souza, Melanie Ursell, Reinhold Vieth, Paul O'Connor, Montreal, QC, Canada, Etobicoke, ON, Canada, Toronto, ON, Canada
OBJECTIVE: To characterize the safety and immunological profile of high-dose oral vitamin D3 (VD3) in multiple sclerosis (MS).
BACKGROUND: Low UV radiation and 25-hydroxyvitamin D (25(OH)D) are associated with increasing risk and prevalence of MS. We have recently established that high-dose oral VD3 is safe in MS with apparent clinical benefit. This is presumably mediated through immune-regulation and a hypothesized shift away from the pro-inflammatory state believed to be key in MS.
DESIGN/METHODS: A prospective controlled 52-week trial matched MS patients for demographic and disease characteristics, with randomization to treatment and control groups. Treatment patients started VD3 at 4,000 IU/d and escalated over 28 weeks to 40,000 IU/d, at which they spent 6 weeks. This was followed by maintenance with 10,000 IU/d for 12 weeks, 4,000 IU/d for 8 weeks and a 4-week wash-out (roughly 14,000 IU/d over 52 weeks). Calcium (1,200 mg/d) was given throughout the trial. T-scores (a measure of T-cell reactivity to test antigens) were measured at the first and last visit. MMP-9/TIMP-1 values and cytokines profiles were measured at visits 1 (0 IU/d), 4 (10,000 IU/d), 7 (40,000 IU/d) and 11 (0 IU/d). Statistical methods included sign rank, Mann-Whitney U, McNemar, Chi-square and repeated measures modeling.
RESULTS: Forty-nine patients were enrolled (25 treatment, 24 control). Despite a maximum mean 25(OH)D of 413nmol/L (66-729), no adverse events, including calcium abnormalities, occurred. T-scores (TCS) dropped significantly over 52 weeks in treatment patients (p=0.002), but not in controls. The proportion of patients with a TCS below the pre-determined threshold was also greater in treatment patients (p=0.032). Reduction in TCS was significantly greater in patients with an end of trial 25(OH)D => 100nmol/L (p=0.032). MMP-9/TIMP-1 and cytokine analyses will be presented.
CONCLUSIONS/RELEVANCE: High-dose VD3 (10,000 IU/d, possibly higher) in MS is safe and tolerable with immunodulatory effects. Such effects may explain clinical improvement in treated patients. Supported by: Direct-MS and the Multiple Sclerosis Society of Canada.
_______________
[P04.142] Serum Vitamin D Levels Are Associated with Multiple Sclerosis Disease Severity
Bijal K. Mehta, Allison S. Drake, Barbara E. Teter, Murali Ramanathan, Nupur Batra, Nitin Agarwal, Robert Zivadinov, Bianca Weinstock-Guttman, Buffalo, NY
OBJECTIVE: To evaluate whether 25-hydroxyvitamin D (25(OH)D) levels are associated with disease severity in patients with multiple sclerosis (MS).
BACKGROUND: Vitamin D deficiency has been implicated as a risk factor for MS. Higher circulating levels of 25(OH)D are associated with a decreased risk of developing MS. In vivo studies have demonstrated that 25(OH)D inhibits EAE induction in mice and also prevents disease progression. However, the association between 25(OH)D and MS disease severity in humans has yet to be elucidated.
DESIGN/METHODS: Clinical, demographic and 25(OH)D data from 228 MS patients enrolled in the New York State Multiple Sclerosis Consortium (NYSMSC) were analyzed (mean age 50.59.5yrs). The Expanded Disability Status Scale (EDSS) was used to measure MS disease severity (median 3.0); serum 25(OH)D level results were obtained from the same commercial laboratory. Serum 25(OH)D levels <32ng/mL were considered less than sufficient. Ordinal regression was performed to assess the impact of several factors on EDSS score.
RESULTS: Mean serum 25(OH)D level was 29.8ng/mL, with 63.4% of patients considered 25(OH)D deficient/insufficient. The ordinal regression model contained the following variables: sex, age, age at symptom onset, season and 25(OH)D level (Chi-square = 49.9, p < 0.001). Correcting for sex, season, age and age of onset, 25(OH)D levels were found to be significantly predictive of EDSS scores (Wald parameter = 4.9, p<0.05).
CONCLUSIONS/RELEVANCE: The results of this study indicate that 25(OH)D levels are significantly associated with MS disease severity. While further studies regarding the role of 25(OH)D in MS are warranted, these results support a potential disease modifying effect of high levels of 25(OH)D.
_____________
[P08.027] Temporal Variation of Onset of Relapses in Multiple Sclerosis: Results from the Northern and Southern Hemispheres in the MSBase Registry
Orla Mary Gray, Damien Jolley, et. al.
OBJECTIVE: To determine if there is a temporal variation in onset of relapses using the MSBase registry, a large, multi-centre cohort study of MS outcomes. To compare the time of onset of relapses in the northern and southern hemispheres.
BACKGROUND: Previous studies into time of onset of relapses have suggested that relapses are seasonal, with more relapses in spring and fewest in winter. The proposed mechanism is that reduced vitamin D levels at spring onset precipitate relapses. However small numbers, differing diagnostic criteria and the involvement of single regions limited these studies.
DESIGN/METHODS: Data was extracted on 16th July 2008. The dataset comprised 7,860 cases with all forms of MS from 33 centres in 16 countries, including 25,784 documented relapses. Relapses with 1st January recorded as day of onset were excluded, leaving 22,684 in total including 5,542 first demyelinating events. Relapses were stratified by hemisphere of residence and compared by season, quartile and month of onset. Statistical analysis was performed using chi-squared test.
RESULTS: 22,684 relapses (19,775 northern, 2,909 southern) were included. Relapses were significantly more common in spring in the northern hemisphere (P<0.0001) and autumn in the southern hemisphere (P<0.0001). June had the highest number of relapses than any other month in either hemisphere (P<0.0001). These results were replicated with analysis of the 5,542 first demyelinating event in MS cases (4,801 northern, 741 southern).
CONCLUSIONS/RELEVANCE: A highly significant temporal variation in onset of relapses is present in both northern and southern hemispheres. However, peak relapse incidence does not occur in the same season in the northern and southern hemispheres.