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Vitamin D as a Risk Factor
Epidemiologic literature first suggested that vitamin D status might be related to the risk of MS. Researchers demonstrated that MS prevalence increases with distance from the equator. A series of retrospective and case–control studies subsequently suggested that patients with MS had lower levels of vitamin D than healthy individuals. These data, however, left open the possibility that having MS and its associated intolerance of heat led to reduced sun exposure, and thus lower levels of vitamin D.
In 2006, Munger and colleagues prospectively examined serum samples obtained from more than seven million US military personnel. They found that, among whites, the risk of MS significantly decreased with increasing levels of 25-hydroxyvitamin D. The effect was most significant in people with vitamin D levels higher than 40 ng/mL. The same association was observed in a later Swedish study that used 30 ng/mL as its threshold for vitamin D sufficiency. In 2016, Munger et al found that insufficient maternal vitamin D during pregnancy may increase the risk of MS in offspring.
Although research by Lucas and colleagues indicated an inverse association between serum vitamin D level and risk of MS, they found a stronger inverse association between ultraviolet (UV) light exposure and risk of MS. The strength of the latter association did not change, whether exposure was measured by skin damage or self-report. In 2017, however, Nielsen and colleagues compared serum vitamin D levels in newborns who subsequently developed MS with those of newborns who did not develop MS. They found a strong association between higher neonatal levels of vitamin D and lower risk of subsequent MS. “One could argue [that] this [result] makes the vitamin D hypothesis stronger than the UV [hypothesis], since the babies, in all likelihood, had not been exposed to much UV [light] at the time they were born,” said Dr. Mowry.
Vitamin D as a Prognostic Factor
Other research has suggested that serum vitamin D level may predict disease activity in MS. Dr. Mowry and colleagues evaluated blood samples taken from children who presented for longitudinal follow-up at pediatric MS centers. The total follow-up period was approximately 18 months. After adjusting for covariates, they found a strong association between higher levels of vitamin D and lower risk of subsequent relapse. “Each 10-ng/mL higher level of vitamin D … was associated with about a one-third reduction in the risk of subsequent relapse,” said Dr. Mowry. A prospective study conducted in Australia found similar results.
In 2012, Dr. Mowry and colleagues measured vitamin D levels in blood samples from 469 patients with relapsing-remitting MS or clinically isolated syndrome (CIS). They found that each additional 10-ng/mL increment of vitamin D level was associated with an approximately 15% lower risk of subsequent new T2 lesions and with an approximately 32% reduced risk of subsequent gadolinium-enhancing lesions. Higher levels of vitamin D also were associated with lower risk of subsequent relapse, but this finding was not statistically significant.
To discover whether vitamin D influences markers known to predict long-term disability, Dr. Mowry and colleagues examined data from a study of atorvastatin in 65 patients with CIS. They measured vitamin D levels at baseline and at month six, and the follow-up period was as long as 18 months. They found that each additional 10-ng/mL increment in vitamin D level was associated with an additional 7.8 mL of preserved gray matter volume. They also observed a trend toward an inverse association between vitamin D levels and the composite end point of three or more new T2 lesions or one or more relapses within a year.
Is Vitamin D Supplementation Appropriate?
“Just because [vitamin D] is available over the counter does not make it safe or effective,” and the supplement should be studied further in clinical trials, said Dr. Mowry. In 2010, Burton et al found that a dose of as much as 40,000 IU/day of vitamin D was safe in the short term and might have immunomodulatory effects in patients with MS. Furthermore, a small Finnish study suggested that a dose of 20,000 IU/week of vitamin D was safe in patients with MS, and also might slow the accumulation of disability.
Hupperts et al studied patients with relapsing-remitting MS who were receiving interferon beta-1a. They randomized 229 participants to vitamin D or placebo and followed them for 48 weeks. In preliminary analyses, the investigators found no difference between treatment groups with respect to the outcome of no evidence of disease activity. Patients who received vitamin D had a lower annualized relapse rate than controls, but the difference was not statistically significant. The active group did have significantly fewer gadolinium-enhancing lesions and new T2 hyperintense lesions, compared with controls, however.
In addition, Dr. Mowry and colleagues are comparing the effects of 5,000-IU and 600-IU doses of vitamin D in patients with MS who are receiving glatiramer acetate. The ongoing study is sponsored by the National MS Society. European studies of the clinical benefit of vitamin D also are under way.
Although the benefits of vitamin D are not completely understood, many neurologists recommend supplementation to their patients with MS. Pharmacokinetic studies have not shown a difference between daily, weekly, or monthly dosing regimens. “As long as you give the same dose of vitamin D, you will get the levels … to the same general area,” said Dr. Mowry. Nevertheless, some studies in other patient populations suggest that very high doses of vitamin D given monthly are probably toxic.
Many studies have suggested that vitamin D3 may be more potent than vitamin D2. “I tend to use [vitamin] D3 when I am supplementing,” said Dr. Mowry. “I aim for levels between 40 and 60 ng/mL, based on our observational data.... For my patients, that largely means they need somewhere between 2,000 and 4,000 IU/day, although sometimes more. I usually recheck the level in three months, based on what we know about the kinetics of vitamin D supplementation. I am cautious in individuals who may be at risk for hypercalcemia or hypercalciuria.”
—Erik Greb
Suggested Reading
Burton JM, Kimball S, Vieth R, et al. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology. 2010;74(23):1852-1859.
Mowry EM. Vitamin D: evidence for its role as a prognostic factor in multiple sclerosis. J Neurol Sci. 2011; 311(1-2):19-22.
Mowry EM, Pelletier D, Gao Z, et al. Vitamin D in clinically isolated syndrome: evidence for possible neuroprotection. Eur J Neurol. 2016;23(2):327-332.
Mowry EM, Waubant E, McCulloch CE, et al. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol. 2012;72(2):234-240.
Munger KL, Åivo J, Hongell K, et al. Vitamin D status during pregnancy and risk of multiple sclerosis in offspring of women in the Finnish Maternity Cohort. JAMA Neurol. 2016;73(5):515-519.
Munger KL, Levin LI, Hollis BW, et al. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296(23):2832-2838.
Nielsen NM, Munger KL, Koch-Henriksen N, et al. Neonatal vitamin D status and risk of multiple sclerosis: a population-based case-control study. Neurology. 2017;88(1):44-51.
Tremlett H, van der Mei IA, Pittas F, et al. Monthly ambient sunlight, infections and relapse rates in multiple sclerosis. Neuroepidemiology. 2008;31(4):271-279.
Vitamin D as a Risk Factor
Epidemiologic literature first suggested that vitamin D status might be related to the risk of MS. Researchers demonstrated that MS prevalence increases with distance from the equator. A series of retrospective and case–control studies subsequently suggested that patients with MS had lower levels of vitamin D than healthy individuals. These data, however, left open the possibility that having MS and its associated intolerance of heat led to reduced sun exposure, and thus lower levels of vitamin D.
In 2006, Munger and colleagues prospectively examined serum samples obtained from more than seven million US military personnel. They found that, among whites, the risk of MS significantly decreased with increasing levels of 25-hydroxyvitamin D. The effect was most significant in people with vitamin D levels higher than 40 ng/mL. The same association was observed in a later Swedish study that used 30 ng/mL as its threshold for vitamin D sufficiency. In 2016, Munger et al found that insufficient maternal vitamin D during pregnancy may increase the risk of MS in offspring.
Although research by Lucas and colleagues indicated an inverse association between serum vitamin D level and risk of MS, they found a stronger inverse association between ultraviolet (UV) light exposure and risk of MS. The strength of the latter association did not change, whether exposure was measured by skin damage or self-report. In 2017, however, Nielsen and colleagues compared serum vitamin D levels in newborns who subsequently developed MS with those of newborns who did not develop MS. They found a strong association between higher neonatal levels of vitamin D and lower risk of subsequent MS. “One could argue [that] this [result] makes the vitamin D hypothesis stronger than the UV [hypothesis], since the babies, in all likelihood, had not been exposed to much UV [light] at the time they were born,” said Dr. Mowry.
Vitamin D as a Prognostic Factor
Other research has suggested that serum vitamin D level may predict disease activity in MS. Dr. Mowry and colleagues evaluated blood samples taken from children who presented for longitudinal follow-up at pediatric MS centers. The total follow-up period was approximately 18 months. After adjusting for covariates, they found a strong association between higher levels of vitamin D and lower risk of subsequent relapse. “Each 10-ng/mL higher level of vitamin D … was associated with about a one-third reduction in the risk of subsequent relapse,” said Dr. Mowry. A prospective study conducted in Australia found similar results.
In 2012, Dr. Mowry and colleagues measured vitamin D levels in blood samples from 469 patients with relapsing-remitting MS or clinically isolated syndrome (CIS). They found that each additional 10-ng/mL increment of vitamin D level was associated with an approximately 15% lower risk of subsequent new T2 lesions and with an approximately 32% reduced risk of subsequent gadolinium-enhancing lesions. Higher levels of vitamin D also were associated with lower risk of subsequent relapse, but this finding was not statistically significant.
To discover whether vitamin D influences markers known to predict long-term disability, Dr. Mowry and colleagues examined data from a study of atorvastatin in 65 patients with CIS. They measured vitamin D levels at baseline and at month six, and the follow-up period was as long as 18 months. They found that each additional 10-ng/mL increment in vitamin D level was associated with an additional 7.8 mL of preserved gray matter volume. They also observed a trend toward an inverse association between vitamin D levels and the composite end point of three or more new T2 lesions or one or more relapses within a year.
Is Vitamin D Supplementation Appropriate?
“Just because [vitamin D] is available over the counter does not make it safe or effective,” and the supplement should be studied further in clinical trials, said Dr. Mowry. In 2010, Burton et al found that a dose of as much as 40,000 IU/day of vitamin D was safe in the short term and might have immunomodulatory effects in patients with MS. Furthermore, a small Finnish study suggested that a dose of 20,000 IU/week of vitamin D was safe in patients with MS, and also might slow the accumulation of disability.
Hupperts et al studied patients with relapsing-remitting MS who were receiving interferon beta-1a. They randomized 229 participants to vitamin D or placebo and followed them for 48 weeks. In preliminary analyses, the investigators found no difference between treatment groups with respect to the outcome of no evidence of disease activity. Patients who received vitamin D had a lower annualized relapse rate than controls, but the difference was not statistically significant. The active group did have significantly fewer gadolinium-enhancing lesions and new T2 hyperintense lesions, compared with controls, however.
In addition, Dr. Mowry and colleagues are comparing the effects of 5,000-IU and 600-IU doses of vitamin D in patients with MS who are receiving glatiramer acetate. The ongoing study is sponsored by the National MS Society. European studies of the clinical benefit of vitamin D also are under way.
Although the benefits of vitamin D are not completely understood, many neurologists recommend supplementation to their patients with MS. Pharmacokinetic studies have not shown a difference between daily, weekly, or monthly dosing regimens. “As long as you give the same dose of vitamin D, you will get the levels … to the same general area,” said Dr. Mowry. Nevertheless, some studies in other patient populations suggest that very high doses of vitamin D given monthly are probably toxic.
Many studies have suggested that vitamin D3 may be more potent than vitamin D2. “I tend to use [vitamin] D3 when I am supplementing,” said Dr. Mowry. “I aim for levels between 40 and 60 ng/mL, based on our observational data.... For my patients, that largely means they need somewhere between 2,000 and 4,000 IU/day, although sometimes more. I usually recheck the level in three months, based on what we know about the kinetics of vitamin D supplementation. I am cautious in individuals who may be at risk for hypercalcemia or hypercalciuria.”
—Erik Greb
Suggested Reading
Burton JM, Kimball S, Vieth R, et al. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology. 2010;74(23):1852-1859.
Mowry EM. Vitamin D: evidence for its role as a prognostic factor in multiple sclerosis. J Neurol Sci. 2011; 311(1-2):19-22.
Mowry EM, Pelletier D, Gao Z, et al. Vitamin D in clinically isolated syndrome: evidence for possible neuroprotection. Eur J Neurol. 2016;23(2):327-332.
Mowry EM, Waubant E, McCulloch CE, et al. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol. 2012;72(2):234-240.
Munger KL, Åivo J, Hongell K, et al. Vitamin D status during pregnancy and risk of multiple sclerosis in offspring of women in the Finnish Maternity Cohort. JAMA Neurol. 2016;73(5):515-519.
Munger KL, Levin LI, Hollis BW, et al. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296(23):2832-2838.
Nielsen NM, Munger KL, Koch-Henriksen N, et al. Neonatal vitamin D status and risk of multiple sclerosis: a population-based case-control study. Neurology. 2017;88(1):44-51.
Tremlett H, van der Mei IA, Pittas F, et al. Monthly ambient sunlight, infections and relapse rates in multiple sclerosis. Neuroepidemiology. 2008;31(4):271-279.
Vitamin D as a Risk Factor
Epidemiologic literature first suggested that vitamin D status might be related to the risk of MS. Researchers demonstrated that MS prevalence increases with distance from the equator. A series of retrospective and case–control studies subsequently suggested that patients with MS had lower levels of vitamin D than healthy individuals. These data, however, left open the possibility that having MS and its associated intolerance of heat led to reduced sun exposure, and thus lower levels of vitamin D.
In 2006, Munger and colleagues prospectively examined serum samples obtained from more than seven million US military personnel. They found that, among whites, the risk of MS significantly decreased with increasing levels of 25-hydroxyvitamin D. The effect was most significant in people with vitamin D levels higher than 40 ng/mL. The same association was observed in a later Swedish study that used 30 ng/mL as its threshold for vitamin D sufficiency. In 2016, Munger et al found that insufficient maternal vitamin D during pregnancy may increase the risk of MS in offspring.
Although research by Lucas and colleagues indicated an inverse association between serum vitamin D level and risk of MS, they found a stronger inverse association between ultraviolet (UV) light exposure and risk of MS. The strength of the latter association did not change, whether exposure was measured by skin damage or self-report. In 2017, however, Nielsen and colleagues compared serum vitamin D levels in newborns who subsequently developed MS with those of newborns who did not develop MS. They found a strong association between higher neonatal levels of vitamin D and lower risk of subsequent MS. “One could argue [that] this [result] makes the vitamin D hypothesis stronger than the UV [hypothesis], since the babies, in all likelihood, had not been exposed to much UV [light] at the time they were born,” said Dr. Mowry.
Vitamin D as a Prognostic Factor
Other research has suggested that serum vitamin D level may predict disease activity in MS. Dr. Mowry and colleagues evaluated blood samples taken from children who presented for longitudinal follow-up at pediatric MS centers. The total follow-up period was approximately 18 months. After adjusting for covariates, they found a strong association between higher levels of vitamin D and lower risk of subsequent relapse. “Each 10-ng/mL higher level of vitamin D … was associated with about a one-third reduction in the risk of subsequent relapse,” said Dr. Mowry. A prospective study conducted in Australia found similar results.
In 2012, Dr. Mowry and colleagues measured vitamin D levels in blood samples from 469 patients with relapsing-remitting MS or clinically isolated syndrome (CIS). They found that each additional 10-ng/mL increment of vitamin D level was associated with an approximately 15% lower risk of subsequent new T2 lesions and with an approximately 32% reduced risk of subsequent gadolinium-enhancing lesions. Higher levels of vitamin D also were associated with lower risk of subsequent relapse, but this finding was not statistically significant.
To discover whether vitamin D influences markers known to predict long-term disability, Dr. Mowry and colleagues examined data from a study of atorvastatin in 65 patients with CIS. They measured vitamin D levels at baseline and at month six, and the follow-up period was as long as 18 months. They found that each additional 10-ng/mL increment in vitamin D level was associated with an additional 7.8 mL of preserved gray matter volume. They also observed a trend toward an inverse association between vitamin D levels and the composite end point of three or more new T2 lesions or one or more relapses within a year.
Is Vitamin D Supplementation Appropriate?
“Just because [vitamin D] is available over the counter does not make it safe or effective,” and the supplement should be studied further in clinical trials, said Dr. Mowry. In 2010, Burton et al found that a dose of as much as 40,000 IU/day of vitamin D was safe in the short term and might have immunomodulatory effects in patients with MS. Furthermore, a small Finnish study suggested that a dose of 20,000 IU/week of vitamin D was safe in patients with MS, and also might slow the accumulation of disability.
Hupperts et al studied patients with relapsing-remitting MS who were receiving interferon beta-1a. They randomized 229 participants to vitamin D or placebo and followed them for 48 weeks. In preliminary analyses, the investigators found no difference between treatment groups with respect to the outcome of no evidence of disease activity. Patients who received vitamin D had a lower annualized relapse rate than controls, but the difference was not statistically significant. The active group did have significantly fewer gadolinium-enhancing lesions and new T2 hyperintense lesions, compared with controls, however.
In addition, Dr. Mowry and colleagues are comparing the effects of 5,000-IU and 600-IU doses of vitamin D in patients with MS who are receiving glatiramer acetate. The ongoing study is sponsored by the National MS Society. European studies of the clinical benefit of vitamin D also are under way.
Although the benefits of vitamin D are not completely understood, many neurologists recommend supplementation to their patients with MS. Pharmacokinetic studies have not shown a difference between daily, weekly, or monthly dosing regimens. “As long as you give the same dose of vitamin D, you will get the levels … to the same general area,” said Dr. Mowry. Nevertheless, some studies in other patient populations suggest that very high doses of vitamin D given monthly are probably toxic.
Many studies have suggested that vitamin D3 may be more potent than vitamin D2. “I tend to use [vitamin] D3 when I am supplementing,” said Dr. Mowry. “I aim for levels between 40 and 60 ng/mL, based on our observational data.... For my patients, that largely means they need somewhere between 2,000 and 4,000 IU/day, although sometimes more. I usually recheck the level in three months, based on what we know about the kinetics of vitamin D supplementation. I am cautious in individuals who may be at risk for hypercalcemia or hypercalciuria.”
—Erik Greb
Suggested Reading
Burton JM, Kimball S, Vieth R, et al. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology. 2010;74(23):1852-1859.
Mowry EM. Vitamin D: evidence for its role as a prognostic factor in multiple sclerosis. J Neurol Sci. 2011; 311(1-2):19-22.
Mowry EM, Pelletier D, Gao Z, et al. Vitamin D in clinically isolated syndrome: evidence for possible neuroprotection. Eur J Neurol. 2016;23(2):327-332.
Mowry EM, Waubant E, McCulloch CE, et al. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol. 2012;72(2):234-240.
Munger KL, Åivo J, Hongell K, et al. Vitamin D status during pregnancy and risk of multiple sclerosis in offspring of women in the Finnish Maternity Cohort. JAMA Neurol. 2016;73(5):515-519.
Munger KL, Levin LI, Hollis BW, et al. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296(23):2832-2838.
Nielsen NM, Munger KL, Koch-Henriksen N, et al. Neonatal vitamin D status and risk of multiple sclerosis: a population-based case-control study. Neurology. 2017;88(1):44-51.
Tremlett H, van der Mei IA, Pittas F, et al. Monthly ambient sunlight, infections and relapse rates in multiple sclerosis. Neuroepidemiology. 2008;31(4):271-279.