Multiple Sclerosis Hub

SAN DIEGO – Despite the popularity of medical marijuana, robust evidence for its use is limited or nonexistent for most medical conditions.

“This is a tough subject to study,” Ellie Grossman, MD, said at the annual meeting of the American College of Physicians. “There is federal money that can only be used in very limited ways to study it. Our science is way behind the times in terms of what our patients are doing and using.”

Typical limitations of marijuana studies include self-report of quantity/duration used and the fact that biochemical/quantifiable measures are lacking. “For inhaled marijuana, there is variability in how much is inhaled and how deeply it’s being inhaled,” said Dr. Grossman, an internist who practices in Somerville, Mass.

[email protected]

SAN DIEGO – Despite the popularity of medical marijuana, robust evidence for its use is limited or nonexistent for most medical conditions.

“This is a tough subject to study,” Ellie Grossman, MD, said at the annual meeting of the American College of Physicians. “There is federal money that can only be used in very limited ways to study it. Our science is way behind the times in terms of what our patients are doing and using.”

Typical limitations of marijuana studies include self-report of quantity/duration used and the fact that biochemical/quantifiable measures are lacking. “For inhaled marijuana, there is variability in how much is inhaled and how deeply it’s being inhaled,” said Dr. Grossman, an internist who practices in Somerville, Mass.

[email protected]

SAN DIEGO – Despite the popularity of medical marijuana, robust evidence for its use is limited or nonexistent for most medical conditions.

“This is a tough subject to study,” Ellie Grossman, MD, said at the annual meeting of the American College of Physicians. “There is federal money that can only be used in very limited ways to study it. Our science is way behind the times in terms of what our patients are doing and using.”

Typical limitations of marijuana studies include self-report of quantity/duration used and the fact that biochemical/quantifiable measures are lacking. “For inhaled marijuana, there is variability in how much is inhaled and how deeply it’s being inhaled,” said Dr. Grossman, an internist who practices in Somerville, Mass.

[email protected]

ORLANDO—Patients with multiple sclerosis (MS) and their physicians still consider self-injected immunomodulating medications as first-line agents, according to the results of a study presented at the ACTRIMS 2017 Forum. The results, based on data from a community health–based suburban neurology practice, also indicated that a smaller percentage than expected of patients on injectable medications switched to an oral medication, and a majority of untreated patients at the initial visit chose to start a self-injectable medication if they started anything.

There are currently 14 FDA-approved immunomodulating medications available for MS and one currently awaiting approval. “This has resulted in patients, in consultation with physicians, having the opportunity to switch from medications that are self injected to medications taken orally or by IV infusion,” said Susan M. Rubin, MD, and colleagues from the Department of Neurology at NorthShore University HealthSystem in Evanston, Illinois. “We speculated that this would result in a high level of treatment changes away from self-injected treatments to the newer options,” Dr. Rubin and colleagues said.

They optimized their electronic medical record by building structured clinical documentation support (SCDS) tools specific to MS practice that standardize initial and annual follow-up visits, write progress notes, and capture data. The toolkit they built documents immunomodulating medications taken, tracks efficacy and adverse events, and notes reasons for discontinuation.

Patients with MS who were referred to the Department of Neurology at NorthShore University HealthSystem were evaluated at initial and annual follow-up visits using SCDS tools by one of three subspecialty neurologists. The researchers created descriptive reports of their cohort, including gender, age at disease onset, disease duration, use of immunomodulating medications, and Expanded Disability Status Scale scores. Patient-reported treatments at their initial visit were compared with treatments at their first annual follow-up visit.

Of the 105 patients in the study, 78% were female. Disease duration was zero to 43 years, with a mean duration of six years. Nearly three-quarters (74%) were not on an immunomodulating medication at first visit. Of those on medication at first visit, 77% were taking an injectable medication. At the annual follow-up visit, 51% started or changed medication, and 49% remained on the same medication. Of the patients who started treatment, 65% started a self-injection medication, 26% started an oral medication, and 9% started an infusion agent.

“Despite the availability of new treatments,” the researchers said, “patients and their physicians were generally content with the current treatment.” They hypothesized that safety concerns reduced the likelihood of change. “It appears that both patients and physicians prioritized safety over possibly greater efficacy when switching medication.”

—Glenn S. Williams

ORLANDO—Patients with multiple sclerosis (MS) and their physicians still consider self-injected immunomodulating medications as first-line agents, according to the results of a study presented at the ACTRIMS 2017 Forum. The results, based on data from a community health–based suburban neurology practice, also indicated that a smaller percentage than expected of patients on injectable medications switched to an oral medication, and a majority of untreated patients at the initial visit chose to start a self-injectable medication if they started anything.

There are currently 14 FDA-approved immunomodulating medications available for MS and one currently awaiting approval. “This has resulted in patients, in consultation with physicians, having the opportunity to switch from medications that are self injected to medications taken orally or by IV infusion,” said Susan M. Rubin, MD, and colleagues from the Department of Neurology at NorthShore University HealthSystem in Evanston, Illinois. “We speculated that this would result in a high level of treatment changes away from self-injected treatments to the newer options,” Dr. Rubin and colleagues said.

They optimized their electronic medical record by building structured clinical documentation support (SCDS) tools specific to MS practice that standardize initial and annual follow-up visits, write progress notes, and capture data. The toolkit they built documents immunomodulating medications taken, tracks efficacy and adverse events, and notes reasons for discontinuation.

Patients with MS who were referred to the Department of Neurology at NorthShore University HealthSystem were evaluated at initial and annual follow-up visits using SCDS tools by one of three subspecialty neurologists. The researchers created descriptive reports of their cohort, including gender, age at disease onset, disease duration, use of immunomodulating medications, and Expanded Disability Status Scale scores. Patient-reported treatments at their initial visit were compared with treatments at their first annual follow-up visit.

Of the 105 patients in the study, 78% were female. Disease duration was zero to 43 years, with a mean duration of six years. Nearly three-quarters (74%) were not on an immunomodulating medication at first visit. Of those on medication at first visit, 77% were taking an injectable medication. At the annual follow-up visit, 51% started or changed medication, and 49% remained on the same medication. Of the patients who started treatment, 65% started a self-injection medication, 26% started an oral medication, and 9% started an infusion agent.

“Despite the availability of new treatments,” the researchers said, “patients and their physicians were generally content with the current treatment.” They hypothesized that safety concerns reduced the likelihood of change. “It appears that both patients and physicians prioritized safety over possibly greater efficacy when switching medication.”

—Glenn S. Williams

ORLANDO—Patients with multiple sclerosis (MS) and their physicians still consider self-injected immunomodulating medications as first-line agents, according to the results of a study presented at the ACTRIMS 2017 Forum. The results, based on data from a community health–based suburban neurology practice, also indicated that a smaller percentage than expected of patients on injectable medications switched to an oral medication, and a majority of untreated patients at the initial visit chose to start a self-injectable medication if they started anything.

There are currently 14 FDA-approved immunomodulating medications available for MS and one currently awaiting approval. “This has resulted in patients, in consultation with physicians, having the opportunity to switch from medications that are self injected to medications taken orally or by IV infusion,” said Susan M. Rubin, MD, and colleagues from the Department of Neurology at NorthShore University HealthSystem in Evanston, Illinois. “We speculated that this would result in a high level of treatment changes away from self-injected treatments to the newer options,” Dr. Rubin and colleagues said.

They optimized their electronic medical record by building structured clinical documentation support (SCDS) tools specific to MS practice that standardize initial and annual follow-up visits, write progress notes, and capture data. The toolkit they built documents immunomodulating medications taken, tracks efficacy and adverse events, and notes reasons for discontinuation.

Patients with MS who were referred to the Department of Neurology at NorthShore University HealthSystem were evaluated at initial and annual follow-up visits using SCDS tools by one of three subspecialty neurologists. The researchers created descriptive reports of their cohort, including gender, age at disease onset, disease duration, use of immunomodulating medications, and Expanded Disability Status Scale scores. Patient-reported treatments at their initial visit were compared with treatments at their first annual follow-up visit.

Of the 105 patients in the study, 78% were female. Disease duration was zero to 43 years, with a mean duration of six years. Nearly three-quarters (74%) were not on an immunomodulating medication at first visit. Of those on medication at first visit, 77% were taking an injectable medication. At the annual follow-up visit, 51% started or changed medication, and 49% remained on the same medication. Of the patients who started treatment, 65% started a self-injection medication, 26% started an oral medication, and 9% started an infusion agent.

“Despite the availability of new treatments,” the researchers said, “patients and their physicians were generally content with the current treatment.” They hypothesized that safety concerns reduced the likelihood of change. “It appears that both patients and physicians prioritized safety over possibly greater efficacy when switching medication.”

—Glenn S. Williams

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.

ORLANDO—RNA expression patterns are highly dynamic, even at the earliest stages of multiple sclerosis (MS) pathogenesis, according to research presented at the ACTRIMS 2017 Forum. Machine learning methods trained and validated with these gene targets are a highly accurate tool that could provide actionable data for health care providers who suspect MS.

RNA sequencing was performed to identify differentially expressed protein-coding and noncoding RNA genes at distinct stages of MS, compared with controls. Expression levels of these genes were validated by real-time polymerase chain reaction (PCR) across all 979 subjects recruited. Ratios of gene expression data were used as inputs to train machine learning classifiers capable of multicategory comparisons. An independent validation testing set consisting of individuals across each control and disease class was used to evaluate the performance of these classifiers. In contrast to protein-coding gene targets where gene expression differences were often twofold or less, lncRNAs were highly differentially expressed across each of the experimental groups compared. Training and validation of machine learning methods revealed that lncRNA gene expression inputs resulted in higher overall accuracy and confidence of machine learning predictions than did protein-coding genes, resulting in greater than 90% accuracy in the validation testing set. 

—Glenn S. Williams

ORLANDO—RNA expression patterns are highly dynamic, even at the earliest stages of multiple sclerosis (MS) pathogenesis, according to research presented at the ACTRIMS 2017 Forum. Machine learning methods trained and validated with these gene targets are a highly accurate tool that could provide actionable data for health care providers who suspect MS.

RNA sequencing was performed to identify differentially expressed protein-coding and noncoding RNA genes at distinct stages of MS, compared with controls. Expression levels of these genes were validated by real-time polymerase chain reaction (PCR) across all 979 subjects recruited. Ratios of gene expression data were used as inputs to train machine learning classifiers capable of multicategory comparisons. An independent validation testing set consisting of individuals across each control and disease class was used to evaluate the performance of these classifiers. In contrast to protein-coding gene targets where gene expression differences were often twofold or less, lncRNAs were highly differentially expressed across each of the experimental groups compared. Training and validation of machine learning methods revealed that lncRNA gene expression inputs resulted in higher overall accuracy and confidence of machine learning predictions than did protein-coding genes, resulting in greater than 90% accuracy in the validation testing set. 

—Glenn S. Williams

ORLANDO—RNA expression patterns are highly dynamic, even at the earliest stages of multiple sclerosis (MS) pathogenesis, according to research presented at the ACTRIMS 2017 Forum. Machine learning methods trained and validated with these gene targets are a highly accurate tool that could provide actionable data for health care providers who suspect MS.

RNA sequencing was performed to identify differentially expressed protein-coding and noncoding RNA genes at distinct stages of MS, compared with controls. Expression levels of these genes were validated by real-time polymerase chain reaction (PCR) across all 979 subjects recruited. Ratios of gene expression data were used as inputs to train machine learning classifiers capable of multicategory comparisons. An independent validation testing set consisting of individuals across each control and disease class was used to evaluate the performance of these classifiers. In contrast to protein-coding gene targets where gene expression differences were often twofold or less, lncRNAs were highly differentially expressed across each of the experimental groups compared. Training and validation of machine learning methods revealed that lncRNA gene expression inputs resulted in higher overall accuracy and confidence of machine learning predictions than did protein-coding genes, resulting in greater than 90% accuracy in the validation testing set. 

—Glenn S. Williams

The humanized monoclonal antibody ocrelizumab became the first drug to receive approval from the Food and Drug Administration for the treatment of primary progressive multiple sclerosis in adults, according to a March 29 announcement from the agency that also said it is approved for relapsing-remitting disease in adults.

The drug has a mechanism of action similar to rituximab (Rituxan) through its selective targeting of CD20-positive B cells, which depletes them from circulation. CD20-positive B cells are thought to be a key contributor to myelin and axonal damage.

[email protected]

The humanized monoclonal antibody ocrelizumab became the first drug to receive approval from the Food and Drug Administration for the treatment of primary progressive multiple sclerosis in adults, according to a March 29 announcement from the agency that also said it is approved for relapsing-remitting disease in adults.

The drug has a mechanism of action similar to rituximab (Rituxan) through its selective targeting of CD20-positive B cells, which depletes them from circulation. CD20-positive B cells are thought to be a key contributor to myelin and axonal damage.

[email protected]

The humanized monoclonal antibody ocrelizumab became the first drug to receive approval from the Food and Drug Administration for the treatment of primary progressive multiple sclerosis in adults, according to a March 29 announcement from the agency that also said it is approved for relapsing-remitting disease in adults.

The drug has a mechanism of action similar to rituximab (Rituxan) through its selective targeting of CD20-positive B cells, which depletes them from circulation. CD20-positive B cells are thought to be a key contributor to myelin and axonal damage.

[email protected]

ORLANDO—Probiotic treatment is associated with the induction of an anti-inflammatory peripheral immune profile in patients with multiple sclerosis (MS), and discontinuing probiotics is associated with a decrease in immune regulatory cells, according to pilot study results presented at the ACTRIMS 2017 Forum. The results suggest that probiotics may be applicable as a therapy for MS. More studies, including controlled clinical trials, are needed to guide treatment decisions, said Howard L. Weiner, MD, Director of the MS Program at Brigham and Women’s Hospital in Newton, Massachusetts, and Robert L. Kroc Professor of Neurology at Harvard Medical School in Boston.

The gut microbiome can modulate neuroimmune function, and studies have found that patients with MS have alterations in the gut microbiome, compared with healthy controls. These findings have led researchers to ask, “Can you treat MS by modulating the microbiome?” Dr. Weiner said. One way to modulate the microbiome is with probiotics, which can be taken as an oral, nontoxic treatment in combination with current therapies. He and his research colleagues conducted a pilot study to investigate the effect of probiotics in patients with MS. “We did not feel that we could do a clinically related study,” he said. Instead, the investigators focused on what happens to the gut microbiome and immune profiles in the blood of patients who receive probiotics.

Two Months of Treatment

The study included nine patients with MS and 13 controls. The investigators gave study participants the probiotic VSL#3. Some formulations of VSL#3 are available in stores. The company that markets the probiotic, Sigma-Tau HealthScience USA, based in Gaithersburg, Maryland, requires a prescription for VSL#3 DS, the double-strength formulation used in the study.

Prior studies of the probiotic have found that VSL#3 provides benefit in animal models of diabetes, colitis, and allergy. Kigerl et al reported that, in mice with spinal cord injury, dysbiosis induced by antibiotics exacerbates neurologic impairment and spinal cord pathology, whereas feeding mice VSL#3 enriched with lactic-acid-producing bacteria triggers a protective immune response, confers neuroprotection, and improves walking. In addition, some doctors prescribe VSL#3 to patients with ulcerative colitis, irritable bowel syndrome, and pouchitis, Dr. Weiner said.

In the pilot study, participants took VSL#3 DS sachets twice daily for two months. Researchers took blood and stool samples from participants before administering the probiotic, at discontinuation of therapy, and three months thereafter.

VSL#3 had no effect on alpha or phylogenetic diversity, but did change the gut microbiome composition. Researchers observed an increase in the relative abundance of specific organisms contained in the probiotic. Methanogens, which are increased in MS, decreased when patients received the probiotic. Administration of VSL#3 also was associated with a decrease in proinflammatory monocytes and decreased expression of activation markers on monocytes and dendritic cells.

When patients stopped probiotic treatment, the numbers of CD39 and IL10 T regulatory cells decreased, and proinflammatory monocytes increased. “We did see changes when you stop treatment, almost as if there is a rebound,” he said. “We are seeing an immune effect in the blood.”

The treatment was well tolerated. “I myself took some,” Dr. Weiner said. “It tastes a little chalky, but otherwise it is fine.” Some patients said they felt better after taking the probiotic. The study was not placebo-controlled, however. Future randomized clinical studies will include MRI scans, he said.

What should neurologists tell patients who want to take a probiotic and ask which probiotic they should take? “We are all asked those questions,” Dr. Weiner said. “I tell them, we really don’t know, but if you would like to take a probiotic, that is fine. But we have no particular recommendations at this time. We need a lot of science before we know what we are doing, as far as treatment, in this regard.”

Changes in the Gut Microbiome in MS

Prior to conducting the pilot study, Sushrut Jangi, MD, research fellow at Brigham and Women’s Hospital, Dr. Weiner, and colleagues studied the gut microbiome in 60 patients with MS and 43 healthy controls. They found that patients with MS had increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas, compared with controls. Methanobrevibacter produces methane, and in another cohort, the researchers detected more methane in the breath of patients with MS than in controls.

In addition, Prevotella and Sutterella were increased, and Sarcina was decreased in patients with MS who were treated with disease-modifying therapy, compared with untreated patients with MS. “It gives us a whole series of targets to try to understand,” he said. The gut microbiome alterations in patients with MS correlated with variations in the expression of genes in circulating T cells and monocytes that have been implicated in MS pathogenesis.

How Are the Gut Microbiome and MS Related?

The nature of the relationship between the gut microbiome and MS is unclear. One possibility is that “the gut could be the key to MS,” Dr. Weiner said. An organism in the gut may trigger MS, and that organism potentially could be altered or used in vaccinations to treat or prevent the disease. Alternatively, the gut microbiome might relate to MS susceptibility. Environmental factors, including diet and antibiotics, could affect the microbiome and MS risk. It is also possible that MS disease-modifying therapies act in part through the gut, Dr. Weiner said.

Various treatments targeting the microbiome are under investigation. For example, researchers are asking whether a particular bacteria or fecal microbiome transplants might help treat MS. “I am very interested in the concept of oral tolerance, where we trigger immune responses in the mucosa,” said Dr. Weiner. “We are beginning a trial of anti-CD3 [monoclonal antibodies], which will be given mucosally to stimulate the gut immune response.”

—Jake Remaly

Suggested Reading

Jangi S, Gandhi R, Cox LM, et al. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun. 2016;7:12015.

Kigerl KA, Hall JC, Wang L, et al. Gut dysbiosis impairs recovery after spinal cord injury. J Exp Med. 2016;213(12):2603-2620.

Kouchaki E, Tamtaji OR, Salami M, et al. Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: A randomized, double-blind, placebo-controlled trial. Clin Nutr. 2016 Sep 16 [Epub ahead of print].

Miyake S, Kim S, Suda W, et al. Dysbiosis in the gut microbiota of patients with multiple sclerosis, with a striking depletion of species belonging to Clostridia XIVa and IV clusters. PLoS One. 2015;10(9):e0137429.

Tremlett H, Waubant E. The multiple sclerosis microbiome? Ann Transl Med. 2017;5(3):53.

ORLANDO—Probiotic treatment is associated with the induction of an anti-inflammatory peripheral immune profile in patients with multiple sclerosis (MS), and discontinuing probiotics is associated with a decrease in immune regulatory cells, according to pilot study results presented at the ACTRIMS 2017 Forum. The results suggest that probiotics may be applicable as a therapy for MS. More studies, including controlled clinical trials, are needed to guide treatment decisions, said Howard L. Weiner, MD, Director of the MS Program at Brigham and Women’s Hospital in Newton, Massachusetts, and Robert L. Kroc Professor of Neurology at Harvard Medical School in Boston.

The gut microbiome can modulate neuroimmune function, and studies have found that patients with MS have alterations in the gut microbiome, compared with healthy controls. These findings have led researchers to ask, “Can you treat MS by modulating the microbiome?” Dr. Weiner said. One way to modulate the microbiome is with probiotics, which can be taken as an oral, nontoxic treatment in combination with current therapies. He and his research colleagues conducted a pilot study to investigate the effect of probiotics in patients with MS. “We did not feel that we could do a clinically related study,” he said. Instead, the investigators focused on what happens to the gut microbiome and immune profiles in the blood of patients who receive probiotics.

Two Months of Treatment

The study included nine patients with MS and 13 controls. The investigators gave study participants the probiotic VSL#3. Some formulations of VSL#3 are available in stores. The company that markets the probiotic, Sigma-Tau HealthScience USA, based in Gaithersburg, Maryland, requires a prescription for VSL#3 DS, the double-strength formulation used in the study.

Prior studies of the probiotic have found that VSL#3 provides benefit in animal models of diabetes, colitis, and allergy. Kigerl et al reported that, in mice with spinal cord injury, dysbiosis induced by antibiotics exacerbates neurologic impairment and spinal cord pathology, whereas feeding mice VSL#3 enriched with lactic-acid-producing bacteria triggers a protective immune response, confers neuroprotection, and improves walking. In addition, some doctors prescribe VSL#3 to patients with ulcerative colitis, irritable bowel syndrome, and pouchitis, Dr. Weiner said.

In the pilot study, participants took VSL#3 DS sachets twice daily for two months. Researchers took blood and stool samples from participants before administering the probiotic, at discontinuation of therapy, and three months thereafter.

VSL#3 had no effect on alpha or phylogenetic diversity, but did change the gut microbiome composition. Researchers observed an increase in the relative abundance of specific organisms contained in the probiotic. Methanogens, which are increased in MS, decreased when patients received the probiotic. Administration of VSL#3 also was associated with a decrease in proinflammatory monocytes and decreased expression of activation markers on monocytes and dendritic cells.

When patients stopped probiotic treatment, the numbers of CD39 and IL10 T regulatory cells decreased, and proinflammatory monocytes increased. “We did see changes when you stop treatment, almost as if there is a rebound,” he said. “We are seeing an immune effect in the blood.”

The treatment was well tolerated. “I myself took some,” Dr. Weiner said. “It tastes a little chalky, but otherwise it is fine.” Some patients said they felt better after taking the probiotic. The study was not placebo-controlled, however. Future randomized clinical studies will include MRI scans, he said.

What should neurologists tell patients who want to take a probiotic and ask which probiotic they should take? “We are all asked those questions,” Dr. Weiner said. “I tell them, we really don’t know, but if you would like to take a probiotic, that is fine. But we have no particular recommendations at this time. We need a lot of science before we know what we are doing, as far as treatment, in this regard.”

Changes in the Gut Microbiome in MS

Prior to conducting the pilot study, Sushrut Jangi, MD, research fellow at Brigham and Women’s Hospital, Dr. Weiner, and colleagues studied the gut microbiome in 60 patients with MS and 43 healthy controls. They found that patients with MS had increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas, compared with controls. Methanobrevibacter produces methane, and in another cohort, the researchers detected more methane in the breath of patients with MS than in controls.

In addition, Prevotella and Sutterella were increased, and Sarcina was decreased in patients with MS who were treated with disease-modifying therapy, compared with untreated patients with MS. “It gives us a whole series of targets to try to understand,” he said. The gut microbiome alterations in patients with MS correlated with variations in the expression of genes in circulating T cells and monocytes that have been implicated in MS pathogenesis.

How Are the Gut Microbiome and MS Related?

The nature of the relationship between the gut microbiome and MS is unclear. One possibility is that “the gut could be the key to MS,” Dr. Weiner said. An organism in the gut may trigger MS, and that organism potentially could be altered or used in vaccinations to treat or prevent the disease. Alternatively, the gut microbiome might relate to MS susceptibility. Environmental factors, including diet and antibiotics, could affect the microbiome and MS risk. It is also possible that MS disease-modifying therapies act in part through the gut, Dr. Weiner said.

Various treatments targeting the microbiome are under investigation. For example, researchers are asking whether a particular bacteria or fecal microbiome transplants might help treat MS. “I am very interested in the concept of oral tolerance, where we trigger immune responses in the mucosa,” said Dr. Weiner. “We are beginning a trial of anti-CD3 [monoclonal antibodies], which will be given mucosally to stimulate the gut immune response.”

—Jake Remaly

Suggested Reading

Jangi S, Gandhi R, Cox LM, et al. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun. 2016;7:12015.

Kigerl KA, Hall JC, Wang L, et al. Gut dysbiosis impairs recovery after spinal cord injury. J Exp Med. 2016;213(12):2603-2620.

Kouchaki E, Tamtaji OR, Salami M, et al. Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: A randomized, double-blind, placebo-controlled trial. Clin Nutr. 2016 Sep 16 [Epub ahead of print].

Miyake S, Kim S, Suda W, et al. Dysbiosis in the gut microbiota of patients with multiple sclerosis, with a striking depletion of species belonging to Clostridia XIVa and IV clusters. PLoS One. 2015;10(9):e0137429.

Tremlett H, Waubant E. The multiple sclerosis microbiome? Ann Transl Med. 2017;5(3):53.

ORLANDO—Probiotic treatment is associated with the induction of an anti-inflammatory peripheral immune profile in patients with multiple sclerosis (MS), and discontinuing probiotics is associated with a decrease in immune regulatory cells, according to pilot study results presented at the ACTRIMS 2017 Forum. The results suggest that probiotics may be applicable as a therapy for MS. More studies, including controlled clinical trials, are needed to guide treatment decisions, said Howard L. Weiner, MD, Director of the MS Program at Brigham and Women’s Hospital in Newton, Massachusetts, and Robert L. Kroc Professor of Neurology at Harvard Medical School in Boston.

The gut microbiome can modulate neuroimmune function, and studies have found that patients with MS have alterations in the gut microbiome, compared with healthy controls. These findings have led researchers to ask, “Can you treat MS by modulating the microbiome?” Dr. Weiner said. One way to modulate the microbiome is with probiotics, which can be taken as an oral, nontoxic treatment in combination with current therapies. He and his research colleagues conducted a pilot study to investigate the effect of probiotics in patients with MS. “We did not feel that we could do a clinically related study,” he said. Instead, the investigators focused on what happens to the gut microbiome and immune profiles in the blood of patients who receive probiotics.

Two Months of Treatment

The study included nine patients with MS and 13 controls. The investigators gave study participants the probiotic VSL#3. Some formulations of VSL#3 are available in stores. The company that markets the probiotic, Sigma-Tau HealthScience USA, based in Gaithersburg, Maryland, requires a prescription for VSL#3 DS, the double-strength formulation used in the study.

Prior studies of the probiotic have found that VSL#3 provides benefit in animal models of diabetes, colitis, and allergy. Kigerl et al reported that, in mice with spinal cord injury, dysbiosis induced by antibiotics exacerbates neurologic impairment and spinal cord pathology, whereas feeding mice VSL#3 enriched with lactic-acid-producing bacteria triggers a protective immune response, confers neuroprotection, and improves walking. In addition, some doctors prescribe VSL#3 to patients with ulcerative colitis, irritable bowel syndrome, and pouchitis, Dr. Weiner said.

In the pilot study, participants took VSL#3 DS sachets twice daily for two months. Researchers took blood and stool samples from participants before administering the probiotic, at discontinuation of therapy, and three months thereafter.

VSL#3 had no effect on alpha or phylogenetic diversity, but did change the gut microbiome composition. Researchers observed an increase in the relative abundance of specific organisms contained in the probiotic. Methanogens, which are increased in MS, decreased when patients received the probiotic. Administration of VSL#3 also was associated with a decrease in proinflammatory monocytes and decreased expression of activation markers on monocytes and dendritic cells.

When patients stopped probiotic treatment, the numbers of CD39 and IL10 T regulatory cells decreased, and proinflammatory monocytes increased. “We did see changes when you stop treatment, almost as if there is a rebound,” he said. “We are seeing an immune effect in the blood.”

The treatment was well tolerated. “I myself took some,” Dr. Weiner said. “It tastes a little chalky, but otherwise it is fine.” Some patients said they felt better after taking the probiotic. The study was not placebo-controlled, however. Future randomized clinical studies will include MRI scans, he said.

What should neurologists tell patients who want to take a probiotic and ask which probiotic they should take? “We are all asked those questions,” Dr. Weiner said. “I tell them, we really don’t know, but if you would like to take a probiotic, that is fine. But we have no particular recommendations at this time. We need a lot of science before we know what we are doing, as far as treatment, in this regard.”

Changes in the Gut Microbiome in MS

Prior to conducting the pilot study, Sushrut Jangi, MD, research fellow at Brigham and Women’s Hospital, Dr. Weiner, and colleagues studied the gut microbiome in 60 patients with MS and 43 healthy controls. They found that patients with MS had increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas, compared with controls. Methanobrevibacter produces methane, and in another cohort, the researchers detected more methane in the breath of patients with MS than in controls.

In addition, Prevotella and Sutterella were increased, and Sarcina was decreased in patients with MS who were treated with disease-modifying therapy, compared with untreated patients with MS. “It gives us a whole series of targets to try to understand,” he said. The gut microbiome alterations in patients with MS correlated with variations in the expression of genes in circulating T cells and monocytes that have been implicated in MS pathogenesis.

How Are the Gut Microbiome and MS Related?

The nature of the relationship between the gut microbiome and MS is unclear. One possibility is that “the gut could be the key to MS,” Dr. Weiner said. An organism in the gut may trigger MS, and that organism potentially could be altered or used in vaccinations to treat or prevent the disease. Alternatively, the gut microbiome might relate to MS susceptibility. Environmental factors, including diet and antibiotics, could affect the microbiome and MS risk. It is also possible that MS disease-modifying therapies act in part through the gut, Dr. Weiner said.

Various treatments targeting the microbiome are under investigation. For example, researchers are asking whether a particular bacteria or fecal microbiome transplants might help treat MS. “I am very interested in the concept of oral tolerance, where we trigger immune responses in the mucosa,” said Dr. Weiner. “We are beginning a trial of anti-CD3 [monoclonal antibodies], which will be given mucosally to stimulate the gut immune response.”

—Jake Remaly

Suggested Reading

Jangi S, Gandhi R, Cox LM, et al. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun. 2016;7:12015.

Kigerl KA, Hall JC, Wang L, et al. Gut dysbiosis impairs recovery after spinal cord injury. J Exp Med. 2016;213(12):2603-2620.

Kouchaki E, Tamtaji OR, Salami M, et al. Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: A randomized, double-blind, placebo-controlled trial. Clin Nutr. 2016 Sep 16 [Epub ahead of print].

Miyake S, Kim S, Suda W, et al. Dysbiosis in the gut microbiota of patients with multiple sclerosis, with a striking depletion of species belonging to Clostridia XIVa and IV clusters. PLoS One. 2015;10(9):e0137429.

Tremlett H, Waubant E. The multiple sclerosis microbiome? Ann Transl Med. 2017;5(3):53.

ORLANDO—Patients with multiple sclerosis (MS) have a 14-year reduction in median life expectancy from onset of the disease, compared with the general population, according to a 60-year Norwegian study presented at the ACTRIMS 2017 Forum. The standardized mortality ratio (SMR) may be nearly threefold higher in patients with MS, compared with controls, and sevenfold higher in patients who are the youngest at onset.

Approximately 1,388 patients with MS with onset between 1953 and 2012 in Hordaland County, Western Norway, participated in the study. Dr. Grytten and colleagues obtained information from patient records at Haukeland University Hospital, and it was linked to the Causes of Death Registry. They estimated survival from disease onset, adjusted for sex, age, and disease course, using the Kaplan-Meier analyses. In addition, researchers used the SMR to examine mortality and causes of death in MS.

In all, 291 patients died, primarily from MS. The median time to death from MS onset was 41 years for all patients, compared with 55 years for the general population. Women with MS had a 43-year median life expectancy from onset, compared with 56 years in the general female population. Men had a 36-year median life expectancy from MS onset, compared with 50 years in the general male population. Patients with relapsing-remitting MS had a 43-year median life expectancy from onset, and individuals with primary progressive MS had a 26-year median life expectancy from onset.

The SMR was 2.7 in the total MS population. SMR was 2.4 in patients with relapsing-remitting MS and 3.9 in patients with primary progressive MS. In addition, SMR was 2.9 in women with MS and 2.5 in men with MS. Patients with onset at age 20 or younger had an SMR of 7.3. For patients age 21 to 30 at onset, SMR was 4.0. SMR was 2.6 for patients age 31 to 40 at onset. SMR was 1.3 in patients who were age 60 or older at onset.

SMR from disease onset during the period from 1953 to 1974 was 3.1. SMR from disease onset between 1975 and 1996 was 2.6, and SMR from disease onset between 1997 and 2012 was 0.7. Among causes of death, the SMR for cancer was 5.4, that for respiratory causes and infections was 4.5, and that for coronary and cerebrovascular causes was 3.28. The SMR of causes of death indicated serious comorbid disease in MS, said the investigators.

Female patients with MS had a longer median time to death, compared with male patients, but had a higher risk of dying than did the general population. Investigators also observed a decrease in mortality throughout the study, which might be attributed to environmental factors such as lifestyle and treatment.

—Erica Tricarico

Suggested Reading

Grytten Torkildsen N, Lie SA, Aarseth JH, et al. Survival and cause of death in multiple sclerosis: results from a 50-year follow-up in Western Norway. Mult Scler. 2008; 14(9):1191-1198.

ORLANDO—Patients with multiple sclerosis (MS) have a 14-year reduction in median life expectancy from onset of the disease, compared with the general population, according to a 60-year Norwegian study presented at the ACTRIMS 2017 Forum. The standardized mortality ratio (SMR) may be nearly threefold higher in patients with MS, compared with controls, and sevenfold higher in patients who are the youngest at onset.

Approximately 1,388 patients with MS with onset between 1953 and 2012 in Hordaland County, Western Norway, participated in the study. Dr. Grytten and colleagues obtained information from patient records at Haukeland University Hospital, and it was linked to the Causes of Death Registry. They estimated survival from disease onset, adjusted for sex, age, and disease course, using the Kaplan-Meier analyses. In addition, researchers used the SMR to examine mortality and causes of death in MS.

In all, 291 patients died, primarily from MS. The median time to death from MS onset was 41 years for all patients, compared with 55 years for the general population. Women with MS had a 43-year median life expectancy from onset, compared with 56 years in the general female population. Men had a 36-year median life expectancy from MS onset, compared with 50 years in the general male population. Patients with relapsing-remitting MS had a 43-year median life expectancy from onset, and individuals with primary progressive MS had a 26-year median life expectancy from onset.

The SMR was 2.7 in the total MS population. SMR was 2.4 in patients with relapsing-remitting MS and 3.9 in patients with primary progressive MS. In addition, SMR was 2.9 in women with MS and 2.5 in men with MS. Patients with onset at age 20 or younger had an SMR of 7.3. For patients age 21 to 30 at onset, SMR was 4.0. SMR was 2.6 for patients age 31 to 40 at onset. SMR was 1.3 in patients who were age 60 or older at onset.

SMR from disease onset during the period from 1953 to 1974 was 3.1. SMR from disease onset between 1975 and 1996 was 2.6, and SMR from disease onset between 1997 and 2012 was 0.7. Among causes of death, the SMR for cancer was 5.4, that for respiratory causes and infections was 4.5, and that for coronary and cerebrovascular causes was 3.28. The SMR of causes of death indicated serious comorbid disease in MS, said the investigators.

Female patients with MS had a longer median time to death, compared with male patients, but had a higher risk of dying than did the general population. Investigators also observed a decrease in mortality throughout the study, which might be attributed to environmental factors such as lifestyle and treatment.

—Erica Tricarico

Suggested Reading

Grytten Torkildsen N, Lie SA, Aarseth JH, et al. Survival and cause of death in multiple sclerosis: results from a 50-year follow-up in Western Norway. Mult Scler. 2008; 14(9):1191-1198.

ORLANDO—Patients with multiple sclerosis (MS) have a 14-year reduction in median life expectancy from onset of the disease, compared with the general population, according to a 60-year Norwegian study presented at the ACTRIMS 2017 Forum. The standardized mortality ratio (SMR) may be nearly threefold higher in patients with MS, compared with controls, and sevenfold higher in patients who are the youngest at onset.

Approximately 1,388 patients with MS with onset between 1953 and 2012 in Hordaland County, Western Norway, participated in the study. Dr. Grytten and colleagues obtained information from patient records at Haukeland University Hospital, and it was linked to the Causes of Death Registry. They estimated survival from disease onset, adjusted for sex, age, and disease course, using the Kaplan-Meier analyses. In addition, researchers used the SMR to examine mortality and causes of death in MS.

In all, 291 patients died, primarily from MS. The median time to death from MS onset was 41 years for all patients, compared with 55 years for the general population. Women with MS had a 43-year median life expectancy from onset, compared with 56 years in the general female population. Men had a 36-year median life expectancy from MS onset, compared with 50 years in the general male population. Patients with relapsing-remitting MS had a 43-year median life expectancy from onset, and individuals with primary progressive MS had a 26-year median life expectancy from onset.

The SMR was 2.7 in the total MS population. SMR was 2.4 in patients with relapsing-remitting MS and 3.9 in patients with primary progressive MS. In addition, SMR was 2.9 in women with MS and 2.5 in men with MS. Patients with onset at age 20 or younger had an SMR of 7.3. For patients age 21 to 30 at onset, SMR was 4.0. SMR was 2.6 for patients age 31 to 40 at onset. SMR was 1.3 in patients who were age 60 or older at onset.

SMR from disease onset during the period from 1953 to 1974 was 3.1. SMR from disease onset between 1975 and 1996 was 2.6, and SMR from disease onset between 1997 and 2012 was 0.7. Among causes of death, the SMR for cancer was 5.4, that for respiratory causes and infections was 4.5, and that for coronary and cerebrovascular causes was 3.28. The SMR of causes of death indicated serious comorbid disease in MS, said the investigators.

Female patients with MS had a longer median time to death, compared with male patients, but had a higher risk of dying than did the general population. Investigators also observed a decrease in mortality throughout the study, which might be attributed to environmental factors such as lifestyle and treatment.

—Erica Tricarico

Suggested Reading

Grytten Torkildsen N, Lie SA, Aarseth JH, et al. Survival and cause of death in multiple sclerosis: results from a 50-year follow-up in Western Norway. Mult Scler. 2008; 14(9):1191-1198.

ORLANDO—A high-salt diet might be a key environmental risk factor for multiple sclerosis (MS), according to an overview presented at the ACTRIMS 2017 Forum. Since most research has been performed in vitro and in animal models, it remains unclear how a high-salt diet affects patients with MS. Researchers have found in experimental models, however, that salt induces inflammation by several mechanisms: it increases frequency of inflammatory TH17 cells, decreases function of suppressor cells, and increases inflammation of antigen-presenting cells.

“There’s been an epidemic of human autoimmune disease over the past 70 years,” said Dr. Hafler. Researchers are working to discover why there has been such a significant rise in cases. “Genetics cannot allow this to happen. There must be something in the environment,” said Dr. Hafler. He and his colleagues sought to understand how a high-salt diet affects MS.

“What we found is if you added sodium chloride to cultures of T cells, you have autoimmune increases in the frequency of TH17 cells,” he said. In addition, salt decreases function of suppressor cells, the Tregs, and increases inflammation of antigen-presenting cells of the immune system, said Dr. Hafler.

Previous research found that mice fed a high-salt diet were more prone to severe experimental autoimmune encephalomyelitis. When the mice were given a high-salt, high-fat diet that mimicked fast food and probiotics, researchers observed a decrease in inflammation.

“It is really surprising to me how diet can really influence the degree of inflammation in these animals,” said Dr. Hafler. “We do not know if this will work in humans, but probiotics may decrease inflammation. We have no information [on] whether a diet with a probiotic would help prevent or treat MS.”

According to Farez et al, a higher sodium intake is associated with increased clinical and radiological disease activity in patients with MS. Other studies have found that environmental factors such as smoking and low vitamin D levels are associated with MS risk, and the risk is genetically mediated. What may be an environmental risk for one individual may not be a risk for another individual, said Dr. Hafler. “It is unlikely that any of these factors by themselves—smoking, vitamin D, fat, and salt—would be critically important, but together, they might have a strong effect,” he said.

Since there is limited research on a high-salt diet in humans, Dr. Hafler does not recommend his patients with MS go on a strict low-salt diet. However, he does advise patients to stay away from processed foods and fast food. He also encourages patients to get most of their calories from fruits and vegetables.

“We are now doing studies in which we put patients and control subjects on a high-salt diet and low[-salt] diet to observe the direct effect in those individuals,” said Dr. Hafler.

—Erica Tricarico

Suggested Reading

Farez MF, Fiol MP, Gaitán MI, et al. Sodium intake is associated with increased disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2015;86(1):26-31.

Jörg S, Kissel J, Manzel A, et al. High salt drives Th17 responses in experimental autoimmune encephalomyelitis without impacting myeloid dendritic cells. Exp Neurol. 2016;279:212-222.

Kleinewietfeld M, Manzel A, Tize J, et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature. 2013;496(7446):518-522.

Paling D, Solanky BS, Riemer F, et al. Sodium accumulation is associated with disability and a progressive course in multiple sclerosis. Brain. 2013;136(Pt 7):2305-2317.

ORLANDO—A high-salt diet might be a key environmental risk factor for multiple sclerosis (MS), according to an overview presented at the ACTRIMS 2017 Forum. Since most research has been performed in vitro and in animal models, it remains unclear how a high-salt diet affects patients with MS. Researchers have found in experimental models, however, that salt induces inflammation by several mechanisms: it increases frequency of inflammatory TH17 cells, decreases function of suppressor cells, and increases inflammation of antigen-presenting cells.

“There’s been an epidemic of human autoimmune disease over the past 70 years,” said Dr. Hafler. Researchers are working to discover why there has been such a significant rise in cases. “Genetics cannot allow this to happen. There must be something in the environment,” said Dr. Hafler. He and his colleagues sought to understand how a high-salt diet affects MS.

“What we found is if you added sodium chloride to cultures of T cells, you have autoimmune increases in the frequency of TH17 cells,” he said. In addition, salt decreases function of suppressor cells, the Tregs, and increases inflammation of antigen-presenting cells of the immune system, said Dr. Hafler.

Previous research found that mice fed a high-salt diet were more prone to severe experimental autoimmune encephalomyelitis. When the mice were given a high-salt, high-fat diet that mimicked fast food and probiotics, researchers observed a decrease in inflammation.

“It is really surprising to me how diet can really influence the degree of inflammation in these animals,” said Dr. Hafler. “We do not know if this will work in humans, but probiotics may decrease inflammation. We have no information [on] whether a diet with a probiotic would help prevent or treat MS.”

According to Farez et al, a higher sodium intake is associated with increased clinical and radiological disease activity in patients with MS. Other studies have found that environmental factors such as smoking and low vitamin D levels are associated with MS risk, and the risk is genetically mediated. What may be an environmental risk for one individual may not be a risk for another individual, said Dr. Hafler. “It is unlikely that any of these factors by themselves—smoking, vitamin D, fat, and salt—would be critically important, but together, they might have a strong effect,” he said.

Since there is limited research on a high-salt diet in humans, Dr. Hafler does not recommend his patients with MS go on a strict low-salt diet. However, he does advise patients to stay away from processed foods and fast food. He also encourages patients to get most of their calories from fruits and vegetables.

“We are now doing studies in which we put patients and control subjects on a high-salt diet and low[-salt] diet to observe the direct effect in those individuals,” said Dr. Hafler.

—Erica Tricarico

Suggested Reading

Farez MF, Fiol MP, Gaitán MI, et al. Sodium intake is associated with increased disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2015;86(1):26-31.

Jörg S, Kissel J, Manzel A, et al. High salt drives Th17 responses in experimental autoimmune encephalomyelitis without impacting myeloid dendritic cells. Exp Neurol. 2016;279:212-222.

Kleinewietfeld M, Manzel A, Tize J, et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature. 2013;496(7446):518-522.

Paling D, Solanky BS, Riemer F, et al. Sodium accumulation is associated with disability and a progressive course in multiple sclerosis. Brain. 2013;136(Pt 7):2305-2317.

ORLANDO—A high-salt diet might be a key environmental risk factor for multiple sclerosis (MS), according to an overview presented at the ACTRIMS 2017 Forum. Since most research has been performed in vitro and in animal models, it remains unclear how a high-salt diet affects patients with MS. Researchers have found in experimental models, however, that salt induces inflammation by several mechanisms: it increases frequency of inflammatory TH17 cells, decreases function of suppressor cells, and increases inflammation of antigen-presenting cells.

“There’s been an epidemic of human autoimmune disease over the past 70 years,” said Dr. Hafler. Researchers are working to discover why there has been such a significant rise in cases. “Genetics cannot allow this to happen. There must be something in the environment,” said Dr. Hafler. He and his colleagues sought to understand how a high-salt diet affects MS.

“What we found is if you added sodium chloride to cultures of T cells, you have autoimmune increases in the frequency of TH17 cells,” he said. In addition, salt decreases function of suppressor cells, the Tregs, and increases inflammation of antigen-presenting cells of the immune system, said Dr. Hafler.

Previous research found that mice fed a high-salt diet were more prone to severe experimental autoimmune encephalomyelitis. When the mice were given a high-salt, high-fat diet that mimicked fast food and probiotics, researchers observed a decrease in inflammation.

“It is really surprising to me how diet can really influence the degree of inflammation in these animals,” said Dr. Hafler. “We do not know if this will work in humans, but probiotics may decrease inflammation. We have no information [on] whether a diet with a probiotic would help prevent or treat MS.”

According to Farez et al, a higher sodium intake is associated with increased clinical and radiological disease activity in patients with MS. Other studies have found that environmental factors such as smoking and low vitamin D levels are associated with MS risk, and the risk is genetically mediated. What may be an environmental risk for one individual may not be a risk for another individual, said Dr. Hafler. “It is unlikely that any of these factors by themselves—smoking, vitamin D, fat, and salt—would be critically important, but together, they might have a strong effect,” he said.

Since there is limited research on a high-salt diet in humans, Dr. Hafler does not recommend his patients with MS go on a strict low-salt diet. However, he does advise patients to stay away from processed foods and fast food. He also encourages patients to get most of their calories from fruits and vegetables.

“We are now doing studies in which we put patients and control subjects on a high-salt diet and low[-salt] diet to observe the direct effect in those individuals,” said Dr. Hafler.

—Erica Tricarico

Suggested Reading

Farez MF, Fiol MP, Gaitán MI, et al. Sodium intake is associated with increased disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2015;86(1):26-31.

Jörg S, Kissel J, Manzel A, et al. High salt drives Th17 responses in experimental autoimmune encephalomyelitis without impacting myeloid dendritic cells. Exp Neurol. 2016;279:212-222.

Kleinewietfeld M, Manzel A, Tize J, et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature. 2013;496(7446):518-522.

Paling D, Solanky BS, Riemer F, et al. Sodium accumulation is associated with disability and a progressive course in multiple sclerosis. Brain. 2013;136(Pt 7):2305-2317.

ORLANDO—Although multiple sclerosis (MS) is more common in women, when men develop MS, it tends to be worse. Studies indicate that MS in men is associated with a faster accrual of disability and worse relapse recovery. In addition, research suggests that male gender is a predictor for more severe forms of MS. Also, there appears to be a higher male-to-female ratio in primary progressive MS (PPMS), compared with relapsing forms of MS.

Role of Sex Chromosomes and Hormones

Studies suggest that women are predisposed to higher rates of MS relapses than men. Kalincik et al found that there was approximately a 1:1 male-to-female ratio in PPMS onset, compared with a 1:3 male-to-female ratio in relapsing-onset MS. “One of the interesting paradigms they looked at was the proportion of relapses or the relapse count over the course of 10 years and the female-to-male ratio and how it has increased to become predominately female with a higher relapse count. This certainly suggests that hormones and sex may be driving a relapsing phenotype,” said Dr. Chitnis.

Raghavan et al found that men appeared to have higher Expanded Disability Status Scale scores over disease duration in relapsing forms of MS compared with PPMS. In addition, when researchers observed optic neuritis as a model of relapse recovery, they found that male gender was associated with worse recovery from optic neuritis despite adjusting for disease severity as well as vitamin D levels.

Is Testosterone Neuroprotective?

Previous studies in MS suggest that low testosterone is associated with worse disability. Studies have also associated low testosterone levels with more cognitive decline in MS. Following up on these clinical observations, Dr. Chitnis and colleagues conducted the CLIMB study, a long-term study of how MS changes over time, to observe testosterone levels in men with MS. Data from the study, which involved nearly 100 men with MS, revealed that there were significantly reduced testosterone levels in a majority of the males.

Although lower levels of testosterone may be a risk factor for rapid disability accrual, testosterone supplementation appears to be neuroprotective. “There is a vast amount of literature now demonstrating in animal models particularly that testosterone does appear to be neuroprotective and anti-inflammatory,” said Dr. Chitnis.

According to Ziehn et al, testosterone seemed to be protective against synaptic preservation in animal models. In addition, research has elucidated that testosterone is able to cross the blood-brain barrier in its free form and directly influence neuronal cells. Other studies suggest that testosterone protects spinal cord neurons from glutamate toxicity, and protects from oxidative stress in neuronal cell lines.

Sex-Stratified MS Risk, Prenatal Exposure, and Puberty

To understand whether testosterone levels predispose men to MS, researchers studied a measure called the second-digit-fourth-digit ratio (2D:4D) and found that it was associated with MS in men. Researchers have also discovered that there may be prenatal risk factors that may increase susceptibility in men. While studies suggest that breast-feeding is associated with a reduced risk of MS in boys, maternal illness and pesticide exposure in pregnancy and during the prenatal stage were associated with an increased risk for pediatric-onset MS.

Puberty also may be a turning point for the initiation of MS in boys, said Dr. Chitnis. “Younger males with MS show evidence of earlier puberty than regional controls. It is unclear if they have lower testosterone, however, research does suggest a disturbance in sex hormones early on,” she said.

Testosterone as an MS Therapy?

Several benefits have been associated with testosterone as a potential therapy, such as improved libido, increased muscle strength, improved bone density, and potentially improved memory and other cognitive measures. However, there are serious risks associated with testosterone therapy such as an increased prostate specific antigen, increased susceptibility to cancer, emotional lability, hypertension, increased hemoglobin, and increased cardiovascular events.

There may be benefits with regard to slowing disease progression and cognitive decline that warrant further study, said Dr. Chitnis. She added that future studies should focus on “mechanisms and interactions of sex hormones and testosterone in boys with MS, as well as safety and efficacy of testosterone in men with MS.”

—Erica Tricarico

Suggested Reading

Bove R, Malik MT, Diaz-Cruz C, et al. The 2D:4D ratio, a proxy for prenatal androgen levels, differs in men with and without MS. Neurology. 2015;85(14):1209-1213.

Kalincik T, Vivek V, Jokubaitis V, et al. Sex as a determinant of relapse incidence and progressive course of multiple sclerosis. Brain. 2013;136(Pt 12):3609-3617.

Raghavan K, Healy BC, Carruthers RL, Chitnis T. Progression rates and sample size estimates for PPMS based on the CLIMB study population. Mult Scler. 2015;21(2):180-188.

Ziehn MO, Avedisian AA, Dervin SM, et al. Therapeutic testosterone administration preserves excitatory synaptic transmission in the hippocampus during autoimmune demyelinating disease. J Neurosci. 2012; 32(36):12312-12324.

ORLANDO—Although multiple sclerosis (MS) is more common in women, when men develop MS, it tends to be worse. Studies indicate that MS in men is associated with a faster accrual of disability and worse relapse recovery. In addition, research suggests that male gender is a predictor for more severe forms of MS. Also, there appears to be a higher male-to-female ratio in primary progressive MS (PPMS), compared with relapsing forms of MS.

Role of Sex Chromosomes and Hormones

Studies suggest that women are predisposed to higher rates of MS relapses than men. Kalincik et al found that there was approximately a 1:1 male-to-female ratio in PPMS onset, compared with a 1:3 male-to-female ratio in relapsing-onset MS. “One of the interesting paradigms they looked at was the proportion of relapses or the relapse count over the course of 10 years and the female-to-male ratio and how it has increased to become predominately female with a higher relapse count. This certainly suggests that hormones and sex may be driving a relapsing phenotype,” said Dr. Chitnis.

Raghavan et al found that men appeared to have higher Expanded Disability Status Scale scores over disease duration in relapsing forms of MS compared with PPMS. In addition, when researchers observed optic neuritis as a model of relapse recovery, they found that male gender was associated with worse recovery from optic neuritis despite adjusting for disease severity as well as vitamin D levels.

Is Testosterone Neuroprotective?

Previous studies in MS suggest that low testosterone is associated with worse disability. Studies have also associated low testosterone levels with more cognitive decline in MS. Following up on these clinical observations, Dr. Chitnis and colleagues conducted the CLIMB study, a long-term study of how MS changes over time, to observe testosterone levels in men with MS. Data from the study, which involved nearly 100 men with MS, revealed that there were significantly reduced testosterone levels in a majority of the males.

Although lower levels of testosterone may be a risk factor for rapid disability accrual, testosterone supplementation appears to be neuroprotective. “There is a vast amount of literature now demonstrating in animal models particularly that testosterone does appear to be neuroprotective and anti-inflammatory,” said Dr. Chitnis.

According to Ziehn et al, testosterone seemed to be protective against synaptic preservation in animal models. In addition, research has elucidated that testosterone is able to cross the blood-brain barrier in its free form and directly influence neuronal cells. Other studies suggest that testosterone protects spinal cord neurons from glutamate toxicity, and protects from oxidative stress in neuronal cell lines.

Sex-Stratified MS Risk, Prenatal Exposure, and Puberty

To understand whether testosterone levels predispose men to MS, researchers studied a measure called the second-digit-fourth-digit ratio (2D:4D) and found that it was associated with MS in men. Researchers have also discovered that there may be prenatal risk factors that may increase susceptibility in men. While studies suggest that breast-feeding is associated with a reduced risk of MS in boys, maternal illness and pesticide exposure in pregnancy and during the prenatal stage were associated with an increased risk for pediatric-onset MS.

Puberty also may be a turning point for the initiation of MS in boys, said Dr. Chitnis. “Younger males with MS show evidence of earlier puberty than regional controls. It is unclear if they have lower testosterone, however, research does suggest a disturbance in sex hormones early on,” she said.

Testosterone as an MS Therapy?

Several benefits have been associated with testosterone as a potential therapy, such as improved libido, increased muscle strength, improved bone density, and potentially improved memory and other cognitive measures. However, there are serious risks associated with testosterone therapy such as an increased prostate specific antigen, increased susceptibility to cancer, emotional lability, hypertension, increased hemoglobin, and increased cardiovascular events.

There may be benefits with regard to slowing disease progression and cognitive decline that warrant further study, said Dr. Chitnis. She added that future studies should focus on “mechanisms and interactions of sex hormones and testosterone in boys with MS, as well as safety and efficacy of testosterone in men with MS.”

—Erica Tricarico

Suggested Reading

Bove R, Malik MT, Diaz-Cruz C, et al. The 2D:4D ratio, a proxy for prenatal androgen levels, differs in men with and without MS. Neurology. 2015;85(14):1209-1213.

Kalincik T, Vivek V, Jokubaitis V, et al. Sex as a determinant of relapse incidence and progressive course of multiple sclerosis. Brain. 2013;136(Pt 12):3609-3617.

Raghavan K, Healy BC, Carruthers RL, Chitnis T. Progression rates and sample size estimates for PPMS based on the CLIMB study population. Mult Scler. 2015;21(2):180-188.

Ziehn MO, Avedisian AA, Dervin SM, et al. Therapeutic testosterone administration preserves excitatory synaptic transmission in the hippocampus during autoimmune demyelinating disease. J Neurosci. 2012; 32(36):12312-12324.

ORLANDO—Although multiple sclerosis (MS) is more common in women, when men develop MS, it tends to be worse. Studies indicate that MS in men is associated with a faster accrual of disability and worse relapse recovery. In addition, research suggests that male gender is a predictor for more severe forms of MS. Also, there appears to be a higher male-to-female ratio in primary progressive MS (PPMS), compared with relapsing forms of MS.

Role of Sex Chromosomes and Hormones

Studies suggest that women are predisposed to higher rates of MS relapses than men. Kalincik et al found that there was approximately a 1:1 male-to-female ratio in PPMS onset, compared with a 1:3 male-to-female ratio in relapsing-onset MS. “One of the interesting paradigms they looked at was the proportion of relapses or the relapse count over the course of 10 years and the female-to-male ratio and how it has increased to become predominately female with a higher relapse count. This certainly suggests that hormones and sex may be driving a relapsing phenotype,” said Dr. Chitnis.

Raghavan et al found that men appeared to have higher Expanded Disability Status Scale scores over disease duration in relapsing forms of MS compared with PPMS. In addition, when researchers observed optic neuritis as a model of relapse recovery, they found that male gender was associated with worse recovery from optic neuritis despite adjusting for disease severity as well as vitamin D levels.

Is Testosterone Neuroprotective?

Previous studies in MS suggest that low testosterone is associated with worse disability. Studies have also associated low testosterone levels with more cognitive decline in MS. Following up on these clinical observations, Dr. Chitnis and colleagues conducted the CLIMB study, a long-term study of how MS changes over time, to observe testosterone levels in men with MS. Data from the study, which involved nearly 100 men with MS, revealed that there were significantly reduced testosterone levels in a majority of the males.

Although lower levels of testosterone may be a risk factor for rapid disability accrual, testosterone supplementation appears to be neuroprotective. “There is a vast amount of literature now demonstrating in animal models particularly that testosterone does appear to be neuroprotective and anti-inflammatory,” said Dr. Chitnis.

According to Ziehn et al, testosterone seemed to be protective against synaptic preservation in animal models. In addition, research has elucidated that testosterone is able to cross the blood-brain barrier in its free form and directly influence neuronal cells. Other studies suggest that testosterone protects spinal cord neurons from glutamate toxicity, and protects from oxidative stress in neuronal cell lines.

Sex-Stratified MS Risk, Prenatal Exposure, and Puberty

To understand whether testosterone levels predispose men to MS, researchers studied a measure called the second-digit-fourth-digit ratio (2D:4D) and found that it was associated with MS in men. Researchers have also discovered that there may be prenatal risk factors that may increase susceptibility in men. While studies suggest that breast-feeding is associated with a reduced risk of MS in boys, maternal illness and pesticide exposure in pregnancy and during the prenatal stage were associated with an increased risk for pediatric-onset MS.

Puberty also may be a turning point for the initiation of MS in boys, said Dr. Chitnis. “Younger males with MS show evidence of earlier puberty than regional controls. It is unclear if they have lower testosterone, however, research does suggest a disturbance in sex hormones early on,” she said.

Testosterone as an MS Therapy?

Several benefits have been associated with testosterone as a potential therapy, such as improved libido, increased muscle strength, improved bone density, and potentially improved memory and other cognitive measures. However, there are serious risks associated with testosterone therapy such as an increased prostate specific antigen, increased susceptibility to cancer, emotional lability, hypertension, increased hemoglobin, and increased cardiovascular events.

There may be benefits with regard to slowing disease progression and cognitive decline that warrant further study, said Dr. Chitnis. She added that future studies should focus on “mechanisms and interactions of sex hormones and testosterone in boys with MS, as well as safety and efficacy of testosterone in men with MS.”

—Erica Tricarico

Suggested Reading

Bove R, Malik MT, Diaz-Cruz C, et al. The 2D:4D ratio, a proxy for prenatal androgen levels, differs in men with and without MS. Neurology. 2015;85(14):1209-1213.

Kalincik T, Vivek V, Jokubaitis V, et al. Sex as a determinant of relapse incidence and progressive course of multiple sclerosis. Brain. 2013;136(Pt 12):3609-3617.

Raghavan K, Healy BC, Carruthers RL, Chitnis T. Progression rates and sample size estimates for PPMS based on the CLIMB study population. Mult Scler. 2015;21(2):180-188.

Ziehn MO, Avedisian AA, Dervin SM, et al. Therapeutic testosterone administration preserves excitatory synaptic transmission in the hippocampus during autoimmune demyelinating disease. J Neurosci. 2012; 32(36):12312-12324.

In patients presenting with a first clinical demyelinating event, early treatment with subcutaneous interferon beta-1a three times per week over five years prolonged the time to clinically definite multiple sclerosis (MS), compared with delayed treatment, according to research published online ahead of print December 30, 2016 in the Journal of Neurology, Neurosurgery and Psychiatry. Compared with delayed treatment, early treatment also prolonged the time to McDonald MS conversion.

Giancarlo Comi, MD, Professor of Neurology at the Scientific Institute H.S. Raffaele in Milan, and colleagues conducted REFLEXION, a preplanned extension of the REFLEX study, to compare the effect of more frequent and early dosing with that of delayed treatment. Eligible patients were between ages 18 and 50, had an Expanded Disability Status Scale (EDSS) score of 5.0 or lower, and a single clinical event suggestive of MS within 60 days of enrollment. In REFLEX, patients had been randomized to interferon beta-1a (44 μg) thrice weekly or once weekly, or placebo. Treatment lasted for 24 months or until a patient developed clinically definite MS.

In REFLEXION, patients first randomized to interferon beta-1a who had not converted to clinically definite MS continued their original dosing regimen. Patients originally receiving placebo who had not converted to clinically definite MS were switched to interferon beta-1a (44 μg thrice weekly). These patients became the delayed-treatment group. Patients who converted to clinically definite MS during REFLEX or REFLEXION received open-label interferon beta-1a 44 μg thrice weekly from then on.

EDSS scores and clinically definite MS assessments were recorded at extension baseline (ie, month 24) and every six months thereafter. The primary end point was time to conversion to clinically definite MS from first randomization to month 36. Time to clinically definite MS to month 60 was a secondary end point.

The extension study included 127 participants originally randomized to interferon beta-1a thrice weekly, 142 participants originally randomized to interferon beta-1a once weekly, and 133 patients originally randomized to placebo. At month 36, the proportion of patients who had converted to clinically definite MS was lower among patients receiving interferon thrice weekly or weekly, compared with the delayed-treatment group (25.1%, 25.7%, and 38.6%, respectively). The risk of conversion to clinically definite MS was significantly reduced for patients receiving early treatment, compared with delayed treatment. The researchers found no significant difference between the early-treatment groups.

The analysis for month 60 also found that both early-treatment groups had longer times to clinically definite MS, compared with delayed treatment. The proportion of patients who converted to clinically definite MS increased at month 60, but was still lower among participants receiving thrice-weekly or weekly interferon than among patients on delayed treatment (32.2%, 36.0%, and 40.4%, respectively). Cumulative probability of conversion was lower with thrice-weekly and weekly early treatment than with delayed treatment (39.2%, 40.7%, and 44.6%, respectively).

—Erik Greb

Suggested Reading

Comi G, De Stefano N, Freedman MS, et al. Subcutaneous interferon β-1a in the treatment of clinically isolated syndromes: 3-year and 5-year results of the phase III dosing frequency-blind multicentre REFLEXION study. J Neurol Neurosurg Psychiatry. 2016 Dec 30 [Epub ahead of print].

In patients presenting with a first clinical demyelinating event, early treatment with subcutaneous interferon beta-1a three times per week over five years prolonged the time to clinically definite multiple sclerosis (MS), compared with delayed treatment, according to research published online ahead of print December 30, 2016 in the Journal of Neurology, Neurosurgery and Psychiatry. Compared with delayed treatment, early treatment also prolonged the time to McDonald MS conversion.

Giancarlo Comi, MD, Professor of Neurology at the Scientific Institute H.S. Raffaele in Milan, and colleagues conducted REFLEXION, a preplanned extension of the REFLEX study, to compare the effect of more frequent and early dosing with that of delayed treatment. Eligible patients were between ages 18 and 50, had an Expanded Disability Status Scale (EDSS) score of 5.0 or lower, and a single clinical event suggestive of MS within 60 days of enrollment. In REFLEX, patients had been randomized to interferon beta-1a (44 μg) thrice weekly or once weekly, or placebo. Treatment lasted for 24 months or until a patient developed clinically definite MS.

In REFLEXION, patients first randomized to interferon beta-1a who had not converted to clinically definite MS continued their original dosing regimen. Patients originally receiving placebo who had not converted to clinically definite MS were switched to interferon beta-1a (44 μg thrice weekly). These patients became the delayed-treatment group. Patients who converted to clinically definite MS during REFLEX or REFLEXION received open-label interferon beta-1a 44 μg thrice weekly from then on.

EDSS scores and clinically definite MS assessments were recorded at extension baseline (ie, month 24) and every six months thereafter. The primary end point was time to conversion to clinically definite MS from first randomization to month 36. Time to clinically definite MS to month 60 was a secondary end point.

The extension study included 127 participants originally randomized to interferon beta-1a thrice weekly, 142 participants originally randomized to interferon beta-1a once weekly, and 133 patients originally randomized to placebo. At month 36, the proportion of patients who had converted to clinically definite MS was lower among patients receiving interferon thrice weekly or weekly, compared with the delayed-treatment group (25.1%, 25.7%, and 38.6%, respectively). The risk of conversion to clinically definite MS was significantly reduced for patients receiving early treatment, compared with delayed treatment. The researchers found no significant difference between the early-treatment groups.

The analysis for month 60 also found that both early-treatment groups had longer times to clinically definite MS, compared with delayed treatment. The proportion of patients who converted to clinically definite MS increased at month 60, but was still lower among participants receiving thrice-weekly or weekly interferon than among patients on delayed treatment (32.2%, 36.0%, and 40.4%, respectively). Cumulative probability of conversion was lower with thrice-weekly and weekly early treatment than with delayed treatment (39.2%, 40.7%, and 44.6%, respectively).

—Erik Greb

Suggested Reading

Comi G, De Stefano N, Freedman MS, et al. Subcutaneous interferon β-1a in the treatment of clinically isolated syndromes: 3-year and 5-year results of the phase III dosing frequency-blind multicentre REFLEXION study. J Neurol Neurosurg Psychiatry. 2016 Dec 30 [Epub ahead of print].

In patients presenting with a first clinical demyelinating event, early treatment with subcutaneous interferon beta-1a three times per week over five years prolonged the time to clinically definite multiple sclerosis (MS), compared with delayed treatment, according to research published online ahead of print December 30, 2016 in the Journal of Neurology, Neurosurgery and Psychiatry. Compared with delayed treatment, early treatment also prolonged the time to McDonald MS conversion.

Giancarlo Comi, MD, Professor of Neurology at the Scientific Institute H.S. Raffaele in Milan, and colleagues conducted REFLEXION, a preplanned extension of the REFLEX study, to compare the effect of more frequent and early dosing with that of delayed treatment. Eligible patients were between ages 18 and 50, had an Expanded Disability Status Scale (EDSS) score of 5.0 or lower, and a single clinical event suggestive of MS within 60 days of enrollment. In REFLEX, patients had been randomized to interferon beta-1a (44 μg) thrice weekly or once weekly, or placebo. Treatment lasted for 24 months or until a patient developed clinically definite MS.

In REFLEXION, patients first randomized to interferon beta-1a who had not converted to clinically definite MS continued their original dosing regimen. Patients originally receiving placebo who had not converted to clinically definite MS were switched to interferon beta-1a (44 μg thrice weekly). These patients became the delayed-treatment group. Patients who converted to clinically definite MS during REFLEX or REFLEXION received open-label interferon beta-1a 44 μg thrice weekly from then on.

EDSS scores and clinically definite MS assessments were recorded at extension baseline (ie, month 24) and every six months thereafter. The primary end point was time to conversion to clinically definite MS from first randomization to month 36. Time to clinically definite MS to month 60 was a secondary end point.

The extension study included 127 participants originally randomized to interferon beta-1a thrice weekly, 142 participants originally randomized to interferon beta-1a once weekly, and 133 patients originally randomized to placebo. At month 36, the proportion of patients who had converted to clinically definite MS was lower among patients receiving interferon thrice weekly or weekly, compared with the delayed-treatment group (25.1%, 25.7%, and 38.6%, respectively). The risk of conversion to clinically definite MS was significantly reduced for patients receiving early treatment, compared with delayed treatment. The researchers found no significant difference between the early-treatment groups.

The analysis for month 60 also found that both early-treatment groups had longer times to clinically definite MS, compared with delayed treatment. The proportion of patients who converted to clinically definite MS increased at month 60, but was still lower among participants receiving thrice-weekly or weekly interferon than among patients on delayed treatment (32.2%, 36.0%, and 40.4%, respectively). Cumulative probability of conversion was lower with thrice-weekly and weekly early treatment than with delayed treatment (39.2%, 40.7%, and 44.6%, respectively).

—Erik Greb

Suggested Reading

Comi G, De Stefano N, Freedman MS, et al. Subcutaneous interferon β-1a in the treatment of clinically isolated syndromes: 3-year and 5-year results of the phase III dosing frequency-blind multicentre REFLEXION study. J Neurol Neurosurg Psychiatry. 2016 Dec 30 [Epub ahead of print].