ICYMI Multiple Sclerosis

NEW ORLEANS—Analysis of pooled data from the CLARITY and ONWARD studies showed that cladribine tablets 3.5 mg/kg decreased annualized relapse rate by 57% and reduced the risk for six-month confirmed disability progression by 39% versus placebo in a population of patients with active relapsing multiple sclerosis (MS). These findings were presented at the 31st Annual Meeting of the Consortium of MS Centers.

Treatment with cladribine tablets in the CLARITY and ONWARD studies demonstrated efficacy versus placebo across a range of patients with active MS. “Combining efficacy data from the double-blind periods of these studies allows assessment of the efficacy of two years’ treatment with cladribine tablets 3.5 mg/kg,” said Gavin Giovannoni, MBBCh, PhD, on behalf of his research colleagues. Dr. Giovannoni is a Professor at the Blizard Institute at Barts and the London School of Medicine and Dentistry in London.

Dr. Giovannoni and colleagues used pooled data from the two-year, double-blind periods of CLARITY and ONWARD to analyze the efficacy of cladribine tablets 3.5 mg/kg in patients with relapsing MS (n = 1,067) and in subgroups defined by baseline characteristics. Patients from ONWARD on cladribine tablets or placebo were also taking interferon beta. Annualized relapse rates and three-month and six-month confirmed disability progression were compared using relative risk ratios from a Poisson regression model, hazard ratios from a Cox proportional hazard model, and 95% confidence intervals for patients treated with cladribine tablets 3.5 mg/kg or placebo. The subgroups analyzed included, among others, patients with no T1 gadolinium-enhancing lesions (n = 759) or one or more T1 gadolinium-enhancing lesions (n = 308) and patients with an Expanded Disability Status Scale (EDSS) score of 3.0 or lower (n = 653) or 3.5 or greater (n = 414).

For annualized relapse rate, consistent benefits were seen with cladribine tablets 3.5 mg/kg versus placebo in the overall population (relative risk ratio: 0.43) and in the subgroups: no T1 gadolinium-enhancing lesions, 0.46; one or more T1 gadolinium-enhancing lesions, 0.38; EDSS of 3.0 or lower, 0.40; EDSS of 3.5 or greater, 0.47. Benefits favored cladribine tablets 3.5 mg/kg versus placebo in the overall population for time to three-month confirmed disability progression (hazard ratio: 0.64) and six-month confirmed disability progression (hazard ratio: 0.61) and in each of these outcomes in a majority of subgroups. For three-month confirmed disability progression: no T1 gadolinium-enhancing lesions, hazard ratio: 0.59; one or more T1 gadolinium-enhancing lesions, hazard ratio: 0.75; EDSS of 3.0 or lower, hazard ratio: 0.76; EDSS of 3.5 or greater, hazard ratio: 0.55. For six-month confirmed disability progression: no T1 gadolinium-enhancing lesions, hazard ratio: 0.59; one or more T1 gadolinium-enhancing lesions, hazard ratio: 0.66; EDSS of 3.0 or lower, hazard ratio: 0.75; EDSS of 3.5 or greater, hazard ratio: 0.51.

This study was supported by EMD Serono.

NEW ORLEANS—Analysis of pooled data from the CLARITY and ONWARD studies showed that cladribine tablets 3.5 mg/kg decreased annualized relapse rate by 57% and reduced the risk for six-month confirmed disability progression by 39% versus placebo in a population of patients with active relapsing multiple sclerosis (MS). These findings were presented at the 31st Annual Meeting of the Consortium of MS Centers.

Treatment with cladribine tablets in the CLARITY and ONWARD studies demonstrated efficacy versus placebo across a range of patients with active MS. “Combining efficacy data from the double-blind periods of these studies allows assessment of the efficacy of two years’ treatment with cladribine tablets 3.5 mg/kg,” said Gavin Giovannoni, MBBCh, PhD, on behalf of his research colleagues. Dr. Giovannoni is a Professor at the Blizard Institute at Barts and the London School of Medicine and Dentistry in London.

Dr. Giovannoni and colleagues used pooled data from the two-year, double-blind periods of CLARITY and ONWARD to analyze the efficacy of cladribine tablets 3.5 mg/kg in patients with relapsing MS (n = 1,067) and in subgroups defined by baseline characteristics. Patients from ONWARD on cladribine tablets or placebo were also taking interferon beta. Annualized relapse rates and three-month and six-month confirmed disability progression were compared using relative risk ratios from a Poisson regression model, hazard ratios from a Cox proportional hazard model, and 95% confidence intervals for patients treated with cladribine tablets 3.5 mg/kg or placebo. The subgroups analyzed included, among others, patients with no T1 gadolinium-enhancing lesions (n = 759) or one or more T1 gadolinium-enhancing lesions (n = 308) and patients with an Expanded Disability Status Scale (EDSS) score of 3.0 or lower (n = 653) or 3.5 or greater (n = 414).

For annualized relapse rate, consistent benefits were seen with cladribine tablets 3.5 mg/kg versus placebo in the overall population (relative risk ratio: 0.43) and in the subgroups: no T1 gadolinium-enhancing lesions, 0.46; one or more T1 gadolinium-enhancing lesions, 0.38; EDSS of 3.0 or lower, 0.40; EDSS of 3.5 or greater, 0.47. Benefits favored cladribine tablets 3.5 mg/kg versus placebo in the overall population for time to three-month confirmed disability progression (hazard ratio: 0.64) and six-month confirmed disability progression (hazard ratio: 0.61) and in each of these outcomes in a majority of subgroups. For three-month confirmed disability progression: no T1 gadolinium-enhancing lesions, hazard ratio: 0.59; one or more T1 gadolinium-enhancing lesions, hazard ratio: 0.75; EDSS of 3.0 or lower, hazard ratio: 0.76; EDSS of 3.5 or greater, hazard ratio: 0.55. For six-month confirmed disability progression: no T1 gadolinium-enhancing lesions, hazard ratio: 0.59; one or more T1 gadolinium-enhancing lesions, hazard ratio: 0.66; EDSS of 3.0 or lower, hazard ratio: 0.75; EDSS of 3.5 or greater, hazard ratio: 0.51.

This study was supported by EMD Serono.

NEW ORLEANS—Analysis of pooled data from the CLARITY and ONWARD studies showed that cladribine tablets 3.5 mg/kg decreased annualized relapse rate by 57% and reduced the risk for six-month confirmed disability progression by 39% versus placebo in a population of patients with active relapsing multiple sclerosis (MS). These findings were presented at the 31st Annual Meeting of the Consortium of MS Centers.

Treatment with cladribine tablets in the CLARITY and ONWARD studies demonstrated efficacy versus placebo across a range of patients with active MS. “Combining efficacy data from the double-blind periods of these studies allows assessment of the efficacy of two years’ treatment with cladribine tablets 3.5 mg/kg,” said Gavin Giovannoni, MBBCh, PhD, on behalf of his research colleagues. Dr. Giovannoni is a Professor at the Blizard Institute at Barts and the London School of Medicine and Dentistry in London.

Dr. Giovannoni and colleagues used pooled data from the two-year, double-blind periods of CLARITY and ONWARD to analyze the efficacy of cladribine tablets 3.5 mg/kg in patients with relapsing MS (n = 1,067) and in subgroups defined by baseline characteristics. Patients from ONWARD on cladribine tablets or placebo were also taking interferon beta. Annualized relapse rates and three-month and six-month confirmed disability progression were compared using relative risk ratios from a Poisson regression model, hazard ratios from a Cox proportional hazard model, and 95% confidence intervals for patients treated with cladribine tablets 3.5 mg/kg or placebo. The subgroups analyzed included, among others, patients with no T1 gadolinium-enhancing lesions (n = 759) or one or more T1 gadolinium-enhancing lesions (n = 308) and patients with an Expanded Disability Status Scale (EDSS) score of 3.0 or lower (n = 653) or 3.5 or greater (n = 414).

For annualized relapse rate, consistent benefits were seen with cladribine tablets 3.5 mg/kg versus placebo in the overall population (relative risk ratio: 0.43) and in the subgroups: no T1 gadolinium-enhancing lesions, 0.46; one or more T1 gadolinium-enhancing lesions, 0.38; EDSS of 3.0 or lower, 0.40; EDSS of 3.5 or greater, 0.47. Benefits favored cladribine tablets 3.5 mg/kg versus placebo in the overall population for time to three-month confirmed disability progression (hazard ratio: 0.64) and six-month confirmed disability progression (hazard ratio: 0.61) and in each of these outcomes in a majority of subgroups. For three-month confirmed disability progression: no T1 gadolinium-enhancing lesions, hazard ratio: 0.59; one or more T1 gadolinium-enhancing lesions, hazard ratio: 0.75; EDSS of 3.0 or lower, hazard ratio: 0.76; EDSS of 3.5 or greater, hazard ratio: 0.55. For six-month confirmed disability progression: no T1 gadolinium-enhancing lesions, hazard ratio: 0.59; one or more T1 gadolinium-enhancing lesions, hazard ratio: 0.66; EDSS of 3.0 or lower, hazard ratio: 0.75; EDSS of 3.5 or greater, hazard ratio: 0.51.

This study was supported by EMD Serono.

NEW ORLEANS—Ublituximab, a novel glycoengineered anti-CD20 antibody, is well tolerated and demonstrates rapid and robust B-cell depletion, according to a report presented at the 31st Annual Meeting of the Consortium of Multiple Sclerosis Centers. “Unlike other anti-CD20s, ublituximab can be delivered in shorter infusions, providing a convenience benefit for patients,” reported Amy Lovett-Racke, PhD, and her research colleagues. Dr. Lovett-Racke is a Professor in the Department of Microbial Infection and Immunity at Ohio State University Medical Center in Columbus.

Patients with relapsing or primary progressive forms of multiple sclerosis (MS) have shown significant clinical improvement after B-cell depletion with an anti-CD20 antibody. Ublituximab is a chimeric monoclonal antibody that targets a unique epitope on the CD20 antigen. It has been glycoengineered to enhance affinity for all variants of FcgRIIIa receptors, demonstrating greater antibody-dependent cellular cytotoxicity (ADCC) activity than rituximab. Ublituximab is currently in phase III trials for the treatment of hematologic malignancies.

To determine the level of B-cell depletion by ublituximab in subjects with relapsing MS, Dr. Lovett-Racke and colleagues conducted a 52-week, phase II, placebo-controlled, multicenter study that was designed to assess the infusion time and optimal dose as well as the safety and tolerability of ublituximab in patients with relapsing MS. The investigators also performed radiologic and clinical analyses. Optimal dosing was determined by B-cell depletion, defined as percentage of CD19+ B cells present following ublituximab administration. This percentage was calculated by gating the entire lymphocyte/myeloid population. Within this population, CD19+ CD3− cells were gated, and the percentage of CD19+ B cells was determined.

To date, B-cell data from 11 subjects have been analyzed up to week four of the 52-week study, encompassing two infusions of ublituximab. No severe adverse events have been reported, including in subjects receiving rapid infusions. Only patients whose B-cell levels were within a normal range (≥ 5% of total lymphocytes) at screening were included in the study. At week four (one week post second infusion), median B-cell depletion was 99% from baseline in ublituximab-treated subjects, while controls maintained similar B-cell levels, as compared with baseline.

This study was supported by TG Therapeutics.

NEW ORLEANS—Ublituximab, a novel glycoengineered anti-CD20 antibody, is well tolerated and demonstrates rapid and robust B-cell depletion, according to a report presented at the 31st Annual Meeting of the Consortium of Multiple Sclerosis Centers. “Unlike other anti-CD20s, ublituximab can be delivered in shorter infusions, providing a convenience benefit for patients,” reported Amy Lovett-Racke, PhD, and her research colleagues. Dr. Lovett-Racke is a Professor in the Department of Microbial Infection and Immunity at Ohio State University Medical Center in Columbus.

Patients with relapsing or primary progressive forms of multiple sclerosis (MS) have shown significant clinical improvement after B-cell depletion with an anti-CD20 antibody. Ublituximab is a chimeric monoclonal antibody that targets a unique epitope on the CD20 antigen. It has been glycoengineered to enhance affinity for all variants of FcgRIIIa receptors, demonstrating greater antibody-dependent cellular cytotoxicity (ADCC) activity than rituximab. Ublituximab is currently in phase III trials for the treatment of hematologic malignancies.

To determine the level of B-cell depletion by ublituximab in subjects with relapsing MS, Dr. Lovett-Racke and colleagues conducted a 52-week, phase II, placebo-controlled, multicenter study that was designed to assess the infusion time and optimal dose as well as the safety and tolerability of ublituximab in patients with relapsing MS. The investigators also performed radiologic and clinical analyses. Optimal dosing was determined by B-cell depletion, defined as percentage of CD19+ B cells present following ublituximab administration. This percentage was calculated by gating the entire lymphocyte/myeloid population. Within this population, CD19+ CD3− cells were gated, and the percentage of CD19+ B cells was determined.

To date, B-cell data from 11 subjects have been analyzed up to week four of the 52-week study, encompassing two infusions of ublituximab. No severe adverse events have been reported, including in subjects receiving rapid infusions. Only patients whose B-cell levels were within a normal range (≥ 5% of total lymphocytes) at screening were included in the study. At week four (one week post second infusion), median B-cell depletion was 99% from baseline in ublituximab-treated subjects, while controls maintained similar B-cell levels, as compared with baseline.

This study was supported by TG Therapeutics.

NEW ORLEANS—Ublituximab, a novel glycoengineered anti-CD20 antibody, is well tolerated and demonstrates rapid and robust B-cell depletion, according to a report presented at the 31st Annual Meeting of the Consortium of Multiple Sclerosis Centers. “Unlike other anti-CD20s, ublituximab can be delivered in shorter infusions, providing a convenience benefit for patients,” reported Amy Lovett-Racke, PhD, and her research colleagues. Dr. Lovett-Racke is a Professor in the Department of Microbial Infection and Immunity at Ohio State University Medical Center in Columbus.

Patients with relapsing or primary progressive forms of multiple sclerosis (MS) have shown significant clinical improvement after B-cell depletion with an anti-CD20 antibody. Ublituximab is a chimeric monoclonal antibody that targets a unique epitope on the CD20 antigen. It has been glycoengineered to enhance affinity for all variants of FcgRIIIa receptors, demonstrating greater antibody-dependent cellular cytotoxicity (ADCC) activity than rituximab. Ublituximab is currently in phase III trials for the treatment of hematologic malignancies.

To determine the level of B-cell depletion by ublituximab in subjects with relapsing MS, Dr. Lovett-Racke and colleagues conducted a 52-week, phase II, placebo-controlled, multicenter study that was designed to assess the infusion time and optimal dose as well as the safety and tolerability of ublituximab in patients with relapsing MS. The investigators also performed radiologic and clinical analyses. Optimal dosing was determined by B-cell depletion, defined as percentage of CD19+ B cells present following ublituximab administration. This percentage was calculated by gating the entire lymphocyte/myeloid population. Within this population, CD19+ CD3− cells were gated, and the percentage of CD19+ B cells was determined.

To date, B-cell data from 11 subjects have been analyzed up to week four of the 52-week study, encompassing two infusions of ublituximab. No severe adverse events have been reported, including in subjects receiving rapid infusions. Only patients whose B-cell levels were within a normal range (≥ 5% of total lymphocytes) at screening were included in the study. At week four (one week post second infusion), median B-cell depletion was 99% from baseline in ublituximab-treated subjects, while controls maintained similar B-cell levels, as compared with baseline.

This study was supported by TG Therapeutics.

NEW ORLEANS—MRI lesion activity and relapses in the phase III TRANSFORMS study predicted relapses in the short and long terms among patients with multiple sclerosis (MS), according to research presented at the 31st Annual Meeting of the Consortium of MS Centers. In addition, baseline Expanded Disability Status Scale (EDSS) score, age, and disease duration predicted six-month confirmed disability progression.

“These results suggest that early use of high-efficacy treatment may help to control disease worsening,” said Aaron L. Boster, MD, Systems Medical Chief of Neuroimmunology at OhioHealth in Columbus, and colleagues.

Disease and treatment history, early MRI lesion activity, and relapses may predict long-term clinical outcomes in patients with relapsing forms of MS. To test the ability of parameters at baseline and during treatment to predict relapses or six-month disability progression in the short and long terms, Dr. Boster and colleagues conducted a post-hoc analysis of the 36-month follow-up of TRANSFORMS, a 12-month, double-blind study in which researchers randomized patients to oral fingolimod or intramuscular interferon beta-1a.

After the 12-month, double-blind study, patients could enter a long-term extension. Upon entering the extension, researchers switched patients who originally received intramuscular interferon beta-1a to fingolimod. The investigators used unadjusted logistic regression to assess which parameters from baseline to month 12 predicted clinical outcomes (ie, relapses or six-month confirmed disability progress, measured using the EDSS) during months 12–24 and months 12–48.

In all, researchers randomized 1,292 patients in TRANSFORMS. Predictors of relapses in the short and long terms included a combination of MRI lesion activity (ie, at least one gadolinium-enhancing lesion or at least two new T2 lesions) and at least one confirmed relapse (odds ratio [OR], 2.776 for months 12–24; OR, 3.703 for months 12–48). The number of confirmed relapses from baseline to month 12 also predicted relapses during the extension.

Novartis Pharmaceuticals supported this study.

NEW ORLEANS—MRI lesion activity and relapses in the phase III TRANSFORMS study predicted relapses in the short and long terms among patients with multiple sclerosis (MS), according to research presented at the 31st Annual Meeting of the Consortium of MS Centers. In addition, baseline Expanded Disability Status Scale (EDSS) score, age, and disease duration predicted six-month confirmed disability progression.

“These results suggest that early use of high-efficacy treatment may help to control disease worsening,” said Aaron L. Boster, MD, Systems Medical Chief of Neuroimmunology at OhioHealth in Columbus, and colleagues.

Disease and treatment history, early MRI lesion activity, and relapses may predict long-term clinical outcomes in patients with relapsing forms of MS. To test the ability of parameters at baseline and during treatment to predict relapses or six-month disability progression in the short and long terms, Dr. Boster and colleagues conducted a post-hoc analysis of the 36-month follow-up of TRANSFORMS, a 12-month, double-blind study in which researchers randomized patients to oral fingolimod or intramuscular interferon beta-1a.

After the 12-month, double-blind study, patients could enter a long-term extension. Upon entering the extension, researchers switched patients who originally received intramuscular interferon beta-1a to fingolimod. The investigators used unadjusted logistic regression to assess which parameters from baseline to month 12 predicted clinical outcomes (ie, relapses or six-month confirmed disability progress, measured using the EDSS) during months 12–24 and months 12–48.

In all, researchers randomized 1,292 patients in TRANSFORMS. Predictors of relapses in the short and long terms included a combination of MRI lesion activity (ie, at least one gadolinium-enhancing lesion or at least two new T2 lesions) and at least one confirmed relapse (odds ratio [OR], 2.776 for months 12–24; OR, 3.703 for months 12–48). The number of confirmed relapses from baseline to month 12 also predicted relapses during the extension.

Novartis Pharmaceuticals supported this study.

NEW ORLEANS—MRI lesion activity and relapses in the phase III TRANSFORMS study predicted relapses in the short and long terms among patients with multiple sclerosis (MS), according to research presented at the 31st Annual Meeting of the Consortium of MS Centers. In addition, baseline Expanded Disability Status Scale (EDSS) score, age, and disease duration predicted six-month confirmed disability progression.

“These results suggest that early use of high-efficacy treatment may help to control disease worsening,” said Aaron L. Boster, MD, Systems Medical Chief of Neuroimmunology at OhioHealth in Columbus, and colleagues.

Disease and treatment history, early MRI lesion activity, and relapses may predict long-term clinical outcomes in patients with relapsing forms of MS. To test the ability of parameters at baseline and during treatment to predict relapses or six-month disability progression in the short and long terms, Dr. Boster and colleagues conducted a post-hoc analysis of the 36-month follow-up of TRANSFORMS, a 12-month, double-blind study in which researchers randomized patients to oral fingolimod or intramuscular interferon beta-1a.

After the 12-month, double-blind study, patients could enter a long-term extension. Upon entering the extension, researchers switched patients who originally received intramuscular interferon beta-1a to fingolimod. The investigators used unadjusted logistic regression to assess which parameters from baseline to month 12 predicted clinical outcomes (ie, relapses or six-month confirmed disability progress, measured using the EDSS) during months 12–24 and months 12–48.

In all, researchers randomized 1,292 patients in TRANSFORMS. Predictors of relapses in the short and long terms included a combination of MRI lesion activity (ie, at least one gadolinium-enhancing lesion or at least two new T2 lesions) and at least one confirmed relapse (odds ratio [OR], 2.776 for months 12–24; OR, 3.703 for months 12–48). The number of confirmed relapses from baseline to month 12 also predicted relapses during the extension.

Novartis Pharmaceuticals supported this study.

 

BOSTON – Prior Epstein-Barr virus (EBV) infection and prior herpes simplex virus (HSV) infection each appear to be associated with development of pediatric-onset multiple sclerosis (MS), according to findings from a large national case-control study.

Samples from 360 children with MS or clinically isolated syndrome and 496 frequency-matched controls recruited from 16 pediatric MS centers across the United States were tested for EBV, cytomegalovirus (CMV), and HSV antibodies and for 25-(OH)-vitamin D levels. After adjusting for age, sex, and race/ethnicity, evidence of a remote infection with EBV was strongly associated with higher risk of pediatric-onset MS (odds ratio, 3.6), Bardia Nourbakhsh, MD, reported at the annual meeting of the American Academy of Neurology.

copyright Zerbor/Thinkstock

HSV-1 and -2 seropositivity was also associated significantly with pediatric onset MS (OR, 1.5), said Dr. Nourbakhsh, who was a clinical fellow at the University of California, San Francisco, when he conducted the research but is now at Johns Hopkins University, Baltimore.

“We didn’t see an association between CMV and the risk of developing pediatric MS,” he said, noting that prior studies had shown a protective effect of prior CMV.

There was a trend toward an association between lower serum vitamin D levels and the risk of developing pediatric MS, but the findings are questionable because of vitamin D supplementation started after diagnosis in most patients, he noted.

Further, analysis showed that race also played a role in the relationships between prior infections and MS.

The association between HSV-1 and -2 infection was significant only among white patients, the association between prior EBV and MS was much stronger in whites than non-whites, and the association between EBV and MS was stronger in non-Hispanics than in Hispanics, he said.

The MS risk variant HLA DRB1*1501 also played a role in the associations. The association between prior HSV-1 and -2 infection and MS risk was apparent only in DRB1-negative individuals, and, conversely, the association between prior EBV and MS risk was much stronger in those who were DRB1-positive, he said.

Patients included in the study had a mean age of 15.2 years, 64% were girls, and the mean disease duration was 354 days. Controls had a mean age of 14.3 years.

“Remote viral infections have been known as one of the most commonly cited risk factors for adult and pediatric MS,” Dr. Nourbakhsh said, noting that a prior case-control study showed these associations and that other studies suggested associations with vitamin D deficiency.

The current study was conducted in an attempt to replicate those prior findings, he said.

The results of this large study support an association between prior EBV and HSV infections and MS risk and a possible association between vitamin D deficiency and MS risk but are limited by lack of testing before disease development and by vitamin D supplementation in almost all patients after diagnosis, he said.

“In the future, hopefully, we can look further at the interaction of genes and environment and the heterogeneity of the effect of risk factors in different subpopulations,” he concluded.

Dr. Nourbakhsh reported having no disclosures.

sworcester@frontlinemedcom.com

 

BOSTON – Prior Epstein-Barr virus (EBV) infection and prior herpes simplex virus (HSV) infection each appear to be associated with development of pediatric-onset multiple sclerosis (MS), according to findings from a large national case-control study.

Samples from 360 children with MS or clinically isolated syndrome and 496 frequency-matched controls recruited from 16 pediatric MS centers across the United States were tested for EBV, cytomegalovirus (CMV), and HSV antibodies and for 25-(OH)-vitamin D levels. After adjusting for age, sex, and race/ethnicity, evidence of a remote infection with EBV was strongly associated with higher risk of pediatric-onset MS (odds ratio, 3.6), Bardia Nourbakhsh, MD, reported at the annual meeting of the American Academy of Neurology.

copyright Zerbor/Thinkstock

HSV-1 and -2 seropositivity was also associated significantly with pediatric onset MS (OR, 1.5), said Dr. Nourbakhsh, who was a clinical fellow at the University of California, San Francisco, when he conducted the research but is now at Johns Hopkins University, Baltimore.

“We didn’t see an association between CMV and the risk of developing pediatric MS,” he said, noting that prior studies had shown a protective effect of prior CMV.

There was a trend toward an association between lower serum vitamin D levels and the risk of developing pediatric MS, but the findings are questionable because of vitamin D supplementation started after diagnosis in most patients, he noted.

Further, analysis showed that race also played a role in the relationships between prior infections and MS.

The association between HSV-1 and -2 infection was significant only among white patients, the association between prior EBV and MS was much stronger in whites than non-whites, and the association between EBV and MS was stronger in non-Hispanics than in Hispanics, he said.

The MS risk variant HLA DRB1*1501 also played a role in the associations. The association between prior HSV-1 and -2 infection and MS risk was apparent only in DRB1-negative individuals, and, conversely, the association between prior EBV and MS risk was much stronger in those who were DRB1-positive, he said.

Patients included in the study had a mean age of 15.2 years, 64% were girls, and the mean disease duration was 354 days. Controls had a mean age of 14.3 years.

“Remote viral infections have been known as one of the most commonly cited risk factors for adult and pediatric MS,” Dr. Nourbakhsh said, noting that a prior case-control study showed these associations and that other studies suggested associations with vitamin D deficiency.

The current study was conducted in an attempt to replicate those prior findings, he said.

The results of this large study support an association between prior EBV and HSV infections and MS risk and a possible association between vitamin D deficiency and MS risk but are limited by lack of testing before disease development and by vitamin D supplementation in almost all patients after diagnosis, he said.

“In the future, hopefully, we can look further at the interaction of genes and environment and the heterogeneity of the effect of risk factors in different subpopulations,” he concluded.

Dr. Nourbakhsh reported having no disclosures.

sworcester@frontlinemedcom.com

 

BOSTON – Prior Epstein-Barr virus (EBV) infection and prior herpes simplex virus (HSV) infection each appear to be associated with development of pediatric-onset multiple sclerosis (MS), according to findings from a large national case-control study.

Samples from 360 children with MS or clinically isolated syndrome and 496 frequency-matched controls recruited from 16 pediatric MS centers across the United States were tested for EBV, cytomegalovirus (CMV), and HSV antibodies and for 25-(OH)-vitamin D levels. After adjusting for age, sex, and race/ethnicity, evidence of a remote infection with EBV was strongly associated with higher risk of pediatric-onset MS (odds ratio, 3.6), Bardia Nourbakhsh, MD, reported at the annual meeting of the American Academy of Neurology.

copyright Zerbor/Thinkstock

HSV-1 and -2 seropositivity was also associated significantly with pediatric onset MS (OR, 1.5), said Dr. Nourbakhsh, who was a clinical fellow at the University of California, San Francisco, when he conducted the research but is now at Johns Hopkins University, Baltimore.

“We didn’t see an association between CMV and the risk of developing pediatric MS,” he said, noting that prior studies had shown a protective effect of prior CMV.

There was a trend toward an association between lower serum vitamin D levels and the risk of developing pediatric MS, but the findings are questionable because of vitamin D supplementation started after diagnosis in most patients, he noted.

Further, analysis showed that race also played a role in the relationships between prior infections and MS.

The association between HSV-1 and -2 infection was significant only among white patients, the association between prior EBV and MS was much stronger in whites than non-whites, and the association between EBV and MS was stronger in non-Hispanics than in Hispanics, he said.

The MS risk variant HLA DRB1*1501 also played a role in the associations. The association between prior HSV-1 and -2 infection and MS risk was apparent only in DRB1-negative individuals, and, conversely, the association between prior EBV and MS risk was much stronger in those who were DRB1-positive, he said.

Patients included in the study had a mean age of 15.2 years, 64% were girls, and the mean disease duration was 354 days. Controls had a mean age of 14.3 years.

“Remote viral infections have been known as one of the most commonly cited risk factors for adult and pediatric MS,” Dr. Nourbakhsh said, noting that a prior case-control study showed these associations and that other studies suggested associations with vitamin D deficiency.

The current study was conducted in an attempt to replicate those prior findings, he said.

The results of this large study support an association between prior EBV and HSV infections and MS risk and a possible association between vitamin D deficiency and MS risk but are limited by lack of testing before disease development and by vitamin D supplementation in almost all patients after diagnosis, he said.

“In the future, hopefully, we can look further at the interaction of genes and environment and the heterogeneity of the effect of risk factors in different subpopulations,” he concluded.

Dr. Nourbakhsh reported having no disclosures.

sworcester@frontlinemedcom.com

BOSTON—Misdiagnosing optic neuritis may expose patients to risks associated with undergoing MRI with a contrast agent, lumbar puncture, and high-dose steroid treatment. It also costs patients and hospitals time and money. Leanne Stunkel, MD, a neurology resident at Washington University in St. Louis, and her colleagues observed a 60% misdiagnosis rate of optic neuritis among patients who were referred to their neuro-ophthalmology clinic, according to a study presented at the 69th Annual Meeting of the American Academy of Neurology.

“The most common [diagnostic] errors were overreliance on a single item of history and failure to consider alternative diagnoses,” said Dr. Stunkel.

Optic neuritis is an acute inflammatory demyelinating condition of the optic nerve. Presenting symptoms include acute or subacute vision loss, pain with eye movement, and changes in color vision, especially affecting the color red, said Dr. Stunkel. Many patients who were referred to their tertiary care clinic for optic neuritis turned out to have other conditions, which prompted the researchers to find out more about optic neuritis misdiagnosis.

Previous studies found a misdiagnosis rate of between 10% and 40%, but none of these studies examined which errors led to these misdiagnoses. To determine how often optic neuritis is misdiagnosed and which diagnostic errors play a role, and to identify diagnoses commonly mistaken for optic neuritis, Dr. Stunkel and colleagues performed a retrospective chart review.

The researchers reviewed new patient encounters between January 2014 and October 2016 to identify patients referred with a diagnosis of optic neuritis. Experienced neuro-ophthalmologists determined the final diagnosis. The researchers then applied the Diagnosis Error Evaluation and Research (DEER) taxonomy tool to identify diagnostic errors in cases in which the patient did not have optic neuritis.

A total of 122 patients were referred for optic neuritis during the study period. Only 40% of these patients were diagnosed with optic neuritis, and 60% of patients had alternative diagnoses. The most common alternative diagnoses were headache with eye pain and visual symptoms (22%), functional visual loss (19%), and other optic neuropathies (16%).

In addition, 15% of patients had retinal or macular problems rather than pathology of the optic nerve. Other diagnoses included neoplasms, congenital disk abnormalities, and inflammatory conditions that affected other parts of the eye.

The most common diagnostic errors were from problems eliciting or interpreting the history (33%). “We saw an overreliance on history of risk factors such as multiple sclerosis or other inflammatory disorders and some failure to elicit the fact that these were brief stereotyped episodes of vision loss, like in a migraine aura,” said Dr. Stunkel.

Twenty-one percent of diagnostic errors were due to errors interpreting physical exam findings, and 14% of errors were due to misinterpretation of diagnostic tests. Finally, 32% of diagnostic errors resulted from failure to consider alternative diagnoses. Of patients who did not have optic neuritis, 17% had already received a lumbar puncture, 17% had received a contrast MRI that turned out to be negative, and 11 patients had inappropriately received IV steroids, said Dr. Stunkel.

Some of the study limitations include that the DEER category assignments were subjective, and that not every referral for optic neuritis was included in the study due to limitations of the clinic’s electronic medical records system, said Dr. Stunkel.

—Erica Tricarico

BOSTON—Misdiagnosing optic neuritis may expose patients to risks associated with undergoing MRI with a contrast agent, lumbar puncture, and high-dose steroid treatment. It also costs patients and hospitals time and money. Leanne Stunkel, MD, a neurology resident at Washington University in St. Louis, and her colleagues observed a 60% misdiagnosis rate of optic neuritis among patients who were referred to their neuro-ophthalmology clinic, according to a study presented at the 69th Annual Meeting of the American Academy of Neurology.

“The most common [diagnostic] errors were overreliance on a single item of history and failure to consider alternative diagnoses,” said Dr. Stunkel.

Optic neuritis is an acute inflammatory demyelinating condition of the optic nerve. Presenting symptoms include acute or subacute vision loss, pain with eye movement, and changes in color vision, especially affecting the color red, said Dr. Stunkel. Many patients who were referred to their tertiary care clinic for optic neuritis turned out to have other conditions, which prompted the researchers to find out more about optic neuritis misdiagnosis.

Previous studies found a misdiagnosis rate of between 10% and 40%, but none of these studies examined which errors led to these misdiagnoses. To determine how often optic neuritis is misdiagnosed and which diagnostic errors play a role, and to identify diagnoses commonly mistaken for optic neuritis, Dr. Stunkel and colleagues performed a retrospective chart review.

The researchers reviewed new patient encounters between January 2014 and October 2016 to identify patients referred with a diagnosis of optic neuritis. Experienced neuro-ophthalmologists determined the final diagnosis. The researchers then applied the Diagnosis Error Evaluation and Research (DEER) taxonomy tool to identify diagnostic errors in cases in which the patient did not have optic neuritis.

A total of 122 patients were referred for optic neuritis during the study period. Only 40% of these patients were diagnosed with optic neuritis, and 60% of patients had alternative diagnoses. The most common alternative diagnoses were headache with eye pain and visual symptoms (22%), functional visual loss (19%), and other optic neuropathies (16%).

In addition, 15% of patients had retinal or macular problems rather than pathology of the optic nerve. Other diagnoses included neoplasms, congenital disk abnormalities, and inflammatory conditions that affected other parts of the eye.

The most common diagnostic errors were from problems eliciting or interpreting the history (33%). “We saw an overreliance on history of risk factors such as multiple sclerosis or other inflammatory disorders and some failure to elicit the fact that these were brief stereotyped episodes of vision loss, like in a migraine aura,” said Dr. Stunkel.

Twenty-one percent of diagnostic errors were due to errors interpreting physical exam findings, and 14% of errors were due to misinterpretation of diagnostic tests. Finally, 32% of diagnostic errors resulted from failure to consider alternative diagnoses. Of patients who did not have optic neuritis, 17% had already received a lumbar puncture, 17% had received a contrast MRI that turned out to be negative, and 11 patients had inappropriately received IV steroids, said Dr. Stunkel.

Some of the study limitations include that the DEER category assignments were subjective, and that not every referral for optic neuritis was included in the study due to limitations of the clinic’s electronic medical records system, said Dr. Stunkel.

—Erica Tricarico

BOSTON—Misdiagnosing optic neuritis may expose patients to risks associated with undergoing MRI with a contrast agent, lumbar puncture, and high-dose steroid treatment. It also costs patients and hospitals time and money. Leanne Stunkel, MD, a neurology resident at Washington University in St. Louis, and her colleagues observed a 60% misdiagnosis rate of optic neuritis among patients who were referred to their neuro-ophthalmology clinic, according to a study presented at the 69th Annual Meeting of the American Academy of Neurology.

“The most common [diagnostic] errors were overreliance on a single item of history and failure to consider alternative diagnoses,” said Dr. Stunkel.

Optic neuritis is an acute inflammatory demyelinating condition of the optic nerve. Presenting symptoms include acute or subacute vision loss, pain with eye movement, and changes in color vision, especially affecting the color red, said Dr. Stunkel. Many patients who were referred to their tertiary care clinic for optic neuritis turned out to have other conditions, which prompted the researchers to find out more about optic neuritis misdiagnosis.

Previous studies found a misdiagnosis rate of between 10% and 40%, but none of these studies examined which errors led to these misdiagnoses. To determine how often optic neuritis is misdiagnosed and which diagnostic errors play a role, and to identify diagnoses commonly mistaken for optic neuritis, Dr. Stunkel and colleagues performed a retrospective chart review.

The researchers reviewed new patient encounters between January 2014 and October 2016 to identify patients referred with a diagnosis of optic neuritis. Experienced neuro-ophthalmologists determined the final diagnosis. The researchers then applied the Diagnosis Error Evaluation and Research (DEER) taxonomy tool to identify diagnostic errors in cases in which the patient did not have optic neuritis.

A total of 122 patients were referred for optic neuritis during the study period. Only 40% of these patients were diagnosed with optic neuritis, and 60% of patients had alternative diagnoses. The most common alternative diagnoses were headache with eye pain and visual symptoms (22%), functional visual loss (19%), and other optic neuropathies (16%).

In addition, 15% of patients had retinal or macular problems rather than pathology of the optic nerve. Other diagnoses included neoplasms, congenital disk abnormalities, and inflammatory conditions that affected other parts of the eye.

The most common diagnostic errors were from problems eliciting or interpreting the history (33%). “We saw an overreliance on history of risk factors such as multiple sclerosis or other inflammatory disorders and some failure to elicit the fact that these were brief stereotyped episodes of vision loss, like in a migraine aura,” said Dr. Stunkel.

Twenty-one percent of diagnostic errors were due to errors interpreting physical exam findings, and 14% of errors were due to misinterpretation of diagnostic tests. Finally, 32% of diagnostic errors resulted from failure to consider alternative diagnoses. Of patients who did not have optic neuritis, 17% had already received a lumbar puncture, 17% had received a contrast MRI that turned out to be negative, and 11 patients had inappropriately received IV steroids, said Dr. Stunkel.

Some of the study limitations include that the DEER category assignments were subjective, and that not every referral for optic neuritis was included in the study due to limitations of the clinic’s electronic medical records system, said Dr. Stunkel.

—Erica Tricarico

 

A variant in the TNFSF13B gene has been linked to susceptibility to both multiple sclerosis and systemic lupus erythematosus, according to a report published online April 26 in the New England Journal of Medicine.

This gene encodes the cytokine B-cell activating factor (BAFF), which is essential for B-cell activation, differentiation, and survival. BAFF is targeted by agents such as belimumab that are used in the treatment of autoimmune disorders, and is primarily produced by monocytes and neutrophils, said Maristella Steri, PhD, of Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato (Italy), and her associates.

The researchers have named this TNFSF13B variation “BAFF-var.”

Previous genome-wide association studies have identified more than 110 independent signals for MS and 43 for SLE but have not yet delineated the effector mechanisms for most of these associations. To explore these mechanisms in greater detail, Dr. Steri and her associates studied the population in Sardinia, Italy, which has the highest prevalences of MS and SLE in the world.

ktsimage/Thinkstock

They performed genome-wide association studies and other genetic investigations in case-control sets of 2,934 patients with MS, 411 with SLE, and 3,392 control subjects, analyzing roughly 12.2 million single-nucleotide polymorphisms (SNPs). They ruled out rs1287404 as a likely variant driving the association and identified BAFF-var as the variant most strongly associated with MS (odds ratio, 1.27).

The investigators then replicated their findings in a series of genetic studies in case-control sets from mainland Italy (2,292 patients with MS, 503 with SLE, and 2,563 controls), Sweden (4,548 patients with MS and 3,481 controls), the United Kingdom (3,176 patients with MS and 2,958 controls), and the Iberian peninsula (1,120 patients with SLE and 1,300 controls). BAFF-var was most common across Sardinia, with a frequency of 26.5%, and became progressively less common moving northward (5.7% in Italy, 4.9% in Spain, 1.8% in the United Kingdom and Sweden).

Taken together, “these findings pinpoint BAFF-var as the variant in TNFSF13B that is most strongly associated with MS,” wrote Dr. Steri and her associates (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMoa1610528).

BAFF-var also proved to be associated with SLE in case-control sets from Sardinia (OR, 1.38), mainland Italy (OR, 1.49), and the Iberian peninsula (OR, 1.55). This indicates that “the effect of BAFF-var is not restricted to MS alone,” they noted.

Further analyses showed that BAFF-var “dramatically” increased levels of soluble BAFF and circulating B cells, especially CD24+CD27+ cells, as well as total IgG, IgA, IgM, and monocytes. In one notable analysis, preclinical blood samples taken from Sardinians participating in a longitudinal study showed elevated levels of soluble BAFF in people who did not go on to develop MS until years later.

“We infer [from this] that BAFF-var is the causal variant driving an increase in soluble BAFF and a cascade of immune effects leading to increased autoimmunity risk,” Dr. Steri and her associates said.

Further study suggested that positive selection specifically favoring BAFF-var, not random genetic drift, accounted for the high frequency of this mutation in Sardinia and its progressively lower frequency moving northward. The most likely possibility is that BAFF-var was positively selected because it provided resistance to malaria, which was “strikingly prevalent” in Sardinia until it was eradicated in the 1950s. In mouse models, BAFF overexpression confers protection against lethal malaria.

“In addition, as shown here, BAFF-var increases antibody production, and classic findings showed that antibody transfer from adults with immunity to malaria to acutely infected children reduced blood-stage parasitemia and disease severity,” the investigators said.

“The evolutionary scenario we propose is that BAFF-var was selected as an adaptive response to malaria infection, resulting in an increased present-day risk of autoimmunity,” they said.

The Italian Foundation for Multiple Sclerosis, the National Institute on Aging, the Italian Ministry of Economy and Finance, the European Union, the National Human Genome Research Institute, and other organizations supported the study. Dr. Steri reported having no relevant disclosures; some of her associates reported ties to numerous industry sources.
 

imnews@frontlinemedcom.com

 

A variant in the TNFSF13B gene has been linked to susceptibility to both multiple sclerosis and systemic lupus erythematosus, according to a report published online April 26 in the New England Journal of Medicine.

This gene encodes the cytokine B-cell activating factor (BAFF), which is essential for B-cell activation, differentiation, and survival. BAFF is targeted by agents such as belimumab that are used in the treatment of autoimmune disorders, and is primarily produced by monocytes and neutrophils, said Maristella Steri, PhD, of Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato (Italy), and her associates.

The researchers have named this TNFSF13B variation “BAFF-var.”

Previous genome-wide association studies have identified more than 110 independent signals for MS and 43 for SLE but have not yet delineated the effector mechanisms for most of these associations. To explore these mechanisms in greater detail, Dr. Steri and her associates studied the population in Sardinia, Italy, which has the highest prevalences of MS and SLE in the world.

ktsimage/Thinkstock

They performed genome-wide association studies and other genetic investigations in case-control sets of 2,934 patients with MS, 411 with SLE, and 3,392 control subjects, analyzing roughly 12.2 million single-nucleotide polymorphisms (SNPs). They ruled out rs1287404 as a likely variant driving the association and identified BAFF-var as the variant most strongly associated with MS (odds ratio, 1.27).

The investigators then replicated their findings in a series of genetic studies in case-control sets from mainland Italy (2,292 patients with MS, 503 with SLE, and 2,563 controls), Sweden (4,548 patients with MS and 3,481 controls), the United Kingdom (3,176 patients with MS and 2,958 controls), and the Iberian peninsula (1,120 patients with SLE and 1,300 controls). BAFF-var was most common across Sardinia, with a frequency of 26.5%, and became progressively less common moving northward (5.7% in Italy, 4.9% in Spain, 1.8% in the United Kingdom and Sweden).

Taken together, “these findings pinpoint BAFF-var as the variant in TNFSF13B that is most strongly associated with MS,” wrote Dr. Steri and her associates (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMoa1610528).

BAFF-var also proved to be associated with SLE in case-control sets from Sardinia (OR, 1.38), mainland Italy (OR, 1.49), and the Iberian peninsula (OR, 1.55). This indicates that “the effect of BAFF-var is not restricted to MS alone,” they noted.

Further analyses showed that BAFF-var “dramatically” increased levels of soluble BAFF and circulating B cells, especially CD24+CD27+ cells, as well as total IgG, IgA, IgM, and monocytes. In one notable analysis, preclinical blood samples taken from Sardinians participating in a longitudinal study showed elevated levels of soluble BAFF in people who did not go on to develop MS until years later.

“We infer [from this] that BAFF-var is the causal variant driving an increase in soluble BAFF and a cascade of immune effects leading to increased autoimmunity risk,” Dr. Steri and her associates said.

Further study suggested that positive selection specifically favoring BAFF-var, not random genetic drift, accounted for the high frequency of this mutation in Sardinia and its progressively lower frequency moving northward. The most likely possibility is that BAFF-var was positively selected because it provided resistance to malaria, which was “strikingly prevalent” in Sardinia until it was eradicated in the 1950s. In mouse models, BAFF overexpression confers protection against lethal malaria.

“In addition, as shown here, BAFF-var increases antibody production, and classic findings showed that antibody transfer from adults with immunity to malaria to acutely infected children reduced blood-stage parasitemia and disease severity,” the investigators said.

“The evolutionary scenario we propose is that BAFF-var was selected as an adaptive response to malaria infection, resulting in an increased present-day risk of autoimmunity,” they said.

The Italian Foundation for Multiple Sclerosis, the National Institute on Aging, the Italian Ministry of Economy and Finance, the European Union, the National Human Genome Research Institute, and other organizations supported the study. Dr. Steri reported having no relevant disclosures; some of her associates reported ties to numerous industry sources.
 

imnews@frontlinemedcom.com

 

A variant in the TNFSF13B gene has been linked to susceptibility to both multiple sclerosis and systemic lupus erythematosus, according to a report published online April 26 in the New England Journal of Medicine.

This gene encodes the cytokine B-cell activating factor (BAFF), which is essential for B-cell activation, differentiation, and survival. BAFF is targeted by agents such as belimumab that are used in the treatment of autoimmune disorders, and is primarily produced by monocytes and neutrophils, said Maristella Steri, PhD, of Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato (Italy), and her associates.

The researchers have named this TNFSF13B variation “BAFF-var.”

Previous genome-wide association studies have identified more than 110 independent signals for MS and 43 for SLE but have not yet delineated the effector mechanisms for most of these associations. To explore these mechanisms in greater detail, Dr. Steri and her associates studied the population in Sardinia, Italy, which has the highest prevalences of MS and SLE in the world.

ktsimage/Thinkstock

They performed genome-wide association studies and other genetic investigations in case-control sets of 2,934 patients with MS, 411 with SLE, and 3,392 control subjects, analyzing roughly 12.2 million single-nucleotide polymorphisms (SNPs). They ruled out rs1287404 as a likely variant driving the association and identified BAFF-var as the variant most strongly associated with MS (odds ratio, 1.27).

The investigators then replicated their findings in a series of genetic studies in case-control sets from mainland Italy (2,292 patients with MS, 503 with SLE, and 2,563 controls), Sweden (4,548 patients with MS and 3,481 controls), the United Kingdom (3,176 patients with MS and 2,958 controls), and the Iberian peninsula (1,120 patients with SLE and 1,300 controls). BAFF-var was most common across Sardinia, with a frequency of 26.5%, and became progressively less common moving northward (5.7% in Italy, 4.9% in Spain, 1.8% in the United Kingdom and Sweden).

Taken together, “these findings pinpoint BAFF-var as the variant in TNFSF13B that is most strongly associated with MS,” wrote Dr. Steri and her associates (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMoa1610528).

BAFF-var also proved to be associated with SLE in case-control sets from Sardinia (OR, 1.38), mainland Italy (OR, 1.49), and the Iberian peninsula (OR, 1.55). This indicates that “the effect of BAFF-var is not restricted to MS alone,” they noted.

Further analyses showed that BAFF-var “dramatically” increased levels of soluble BAFF and circulating B cells, especially CD24+CD27+ cells, as well as total IgG, IgA, IgM, and monocytes. In one notable analysis, preclinical blood samples taken from Sardinians participating in a longitudinal study showed elevated levels of soluble BAFF in people who did not go on to develop MS until years later.

“We infer [from this] that BAFF-var is the causal variant driving an increase in soluble BAFF and a cascade of immune effects leading to increased autoimmunity risk,” Dr. Steri and her associates said.

Further study suggested that positive selection specifically favoring BAFF-var, not random genetic drift, accounted for the high frequency of this mutation in Sardinia and its progressively lower frequency moving northward. The most likely possibility is that BAFF-var was positively selected because it provided resistance to malaria, which was “strikingly prevalent” in Sardinia until it was eradicated in the 1950s. In mouse models, BAFF overexpression confers protection against lethal malaria.

“In addition, as shown here, BAFF-var increases antibody production, and classic findings showed that antibody transfer from adults with immunity to malaria to acutely infected children reduced blood-stage parasitemia and disease severity,” the investigators said.

“The evolutionary scenario we propose is that BAFF-var was selected as an adaptive response to malaria infection, resulting in an increased present-day risk of autoimmunity,” they said.

The Italian Foundation for Multiple Sclerosis, the National Institute on Aging, the Italian Ministry of Economy and Finance, the European Union, the National Human Genome Research Institute, and other organizations supported the study. Dr. Steri reported having no relevant disclosures; some of her associates reported ties to numerous industry sources.
 

imnews@frontlinemedcom.com

 

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.

Then there’s the issue of recall bias and the question as to whether oral cannabinoids equate to the plant-derived forms of medical marijuana that patients obtain from their local dispensaries.

That matters, because the majority of published studies on the topic have evaluated oral cannabinoids, not the plant form. “So, what we’re studying is vastly different from what our patients are using,” she said.

The most solid indication clinicians have for recommending medical marijuana is for chronic pain, and the most common condition studied has been neuropathy.

“Most evidence compares cannabinoid to placebo,” said Dr. Grossman, primary care lead for behavioral health integration at Cambridge (Mass.) Health Alliance. “There’s almost nothing out there comparing cannabinoid to any other pain-relieving agent that a patient might choose to use.

“A lot of the literature comes from oral synthesized agents,” she continued. “There’s a little bit of science about inhaled forms, but a lot of this is very different from what my patient got last week in a medical marijuana dispensary in Massachusetts.”

Results from a systematic review of 79 studies of cannabinoids for medical use in 6,462 study participants showed that, compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs. 20%; odds ratio, 3.82), reduction in pain (37% vs. 31%; OR, 1.41), a greater average reduction in numerical rating scale pain assessment (on a 0- to 10-point scale; weighted mean difference of –0.46), and average reduction in the Ashworth spasticity scale (–0.36) (JAMA 2015 Jun 23-30;313[24]:2456-73).

A separate meta-analysis of studies compared inhaled cannabis sativa to placebo for chronic painful neuropathy. The researchers found that those patients who used inhaled cannabis sativa were 3.2 times more likely to achieve a 30% or greater reduction in pain, compared with those in the placebo group (J. Pain 2015 Dec;16[12]:1221-32).

However, Dr. Grossman cautioned that the number of patients studied was fewer than 200, “so, you could argue that this is a body of knowledge where the jury is still out.”

According to a 2017 report from the National Academy of Sciences titled, “The Health Effects of Cannabis and Cannabinoids,” another area in which the knowledge base is less solid is the use of oral cannabinoids for chemotherapy-induced nausea and vomiting.

“There’s a reasonable amount of evidence showing that some of these are better than placebo for relief of these symptoms,” Dr. Grossman said. “That said, the jury’s out as to whether they are any better than our other antiemetic agents. And there are no studies comparing them to neurokinin-1 inhibitors, which are the newest class of drug often used by oncologists for this indication. There is also no good evidence about inhaled plant cannabis.”

Studies of oral cannabinoids for multiple-sclerosis–related spasticity have demonstrated a small improvement on patient-reported spasticity (less than 1 point on a 10-point scale), but there was no improvement in clinician-reported outcomes. At the same time, their use for weight loss/anorexia in HIV “is very limited, and there are no studies of plant-derived cannabis,” Dr. Grossman said.

According to the National Academy of Sciences report, some evidence supports the use of oral cannabinoids for short-term sleep outcomes in patients with chronic diseases such as fibromyalgia and MS. One small study of oral cannabinoid for anxiety found that it improved social anxiety symptoms on the public speaking test, but there have been no studies using inhaled cannabinoids/marijuana.

The health risks of medical marijuana are largely unknown, Dr. Grossman said, noting that most evidence on longer‐term health risks comes from epidemiologic studies of recreational cannabis users.

“Medical marijuana users tend to be older and tend to be sicker,” she said. “We don’t know anything about the long-term effects in that sicker population.”

Among healthier people, Dr. Grossman continued, cannabis use is associated with increased risk of cough, wheeze, and sputum/phlegm. “There’s also an increased risk of motor vehicle accidents,” she said. “That is certainly a concern in places where they’re legalizing marijuana.”

Cannabis use is associated with lower neonatal birth weight, case reports/series of unintentional pediatric ingestions, and a possible increase in suicidal ideation, suicide attempts, and completed suicides.

“The evidence is very limited regarding associations with myocardial infarction, stroke, COPD, and mortality,” she added. “We don’t really know.”

Dr. Grossman reported having no financial disclosures.

 

dbrunk@frontlinemedcom.com

 

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.

Then there’s the issue of recall bias and the question as to whether oral cannabinoids equate to the plant-derived forms of medical marijuana that patients obtain from their local dispensaries.

That matters, because the majority of published studies on the topic have evaluated oral cannabinoids, not the plant form. “So, what we’re studying is vastly different from what our patients are using,” she said.

The most solid indication clinicians have for recommending medical marijuana is for chronic pain, and the most common condition studied has been neuropathy.

“Most evidence compares cannabinoid to placebo,” said Dr. Grossman, primary care lead for behavioral health integration at Cambridge (Mass.) Health Alliance. “There’s almost nothing out there comparing cannabinoid to any other pain-relieving agent that a patient might choose to use.

“A lot of the literature comes from oral synthesized agents,” she continued. “There’s a little bit of science about inhaled forms, but a lot of this is very different from what my patient got last week in a medical marijuana dispensary in Massachusetts.”

Results from a systematic review of 79 studies of cannabinoids for medical use in 6,462 study participants showed that, compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs. 20%; odds ratio, 3.82), reduction in pain (37% vs. 31%; OR, 1.41), a greater average reduction in numerical rating scale pain assessment (on a 0- to 10-point scale; weighted mean difference of –0.46), and average reduction in the Ashworth spasticity scale (–0.36) (JAMA 2015 Jun 23-30;313[24]:2456-73).

A separate meta-analysis of studies compared inhaled cannabis sativa to placebo for chronic painful neuropathy. The researchers found that those patients who used inhaled cannabis sativa were 3.2 times more likely to achieve a 30% or greater reduction in pain, compared with those in the placebo group (J. Pain 2015 Dec;16[12]:1221-32).

However, Dr. Grossman cautioned that the number of patients studied was fewer than 200, “so, you could argue that this is a body of knowledge where the jury is still out.”

According to a 2017 report from the National Academy of Sciences titled, “The Health Effects of Cannabis and Cannabinoids,” another area in which the knowledge base is less solid is the use of oral cannabinoids for chemotherapy-induced nausea and vomiting.

“There’s a reasonable amount of evidence showing that some of these are better than placebo for relief of these symptoms,” Dr. Grossman said. “That said, the jury’s out as to whether they are any better than our other antiemetic agents. And there are no studies comparing them to neurokinin-1 inhibitors, which are the newest class of drug often used by oncologists for this indication. There is also no good evidence about inhaled plant cannabis.”

Studies of oral cannabinoids for multiple-sclerosis–related spasticity have demonstrated a small improvement on patient-reported spasticity (less than 1 point on a 10-point scale), but there was no improvement in clinician-reported outcomes. At the same time, their use for weight loss/anorexia in HIV “is very limited, and there are no studies of plant-derived cannabis,” Dr. Grossman said.

According to the National Academy of Sciences report, some evidence supports the use of oral cannabinoids for short-term sleep outcomes in patients with chronic diseases such as fibromyalgia and MS. One small study of oral cannabinoid for anxiety found that it improved social anxiety symptoms on the public speaking test, but there have been no studies using inhaled cannabinoids/marijuana.

The health risks of medical marijuana are largely unknown, Dr. Grossman said, noting that most evidence on longer‐term health risks comes from epidemiologic studies of recreational cannabis users.

“Medical marijuana users tend to be older and tend to be sicker,” she said. “We don’t know anything about the long-term effects in that sicker population.”

Among healthier people, Dr. Grossman continued, cannabis use is associated with increased risk of cough, wheeze, and sputum/phlegm. “There’s also an increased risk of motor vehicle accidents,” she said. “That is certainly a concern in places where they’re legalizing marijuana.”

Cannabis use is associated with lower neonatal birth weight, case reports/series of unintentional pediatric ingestions, and a possible increase in suicidal ideation, suicide attempts, and completed suicides.

“The evidence is very limited regarding associations with myocardial infarction, stroke, COPD, and mortality,” she added. “We don’t really know.”

Dr. Grossman reported having no financial disclosures.

 

dbrunk@frontlinemedcom.com

 

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.

Then there’s the issue of recall bias and the question as to whether oral cannabinoids equate to the plant-derived forms of medical marijuana that patients obtain from their local dispensaries.

That matters, because the majority of published studies on the topic have evaluated oral cannabinoids, not the plant form. “So, what we’re studying is vastly different from what our patients are using,” she said.

The most solid indication clinicians have for recommending medical marijuana is for chronic pain, and the most common condition studied has been neuropathy.

“Most evidence compares cannabinoid to placebo,” said Dr. Grossman, primary care lead for behavioral health integration at Cambridge (Mass.) Health Alliance. “There’s almost nothing out there comparing cannabinoid to any other pain-relieving agent that a patient might choose to use.

“A lot of the literature comes from oral synthesized agents,” she continued. “There’s a little bit of science about inhaled forms, but a lot of this is very different from what my patient got last week in a medical marijuana dispensary in Massachusetts.”

Results from a systematic review of 79 studies of cannabinoids for medical use in 6,462 study participants showed that, compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs. 20%; odds ratio, 3.82), reduction in pain (37% vs. 31%; OR, 1.41), a greater average reduction in numerical rating scale pain assessment (on a 0- to 10-point scale; weighted mean difference of –0.46), and average reduction in the Ashworth spasticity scale (–0.36) (JAMA 2015 Jun 23-30;313[24]:2456-73).

A separate meta-analysis of studies compared inhaled cannabis sativa to placebo for chronic painful neuropathy. The researchers found that those patients who used inhaled cannabis sativa were 3.2 times more likely to achieve a 30% or greater reduction in pain, compared with those in the placebo group (J. Pain 2015 Dec;16[12]:1221-32).

However, Dr. Grossman cautioned that the number of patients studied was fewer than 200, “so, you could argue that this is a body of knowledge where the jury is still out.”

According to a 2017 report from the National Academy of Sciences titled, “The Health Effects of Cannabis and Cannabinoids,” another area in which the knowledge base is less solid is the use of oral cannabinoids for chemotherapy-induced nausea and vomiting.

“There’s a reasonable amount of evidence showing that some of these are better than placebo for relief of these symptoms,” Dr. Grossman said. “That said, the jury’s out as to whether they are any better than our other antiemetic agents. And there are no studies comparing them to neurokinin-1 inhibitors, which are the newest class of drug often used by oncologists for this indication. There is also no good evidence about inhaled plant cannabis.”

Studies of oral cannabinoids for multiple-sclerosis–related spasticity have demonstrated a small improvement on patient-reported spasticity (less than 1 point on a 10-point scale), but there was no improvement in clinician-reported outcomes. At the same time, their use for weight loss/anorexia in HIV “is very limited, and there are no studies of plant-derived cannabis,” Dr. Grossman said.

According to the National Academy of Sciences report, some evidence supports the use of oral cannabinoids for short-term sleep outcomes in patients with chronic diseases such as fibromyalgia and MS. One small study of oral cannabinoid for anxiety found that it improved social anxiety symptoms on the public speaking test, but there have been no studies using inhaled cannabinoids/marijuana.

The health risks of medical marijuana are largely unknown, Dr. Grossman said, noting that most evidence on longer‐term health risks comes from epidemiologic studies of recreational cannabis users.

“Medical marijuana users tend to be older and tend to be sicker,” she said. “We don’t know anything about the long-term effects in that sicker population.”

Among healthier people, Dr. Grossman continued, cannabis use is associated with increased risk of cough, wheeze, and sputum/phlegm. “There’s also an increased risk of motor vehicle accidents,” she said. “That is certainly a concern in places where they’re legalizing marijuana.”

Cannabis use is associated with lower neonatal birth weight, case reports/series of unintentional pediatric ingestions, and a possible increase in suicidal ideation, suicide attempts, and completed suicides.

“The evidence is very limited regarding associations with myocardial infarction, stroke, COPD, and mortality,” she added. “We don’t really know.”

Dr. Grossman reported having no financial disclosures.

 

dbrunk@frontlinemedcom.com

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

ORLANDO—Low serum levels of vitamin D are associated with the risk of developing multiple sclerosis (MS), as well as with disease activity in MS, according to an overview provided at the ACTRIMS 2017 Forum. Whether vitamin D supplementation affects the course of the disease remains uncertain, but the question is being examined in ongoing clinical trials. Small pilot trials have not revealed safety problems, but “we should remain cautious when talking to our patients about vitamin D supplementation,” said Ellen Mowry, MD, Associate Professor of Neurology and Epidemiology at the Johns Hopkins University in Baltimore.

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—Low serum levels of vitamin D are associated with the risk of developing multiple sclerosis (MS), as well as with disease activity in MS, according to an overview provided at the ACTRIMS 2017 Forum. Whether vitamin D supplementation affects the course of the disease remains uncertain, but the question is being examined in ongoing clinical trials. Small pilot trials have not revealed safety problems, but “we should remain cautious when talking to our patients about vitamin D supplementation,” said Ellen Mowry, MD, Associate Professor of Neurology and Epidemiology at the Johns Hopkins University in Baltimore.

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—Low serum levels of vitamin D are associated with the risk of developing multiple sclerosis (MS), as well as with disease activity in MS, according to an overview provided at the ACTRIMS 2017 Forum. Whether vitamin D supplementation affects the course of the disease remains uncertain, but the question is being examined in ongoing clinical trials. Small pilot trials have not revealed safety problems, but “we should remain cautious when talking to our patients about vitamin D supplementation,” said Ellen Mowry, MD, Associate Professor of Neurology and Epidemiology at the Johns Hopkins University in Baltimore.

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.

“Using RNA sequencing, we have identified messenger RNAs (mRNAs), which are classic protein-coding genes, and long, noncoding RNAs (lncRNAs), which are a newly discovered class of RNA molecule that plays important roles in regulating gene expression,” said Charles F. Spurlock III, PhD, and colleagues. Dr. Spurlock is an Instructor in Medicine in the Rheumatology Division of Vanderbilt University and Chief Executive Officer at IQuity, both in Nashville. He and his research colleagues identified RNA patterns that differ between patients with MS, patients with other neurologic diseases, and healthy controls. The goal of their research was to explore whether lncRNA expression levels could serve as biomarkers for MS and provide clinically useful information to health care providers. Peripheral whole blood was collected into PAXgene tubes from 161 healthy control subjects, 185 unaffected first-degree relatives of patients with MS, 84 subjects with a clinically isolated syndrome who later progressed to clinically definite MS, 90 subjects diagnosed with MS before initiation of treatment, 212 patients diagnosed with MS after initiation of treatment, 132 patients with other inflammatory neurologic disorders, and 115 patients with noninflammatory neurologic disorders.

 

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.

“Using RNA sequencing, we have identified messenger RNAs (mRNAs), which are classic protein-coding genes, and long, noncoding RNAs (lncRNAs), which are a newly discovered class of RNA molecule that plays important roles in regulating gene expression,” said Charles F. Spurlock III, PhD, and colleagues. Dr. Spurlock is an Instructor in Medicine in the Rheumatology Division of Vanderbilt University and Chief Executive Officer at IQuity, both in Nashville. He and his research colleagues identified RNA patterns that differ between patients with MS, patients with other neurologic diseases, and healthy controls. The goal of their research was to explore whether lncRNA expression levels could serve as biomarkers for MS and provide clinically useful information to health care providers. Peripheral whole blood was collected into PAXgene tubes from 161 healthy control subjects, 185 unaffected first-degree relatives of patients with MS, 84 subjects with a clinically isolated syndrome who later progressed to clinically definite MS, 90 subjects diagnosed with MS before initiation of treatment, 212 patients diagnosed with MS after initiation of treatment, 132 patients with other inflammatory neurologic disorders, and 115 patients with noninflammatory neurologic disorders.

 

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.

“Using RNA sequencing, we have identified messenger RNAs (mRNAs), which are classic protein-coding genes, and long, noncoding RNAs (lncRNAs), which are a newly discovered class of RNA molecule that plays important roles in regulating gene expression,” said Charles F. Spurlock III, PhD, and colleagues. Dr. Spurlock is an Instructor in Medicine in the Rheumatology Division of Vanderbilt University and Chief Executive Officer at IQuity, both in Nashville. He and his research colleagues identified RNA patterns that differ between patients with MS, patients with other neurologic diseases, and healthy controls. The goal of their research was to explore whether lncRNA expression levels could serve as biomarkers for MS and provide clinically useful information to health care providers. Peripheral whole blood was collected into PAXgene tubes from 161 healthy control subjects, 185 unaffected first-degree relatives of patients with MS, 84 subjects with a clinically isolated syndrome who later progressed to clinically definite MS, 90 subjects diagnosed with MS before initiation of treatment, 212 patients diagnosed with MS after initiation of treatment, 132 patients with other inflammatory neurologic disorders, and 115 patients with noninflammatory neurologic disorders.

 

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