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MRI Lesion Activity and Relapses May Predict Short- and Long-Term Outcomes in MS
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.
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.
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.
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.
Study supports link between pediatric MS and remote viral infections
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.
“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.
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.
“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.
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.
“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.
Key clinical point:
Major finding: Remote infections with EBV and HSV were associated with higher risk of pediatric-onset MS (odds ratios, 3.6 and 1.5, respectively).
Data source: A study of 360 pediatric MS patients and 496 controls.
Disclosures: Dr. Nourbakhsh reported having no disclosures.
How Often Is Optic Neuritis Misdiagnosed?
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
Top Acthar prescribers reap hefty payments from drug maker
BOSTON – A new analysis finds that some of the biggest neurologist prescribers of repository corticotropin gel (Acthar) – the extraordinarily expensive multiple sclerosis (MS) relapse drug – reaped extensive payments from its manufacturer, with one taking in $130,307 in a single year.
Together, 51 neurologists accounted for 980 Medicare claims worth more than $39 million in Acthar spending in 2014, almost half of the entire estimated $83 million in Medicare spending on neurologist-prescribed Acthar that year.
“There is a small group of neurologists – less than 1% – who are prescribing Acthar at considerable cost to Medicare and may do this in part because of financial relationships with the company that sells Acthar,” said study lead author Dennis Bourdette, MD, chair and research professor of neurology at Oregon Health and Science University, Portland.
Dr. Bourdette acknowledges that the research doesn’t prove a causal relationship between payments and prescriptions. In response to questions, Acthar manufacturer Mallinckrodt Pharmaceuticals, already under fire for the $34,000-per-vial cost of the drug, questioned the study design and denied wrongdoing in a statement: “Mallinckrodt is committed to following the highest standards for integrity and compliance in all of our business practices, including our collaboration with physicians.”
Acthar, also known as H.P. Acthar, is the poster child for stunningly expensive medication. According to the Federal Trade Commission, the cost of the drug rose from $40 per vial in 2001 to more than $34,000 this year. The New York Times reports that Medicare spending on Acthar topped half a billion in 2015.
Earlier this year, Mallinckrodt ARD (formerly Questcor) and its parent company agreed to pay a $100 million fine to settle charges that it created an illegal monopoly over the drug.
Dr. Bourdette and colleagues released their findings at the annual meeting of the American Academy of Neurology.
In an interview, Dr. Bourdette said the study’s roots lie in his concern about the medication, whose transformation from an inexpensive 1950s-era medication for pulmonary sarcoidosis to high-priced MS treatment has drawn national media attention.
“I believe that Acthar is tremendously overpriced and a waste of health care money,” Dr. Bourdette said. “I wanted to find out how extensive an economic problem it was and how much money Medicare was spending on it since this data was easily accessible.”
According to the study, Medicare spent $1.3 billion from 2011 to 2015 on Acthar, with about 25% of the cost due to prescriptions from neurologists. “When I discovered that a relatively small number of neurologists was prescribing it commonly at a cost of $40-$50 million a year to Medicare, I was interested in determining why they were prescribing this expensive therapy and postulated that it might be related to financial support they were receiving from the manufacturer,” Dr. Bourdette said.
The researchers examined the Medicare Part D Public Use File to determine which neurologists prescribed Acthar frequently in 2014. They identified 51 who prescribed Acthar 10 or more times that year and were frequent prescribers of MS disease-modifying therapy, indicating they treated many people with MS.
The 51 neurologists accounted for a mean of 19 Acthar claims each in 2014 (range, 11-50) totaling a mean annual cost of $770,145 (range, $354,479-$3,623,509). Together, the neurologists accounted for total Medicare spending on Acthar of $39,277,380.
The researchers also chose a control group – 51 neurologists who prescribed glatiramer acetate (Copaxone) more than 10 times in 2014 and also prescribed a similar frequency of all MS disease-modifying therapies as the high-frequency Acthar group.
“Acthar is used episodically to treat MS relapses, and glatiramer acetate is taken chronically to prevent relapses and disability,” Dr. Bourdette said. He added that glatiramer acetate is now available in a generic, but it wasn’t in 2014.
The Acthar and Copaxone groups were nearly identical in terms of gender (about two-thirds men) and years since graduation (a mean of 26), but the Acthar prescribers were more likely to work in small practices (1-10 doctors), file more prescription claims, see more Medicare patients, and practice in the South or West. The demographic information came from CMS Physician Compare.
In terms of overall drug maker payments, neurologists in the Acthar group accepted much more (median, $54,270; range, $623-$369,847) than did the Copaxone group (median, $1,747, range, $0-$256,305, P less than .001). Payment information came from the federal Open Payments database.
As for payments directly from the manufacturers of the two drugs, the Acthar prescribers accepted a median of $5,344 (range, $0-$130,307) from its manufacturer, while the Copaxone prescribers accepted a median of $137 (range, $0-$168,373) from Teva (P = .003).
“The payments are primarily for giving lectures or serving on advisory boards,” Dr. Bourdette said. “These types of payments are commonly made by pharmaceutical companies to physicians who participate in these types of activities.”
In a statement, Mallinckrodt Pharmaceuticals contends that the study inappropriately compares Acthar, often a later-line therapy, to Copaxone, which it says is often a first-line therapy.
Dr. Bourdette responded that the researchers chose a comparison group of top prescribers of Copaxone “as a marker of neurologists who treated a significant number of patients with MS.”
Mallinckrodt also notes that “there may be unmeasured confounding factors in the matching process between the comparator physician groups. These could include differences in the patient characteristics managed by these physicians including disease severity affecting prescribing patterns.”
The researchers agree that there may be differences between the groups, Dr. Bourdette said. However, he added, “the fact remains that the two groups differed in the amount of money they received as open-source payments from pharmaceutical companies. We doubt that the severity of their case mixes should lead to one group receiving more pharmaceutical open-source payments than another.”
Finally, Mallinckrodt says there’s no proof of a causal connection between the payments and the prescriptions; the study authors agree. And, the company says, “this pattern of correlation would be expected in any scenario where a small number of prescribers are the experts in the use of a later-line drug to treat a limited subset of patients.”
Dr. Bourdette rejects this contention. Few of the high Acthar prescribers practice at academic centers, he said, and few are recognized for their MS expertise. “So to suggest that they are experts in the use of Acthar for the treatment of MS when they are not as a group recognized as being experts on the treatment of MS in general is incredible,” he said. “Why a small group of neurologists prescribe Acthar remains a mystery, but it is not because the majority are leaders in the field of MS therapeutics.”
In an interview, Eric G. Campbell, PhD, professor of medicine and director of research at the Mongan Institute Health Policy Center at Harvard Medical School, Boston, said the study findings fit in with previous research that has found that “the more money that people get, the more they use the drug.
“Any reasonable person looking at this data would assume or at least consider very strongly that there is a causal relationship here,” he said.
What should be done? “There are lots of ways to stop this,” Dr. Campbell said. “One could simply impose rules that forbid doctors who accept payments for marketing drugs from billing Medicare or private payers for the care they provide. Large provider organizations could pass rules that forbid this kind of behavior. Finally, the government could vigorously pursue stiff penalties against physicians who accept payments that are really nothing more than incentives to encourage or sustain prescribing practices.”
The study was supported by a National Multiple Sclerosis Society grant. Dr. Bourdette said that he provides consulting to Magellan Healthcare, a company that provides recommendations to insurance companies on the approval of high-cost therapies. Dr. Campbell disclosed that he serves as an expert witness on law cases related to conflicts of interest in medicine.
BOSTON – A new analysis finds that some of the biggest neurologist prescribers of repository corticotropin gel (Acthar) – the extraordinarily expensive multiple sclerosis (MS) relapse drug – reaped extensive payments from its manufacturer, with one taking in $130,307 in a single year.
Together, 51 neurologists accounted for 980 Medicare claims worth more than $39 million in Acthar spending in 2014, almost half of the entire estimated $83 million in Medicare spending on neurologist-prescribed Acthar that year.
“There is a small group of neurologists – less than 1% – who are prescribing Acthar at considerable cost to Medicare and may do this in part because of financial relationships with the company that sells Acthar,” said study lead author Dennis Bourdette, MD, chair and research professor of neurology at Oregon Health and Science University, Portland.
Dr. Bourdette acknowledges that the research doesn’t prove a causal relationship between payments and prescriptions. In response to questions, Acthar manufacturer Mallinckrodt Pharmaceuticals, already under fire for the $34,000-per-vial cost of the drug, questioned the study design and denied wrongdoing in a statement: “Mallinckrodt is committed to following the highest standards for integrity and compliance in all of our business practices, including our collaboration with physicians.”
Acthar, also known as H.P. Acthar, is the poster child for stunningly expensive medication. According to the Federal Trade Commission, the cost of the drug rose from $40 per vial in 2001 to more than $34,000 this year. The New York Times reports that Medicare spending on Acthar topped half a billion in 2015.
Earlier this year, Mallinckrodt ARD (formerly Questcor) and its parent company agreed to pay a $100 million fine to settle charges that it created an illegal monopoly over the drug.
Dr. Bourdette and colleagues released their findings at the annual meeting of the American Academy of Neurology.
In an interview, Dr. Bourdette said the study’s roots lie in his concern about the medication, whose transformation from an inexpensive 1950s-era medication for pulmonary sarcoidosis to high-priced MS treatment has drawn national media attention.
“I believe that Acthar is tremendously overpriced and a waste of health care money,” Dr. Bourdette said. “I wanted to find out how extensive an economic problem it was and how much money Medicare was spending on it since this data was easily accessible.”
According to the study, Medicare spent $1.3 billion from 2011 to 2015 on Acthar, with about 25% of the cost due to prescriptions from neurologists. “When I discovered that a relatively small number of neurologists was prescribing it commonly at a cost of $40-$50 million a year to Medicare, I was interested in determining why they were prescribing this expensive therapy and postulated that it might be related to financial support they were receiving from the manufacturer,” Dr. Bourdette said.
The researchers examined the Medicare Part D Public Use File to determine which neurologists prescribed Acthar frequently in 2014. They identified 51 who prescribed Acthar 10 or more times that year and were frequent prescribers of MS disease-modifying therapy, indicating they treated many people with MS.
The 51 neurologists accounted for a mean of 19 Acthar claims each in 2014 (range, 11-50) totaling a mean annual cost of $770,145 (range, $354,479-$3,623,509). Together, the neurologists accounted for total Medicare spending on Acthar of $39,277,380.
The researchers also chose a control group – 51 neurologists who prescribed glatiramer acetate (Copaxone) more than 10 times in 2014 and also prescribed a similar frequency of all MS disease-modifying therapies as the high-frequency Acthar group.
“Acthar is used episodically to treat MS relapses, and glatiramer acetate is taken chronically to prevent relapses and disability,” Dr. Bourdette said. He added that glatiramer acetate is now available in a generic, but it wasn’t in 2014.
The Acthar and Copaxone groups were nearly identical in terms of gender (about two-thirds men) and years since graduation (a mean of 26), but the Acthar prescribers were more likely to work in small practices (1-10 doctors), file more prescription claims, see more Medicare patients, and practice in the South or West. The demographic information came from CMS Physician Compare.
In terms of overall drug maker payments, neurologists in the Acthar group accepted much more (median, $54,270; range, $623-$369,847) than did the Copaxone group (median, $1,747, range, $0-$256,305, P less than .001). Payment information came from the federal Open Payments database.
As for payments directly from the manufacturers of the two drugs, the Acthar prescribers accepted a median of $5,344 (range, $0-$130,307) from its manufacturer, while the Copaxone prescribers accepted a median of $137 (range, $0-$168,373) from Teva (P = .003).
“The payments are primarily for giving lectures or serving on advisory boards,” Dr. Bourdette said. “These types of payments are commonly made by pharmaceutical companies to physicians who participate in these types of activities.”
In a statement, Mallinckrodt Pharmaceuticals contends that the study inappropriately compares Acthar, often a later-line therapy, to Copaxone, which it says is often a first-line therapy.
Dr. Bourdette responded that the researchers chose a comparison group of top prescribers of Copaxone “as a marker of neurologists who treated a significant number of patients with MS.”
Mallinckrodt also notes that “there may be unmeasured confounding factors in the matching process between the comparator physician groups. These could include differences in the patient characteristics managed by these physicians including disease severity affecting prescribing patterns.”
The researchers agree that there may be differences between the groups, Dr. Bourdette said. However, he added, “the fact remains that the two groups differed in the amount of money they received as open-source payments from pharmaceutical companies. We doubt that the severity of their case mixes should lead to one group receiving more pharmaceutical open-source payments than another.”
Finally, Mallinckrodt says there’s no proof of a causal connection between the payments and the prescriptions; the study authors agree. And, the company says, “this pattern of correlation would be expected in any scenario where a small number of prescribers are the experts in the use of a later-line drug to treat a limited subset of patients.”
Dr. Bourdette rejects this contention. Few of the high Acthar prescribers practice at academic centers, he said, and few are recognized for their MS expertise. “So to suggest that they are experts in the use of Acthar for the treatment of MS when they are not as a group recognized as being experts on the treatment of MS in general is incredible,” he said. “Why a small group of neurologists prescribe Acthar remains a mystery, but it is not because the majority are leaders in the field of MS therapeutics.”
In an interview, Eric G. Campbell, PhD, professor of medicine and director of research at the Mongan Institute Health Policy Center at Harvard Medical School, Boston, said the study findings fit in with previous research that has found that “the more money that people get, the more they use the drug.
“Any reasonable person looking at this data would assume or at least consider very strongly that there is a causal relationship here,” he said.
What should be done? “There are lots of ways to stop this,” Dr. Campbell said. “One could simply impose rules that forbid doctors who accept payments for marketing drugs from billing Medicare or private payers for the care they provide. Large provider organizations could pass rules that forbid this kind of behavior. Finally, the government could vigorously pursue stiff penalties against physicians who accept payments that are really nothing more than incentives to encourage or sustain prescribing practices.”
The study was supported by a National Multiple Sclerosis Society grant. Dr. Bourdette said that he provides consulting to Magellan Healthcare, a company that provides recommendations to insurance companies on the approval of high-cost therapies. Dr. Campbell disclosed that he serves as an expert witness on law cases related to conflicts of interest in medicine.
BOSTON – A new analysis finds that some of the biggest neurologist prescribers of repository corticotropin gel (Acthar) – the extraordinarily expensive multiple sclerosis (MS) relapse drug – reaped extensive payments from its manufacturer, with one taking in $130,307 in a single year.
Together, 51 neurologists accounted for 980 Medicare claims worth more than $39 million in Acthar spending in 2014, almost half of the entire estimated $83 million in Medicare spending on neurologist-prescribed Acthar that year.
“There is a small group of neurologists – less than 1% – who are prescribing Acthar at considerable cost to Medicare and may do this in part because of financial relationships with the company that sells Acthar,” said study lead author Dennis Bourdette, MD, chair and research professor of neurology at Oregon Health and Science University, Portland.
Dr. Bourdette acknowledges that the research doesn’t prove a causal relationship between payments and prescriptions. In response to questions, Acthar manufacturer Mallinckrodt Pharmaceuticals, already under fire for the $34,000-per-vial cost of the drug, questioned the study design and denied wrongdoing in a statement: “Mallinckrodt is committed to following the highest standards for integrity and compliance in all of our business practices, including our collaboration with physicians.”
Acthar, also known as H.P. Acthar, is the poster child for stunningly expensive medication. According to the Federal Trade Commission, the cost of the drug rose from $40 per vial in 2001 to more than $34,000 this year. The New York Times reports that Medicare spending on Acthar topped half a billion in 2015.
Earlier this year, Mallinckrodt ARD (formerly Questcor) and its parent company agreed to pay a $100 million fine to settle charges that it created an illegal monopoly over the drug.
Dr. Bourdette and colleagues released their findings at the annual meeting of the American Academy of Neurology.
In an interview, Dr. Bourdette said the study’s roots lie in his concern about the medication, whose transformation from an inexpensive 1950s-era medication for pulmonary sarcoidosis to high-priced MS treatment has drawn national media attention.
“I believe that Acthar is tremendously overpriced and a waste of health care money,” Dr. Bourdette said. “I wanted to find out how extensive an economic problem it was and how much money Medicare was spending on it since this data was easily accessible.”
According to the study, Medicare spent $1.3 billion from 2011 to 2015 on Acthar, with about 25% of the cost due to prescriptions from neurologists. “When I discovered that a relatively small number of neurologists was prescribing it commonly at a cost of $40-$50 million a year to Medicare, I was interested in determining why they were prescribing this expensive therapy and postulated that it might be related to financial support they were receiving from the manufacturer,” Dr. Bourdette said.
The researchers examined the Medicare Part D Public Use File to determine which neurologists prescribed Acthar frequently in 2014. They identified 51 who prescribed Acthar 10 or more times that year and were frequent prescribers of MS disease-modifying therapy, indicating they treated many people with MS.
The 51 neurologists accounted for a mean of 19 Acthar claims each in 2014 (range, 11-50) totaling a mean annual cost of $770,145 (range, $354,479-$3,623,509). Together, the neurologists accounted for total Medicare spending on Acthar of $39,277,380.
The researchers also chose a control group – 51 neurologists who prescribed glatiramer acetate (Copaxone) more than 10 times in 2014 and also prescribed a similar frequency of all MS disease-modifying therapies as the high-frequency Acthar group.
“Acthar is used episodically to treat MS relapses, and glatiramer acetate is taken chronically to prevent relapses and disability,” Dr. Bourdette said. He added that glatiramer acetate is now available in a generic, but it wasn’t in 2014.
The Acthar and Copaxone groups were nearly identical in terms of gender (about two-thirds men) and years since graduation (a mean of 26), but the Acthar prescribers were more likely to work in small practices (1-10 doctors), file more prescription claims, see more Medicare patients, and practice in the South or West. The demographic information came from CMS Physician Compare.
In terms of overall drug maker payments, neurologists in the Acthar group accepted much more (median, $54,270; range, $623-$369,847) than did the Copaxone group (median, $1,747, range, $0-$256,305, P less than .001). Payment information came from the federal Open Payments database.
As for payments directly from the manufacturers of the two drugs, the Acthar prescribers accepted a median of $5,344 (range, $0-$130,307) from its manufacturer, while the Copaxone prescribers accepted a median of $137 (range, $0-$168,373) from Teva (P = .003).
“The payments are primarily for giving lectures or serving on advisory boards,” Dr. Bourdette said. “These types of payments are commonly made by pharmaceutical companies to physicians who participate in these types of activities.”
In a statement, Mallinckrodt Pharmaceuticals contends that the study inappropriately compares Acthar, often a later-line therapy, to Copaxone, which it says is often a first-line therapy.
Dr. Bourdette responded that the researchers chose a comparison group of top prescribers of Copaxone “as a marker of neurologists who treated a significant number of patients with MS.”
Mallinckrodt also notes that “there may be unmeasured confounding factors in the matching process between the comparator physician groups. These could include differences in the patient characteristics managed by these physicians including disease severity affecting prescribing patterns.”
The researchers agree that there may be differences between the groups, Dr. Bourdette said. However, he added, “the fact remains that the two groups differed in the amount of money they received as open-source payments from pharmaceutical companies. We doubt that the severity of their case mixes should lead to one group receiving more pharmaceutical open-source payments than another.”
Finally, Mallinckrodt says there’s no proof of a causal connection between the payments and the prescriptions; the study authors agree. And, the company says, “this pattern of correlation would be expected in any scenario where a small number of prescribers are the experts in the use of a later-line drug to treat a limited subset of patients.”
Dr. Bourdette rejects this contention. Few of the high Acthar prescribers practice at academic centers, he said, and few are recognized for their MS expertise. “So to suggest that they are experts in the use of Acthar for the treatment of MS when they are not as a group recognized as being experts on the treatment of MS in general is incredible,” he said. “Why a small group of neurologists prescribe Acthar remains a mystery, but it is not because the majority are leaders in the field of MS therapeutics.”
In an interview, Eric G. Campbell, PhD, professor of medicine and director of research at the Mongan Institute Health Policy Center at Harvard Medical School, Boston, said the study findings fit in with previous research that has found that “the more money that people get, the more they use the drug.
“Any reasonable person looking at this data would assume or at least consider very strongly that there is a causal relationship here,” he said.
What should be done? “There are lots of ways to stop this,” Dr. Campbell said. “One could simply impose rules that forbid doctors who accept payments for marketing drugs from billing Medicare or private payers for the care they provide. Large provider organizations could pass rules that forbid this kind of behavior. Finally, the government could vigorously pursue stiff penalties against physicians who accept payments that are really nothing more than incentives to encourage or sustain prescribing practices.”
The study was supported by a National Multiple Sclerosis Society grant. Dr. Bourdette said that he provides consulting to Magellan Healthcare, a company that provides recommendations to insurance companies on the approval of high-cost therapies. Dr. Campbell disclosed that he serves as an expert witness on law cases related to conflicts of interest in medicine.
AT AAN 2017
Key clinical point:
Major finding: The top Acthar prescribers reaped much more in payments from drug makers overall in 2014 than did a control group of top prescribers of another MS drug (median of $54,270 vs. $1,747; P less than .001) and from the manufacturer of each drug (median of $5,344 vs. $137; P = .003).
Data source: Medicare Part D Public Use File, CMS Physician Compare, Open Payments database, 2014.
Disclosures: The work was supported by a National Multiple Sclerosis Society grant. Dr. Bourdette provides consulting to Magellan Healthcare, a company that provides recommendations to insurance companies on the approval of high-cost therapies.
TNFSF13B variant linked to MS and SLE
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. 
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.
Perhaps the next challenge is the clinical application of the findings from Steri et al. is to determine whether BAFF-var status can be used to stratify patients for a specific therapy.
These data clearly point in that direction, but the discriminatory power of this single variant may not be sufficient for clinical decision making.
In contrast, it does seem reasonable to examine whether stratifying patients according to their BAFF-var status would be useful in clinical trials assessing B-cell–directed therapies.
Thomas Korn, MD, of the Technical University of Munich and the Munich Cluster for Systems Neurology, reported ties to Biogen, Novartis, Merck Serono, and Bayer. Mohamed Oukka, PhD, of the University of Washington, Seattle, and the Center for Immunity and Immunotherapies at Seattle Children’s Research Institute, reported having no relevant disclosures. They made these remarks in an editorial accompanying Dr. Steri’s report (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMe1700720).
Perhaps the next challenge is the clinical application of the findings from Steri et al. is to determine whether BAFF-var status can be used to stratify patients for a specific therapy.
These data clearly point in that direction, but the discriminatory power of this single variant may not be sufficient for clinical decision making.
In contrast, it does seem reasonable to examine whether stratifying patients according to their BAFF-var status would be useful in clinical trials assessing B-cell–directed therapies.
Thomas Korn, MD, of the Technical University of Munich and the Munich Cluster for Systems Neurology, reported ties to Biogen, Novartis, Merck Serono, and Bayer. Mohamed Oukka, PhD, of the University of Washington, Seattle, and the Center for Immunity and Immunotherapies at Seattle Children’s Research Institute, reported having no relevant disclosures. They made these remarks in an editorial accompanying Dr. Steri’s report (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMe1700720).
Perhaps the next challenge is the clinical application of the findings from Steri et al. is to determine whether BAFF-var status can be used to stratify patients for a specific therapy.
These data clearly point in that direction, but the discriminatory power of this single variant may not be sufficient for clinical decision making.
In contrast, it does seem reasonable to examine whether stratifying patients according to their BAFF-var status would be useful in clinical trials assessing B-cell–directed therapies.
Thomas Korn, MD, of the Technical University of Munich and the Munich Cluster for Systems Neurology, reported ties to Biogen, Novartis, Merck Serono, and Bayer. Mohamed Oukka, PhD, of the University of Washington, Seattle, and the Center for Immunity and Immunotherapies at Seattle Children’s Research Institute, reported having no relevant disclosures. They made these remarks in an editorial accompanying Dr. Steri’s report (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMe1700720).
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.
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.
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.
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.
Key clinical point: A variant in the TNFSF13B gene has been linked to susceptibility to both multiple sclerosis and systemic lupus erythematosus.
Major finding: BAFF-var was the TNFSF13B variant most strongly associated with MS in Sardinia (OR, 1.27), and was also associated with SLE in Sardinia (OR, 1.38), mainland Italy (OR, 1.49), and the Iberian peninsula (OR, 1.55).
Data source: A series of genome-wide association studies and other genetic studies involving thousands of patients with MS or SLE in Sardinia and confirmed in thousands of patients across Italy, Spain, Sweden, and the United Kingdom.
Disclosures: 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.
Kids with MS face higher risk of mental disorders
BOSTON – Children with multiple sclerosis (MS) and related conditions are as much as 10 times more likely than the general population to need to be hospitalized for various psychiatric conditions, a study showed.
“The true prevalence of morbidity is almost certainly higher than suggested by our data,” said study lead author Julia Pakpoor, BM BCh, who presented data from her research at the annual meeting of the American Academy of Neurology.
While several studies have examined links between MS and mental illness in adults, there’s been little research into the topic in children. The number of children with the disease is far from tiny, however. According to the National MS Society, an estimated 8,000-10,000 children have the condition in the United States.
The researchers tracked future psychiatric visits by these patients and compared them with a reference cohort of more than 1.1 million children.
The risks of mental conditions in children with MS, compared with the reference cohort, were as follows: psychotic disorders (relative risk [RR] = 10.76; 95% confidence interval [CI], 2.93-27.63; P less than .001), mood disorders (RR = 2.57; 95% CI, 1.03-5.31; P = .022), and intellectual disability (RR = 6.08; 95% CI, 1.25-17.80; P = .004).
The children with other CNS demyelinating diseases also had higher risk levels, compared with the reference cohort: psychotic disorders (RR = 5.77; 95% CI, 2.48-11.41; P less than .001), anxiety, stress-related, and somatoform disorders that cause symptoms like pain (RR = 2.38; 95% CI, 1.39-3.81; P less than .001); intellectual disability (RR = 6.56; 95% CI, 3.66-10.84; P less than .001), and other behavioral disorders (RR = 8.99; 95% CI, 5.13-14.62; P less than .001).
The researchers also reported evidence of a reverse trend. Children with several mental conditions had greater risk than did the reference cohort to go on to develop CNS demyelinating diseases, specifically anxiety, stress-related, and somatoform disorders (RR = 3.15; 95% CI, 1.70-5.39; P less than .001), ADHD (RR = 3.88; 95% CI, 1.75-7.48; P less than .001), autism (RR = 3.80; 95% CI, 2.05-6.50; P less than .001), intellectual disability (RR = 6.33; 95% CI, 2.86-12.21; P less than .001), and other behavioral disorders (RR = 8.30; 95% CI, 5.17-12.75; P less than .001).
“We detected strong associations, and further associations likely exist,” Dr. Pakpoor said.
She acknowledged that the research is limited because it includes information only about patients admitted to a hospital. “There may be many more with psychiatric conditions that are mild,” she said. “We’re probably detecting cases that are more severe.”
In an interview, Flavia M. Nelson, MD, interim chief of the multiple sclerosis division at the University of Texas Health Science Center at Houston, said she often sees psychiatric conditions in her pediatric patients.
Conditions such as depression and anxiety disorders are common, she said, and the pediatric patients often suffer from isolation. “There’s a lot of fear about what this will do to their lives,” she said. Some patients have even refused to go to college because they fear that “they’ll have a disabling attack and everyone will know.”
As for the link between psychiatric illness and MS, Dr. Nelson said the disorders may develop because stress, fear, and anxiety push young people to their limits. “I had one patient who developed tics and rage,” she said. “That was his way of coping with the disease.”
Dr. Nelson suggested doing cognitive testing on young patients and referring them to counseling, especially in light of the fact that teens often put up walls when they don’t know how to express their feelings. Simply asking questions may not be enough to draw them out, she said, so professional counseling can be helpful.
No specific funding was reported. Dr. Pakpoor reported no relevant disclosures. Dr. Nelson has received personal compensation for activities with Bayer, Sanofi-Genzyme, Genentech, Novartis, Teva, and the Consortium of Multiple Sclerosis Centers. She has received research support from the National Institutes of Health, the National MS Society, and Novartis.
BOSTON – Children with multiple sclerosis (MS) and related conditions are as much as 10 times more likely than the general population to need to be hospitalized for various psychiatric conditions, a study showed.
“The true prevalence of morbidity is almost certainly higher than suggested by our data,” said study lead author Julia Pakpoor, BM BCh, who presented data from her research at the annual meeting of the American Academy of Neurology.
While several studies have examined links between MS and mental illness in adults, there’s been little research into the topic in children. The number of children with the disease is far from tiny, however. According to the National MS Society, an estimated 8,000-10,000 children have the condition in the United States.
The researchers tracked future psychiatric visits by these patients and compared them with a reference cohort of more than 1.1 million children.
The risks of mental conditions in children with MS, compared with the reference cohort, were as follows: psychotic disorders (relative risk [RR] = 10.76; 95% confidence interval [CI], 2.93-27.63; P less than .001), mood disorders (RR = 2.57; 95% CI, 1.03-5.31; P = .022), and intellectual disability (RR = 6.08; 95% CI, 1.25-17.80; P = .004).
The children with other CNS demyelinating diseases also had higher risk levels, compared with the reference cohort: psychotic disorders (RR = 5.77; 95% CI, 2.48-11.41; P less than .001), anxiety, stress-related, and somatoform disorders that cause symptoms like pain (RR = 2.38; 95% CI, 1.39-3.81; P less than .001); intellectual disability (RR = 6.56; 95% CI, 3.66-10.84; P less than .001), and other behavioral disorders (RR = 8.99; 95% CI, 5.13-14.62; P less than .001).
The researchers also reported evidence of a reverse trend. Children with several mental conditions had greater risk than did the reference cohort to go on to develop CNS demyelinating diseases, specifically anxiety, stress-related, and somatoform disorders (RR = 3.15; 95% CI, 1.70-5.39; P less than .001), ADHD (RR = 3.88; 95% CI, 1.75-7.48; P less than .001), autism (RR = 3.80; 95% CI, 2.05-6.50; P less than .001), intellectual disability (RR = 6.33; 95% CI, 2.86-12.21; P less than .001), and other behavioral disorders (RR = 8.30; 95% CI, 5.17-12.75; P less than .001).
“We detected strong associations, and further associations likely exist,” Dr. Pakpoor said.
She acknowledged that the research is limited because it includes information only about patients admitted to a hospital. “There may be many more with psychiatric conditions that are mild,” she said. “We’re probably detecting cases that are more severe.”
In an interview, Flavia M. Nelson, MD, interim chief of the multiple sclerosis division at the University of Texas Health Science Center at Houston, said she often sees psychiatric conditions in her pediatric patients.
Conditions such as depression and anxiety disorders are common, she said, and the pediatric patients often suffer from isolation. “There’s a lot of fear about what this will do to their lives,” she said. Some patients have even refused to go to college because they fear that “they’ll have a disabling attack and everyone will know.”
As for the link between psychiatric illness and MS, Dr. Nelson said the disorders may develop because stress, fear, and anxiety push young people to their limits. “I had one patient who developed tics and rage,” she said. “That was his way of coping with the disease.”
Dr. Nelson suggested doing cognitive testing on young patients and referring them to counseling, especially in light of the fact that teens often put up walls when they don’t know how to express their feelings. Simply asking questions may not be enough to draw them out, she said, so professional counseling can be helpful.
No specific funding was reported. Dr. Pakpoor reported no relevant disclosures. Dr. Nelson has received personal compensation for activities with Bayer, Sanofi-Genzyme, Genentech, Novartis, Teva, and the Consortium of Multiple Sclerosis Centers. She has received research support from the National Institutes of Health, the National MS Society, and Novartis.
BOSTON – Children with multiple sclerosis (MS) and related conditions are as much as 10 times more likely than the general population to need to be hospitalized for various psychiatric conditions, a study showed.
“The true prevalence of morbidity is almost certainly higher than suggested by our data,” said study lead author Julia Pakpoor, BM BCh, who presented data from her research at the annual meeting of the American Academy of Neurology.
While several studies have examined links between MS and mental illness in adults, there’s been little research into the topic in children. The number of children with the disease is far from tiny, however. According to the National MS Society, an estimated 8,000-10,000 children have the condition in the United States.
The researchers tracked future psychiatric visits by these patients and compared them with a reference cohort of more than 1.1 million children.
The risks of mental conditions in children with MS, compared with the reference cohort, were as follows: psychotic disorders (relative risk [RR] = 10.76; 95% confidence interval [CI], 2.93-27.63; P less than .001), mood disorders (RR = 2.57; 95% CI, 1.03-5.31; P = .022), and intellectual disability (RR = 6.08; 95% CI, 1.25-17.80; P = .004).
The children with other CNS demyelinating diseases also had higher risk levels, compared with the reference cohort: psychotic disorders (RR = 5.77; 95% CI, 2.48-11.41; P less than .001), anxiety, stress-related, and somatoform disorders that cause symptoms like pain (RR = 2.38; 95% CI, 1.39-3.81; P less than .001); intellectual disability (RR = 6.56; 95% CI, 3.66-10.84; P less than .001), and other behavioral disorders (RR = 8.99; 95% CI, 5.13-14.62; P less than .001).
The researchers also reported evidence of a reverse trend. Children with several mental conditions had greater risk than did the reference cohort to go on to develop CNS demyelinating diseases, specifically anxiety, stress-related, and somatoform disorders (RR = 3.15; 95% CI, 1.70-5.39; P less than .001), ADHD (RR = 3.88; 95% CI, 1.75-7.48; P less than .001), autism (RR = 3.80; 95% CI, 2.05-6.50; P less than .001), intellectual disability (RR = 6.33; 95% CI, 2.86-12.21; P less than .001), and other behavioral disorders (RR = 8.30; 95% CI, 5.17-12.75; P less than .001).
“We detected strong associations, and further associations likely exist,” Dr. Pakpoor said.
She acknowledged that the research is limited because it includes information only about patients admitted to a hospital. “There may be many more with psychiatric conditions that are mild,” she said. “We’re probably detecting cases that are more severe.”
In an interview, Flavia M. Nelson, MD, interim chief of the multiple sclerosis division at the University of Texas Health Science Center at Houston, said she often sees psychiatric conditions in her pediatric patients.
Conditions such as depression and anxiety disorders are common, she said, and the pediatric patients often suffer from isolation. “There’s a lot of fear about what this will do to their lives,” she said. Some patients have even refused to go to college because they fear that “they’ll have a disabling attack and everyone will know.”
As for the link between psychiatric illness and MS, Dr. Nelson said the disorders may develop because stress, fear, and anxiety push young people to their limits. “I had one patient who developed tics and rage,” she said. “That was his way of coping with the disease.”
Dr. Nelson suggested doing cognitive testing on young patients and referring them to counseling, especially in light of the fact that teens often put up walls when they don’t know how to express their feelings. Simply asking questions may not be enough to draw them out, she said, so professional counseling can be helpful.
No specific funding was reported. Dr. Pakpoor reported no relevant disclosures. Dr. Nelson has received personal compensation for activities with Bayer, Sanofi-Genzyme, Genentech, Novartis, Teva, and the Consortium of Multiple Sclerosis Centers. She has received research support from the National Institutes of Health, the National MS Society, and Novartis.
Key clinical point: Children with MS and similar conditions are at higher risk of a long list of psychiatric disorders.
Major finding:
Data source: An analysis of children admitted to hospitals in England from 1999 to 2011 with MS (n = 201) and other CNS demyelinating diseases (n = 1,097) plus a reference cohort of more than 1.1 million.
Disclosures: No specific funding or disclosures were reported.
Evidence for medical marijuana largely up in smoke
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.
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.
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.
EXPERT ANALYSIS AT ACP INTERNAL MEDICINE
Disease-Modifying Treatment Changes in Clinical Practice
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 star
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 star
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 star
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
Can Vitamin D Benefit Patients With MS?
Vitamin D as a Risk Factor
Epidemiologic literature first suggested that vitamin D status might be related to the risk of MS. Researchers demonstrated that MS prevalence increases with distance from the equator. A series of retrospective and case–control studies subsequently suggested that patients with MS had lower levels of vitamin D than healthy individuals. These data, however, left open the possibility that having MS and its associated intolerance of heat led to reduced sun exposure, and thus lower levels of vitamin D.
In 2006, Munger and colleagues prospectively examined serum samples obtained from more than seven million US military personnel. They found that, among whites, the risk of MS significantly decreased with increasing levels of 25-hydroxyvitamin D. The effect was most significant in people with vitamin D levels higher than 40 ng/mL. The same association was observed in a later Swedish study that used 30 ng/mL as its threshold for vitamin D sufficiency. In 2016, Munger et al found that insufficient maternal vitamin D during pregnancy may increase the risk of MS in offspring.
Although research by Lucas and colleagues indicated an inverse association between serum vitamin D level and risk of MS, they found a stronger inverse association between ultraviolet (UV) light exposure and risk of MS. The strength of the latter association did not change, whether exposure was measured by skin damage or self-report. In 2017, however, Nielsen and colleagues compared serum vitamin D levels in newborns who subsequently developed MS with those of newborns who did not develop MS. They found a strong association between higher neonatal levels of vitamin D and lower risk of subsequent MS. “One could argue [that] this [result] makes the vitamin D hypothesis stronger than the UV [hypothesis], since the babies, in all likelihood, had not been exposed to much UV [light] at the time they were born,” said Dr. Mowry.
Vitamin D as a Prognostic Factor
Other research has suggested that serum vitamin D level may predict disease activity in MS. Dr. Mowry and colleagues evaluated blood samples taken from children who presented for longitudinal follow-up at pediatric MS centers. The total follow-up period was approximately 18 months. After adjusting for covariates, they found a strong association between higher levels of vitamin D and lower risk of subsequent relapse. “Each 10-ng/mL higher level of vitamin D … was associated with about a one-third reduction in the risk of subsequent relapse,” said Dr. Mowry. A prospective study conducted in Australia found similar results.
In 2012, Dr. Mowry and colleagues measured vitamin D levels in blood samples from 469 patients with relapsing-remitting MS or clinically isolated syndrome (CIS). They found that each additional 10-ng/mL increment of vitamin D level was associated with an approximately 15% lower risk of subsequent new T2 lesions and with an approximately 32% reduced risk of subsequent gadolinium-enhancing lesions. Higher levels of vitamin D also were associated with lower risk of subsequent relapse, but this finding was not statistically significant.
To discover whether vitamin D influences markers known to predict long-term disability, Dr. Mowry and colleagues examined data from a study of atorvastatin in 65 patients with CIS. They measured vitamin D levels at baseline and at month six, and the follow-up period was as long as 18 months. They found that each additional 10-ng/mL increment in vitamin D level was associated with an additional 7.8 mL of preserved gray matter volume. They also observed a trend toward an inverse association between vitamin D levels and the composite end point of three or more new T2 lesions or one or more relapses within a year.
Is Vitamin D Supplementation Appropriate?
“Just because [vitamin D] is available over the counter does not make it safe or effective,” and the supplement should be studied further in clinical trials, said Dr. Mowry. In 2010, Burton et al found that a dose of as much as 40,000 IU/day of vitamin D was safe in the short term and might have immunomodulatory effects in patients with MS. Furthermore, a small Finnish study suggested that a dose of 20,000 IU/week of vitamin D was safe in patients with MS, and also might slow the accumulation of disability.
Hupperts et al studied patients with relapsing-remitting MS who were receiving interferon beta-1a. They randomized 229 participants to vitamin D or placebo and followed them for 48 weeks. In preliminary analyses, the investigators found no difference between treatment groups with respect to the outcome of no evidence of disease activity. Patients who received vitamin D had a lower annualized relapse rate than controls, but the difference was not statistically significant. The active group did have significantly fewer gadolinium-enhancing lesions and new T2 hyperintense lesions, compared with controls, however.
In addition, Dr. Mowry and colleagues are comparing the effects of 5,000-IU and 600-IU doses of vitamin D in patients with MS who are receiving glatiramer acetate. The ongoing study is sponsored by the National MS Society. European studies of the clinical benefit of vitamin D also are under way.
Although the benefits of vitamin D are not completely understood, many neurologists recommend supplementation to their patients with MS. Pharmacokinetic studies have not shown a difference between daily, weekly, or monthly dosing regimens. “As long as you give the same dose of vitamin D, you will get the levels … to the same general area,” said Dr. Mowry. Nevertheless, some studies in other patient populations suggest that very high doses of vitamin D given monthly are probably toxic.
Many studies have suggested that vitamin D3 may be more potent than vitamin D2. “I tend to use [vitamin] D3 when I am supplementing,” said Dr. Mowry. “I aim for levels between 40 and 60 ng/mL, based on our observational data.... For my patients, that largely means they need somewhere between 2,000 and 4,000 IU/day, although sometimes more. I usually recheck the level in three months, based on what we know about the kinetics of vitamin D supplementation. I am cautious in individuals who may be at risk for hypercalcemia or hypercalciuria.”
—Erik Greb
Suggested Reading
Burton JM, Kimball S, Vieth R, et al. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology. 2010;74(23):1852-1859.
Mowry EM. Vitamin D: evidence for its role as a prognostic factor in multiple sclerosis. J Neurol Sci. 2011; 311(1-2):19-22.
Mowry EM, Pelletier D, Gao Z, et al. Vitamin D in clinically isolated syndrome: evidence for possible neuroprotection. Eur J Neurol. 2016;23(2):327-332.
Mowry EM, Waubant E, McCulloch CE, et al. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol. 2012;72(2):234-240.
Munger KL, Åivo J, Hongell K, et al. Vitamin D status during pregnancy and risk of multiple sclerosis in offspring of women in the Finnish Maternity Cohort. JAMA Neurol. 2016;73(5):515-519.
Munger KL, Levin LI, Hollis BW, et al. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296(23):2832-2838.
Nielsen NM, Munger KL, Koch-Henriksen N, et al. Neonatal vitamin D status and risk of multiple sclerosis: a population-based case-control study. Neurology. 2017;88(1):44-51.
Tremlett H, van der Mei IA, Pittas F, et al. Monthly ambient sunlight, infections and relapse rates in multiple sclerosis. Neuroepidemiology. 2008;31(4):271-279.
Vitamin D as a Risk Factor
Epidemiologic literature first suggested that vitamin D status might be related to the risk of MS. Researchers demonstrated that MS prevalence increases with distance from the equator. A series of retrospective and case–control studies subsequently suggested that patients with MS had lower levels of vitamin D than healthy individuals. These data, however, left open the possibility that having MS and its associated intolerance of heat led to reduced sun exposure, and thus lower levels of vitamin D.
In 2006, Munger and colleagues prospectively examined serum samples obtained from more than seven million US military personnel. They found that, among whites, the risk of MS significantly decreased with increasing levels of 25-hydroxyvitamin D. The effect was most significant in people with vitamin D levels higher than 40 ng/mL. The same association was observed in a later Swedish study that used 30 ng/mL as its threshold for vitamin D sufficiency. In 2016, Munger et al found that insufficient maternal vitamin D during pregnancy may increase the risk of MS in offspring.
Although research by Lucas and colleagues indicated an inverse association between serum vitamin D level and risk of MS, they found a stronger inverse association between ultraviolet (UV) light exposure and risk of MS. The strength of the latter association did not change, whether exposure was measured by skin damage or self-report. In 2017, however, Nielsen and colleagues compared serum vitamin D levels in newborns who subsequently developed MS with those of newborns who did not develop MS. They found a strong association between higher neonatal levels of vitamin D and lower risk of subsequent MS. “One could argue [that] this [result] makes the vitamin D hypothesis stronger than the UV [hypothesis], since the babies, in all likelihood, had not been exposed to much UV [light] at the time they were born,” said Dr. Mowry.
Vitamin D as a Prognostic Factor
Other research has suggested that serum vitamin D level may predict disease activity in MS. Dr. Mowry and colleagues evaluated blood samples taken from children who presented for longitudinal follow-up at pediatric MS centers. The total follow-up period was approximately 18 months. After adjusting for covariates, they found a strong association between higher levels of vitamin D and lower risk of subsequent relapse. “Each 10-ng/mL higher level of vitamin D … was associated with about a one-third reduction in the risk of subsequent relapse,” said Dr. Mowry. A prospective study conducted in Australia found similar results.
In 2012, Dr. Mowry and colleagues measured vitamin D levels in blood samples from 469 patients with relapsing-remitting MS or clinically isolated syndrome (CIS). They found that each additional 10-ng/mL increment of vitamin D level was associated with an approximately 15% lower risk of subsequent new T2 lesions and with an approximately 32% reduced risk of subsequent gadolinium-enhancing lesions. Higher levels of vitamin D also were associated with lower risk of subsequent relapse, but this finding was not statistically significant.
To discover whether vitamin D influences markers known to predict long-term disability, Dr. Mowry and colleagues examined data from a study of atorvastatin in 65 patients with CIS. They measured vitamin D levels at baseline and at month six, and the follow-up period was as long as 18 months. They found that each additional 10-ng/mL increment in vitamin D level was associated with an additional 7.8 mL of preserved gray matter volume. They also observed a trend toward an inverse association between vitamin D levels and the composite end point of three or more new T2 lesions or one or more relapses within a year.
Is Vitamin D Supplementation Appropriate?
“Just because [vitamin D] is available over the counter does not make it safe or effective,” and the supplement should be studied further in clinical trials, said Dr. Mowry. In 2010, Burton et al found that a dose of as much as 40,000 IU/day of vitamin D was safe in the short term and might have immunomodulatory effects in patients with MS. Furthermore, a small Finnish study suggested that a dose of 20,000 IU/week of vitamin D was safe in patients with MS, and also might slow the accumulation of disability.
Hupperts et al studied patients with relapsing-remitting MS who were receiving interferon beta-1a. They randomized 229 participants to vitamin D or placebo and followed them for 48 weeks. In preliminary analyses, the investigators found no difference between treatment groups with respect to the outcome of no evidence of disease activity. Patients who received vitamin D had a lower annualized relapse rate than controls, but the difference was not statistically significant. The active group did have significantly fewer gadolinium-enhancing lesions and new T2 hyperintense lesions, compared with controls, however.
In addition, Dr. Mowry and colleagues are comparing the effects of 5,000-IU and 600-IU doses of vitamin D in patients with MS who are receiving glatiramer acetate. The ongoing study is sponsored by the National MS Society. European studies of the clinical benefit of vitamin D also are under way.
Although the benefits of vitamin D are not completely understood, many neurologists recommend supplementation to their patients with MS. Pharmacokinetic studies have not shown a difference between daily, weekly, or monthly dosing regimens. “As long as you give the same dose of vitamin D, you will get the levels … to the same general area,” said Dr. Mowry. Nevertheless, some studies in other patient populations suggest that very high doses of vitamin D given monthly are probably toxic.
Many studies have suggested that vitamin D3 may be more potent than vitamin D2. “I tend to use [vitamin] D3 when I am supplementing,” said Dr. Mowry. “I aim for levels between 40 and 60 ng/mL, based on our observational data.... For my patients, that largely means they need somewhere between 2,000 and 4,000 IU/day, although sometimes more. I usually recheck the level in three months, based on what we know about the kinetics of vitamin D supplementation. I am cautious in individuals who may be at risk for hypercalcemia or hypercalciuria.”
—Erik Greb
Suggested Reading
Burton JM, Kimball S, Vieth R, et al. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology. 2010;74(23):1852-1859.
Mowry EM. Vitamin D: evidence for its role as a prognostic factor in multiple sclerosis. J Neurol Sci. 2011; 311(1-2):19-22.
Mowry EM, Pelletier D, Gao Z, et al. Vitamin D in clinically isolated syndrome: evidence for possible neuroprotection. Eur J Neurol. 2016;23(2):327-332.
Mowry EM, Waubant E, McCulloch CE, et al. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol. 2012;72(2):234-240.
Munger KL, Åivo J, Hongell K, et al. Vitamin D status during pregnancy and risk of multiple sclerosis in offspring of women in the Finnish Maternity Cohort. JAMA Neurol. 2016;73(5):515-519.
Munger KL, Levin LI, Hollis BW, et al. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296(23):2832-2838.
Nielsen NM, Munger KL, Koch-Henriksen N, et al. Neonatal vitamin D status and risk of multiple sclerosis: a population-based case-control study. Neurology. 2017;88(1):44-51.
Tremlett H, van der Mei IA, Pittas F, et al. Monthly ambient sunlight, infections and relapse rates in multiple sclerosis. Neuroepidemiology. 2008;31(4):271-279.
Vitamin D as a Risk Factor
Epidemiologic literature first suggested that vitamin D status might be related to the risk of MS. Researchers demonstrated that MS prevalence increases with distance from the equator. A series of retrospective and case–control studies subsequently suggested that patients with MS had lower levels of vitamin D than healthy individuals. These data, however, left open the possibility that having MS and its associated intolerance of heat led to reduced sun exposure, and thus lower levels of vitamin D.
In 2006, Munger and colleagues prospectively examined serum samples obtained from more than seven million US military personnel. They found that, among whites, the risk of MS significantly decreased with increasing levels of 25-hydroxyvitamin D. The effect was most significant in people with vitamin D levels higher than 40 ng/mL. The same association was observed in a later Swedish study that used 30 ng/mL as its threshold for vitamin D sufficiency. In 2016, Munger et al found that insufficient maternal vitamin D during pregnancy may increase the risk of MS in offspring.
Although research by Lucas and colleagues indicated an inverse association between serum vitamin D level and risk of MS, they found a stronger inverse association between ultraviolet (UV) light exposure and risk of MS. The strength of the latter association did not change, whether exposure was measured by skin damage or self-report. In 2017, however, Nielsen and colleagues compared serum vitamin D levels in newborns who subsequently developed MS with those of newborns who did not develop MS. They found a strong association between higher neonatal levels of vitamin D and lower risk of subsequent MS. “One could argue [that] this [result] makes the vitamin D hypothesis stronger than the UV [hypothesis], since the babies, in all likelihood, had not been exposed to much UV [light] at the time they were born,” said Dr. Mowry.
Vitamin D as a Prognostic Factor
Other research has suggested that serum vitamin D level may predict disease activity in MS. Dr. Mowry and colleagues evaluated blood samples taken from children who presented for longitudinal follow-up at pediatric MS centers. The total follow-up period was approximately 18 months. After adjusting for covariates, they found a strong association between higher levels of vitamin D and lower risk of subsequent relapse. “Each 10-ng/mL higher level of vitamin D … was associated with about a one-third reduction in the risk of subsequent relapse,” said Dr. Mowry. A prospective study conducted in Australia found similar results.
In 2012, Dr. Mowry and colleagues measured vitamin D levels in blood samples from 469 patients with relapsing-remitting MS or clinically isolated syndrome (CIS). They found that each additional 10-ng/mL increment of vitamin D level was associated with an approximately 15% lower risk of subsequent new T2 lesions and with an approximately 32% reduced risk of subsequent gadolinium-enhancing lesions. Higher levels of vitamin D also were associated with lower risk of subsequent relapse, but this finding was not statistically significant.
To discover whether vitamin D influences markers known to predict long-term disability, Dr. Mowry and colleagues examined data from a study of atorvastatin in 65 patients with CIS. They measured vitamin D levels at baseline and at month six, and the follow-up period was as long as 18 months. They found that each additional 10-ng/mL increment in vitamin D level was associated with an additional 7.8 mL of preserved gray matter volume. They also observed a trend toward an inverse association between vitamin D levels and the composite end point of three or more new T2 lesions or one or more relapses within a year.
Is Vitamin D Supplementation Appropriate?
“Just because [vitamin D] is available over the counter does not make it safe or effective,” and the supplement should be studied further in clinical trials, said Dr. Mowry. In 2010, Burton et al found that a dose of as much as 40,000 IU/day of vitamin D was safe in the short term and might have immunomodulatory effects in patients with MS. Furthermore, a small Finnish study suggested that a dose of 20,000 IU/week of vitamin D was safe in patients with MS, and also might slow the accumulation of disability.
Hupperts et al studied patients with relapsing-remitting MS who were receiving interferon beta-1a. They randomized 229 participants to vitamin D or placebo and followed them for 48 weeks. In preliminary analyses, the investigators found no difference between treatment groups with respect to the outcome of no evidence of disease activity. Patients who received vitamin D had a lower annualized relapse rate than controls, but the difference was not statistically significant. The active group did have significantly fewer gadolinium-enhancing lesions and new T2 hyperintense lesions, compared with controls, however.
In addition, Dr. Mowry and colleagues are comparing the effects of 5,000-IU and 600-IU doses of vitamin D in patients with MS who are receiving glatiramer acetate. The ongoing study is sponsored by the National MS Society. European studies of the clinical benefit of vitamin D also are under way.
Although the benefits of vitamin D are not completely understood, many neurologists recommend supplementation to their patients with MS. Pharmacokinetic studies have not shown a difference between daily, weekly, or monthly dosing regimens. “As long as you give the same dose of vitamin D, you will get the levels … to the same general area,” said Dr. Mowry. Nevertheless, some studies in other patient populations suggest that very high doses of vitamin D given monthly are probably toxic.
Many studies have suggested that vitamin D3 may be more potent than vitamin D2. “I tend to use [vitamin] D3 when I am supplementing,” said Dr. Mowry. “I aim for levels between 40 and 60 ng/mL, based on our observational data.... For my patients, that largely means they need somewhere between 2,000 and 4,000 IU/day, although sometimes more. I usually recheck the level in three months, based on what we know about the kinetics of vitamin D supplementation. I am cautious in individuals who may be at risk for hypercalcemia or hypercalciuria.”
—Erik Greb
Suggested Reading
Burton JM, Kimball S, Vieth R, et al. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology. 2010;74(23):1852-1859.
Mowry EM. Vitamin D: evidence for its role as a prognostic factor in multiple sclerosis. J Neurol Sci. 2011; 311(1-2):19-22.
Mowry EM, Pelletier D, Gao Z, et al. Vitamin D in clinically isolated syndrome: evidence for possible neuroprotection. Eur J Neurol. 2016;23(2):327-332.
Mowry EM, Waubant E, McCulloch CE, et al. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol. 2012;72(2):234-240.
Munger KL, Åivo J, Hongell K, et al. Vitamin D status during pregnancy and risk of multiple sclerosis in offspring of women in the Finnish Maternity Cohort. JAMA Neurol. 2016;73(5):515-519.
Munger KL, Levin LI, Hollis BW, et al. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296(23):2832-2838.
Nielsen NM, Munger KL, Koch-Henriksen N, et al. Neonatal vitamin D status and risk of multiple sclerosis: a population-based case-control study. Neurology. 2017;88(1):44-51.
Tremlett H, van der Mei IA, Pittas F, et al. Monthly ambient sunlight, infections and relapse rates in multiple sclerosis. Neuroepidemiology. 2008;31(4):271-279.
Can Gene Expression–Based Technologies Help Diagnose MS?
ORLANDO—RNA expression patterns are highly dynamic, even at the earliest stages of multiple sclerosis (MS) pathogenesis, according to research presented at the ACTRIMS 2017 Forum. Machine learning methods trained and validated with these gene targets are a highly accurate tool that could provide actionable data for health care providers who suspect MS.
RNA sequencing was performed to identify differentially expressed protein-coding and noncoding RNA genes at distinct stages of MS, compared with controls. Expression levels of these genes were validated by real-time polymerase chain reaction (PCR) across all 979 subjects recruited. Ratios of gene expression data were used as inputs to train machine learning classifiers capable of multicategory comparisons. An independent validation testing set consisting of individuals across each control
—Glenn S. Williams
ORLANDO—RNA expression patterns are highly dynamic, even at the earliest stages of multiple sclerosis (MS) pathogenesis, according to research presented at the ACTRIMS 2017 Forum. Machine learning methods trained and validated with these gene targets are a highly accurate tool that could provide actionable data for health care providers who suspect MS.
RNA sequencing was performed to identify differentially expressed protein-coding and noncoding RNA genes at distinct stages of MS, compared with controls. Expression levels of these genes were validated by real-time polymerase chain reaction (PCR) across all 979 subjects recruited. Ratios of gene expression data were used as inputs to train machine learning classifiers capable of multicategory comparisons. An independent validation testing set consisting of individuals across each control
—Glenn S. Williams
ORLANDO—RNA expression patterns are highly dynamic, even at the earliest stages of multiple sclerosis (MS) pathogenesis, according to research presented at the ACTRIMS 2017 Forum. Machine learning methods trained and validated with these gene targets are a highly accurate tool that could provide actionable data for health care providers who suspect MS.
RNA sequencing was performed to identify differentially expressed protein-coding and noncoding RNA genes at distinct stages of MS, compared with controls. Expression levels of these genes were validated by real-time polymerase chain reaction (PCR) across all 979 subjects recruited. Ratios of gene expression data were used as inputs to train machine learning classifiers capable of multicategory comparisons. An independent validation testing set consisting of individuals across each control
—Glenn S. Williams