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Natalizumab May Be Associated With Increased Disease Activity During Pregnancy
Women with relapsing-remitting multiple sclerosis (MS) who discontinue natalizumab treatment before pregnancy may have increased disease activity, according to a study published March 6 in Neurology. In addition, taking natalizumab during the first trimester of pregnancy increases the risk of miscarriage, although the risk remains similar to that of the general population, according to an accompanying study.
An Analysis of Pregnancy Data
Emilio Portaccio, MD, of the Don Carlo Gnocchi Foundation in Florence, Italy, and colleagues analyzed data for all pregnancies between 2009 and 2015 in patients with MS who presented to 19 Italian sites. They compared data for 83 patients receiving natalizumab with those for 350 control patients who were receiving injectable immunomodulatory agents or no treatment. The investigators followed up with the women every six months, at each relapse, and at one year after birth.
The patients receiving natalizumab had 92 pregnancies. Approximately 37% of women receiving natalizumab had at least one relapse during pregnancy, compared with 10% of controls. Relapse rate during pregnancy was higher among patients whose last infusion occurred before the last menstrual period (55.9%) than among patients whose last infusion occurred after the last menstrual period (20%) or controls (10%). Receiving the last natalizumab infusion before the last menstrual period was the only predictor of relapse during pregnancy. In the first trimester after delivery, the rate of relapse was 21.7% in natalizumab-treated patients and 13.7% in controls.
Twelve patients had disability worsening at the end of the one-year follow-up. In 11 of these patients, disability accumulation resulted from relapses during pregnancy or after delivery. Disease progression was reduced in patients for whom medication was reintroduced earlier after delivery.
About 75% of pregnancies in women receiving natalizumab had treatment exposure, and the mean duration of exposure was 1.2 weeks. The odds ratio of spontaneous abortion was 3.9 among patients receiving natalizumab, compared with controls. The rate of spontaneous abortion among natalizumab-treated patients (17.4%) was similar to that observed for the general Italian population (14%), however. The rate of major congenital anomalies was 3.7% in patients exposed to natalizumab, 1.3% in patients exposed to interferon beta, and 0.9% in untreated patients. The differences between groups were not significant. Exposure to natalizumab and exposure to interferon beta were associated with a lower length of the newborn.
Relapse Severity Was Not Measured
One limitation of the studies is that the women treated with natalizumab may have been different from women not treated with natalizumab in ways that the investigators did not measure. In addition, the researchers did not measure relapse severity.
“Our findings suggest that if women who take natalizumab for MS want to become pregnant, it may be best to continue treatment up until a pregnancy test is positive and then at that point discontinue use,” said Dr. Portaccio. “While there is still a risk of increased disease activity, this course of action may lower that risk.”
—Erik Greb
Suggested Reading
Portaccio E, Annovazzi P, Ghezzi A, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: I: Fetal risks. Neurology. 2018;90(10):e823-e831.
Portaccio E, Moiola L, Martinelli V, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: II: Maternal risks. Neurology. 2018;90(10):e832-e839.
Women with relapsing-remitting multiple sclerosis (MS) who discontinue natalizumab treatment before pregnancy may have increased disease activity, according to a study published March 6 in Neurology. In addition, taking natalizumab during the first trimester of pregnancy increases the risk of miscarriage, although the risk remains similar to that of the general population, according to an accompanying study.
An Analysis of Pregnancy Data
Emilio Portaccio, MD, of the Don Carlo Gnocchi Foundation in Florence, Italy, and colleagues analyzed data for all pregnancies between 2009 and 2015 in patients with MS who presented to 19 Italian sites. They compared data for 83 patients receiving natalizumab with those for 350 control patients who were receiving injectable immunomodulatory agents or no treatment. The investigators followed up with the women every six months, at each relapse, and at one year after birth.
The patients receiving natalizumab had 92 pregnancies. Approximately 37% of women receiving natalizumab had at least one relapse during pregnancy, compared with 10% of controls. Relapse rate during pregnancy was higher among patients whose last infusion occurred before the last menstrual period (55.9%) than among patients whose last infusion occurred after the last menstrual period (20%) or controls (10%). Receiving the last natalizumab infusion before the last menstrual period was the only predictor of relapse during pregnancy. In the first trimester after delivery, the rate of relapse was 21.7% in natalizumab-treated patients and 13.7% in controls.
Twelve patients had disability worsening at the end of the one-year follow-up. In 11 of these patients, disability accumulation resulted from relapses during pregnancy or after delivery. Disease progression was reduced in patients for whom medication was reintroduced earlier after delivery.
About 75% of pregnancies in women receiving natalizumab had treatment exposure, and the mean duration of exposure was 1.2 weeks. The odds ratio of spontaneous abortion was 3.9 among patients receiving natalizumab, compared with controls. The rate of spontaneous abortion among natalizumab-treated patients (17.4%) was similar to that observed for the general Italian population (14%), however. The rate of major congenital anomalies was 3.7% in patients exposed to natalizumab, 1.3% in patients exposed to interferon beta, and 0.9% in untreated patients. The differences between groups were not significant. Exposure to natalizumab and exposure to interferon beta were associated with a lower length of the newborn.
Relapse Severity Was Not Measured
One limitation of the studies is that the women treated with natalizumab may have been different from women not treated with natalizumab in ways that the investigators did not measure. In addition, the researchers did not measure relapse severity.
“Our findings suggest that if women who take natalizumab for MS want to become pregnant, it may be best to continue treatment up until a pregnancy test is positive and then at that point discontinue use,” said Dr. Portaccio. “While there is still a risk of increased disease activity, this course of action may lower that risk.”
—Erik Greb
Suggested Reading
Portaccio E, Annovazzi P, Ghezzi A, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: I: Fetal risks. Neurology. 2018;90(10):e823-e831.
Portaccio E, Moiola L, Martinelli V, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: II: Maternal risks. Neurology. 2018;90(10):e832-e839.
Women with relapsing-remitting multiple sclerosis (MS) who discontinue natalizumab treatment before pregnancy may have increased disease activity, according to a study published March 6 in Neurology. In addition, taking natalizumab during the first trimester of pregnancy increases the risk of miscarriage, although the risk remains similar to that of the general population, according to an accompanying study.
An Analysis of Pregnancy Data
Emilio Portaccio, MD, of the Don Carlo Gnocchi Foundation in Florence, Italy, and colleagues analyzed data for all pregnancies between 2009 and 2015 in patients with MS who presented to 19 Italian sites. They compared data for 83 patients receiving natalizumab with those for 350 control patients who were receiving injectable immunomodulatory agents or no treatment. The investigators followed up with the women every six months, at each relapse, and at one year after birth.
The patients receiving natalizumab had 92 pregnancies. Approximately 37% of women receiving natalizumab had at least one relapse during pregnancy, compared with 10% of controls. Relapse rate during pregnancy was higher among patients whose last infusion occurred before the last menstrual period (55.9%) than among patients whose last infusion occurred after the last menstrual period (20%) or controls (10%). Receiving the last natalizumab infusion before the last menstrual period was the only predictor of relapse during pregnancy. In the first trimester after delivery, the rate of relapse was 21.7% in natalizumab-treated patients and 13.7% in controls.
Twelve patients had disability worsening at the end of the one-year follow-up. In 11 of these patients, disability accumulation resulted from relapses during pregnancy or after delivery. Disease progression was reduced in patients for whom medication was reintroduced earlier after delivery.
About 75% of pregnancies in women receiving natalizumab had treatment exposure, and the mean duration of exposure was 1.2 weeks. The odds ratio of spontaneous abortion was 3.9 among patients receiving natalizumab, compared with controls. The rate of spontaneous abortion among natalizumab-treated patients (17.4%) was similar to that observed for the general Italian population (14%), however. The rate of major congenital anomalies was 3.7% in patients exposed to natalizumab, 1.3% in patients exposed to interferon beta, and 0.9% in untreated patients. The differences between groups were not significant. Exposure to natalizumab and exposure to interferon beta were associated with a lower length of the newborn.
Relapse Severity Was Not Measured
One limitation of the studies is that the women treated with natalizumab may have been different from women not treated with natalizumab in ways that the investigators did not measure. In addition, the researchers did not measure relapse severity.
“Our findings suggest that if women who take natalizumab for MS want to become pregnant, it may be best to continue treatment up until a pregnancy test is positive and then at that point discontinue use,” said Dr. Portaccio. “While there is still a risk of increased disease activity, this course of action may lower that risk.”
—Erik Greb
Suggested Reading
Portaccio E, Annovazzi P, Ghezzi A, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: I: Fetal risks. Neurology. 2018;90(10):e823-e831.
Portaccio E, Moiola L, Martinelli V, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: II: Maternal risks. Neurology. 2018;90(10):e832-e839.
Are Complementary and Alternative Treatments Effective for MS?
Cannabis extract, physical activity, and cognitive behavioral therapy are complementary and alternative medicines (CAMs) with the strongest evidence of efficacy for multiple sclerosis (MS), according to a systematic review published in the January issue of Journal of Neurology, Neurosurgery and Psychiatry. However, there is little class I and class II evidence to support the effect of CAMs.
“We found little evidence for CAM treatments of MS, and class I evidence was almost universally lacking,” said Suzi B. Claflin, PhD, a postdoctoral research fellow at Menzies Institute for Medical Research at the University of Tasmania in Hobart, Australia, and colleagues. Some CAM treatments were evaluated in a single study, and when treatments were evaluated in more than one study, the studies “had different designs and methodologies, and in some cases, contradictory results.”
A Systematic Review
There is an in interest in CAM treatments among the MS community, possibly due to perceived and actual shortcomings of available pharmacologic treatments, said the researchers. Cross-sectional studies have found that 37% to 100% of patients with MS have used CAMs at some point in their lives, and up to 51.8% of these patients have used CAMs in the past year. Despite the common use of CAMs, there is a lack of understanding of their efficacy, the authors noted.
The World Health Organization has defined CAM as “a broad set of health care practices that are not part of [a] country’s own tradition and are not integrated into the dominant health care system.” For the present review, however, the researchers defined CAM broadly as a noninvasive therapy used in addition to or in lieu of the standard pharmacologic treatment of MS.
To provide an overview of the modern evidence for CAM use in patients with MS and to highlight future directions for research, Dr. Claflin and colleagues conducted a systematic review of full research articles published between January 1, 2001, and January 18, 2017, that were written in English, had only human participants, and tested the effect of a CAM treatment on health outcomes in patients with MS only. The researchers included in their review studies with at least 50 participants that provided class I or class II evidence of efficacy. In all, they included 38 studies and divided them into the following five CAM types: cannabis, diet, exercise, psychologic approaches, and other.
Best-Supported Evidence
Five studies found significant beneficial effects of cannabis extract for incontinence, pain, spasticity, and muscle stiffness, whereas two studies found no effect of cannabis extract on primary outcomes. A single study found a positive effect of tetrahydrocannabinol extract on incontinence, and one study found no effect for this treatment on spasticity.
Psychologic approaches such as cognitive behavioral therapy (CBT) appear to be effective in treating MS-related psychologic symptoms. Seven class II studies found that CBT significantly improved depression, fatigue, distress, and general health. In one study, there was no effect of CBT on functional impairment. In a single study, there was no effect of cognitive rehabilitation on function. In another study, mindfulness significantly improved health-related quality of life, depression, and fatigue.
Among exercise treatments, some balance and gait training techniques significantly improved fatigue, balance, walking, and endurance, while other techniques did not. Exercise generally was found to improve muscle strength and mobility-related health outcomes in several studies, and may have some effect on psychologic symptoms. In several studies, however, primary outcomes were not significantly affected. In a single study, yoga had no effect on attention and alertness. In another study, group yoga was not effective in improving MS Impact Scale scores, but some effects on secondary outcomes were observed.
Least-Supported Evidence
Among dietary treatments, biotin had a significant effect on disability progression in one study. In another single study, there was no effect of gingko biloba on cognitive function. Two studies of polyunsaturated fatty acid supplementation for disability had contradictory results: one study found that the treatment reduced relapse rate, and another study found no effect on gadolinium-enhancing lesions. In addition, three studies found no effect of vitamin D supplementation after MS onset on primary outcomes, but one of the studies found some suggestion of benefit of vitamin D as an add-on treatment.
Among other CAMs, acupressure significantly reduced fatigue in a single study. In another single study, amphetamine salts improved processing speed. Two studies found contradictory results for the efficacy of reflexology for pain. Finally, one study found a positive effect of relaxation on stress and depression, and one study found a positive effect of relaxation on pain.
“In order to improve our understanding of the effects of CAM on MS health outcomes, future work should cultivate methodological consistency by establishing standard control or comparator groups and outcome measures,” said Dr. Claflin and colleagues. “This field would also be well served by establishing outcomes of interest, which would allow for greater replication and the accrual of a depth of evidence about an outcome.”
—Erica Tricarico
Suggested Reading
Claflin SB, van der Mei IAF, Taylor BV. Complementary and alternative treatments of multiple sclerosis: a review of the evidence from 2001 to 2016. J Neurol Neurosurg Psychiatry. 2018;89(1):34-41.
Cannabis extract, physical activity, and cognitive behavioral therapy are complementary and alternative medicines (CAMs) with the strongest evidence of efficacy for multiple sclerosis (MS), according to a systematic review published in the January issue of Journal of Neurology, Neurosurgery and Psychiatry. However, there is little class I and class II evidence to support the effect of CAMs.
“We found little evidence for CAM treatments of MS, and class I evidence was almost universally lacking,” said Suzi B. Claflin, PhD, a postdoctoral research fellow at Menzies Institute for Medical Research at the University of Tasmania in Hobart, Australia, and colleagues. Some CAM treatments were evaluated in a single study, and when treatments were evaluated in more than one study, the studies “had different designs and methodologies, and in some cases, contradictory results.”
A Systematic Review
There is an in interest in CAM treatments among the MS community, possibly due to perceived and actual shortcomings of available pharmacologic treatments, said the researchers. Cross-sectional studies have found that 37% to 100% of patients with MS have used CAMs at some point in their lives, and up to 51.8% of these patients have used CAMs in the past year. Despite the common use of CAMs, there is a lack of understanding of their efficacy, the authors noted.
The World Health Organization has defined CAM as “a broad set of health care practices that are not part of [a] country’s own tradition and are not integrated into the dominant health care system.” For the present review, however, the researchers defined CAM broadly as a noninvasive therapy used in addition to or in lieu of the standard pharmacologic treatment of MS.
To provide an overview of the modern evidence for CAM use in patients with MS and to highlight future directions for research, Dr. Claflin and colleagues conducted a systematic review of full research articles published between January 1, 2001, and January 18, 2017, that were written in English, had only human participants, and tested the effect of a CAM treatment on health outcomes in patients with MS only. The researchers included in their review studies with at least 50 participants that provided class I or class II evidence of efficacy. In all, they included 38 studies and divided them into the following five CAM types: cannabis, diet, exercise, psychologic approaches, and other.
Best-Supported Evidence
Five studies found significant beneficial effects of cannabis extract for incontinence, pain, spasticity, and muscle stiffness, whereas two studies found no effect of cannabis extract on primary outcomes. A single study found a positive effect of tetrahydrocannabinol extract on incontinence, and one study found no effect for this treatment on spasticity.
Psychologic approaches such as cognitive behavioral therapy (CBT) appear to be effective in treating MS-related psychologic symptoms. Seven class II studies found that CBT significantly improved depression, fatigue, distress, and general health. In one study, there was no effect of CBT on functional impairment. In a single study, there was no effect of cognitive rehabilitation on function. In another study, mindfulness significantly improved health-related quality of life, depression, and fatigue.
Among exercise treatments, some balance and gait training techniques significantly improved fatigue, balance, walking, and endurance, while other techniques did not. Exercise generally was found to improve muscle strength and mobility-related health outcomes in several studies, and may have some effect on psychologic symptoms. In several studies, however, primary outcomes were not significantly affected. In a single study, yoga had no effect on attention and alertness. In another study, group yoga was not effective in improving MS Impact Scale scores, but some effects on secondary outcomes were observed.
Least-Supported Evidence
Among dietary treatments, biotin had a significant effect on disability progression in one study. In another single study, there was no effect of gingko biloba on cognitive function. Two studies of polyunsaturated fatty acid supplementation for disability had contradictory results: one study found that the treatment reduced relapse rate, and another study found no effect on gadolinium-enhancing lesions. In addition, three studies found no effect of vitamin D supplementation after MS onset on primary outcomes, but one of the studies found some suggestion of benefit of vitamin D as an add-on treatment.
Among other CAMs, acupressure significantly reduced fatigue in a single study. In another single study, amphetamine salts improved processing speed. Two studies found contradictory results for the efficacy of reflexology for pain. Finally, one study found a positive effect of relaxation on stress and depression, and one study found a positive effect of relaxation on pain.
“In order to improve our understanding of the effects of CAM on MS health outcomes, future work should cultivate methodological consistency by establishing standard control or comparator groups and outcome measures,” said Dr. Claflin and colleagues. “This field would also be well served by establishing outcomes of interest, which would allow for greater replication and the accrual of a depth of evidence about an outcome.”
—Erica Tricarico
Suggested Reading
Claflin SB, van der Mei IAF, Taylor BV. Complementary and alternative treatments of multiple sclerosis: a review of the evidence from 2001 to 2016. J Neurol Neurosurg Psychiatry. 2018;89(1):34-41.
Cannabis extract, physical activity, and cognitive behavioral therapy are complementary and alternative medicines (CAMs) with the strongest evidence of efficacy for multiple sclerosis (MS), according to a systematic review published in the January issue of Journal of Neurology, Neurosurgery and Psychiatry. However, there is little class I and class II evidence to support the effect of CAMs.
“We found little evidence for CAM treatments of MS, and class I evidence was almost universally lacking,” said Suzi B. Claflin, PhD, a postdoctoral research fellow at Menzies Institute for Medical Research at the University of Tasmania in Hobart, Australia, and colleagues. Some CAM treatments were evaluated in a single study, and when treatments were evaluated in more than one study, the studies “had different designs and methodologies, and in some cases, contradictory results.”
A Systematic Review
There is an in interest in CAM treatments among the MS community, possibly due to perceived and actual shortcomings of available pharmacologic treatments, said the researchers. Cross-sectional studies have found that 37% to 100% of patients with MS have used CAMs at some point in their lives, and up to 51.8% of these patients have used CAMs in the past year. Despite the common use of CAMs, there is a lack of understanding of their efficacy, the authors noted.
The World Health Organization has defined CAM as “a broad set of health care practices that are not part of [a] country’s own tradition and are not integrated into the dominant health care system.” For the present review, however, the researchers defined CAM broadly as a noninvasive therapy used in addition to or in lieu of the standard pharmacologic treatment of MS.
To provide an overview of the modern evidence for CAM use in patients with MS and to highlight future directions for research, Dr. Claflin and colleagues conducted a systematic review of full research articles published between January 1, 2001, and January 18, 2017, that were written in English, had only human participants, and tested the effect of a CAM treatment on health outcomes in patients with MS only. The researchers included in their review studies with at least 50 participants that provided class I or class II evidence of efficacy. In all, they included 38 studies and divided them into the following five CAM types: cannabis, diet, exercise, psychologic approaches, and other.
Best-Supported Evidence
Five studies found significant beneficial effects of cannabis extract for incontinence, pain, spasticity, and muscle stiffness, whereas two studies found no effect of cannabis extract on primary outcomes. A single study found a positive effect of tetrahydrocannabinol extract on incontinence, and one study found no effect for this treatment on spasticity.
Psychologic approaches such as cognitive behavioral therapy (CBT) appear to be effective in treating MS-related psychologic symptoms. Seven class II studies found that CBT significantly improved depression, fatigue, distress, and general health. In one study, there was no effect of CBT on functional impairment. In a single study, there was no effect of cognitive rehabilitation on function. In another study, mindfulness significantly improved health-related quality of life, depression, and fatigue.
Among exercise treatments, some balance and gait training techniques significantly improved fatigue, balance, walking, and endurance, while other techniques did not. Exercise generally was found to improve muscle strength and mobility-related health outcomes in several studies, and may have some effect on psychologic symptoms. In several studies, however, primary outcomes were not significantly affected. In a single study, yoga had no effect on attention and alertness. In another study, group yoga was not effective in improving MS Impact Scale scores, but some effects on secondary outcomes were observed.
Least-Supported Evidence
Among dietary treatments, biotin had a significant effect on disability progression in one study. In another single study, there was no effect of gingko biloba on cognitive function. Two studies of polyunsaturated fatty acid supplementation for disability had contradictory results: one study found that the treatment reduced relapse rate, and another study found no effect on gadolinium-enhancing lesions. In addition, three studies found no effect of vitamin D supplementation after MS onset on primary outcomes, but one of the studies found some suggestion of benefit of vitamin D as an add-on treatment.
Among other CAMs, acupressure significantly reduced fatigue in a single study. In another single study, amphetamine salts improved processing speed. Two studies found contradictory results for the efficacy of reflexology for pain. Finally, one study found a positive effect of relaxation on stress and depression, and one study found a positive effect of relaxation on pain.
“In order to improve our understanding of the effects of CAM on MS health outcomes, future work should cultivate methodological consistency by establishing standard control or comparator groups and outcome measures,” said Dr. Claflin and colleagues. “This field would also be well served by establishing outcomes of interest, which would allow for greater replication and the accrual of a depth of evidence about an outcome.”
—Erica Tricarico
Suggested Reading
Claflin SB, van der Mei IAF, Taylor BV. Complementary and alternative treatments of multiple sclerosis: a review of the evidence from 2001 to 2016. J Neurol Neurosurg Psychiatry. 2018;89(1):34-41.
Frankincense extract may reduce disease activity in relapsing-remitting MS
A standardized frankincense extract was safe, well tolerated, and potentially efficacious as an oral treatment in patients with relapsing-remitting multiple sclerosis (RRMS), according to results of a small, nonrandomized study.
Patients receiving the herbal treatment had significantly fewer contrast-enhancing lesions on MRI versus baseline in the study, which was published in the Journal of Neurology, Neurosurgery & Psychiatry.
“Despite our encouraging results, it is difficult to forecast the efficacy of a standardized frankincense extract in RRMS,” Dr. Stürner and her colleagues wrote in their report on the study.
Boswellic acids, believed to be the active compound in frankincense, has been used as an anti-inflammatory substance for thousands of years in Eastern medicine, according to the study authors.
Frankincense extracts were safe and well tolerated in several small, randomized trials including patients with inflammatory or autoimmune diseases, they noted.
Dr. Stürner and her colleagues tested a standardized frankincense extract in the SABA phase 2a trial, an investigator-initiated, open-label, pilot study including 38 patients with RRMS.
Patients underwent observation for 4 months, then were treated with the extract for up to 8 months plus an optional extension phase of up to 36 months. A total of 28 patients completed the initial treatment period, and 18 participated in the extension period, according to the study results.
The median number of monthly contrast-enhancing lesions was significantly reduced from 1.00 at baseline to 0.50 during the initial treatment period (P less than .0001). In addition, significantly less brain atrophy was noted after the treatment phase as compared with the baseline observation phase (P = .0081).
Adverse events, mainly infections or gastrointestinal symptoms, were mild (57.7%) or moderate (38.6%), investigators added.
Treatment significantly increased regulatory CD4-positive T cell markers and decreased interleukin-17A–producing CD8-positive T cells, according to results of mechanistic studies that were also reported.
Other anti-inflammatory drugs that have been licensed act broadly on the immune system, according to investigators, and so those agents require careful monitoring for side effects.
“The right balance between efficacy and safety profile becomes increasingly more important for a young patient population, who require long-term treatment,” Dr. Stürner and her coauthors wrote. “The results of the SABA trial are promising from this perspective.”
The study was funded in part by Alpinia Laudanum Institute, which supplied the standardized frankincense extract at no charge. Individual authors reported competing interests with Alpinia Laudanum, Biogen, Sanofi Genzyme, Novartis, Merck Serono, and others.
SOURCE: Stürner KH et al. J Neurol Neurosurg Psychiatry. 2018 Apr;89(4):330-8.
Results of the SABA phase 2a trial suggest that frankincense could be a new therapeutic agent for mildly disabled young patients with RRMS who require long-term treatment, according to Dr. Francesco Patti.
In the study, administration of standardized oral frankincense extract significantly reduced the median number and volume of contrast-enhancing lesions and the number of new T2 lesions. The treatment also increased brain parenchymal volume and reduced the annualized relapse rate. While disability scores remained unchanged, measures of function and quality of life improved.
The treatment effects also appeared to be durable, based on the extension phase results.
Blood and immunologic findings suggested that the treatment was not toxic and that it exerted immunomodulatory activity by reduction of IL-17–producing CD8-positive T cells, as well as anti-inflammatory properties through inhibitory effects on 5-lipo-oxygenase, microsomial prostaglandin E2 synthase-1, LL-37, and nuclear factor-kB activities.
“This mechanism of action, attributing a role of these enzymes in neuroinflammation, might offer a new therapeutic approach,” he concluded in his editorial.
Francesco Patti, MD , is with the Multiple Sclerosis Hub Center, University of Catania (Italy). These comments are derived from his editorial ( J Neurol Neurosurg Psychiatry. 2018;89:327 ). Dr. Patti declared no competing interests related to the editorial.
Results of the SABA phase 2a trial suggest that frankincense could be a new therapeutic agent for mildly disabled young patients with RRMS who require long-term treatment, according to Dr. Francesco Patti.
In the study, administration of standardized oral frankincense extract significantly reduced the median number and volume of contrast-enhancing lesions and the number of new T2 lesions. The treatment also increased brain parenchymal volume and reduced the annualized relapse rate. While disability scores remained unchanged, measures of function and quality of life improved.
The treatment effects also appeared to be durable, based on the extension phase results.
Blood and immunologic findings suggested that the treatment was not toxic and that it exerted immunomodulatory activity by reduction of IL-17–producing CD8-positive T cells, as well as anti-inflammatory properties through inhibitory effects on 5-lipo-oxygenase, microsomial prostaglandin E2 synthase-1, LL-37, and nuclear factor-kB activities.
“This mechanism of action, attributing a role of these enzymes in neuroinflammation, might offer a new therapeutic approach,” he concluded in his editorial.
Francesco Patti, MD , is with the Multiple Sclerosis Hub Center, University of Catania (Italy). These comments are derived from his editorial ( J Neurol Neurosurg Psychiatry. 2018;89:327 ). Dr. Patti declared no competing interests related to the editorial.
Results of the SABA phase 2a trial suggest that frankincense could be a new therapeutic agent for mildly disabled young patients with RRMS who require long-term treatment, according to Dr. Francesco Patti.
In the study, administration of standardized oral frankincense extract significantly reduced the median number and volume of contrast-enhancing lesions and the number of new T2 lesions. The treatment also increased brain parenchymal volume and reduced the annualized relapse rate. While disability scores remained unchanged, measures of function and quality of life improved.
The treatment effects also appeared to be durable, based on the extension phase results.
Blood and immunologic findings suggested that the treatment was not toxic and that it exerted immunomodulatory activity by reduction of IL-17–producing CD8-positive T cells, as well as anti-inflammatory properties through inhibitory effects on 5-lipo-oxygenase, microsomial prostaglandin E2 synthase-1, LL-37, and nuclear factor-kB activities.
“This mechanism of action, attributing a role of these enzymes in neuroinflammation, might offer a new therapeutic approach,” he concluded in his editorial.
Francesco Patti, MD , is with the Multiple Sclerosis Hub Center, University of Catania (Italy). These comments are derived from his editorial ( J Neurol Neurosurg Psychiatry. 2018;89:327 ). Dr. Patti declared no competing interests related to the editorial.
A standardized frankincense extract was safe, well tolerated, and potentially efficacious as an oral treatment in patients with relapsing-remitting multiple sclerosis (RRMS), according to results of a small, nonrandomized study.
Patients receiving the herbal treatment had significantly fewer contrast-enhancing lesions on MRI versus baseline in the study, which was published in the Journal of Neurology, Neurosurgery & Psychiatry.
“Despite our encouraging results, it is difficult to forecast the efficacy of a standardized frankincense extract in RRMS,” Dr. Stürner and her colleagues wrote in their report on the study.
Boswellic acids, believed to be the active compound in frankincense, has been used as an anti-inflammatory substance for thousands of years in Eastern medicine, according to the study authors.
Frankincense extracts were safe and well tolerated in several small, randomized trials including patients with inflammatory or autoimmune diseases, they noted.
Dr. Stürner and her colleagues tested a standardized frankincense extract in the SABA phase 2a trial, an investigator-initiated, open-label, pilot study including 38 patients with RRMS.
Patients underwent observation for 4 months, then were treated with the extract for up to 8 months plus an optional extension phase of up to 36 months. A total of 28 patients completed the initial treatment period, and 18 participated in the extension period, according to the study results.
The median number of monthly contrast-enhancing lesions was significantly reduced from 1.00 at baseline to 0.50 during the initial treatment period (P less than .0001). In addition, significantly less brain atrophy was noted after the treatment phase as compared with the baseline observation phase (P = .0081).
Adverse events, mainly infections or gastrointestinal symptoms, were mild (57.7%) or moderate (38.6%), investigators added.
Treatment significantly increased regulatory CD4-positive T cell markers and decreased interleukin-17A–producing CD8-positive T cells, according to results of mechanistic studies that were also reported.
Other anti-inflammatory drugs that have been licensed act broadly on the immune system, according to investigators, and so those agents require careful monitoring for side effects.
“The right balance between efficacy and safety profile becomes increasingly more important for a young patient population, who require long-term treatment,” Dr. Stürner and her coauthors wrote. “The results of the SABA trial are promising from this perspective.”
The study was funded in part by Alpinia Laudanum Institute, which supplied the standardized frankincense extract at no charge. Individual authors reported competing interests with Alpinia Laudanum, Biogen, Sanofi Genzyme, Novartis, Merck Serono, and others.
SOURCE: Stürner KH et al. J Neurol Neurosurg Psychiatry. 2018 Apr;89(4):330-8.
A standardized frankincense extract was safe, well tolerated, and potentially efficacious as an oral treatment in patients with relapsing-remitting multiple sclerosis (RRMS), according to results of a small, nonrandomized study.
Patients receiving the herbal treatment had significantly fewer contrast-enhancing lesions on MRI versus baseline in the study, which was published in the Journal of Neurology, Neurosurgery & Psychiatry.
“Despite our encouraging results, it is difficult to forecast the efficacy of a standardized frankincense extract in RRMS,” Dr. Stürner and her colleagues wrote in their report on the study.
Boswellic acids, believed to be the active compound in frankincense, has been used as an anti-inflammatory substance for thousands of years in Eastern medicine, according to the study authors.
Frankincense extracts were safe and well tolerated in several small, randomized trials including patients with inflammatory or autoimmune diseases, they noted.
Dr. Stürner and her colleagues tested a standardized frankincense extract in the SABA phase 2a trial, an investigator-initiated, open-label, pilot study including 38 patients with RRMS.
Patients underwent observation for 4 months, then were treated with the extract for up to 8 months plus an optional extension phase of up to 36 months. A total of 28 patients completed the initial treatment period, and 18 participated in the extension period, according to the study results.
The median number of monthly contrast-enhancing lesions was significantly reduced from 1.00 at baseline to 0.50 during the initial treatment period (P less than .0001). In addition, significantly less brain atrophy was noted after the treatment phase as compared with the baseline observation phase (P = .0081).
Adverse events, mainly infections or gastrointestinal symptoms, were mild (57.7%) or moderate (38.6%), investigators added.
Treatment significantly increased regulatory CD4-positive T cell markers and decreased interleukin-17A–producing CD8-positive T cells, according to results of mechanistic studies that were also reported.
Other anti-inflammatory drugs that have been licensed act broadly on the immune system, according to investigators, and so those agents require careful monitoring for side effects.
“The right balance between efficacy and safety profile becomes increasingly more important for a young patient population, who require long-term treatment,” Dr. Stürner and her coauthors wrote. “The results of the SABA trial are promising from this perspective.”
The study was funded in part by Alpinia Laudanum Institute, which supplied the standardized frankincense extract at no charge. Individual authors reported competing interests with Alpinia Laudanum, Biogen, Sanofi Genzyme, Novartis, Merck Serono, and others.
SOURCE: Stürner KH et al. J Neurol Neurosurg Psychiatry. 2018 Apr;89(4):330-8.
FROM Journal of Neurology, Neurosurgery & Psychiatry
Key clinical point:
Major finding: The median number of monthly contrast-enhancing lesions was significantly reduced from 1.00 at baseline to 0.50 on treatment (P less than .0001).
Study details: The SABA phase 2a trial, an investigator-initiated, open-label, pilot study including 38 patients with RRMS.
Disclosures: The study was funded in part by Alpinia Laudanum Institute, which supplied the standardized frankincense extract at no charge. Individual authors reported competing interests with Alpinia Laudanum, Biogen, Sanofi Genzyme, Novartis, Merck Serono, and others.
Source: Stürner KH et al. J Neurol Neurosurg Psychiatry. 2018;89:330-8.
Siponimod trial ‘first’ to show delayed disability in secondary progressive MS
Phase 3 data with siponimod, Novartis’ investigational treatment for multiple sclerosis, show a 21% reduction in the time to disease progression versus placebo in patients with the secondary progressive subtype of the disease.
A significantly lower percentage of patients with secondary progressive multiple sclerosis (SPMS) treated with siponimod met the primary endpoint of confirmed disease progression (CDP) at 3 months, compared with those who received placebo in the EXPAND trial (26% vs. 32% of patients; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.65–0.95; P = .013).
No significant difference between siponimod and placebo was seen in one of the two main secondary outcomes of the study – the time to 3-month confirmed worsening of the timed 25-foot walk test (T25FW). This result led Luanne Metz, MD, and Wei-Qiao Liu, MD, both of the department of clinical neurosciences and the Hotchkiss Brain Institute at the University of Calgary (Alta.), to take a cautionary view of the findings in an editorial about the trial’s results.
“Although siponimod seems to reduce the time to confirmed disability in SPMS, the treatment effect was small,” Dr. Metz and Dr. Liu argued.
“In our opinion, the reduction in the proportion of participants reaching the primary endpoint of only 6% and the absence of a significant difference for the key secondary clinical outcome [T25FW] are disappointing results and do not suggest that siponimod is an effective treatment for SPMS,” the two wrote.
“Confidence in the treatment benefit of siponimod in progressive MS will, in our opinion, require confirmation in a second trial. Trials of other novel treatments that target noninflammatory mechanisms are still needed,” they said.
EXPAND (Exploring the efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis) was an event- and exposure-driven double-blind trial that recruited patients with SPMS over a 2-year period starting in February 2013. Of 1,651 patients who were recruited, randomized, and actually received treatment, 1,099 were treated with oral siponimod, 2 mg once daily, and 546 were given a matching placebo.
Treatment was for up to 3 years or until 374 CDP events assessed via the Expanded Disability Status Scale (EDSS) had occurred. Patients who had CDP after 6 months in the double-blind trial could be re-consented and continue with double-blind treatment, switch to open-label siponimod, or stop study treatment and either remain on no treatment or receive another disease-modifying treatment.
On average, the patients had been diagnosed with SPMS for a mean of 3.8 years and had been first diagnosed with MS around 17 years prior to this.
The primary endpoint of the trial – CDP at 3 months – was first reported in 2016 at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). CDP was defined as a 0.5- to 1-point increase in EDSS depending on the baseline score.
A host of additional secondary endpoints were studied, with the risk of 6-month CDP being significantly reduced by siponimod versus placebo (HR, 0.74; 95% CI, 0.60-0.92; P = .0058).
The change from baseline in T2 lesion volume – the second of the two main secondary endpoints studied – showed a potential benefit of siponimod treatment over placebo, with a lower mean-adjusted increase in lesion volume over months 12 and 24 (183.9 mm3 vs. 879.2 mm3; P less than .0001).
More patients receiving siponimod than placebo were free from new or enlarging T2 lesions (57% vs. 37%) or T1 gadolinium-enhancing lesions (89% vs. 67%), and brain volume decreased at a lower rate with siponimod than with placebo.
Adverse events occurred at a higher rate with siponimod than with placebo (89% of patients vs. 82%), of which 18% and 15%, respectively, were defined as serious.
Adverse events seen more commonly in siponimod- than in placebo-treated patients were lymphopenia (1% vs. 0%), abnormal liver-related investigations (12% vs. 4%), hypertension (10% vs. 8%), and bradycardia (4% vs. 3%) and bradyarrhythmia (3% vs. 0.4%) at the start of treatment, which were mitigated by dose titration. Other adverse events that occurred less often but more frequently with siponimod included macular edema (2% vs. less than 1%), reactivation of varicella zoster (2% vs. 1%), and convulsions (2% vs. less than 1%).
“The safety profile of siponimod in EXPAND was generally aligned with that of other drugs in the class,” Dr. Kappos and his colleagues observed.
Siponimod, also known as BAF312, is a selective sphingosine 1-phosphate (S1P) receptor modulator that targets the targets the S1P 1 and 5 receptor subtypes; the other currently approved drug in its class is fingolimod (Gilenya), which is currently indicated for treating the relapsing-remitting form of multiple sclerosis (RRMS).
Phase 2 data have shown that siponimod could also be a promising treatment for RRMS, with reduced relapse rates and fewer brain lesions seen versus placebo (JAMA Neurol. 2016;73[9]:1089-98).
The EXPAND study was funded by Novartis. The lead author Dr. Kappos has received research and educational support funding via his institution from Novartis and multiple other pharmaceutical companies. Editorial author Dr. Metz has received grants from Roche and Biogen and personal fees from EMD Serono. The other editorial author, Dr. Liu, reported receiving personal fees from Novartis and personal fees and grants from EMD Serono. Dr. Liu was a back-up treating neurologist in the EXPAND trial.
SOURCE: Kappos L et al. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30475-6, and Metz L and Liu W. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30426-4.
Phase 3 data with siponimod, Novartis’ investigational treatment for multiple sclerosis, show a 21% reduction in the time to disease progression versus placebo in patients with the secondary progressive subtype of the disease.
A significantly lower percentage of patients with secondary progressive multiple sclerosis (SPMS) treated with siponimod met the primary endpoint of confirmed disease progression (CDP) at 3 months, compared with those who received placebo in the EXPAND trial (26% vs. 32% of patients; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.65–0.95; P = .013).
No significant difference between siponimod and placebo was seen in one of the two main secondary outcomes of the study – the time to 3-month confirmed worsening of the timed 25-foot walk test (T25FW). This result led Luanne Metz, MD, and Wei-Qiao Liu, MD, both of the department of clinical neurosciences and the Hotchkiss Brain Institute at the University of Calgary (Alta.), to take a cautionary view of the findings in an editorial about the trial’s results.
“Although siponimod seems to reduce the time to confirmed disability in SPMS, the treatment effect was small,” Dr. Metz and Dr. Liu argued.
“In our opinion, the reduction in the proportion of participants reaching the primary endpoint of only 6% and the absence of a significant difference for the key secondary clinical outcome [T25FW] are disappointing results and do not suggest that siponimod is an effective treatment for SPMS,” the two wrote.
“Confidence in the treatment benefit of siponimod in progressive MS will, in our opinion, require confirmation in a second trial. Trials of other novel treatments that target noninflammatory mechanisms are still needed,” they said.
EXPAND (Exploring the efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis) was an event- and exposure-driven double-blind trial that recruited patients with SPMS over a 2-year period starting in February 2013. Of 1,651 patients who were recruited, randomized, and actually received treatment, 1,099 were treated with oral siponimod, 2 mg once daily, and 546 were given a matching placebo.
Treatment was for up to 3 years or until 374 CDP events assessed via the Expanded Disability Status Scale (EDSS) had occurred. Patients who had CDP after 6 months in the double-blind trial could be re-consented and continue with double-blind treatment, switch to open-label siponimod, or stop study treatment and either remain on no treatment or receive another disease-modifying treatment.
On average, the patients had been diagnosed with SPMS for a mean of 3.8 years and had been first diagnosed with MS around 17 years prior to this.
The primary endpoint of the trial – CDP at 3 months – was first reported in 2016 at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). CDP was defined as a 0.5- to 1-point increase in EDSS depending on the baseline score.
A host of additional secondary endpoints were studied, with the risk of 6-month CDP being significantly reduced by siponimod versus placebo (HR, 0.74; 95% CI, 0.60-0.92; P = .0058).
The change from baseline in T2 lesion volume – the second of the two main secondary endpoints studied – showed a potential benefit of siponimod treatment over placebo, with a lower mean-adjusted increase in lesion volume over months 12 and 24 (183.9 mm3 vs. 879.2 mm3; P less than .0001).
More patients receiving siponimod than placebo were free from new or enlarging T2 lesions (57% vs. 37%) or T1 gadolinium-enhancing lesions (89% vs. 67%), and brain volume decreased at a lower rate with siponimod than with placebo.
Adverse events occurred at a higher rate with siponimod than with placebo (89% of patients vs. 82%), of which 18% and 15%, respectively, were defined as serious.
Adverse events seen more commonly in siponimod- than in placebo-treated patients were lymphopenia (1% vs. 0%), abnormal liver-related investigations (12% vs. 4%), hypertension (10% vs. 8%), and bradycardia (4% vs. 3%) and bradyarrhythmia (3% vs. 0.4%) at the start of treatment, which were mitigated by dose titration. Other adverse events that occurred less often but more frequently with siponimod included macular edema (2% vs. less than 1%), reactivation of varicella zoster (2% vs. 1%), and convulsions (2% vs. less than 1%).
“The safety profile of siponimod in EXPAND was generally aligned with that of other drugs in the class,” Dr. Kappos and his colleagues observed.
Siponimod, also known as BAF312, is a selective sphingosine 1-phosphate (S1P) receptor modulator that targets the targets the S1P 1 and 5 receptor subtypes; the other currently approved drug in its class is fingolimod (Gilenya), which is currently indicated for treating the relapsing-remitting form of multiple sclerosis (RRMS).
Phase 2 data have shown that siponimod could also be a promising treatment for RRMS, with reduced relapse rates and fewer brain lesions seen versus placebo (JAMA Neurol. 2016;73[9]:1089-98).
The EXPAND study was funded by Novartis. The lead author Dr. Kappos has received research and educational support funding via his institution from Novartis and multiple other pharmaceutical companies. Editorial author Dr. Metz has received grants from Roche and Biogen and personal fees from EMD Serono. The other editorial author, Dr. Liu, reported receiving personal fees from Novartis and personal fees and grants from EMD Serono. Dr. Liu was a back-up treating neurologist in the EXPAND trial.
SOURCE: Kappos L et al. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30475-6, and Metz L and Liu W. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30426-4.
Phase 3 data with siponimod, Novartis’ investigational treatment for multiple sclerosis, show a 21% reduction in the time to disease progression versus placebo in patients with the secondary progressive subtype of the disease.
A significantly lower percentage of patients with secondary progressive multiple sclerosis (SPMS) treated with siponimod met the primary endpoint of confirmed disease progression (CDP) at 3 months, compared with those who received placebo in the EXPAND trial (26% vs. 32% of patients; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.65–0.95; P = .013).
No significant difference between siponimod and placebo was seen in one of the two main secondary outcomes of the study – the time to 3-month confirmed worsening of the timed 25-foot walk test (T25FW). This result led Luanne Metz, MD, and Wei-Qiao Liu, MD, both of the department of clinical neurosciences and the Hotchkiss Brain Institute at the University of Calgary (Alta.), to take a cautionary view of the findings in an editorial about the trial’s results.
“Although siponimod seems to reduce the time to confirmed disability in SPMS, the treatment effect was small,” Dr. Metz and Dr. Liu argued.
“In our opinion, the reduction in the proportion of participants reaching the primary endpoint of only 6% and the absence of a significant difference for the key secondary clinical outcome [T25FW] are disappointing results and do not suggest that siponimod is an effective treatment for SPMS,” the two wrote.
“Confidence in the treatment benefit of siponimod in progressive MS will, in our opinion, require confirmation in a second trial. Trials of other novel treatments that target noninflammatory mechanisms are still needed,” they said.
EXPAND (Exploring the efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis) was an event- and exposure-driven double-blind trial that recruited patients with SPMS over a 2-year period starting in February 2013. Of 1,651 patients who were recruited, randomized, and actually received treatment, 1,099 were treated with oral siponimod, 2 mg once daily, and 546 were given a matching placebo.
Treatment was for up to 3 years or until 374 CDP events assessed via the Expanded Disability Status Scale (EDSS) had occurred. Patients who had CDP after 6 months in the double-blind trial could be re-consented and continue with double-blind treatment, switch to open-label siponimod, or stop study treatment and either remain on no treatment or receive another disease-modifying treatment.
On average, the patients had been diagnosed with SPMS for a mean of 3.8 years and had been first diagnosed with MS around 17 years prior to this.
The primary endpoint of the trial – CDP at 3 months – was first reported in 2016 at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). CDP was defined as a 0.5- to 1-point increase in EDSS depending on the baseline score.
A host of additional secondary endpoints were studied, with the risk of 6-month CDP being significantly reduced by siponimod versus placebo (HR, 0.74; 95% CI, 0.60-0.92; P = .0058).
The change from baseline in T2 lesion volume – the second of the two main secondary endpoints studied – showed a potential benefit of siponimod treatment over placebo, with a lower mean-adjusted increase in lesion volume over months 12 and 24 (183.9 mm3 vs. 879.2 mm3; P less than .0001).
More patients receiving siponimod than placebo were free from new or enlarging T2 lesions (57% vs. 37%) or T1 gadolinium-enhancing lesions (89% vs. 67%), and brain volume decreased at a lower rate with siponimod than with placebo.
Adverse events occurred at a higher rate with siponimod than with placebo (89% of patients vs. 82%), of which 18% and 15%, respectively, were defined as serious.
Adverse events seen more commonly in siponimod- than in placebo-treated patients were lymphopenia (1% vs. 0%), abnormal liver-related investigations (12% vs. 4%), hypertension (10% vs. 8%), and bradycardia (4% vs. 3%) and bradyarrhythmia (3% vs. 0.4%) at the start of treatment, which were mitigated by dose titration. Other adverse events that occurred less often but more frequently with siponimod included macular edema (2% vs. less than 1%), reactivation of varicella zoster (2% vs. 1%), and convulsions (2% vs. less than 1%).
“The safety profile of siponimod in EXPAND was generally aligned with that of other drugs in the class,” Dr. Kappos and his colleagues observed.
Siponimod, also known as BAF312, is a selective sphingosine 1-phosphate (S1P) receptor modulator that targets the targets the S1P 1 and 5 receptor subtypes; the other currently approved drug in its class is fingolimod (Gilenya), which is currently indicated for treating the relapsing-remitting form of multiple sclerosis (RRMS).
Phase 2 data have shown that siponimod could also be a promising treatment for RRMS, with reduced relapse rates and fewer brain lesions seen versus placebo (JAMA Neurol. 2016;73[9]:1089-98).
The EXPAND study was funded by Novartis. The lead author Dr. Kappos has received research and educational support funding via his institution from Novartis and multiple other pharmaceutical companies. Editorial author Dr. Metz has received grants from Roche and Biogen and personal fees from EMD Serono. The other editorial author, Dr. Liu, reported receiving personal fees from Novartis and personal fees and grants from EMD Serono. Dr. Liu was a back-up treating neurologist in the EXPAND trial.
SOURCE: Kappos L et al. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30475-6, and Metz L and Liu W. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30426-4.
FROM THE LANCET
Key clinical point:
Major finding: A significantly lower percentage of patients had confirmed disease progression at 3 months if treated with siponimod (26% vs. 32% with placebo; hazard ratio, 0.79; 95% confidence interval, 0.65–0.95; P = .013).
Study details: A double-blind, randomized, multicenter, placebo-controlled, phase 3 study of siponimod involving 1,651 patients with SPMS.
Disclosures: The EXPAND study was funded by Novartis. The lead author Dr. Kappos has received research and educational support funding via his institution from Novartis and multiple other pharmaceutical companies. Editorial author Dr. Metz has received grants from Roche and Biogen and personal fees from EMD Serono. The other editorial author, Dr. Liu, reported receiving personal fees from Novartis and personal fees and grants from EMD Serono. Dr. Liu was a back-up treating neurologist in the EXPAND trial.
Source: Kappos L et al. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30475-6, and Metz L and Liu W. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30426-4.
MRI finds PML in some natalizumab-treated patients despite negative CSF, no symptoms
Some multiple sclerosis patients who are treated with natalizumab can have small progressive multifocal leukoencephalopathy (PML) lesions seen on MRI yet have undetectable JC virus DNA in their cerebrospinal fluid, a cross-sectional, retrospective study has revealed.
The findings show that for some people with MS, PML diagnosis could be delayed if cerebrospinal fluid (CSF) sampling is negative and patients are asymptomatic, potentially resulting in worse functional outcomes and survival rates, according to the authors, led by Martijn T. Wijburg, MD, of the MS Center at VU University Medical Center in Amsterdam.
PML, a lytic infection of glial and neuronal cells by the JCV, can be diagnosed when a patient exhibits clinical symptoms, JC virus DNA is detected in CSF by PCR, and specific brain lesions are seen on MRI, according to a consensus statement from the Neuroinfectious Disease section of the American Academy of Neurology.
Dr. Wijburg and his coinvestigators reviewed data from Dutch and Belgian patients considered to have natalizumab (Tysabri)-associated PML during January 2007 and December 2014.
Patients were required to meet one of the following criteria:
• Definite or probable PML, based a positive PCR and MRI findings suggestive of PML, with or without PML symptoms.
• In the absence of a positive PCR, the presence of all four of the following features: high risk of PML development, such as positive anti-JCV serostatus and natalizumab treatment duration greater than 12 months; no MS disease activity prior to PML suspicion; MRI lesions highly suggestive of PML, with lesion characteristics as previously reported and absence of lesion characteristics suggestive of other diseases, as judged by an experienced neuroradiologist; and a lesion evolution on follow-up MRI scans suggestive of PML, including development of immune reconstitution inflammatory syndrome.
In the study of 56 patients (37 women), 9 patients (16.1%) had undetectable JCV DNA in CSF and 14 (25%) were asymptomatic for PML. At the time of PML diagnosis, the median age was 45 years, and the median natalizumab treatment duration was 43 months. Results showed that patients with a positive PCR had larger total PML lesion volumes than did those with undetectable JCV DNA (median volume, 22.9 mL vs. 6.7 mL; P = .008). Logistic regression showed that a lower PML lesion volume significantly increased the probability for undetectable JCV DNA.
The research team also observed a positive correlation between PML lesion volume and JCV copy numbers (Spearman’s rho, 0.32; P = .03). PML lesion volume was also higher in patients with PML symptoms and in patients with more widespread lesion dissemination. But no association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms.
The findings appear to show that patients with a smaller PML lesion volume were more likely to have a negative test result for JCV, which may lead to a delayed diagnosis of PML. Patients with smaller lesion volume were also more likely to be asymptomatic, which may further delay a diagnosis.
“This can result in a therapeutic dilemma. Unjustly excluding PML may have serious consequences (e.g., when switching from [natalizumab] to even more potent immunosuppressive treatments, such as alemtuzumab),” they wrote.
“In patients with [natalizumab-associated PML], both the probability for a positive CSF JCV PCR result and the JCV viral load are associated with the total PML lesion volume ... as a consequence, patients with smaller PML lesion volumes are more likely to have undetectable JCV DNA, and PML can thus not reliably be excluded based on a negative PCR,” they concluded.
They warned that strict pharmacovigilance by MRI “will lead to identification of smaller [PML] lesions that associate with a higher likelihood of negative polymerase chain reaction results, which hampers a formal diagnosis of [PML] and may complicate patient treatment.”
Meticulous clinical and MRI follow-up in combination with repeated CSF JCV PCR testing was warranted in these patients, the researchers advised.
They suggested that complementary PML diagnostic approaches, such as assessing intrathecal antibody synthesis to JCV by determining the CSF JCV antibody index, may also be of additional value.
“Furthermore, undetectable JCV DNA does not completely preclude the presence of JCV DNA. Further development and improvement of ultrasensitive PCR assays may improve the diagnostic accuracy in the future,” they added.
The study was supported by the Dutch Foundation for MS Research. Individual authors reported support for the research from the Charcot Foundation, the Hertie Foundation, and the National Institutes of Health. Several of the authors reported receiving consultancy fees from pharmaceutical companies.
SOURCE: Wijburg M et al. JAMA Neurol. 2018 Mar 12. doi: 10.1001/jamaneurol.2018.0094
Dr. Wijburg and colleagues raise an important point in our understanding of the development of PML by showing that small brain lesions may be present at what may be the start of JCV infection when the virus is still undetectable in CSF. However, it is not yet clear how well the relationship between viral load in CSF and MRI brain lesions approximates the stages of the disease and the processes with which it affects its target brain cells.
In some cases in which CSF testing is negative, repeat testing may be worthwhile because some patients have been known to test positive only weeks after testing negative.
Suspicion for PML may be increased when MRI shows signs of PML despite negative CSF testing, but it is to early to rely on MRI alone for diagnosis.
Eugene O. Major, PhD, is with the division of neuroimmunology and neurovirology at the National Institute of Neurological Disorders and Stroke, Bethesda, Md. He reported serving on the Progressive Multifocal Leukoencephalopathy Consortium Science advisory board and has received consulting fees while serving on independent adjudication committees for Takeda/Millennium, Roche/Genentech, and GlaxoSmithKline. He also has patent rights at the National Institutes of Health as coinventor of the Ultrasensitive Quantitative Polymerase Chain Reaction Multiplex assay for the detection of JC virus DNA–distinguishing viral variants. His comments are derived from an editorial accompanying Dr. Wijburg and colleagues’ report (JAMA Neurol. 2018 Mar 12. doi: 10.1001/jamaneurol.2018.0004).
Dr. Wijburg and colleagues raise an important point in our understanding of the development of PML by showing that small brain lesions may be present at what may be the start of JCV infection when the virus is still undetectable in CSF. However, it is not yet clear how well the relationship between viral load in CSF and MRI brain lesions approximates the stages of the disease and the processes with which it affects its target brain cells.
In some cases in which CSF testing is negative, repeat testing may be worthwhile because some patients have been known to test positive only weeks after testing negative.
Suspicion for PML may be increased when MRI shows signs of PML despite negative CSF testing, but it is to early to rely on MRI alone for diagnosis.
Eugene O. Major, PhD, is with the division of neuroimmunology and neurovirology at the National Institute of Neurological Disorders and Stroke, Bethesda, Md. He reported serving on the Progressive Multifocal Leukoencephalopathy Consortium Science advisory board and has received consulting fees while serving on independent adjudication committees for Takeda/Millennium, Roche/Genentech, and GlaxoSmithKline. He also has patent rights at the National Institutes of Health as coinventor of the Ultrasensitive Quantitative Polymerase Chain Reaction Multiplex assay for the detection of JC virus DNA–distinguishing viral variants. His comments are derived from an editorial accompanying Dr. Wijburg and colleagues’ report (JAMA Neurol. 2018 Mar 12. doi: 10.1001/jamaneurol.2018.0004).
Dr. Wijburg and colleagues raise an important point in our understanding of the development of PML by showing that small brain lesions may be present at what may be the start of JCV infection when the virus is still undetectable in CSF. However, it is not yet clear how well the relationship between viral load in CSF and MRI brain lesions approximates the stages of the disease and the processes with which it affects its target brain cells.
In some cases in which CSF testing is negative, repeat testing may be worthwhile because some patients have been known to test positive only weeks after testing negative.
Suspicion for PML may be increased when MRI shows signs of PML despite negative CSF testing, but it is to early to rely on MRI alone for diagnosis.
Eugene O. Major, PhD, is with the division of neuroimmunology and neurovirology at the National Institute of Neurological Disorders and Stroke, Bethesda, Md. He reported serving on the Progressive Multifocal Leukoencephalopathy Consortium Science advisory board and has received consulting fees while serving on independent adjudication committees for Takeda/Millennium, Roche/Genentech, and GlaxoSmithKline. He also has patent rights at the National Institutes of Health as coinventor of the Ultrasensitive Quantitative Polymerase Chain Reaction Multiplex assay for the detection of JC virus DNA–distinguishing viral variants. His comments are derived from an editorial accompanying Dr. Wijburg and colleagues’ report (JAMA Neurol. 2018 Mar 12. doi: 10.1001/jamaneurol.2018.0004).
Some multiple sclerosis patients who are treated with natalizumab can have small progressive multifocal leukoencephalopathy (PML) lesions seen on MRI yet have undetectable JC virus DNA in their cerebrospinal fluid, a cross-sectional, retrospective study has revealed.
The findings show that for some people with MS, PML diagnosis could be delayed if cerebrospinal fluid (CSF) sampling is negative and patients are asymptomatic, potentially resulting in worse functional outcomes and survival rates, according to the authors, led by Martijn T. Wijburg, MD, of the MS Center at VU University Medical Center in Amsterdam.
PML, a lytic infection of glial and neuronal cells by the JCV, can be diagnosed when a patient exhibits clinical symptoms, JC virus DNA is detected in CSF by PCR, and specific brain lesions are seen on MRI, according to a consensus statement from the Neuroinfectious Disease section of the American Academy of Neurology.
Dr. Wijburg and his coinvestigators reviewed data from Dutch and Belgian patients considered to have natalizumab (Tysabri)-associated PML during January 2007 and December 2014.
Patients were required to meet one of the following criteria:
• Definite or probable PML, based a positive PCR and MRI findings suggestive of PML, with or without PML symptoms.
• In the absence of a positive PCR, the presence of all four of the following features: high risk of PML development, such as positive anti-JCV serostatus and natalizumab treatment duration greater than 12 months; no MS disease activity prior to PML suspicion; MRI lesions highly suggestive of PML, with lesion characteristics as previously reported and absence of lesion characteristics suggestive of other diseases, as judged by an experienced neuroradiologist; and a lesion evolution on follow-up MRI scans suggestive of PML, including development of immune reconstitution inflammatory syndrome.
In the study of 56 patients (37 women), 9 patients (16.1%) had undetectable JCV DNA in CSF and 14 (25%) were asymptomatic for PML. At the time of PML diagnosis, the median age was 45 years, and the median natalizumab treatment duration was 43 months. Results showed that patients with a positive PCR had larger total PML lesion volumes than did those with undetectable JCV DNA (median volume, 22.9 mL vs. 6.7 mL; P = .008). Logistic regression showed that a lower PML lesion volume significantly increased the probability for undetectable JCV DNA.
The research team also observed a positive correlation between PML lesion volume and JCV copy numbers (Spearman’s rho, 0.32; P = .03). PML lesion volume was also higher in patients with PML symptoms and in patients with more widespread lesion dissemination. But no association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms.
The findings appear to show that patients with a smaller PML lesion volume were more likely to have a negative test result for JCV, which may lead to a delayed diagnosis of PML. Patients with smaller lesion volume were also more likely to be asymptomatic, which may further delay a diagnosis.
“This can result in a therapeutic dilemma. Unjustly excluding PML may have serious consequences (e.g., when switching from [natalizumab] to even more potent immunosuppressive treatments, such as alemtuzumab),” they wrote.
“In patients with [natalizumab-associated PML], both the probability for a positive CSF JCV PCR result and the JCV viral load are associated with the total PML lesion volume ... as a consequence, patients with smaller PML lesion volumes are more likely to have undetectable JCV DNA, and PML can thus not reliably be excluded based on a negative PCR,” they concluded.
They warned that strict pharmacovigilance by MRI “will lead to identification of smaller [PML] lesions that associate with a higher likelihood of negative polymerase chain reaction results, which hampers a formal diagnosis of [PML] and may complicate patient treatment.”
Meticulous clinical and MRI follow-up in combination with repeated CSF JCV PCR testing was warranted in these patients, the researchers advised.
They suggested that complementary PML diagnostic approaches, such as assessing intrathecal antibody synthesis to JCV by determining the CSF JCV antibody index, may also be of additional value.
“Furthermore, undetectable JCV DNA does not completely preclude the presence of JCV DNA. Further development and improvement of ultrasensitive PCR assays may improve the diagnostic accuracy in the future,” they added.
The study was supported by the Dutch Foundation for MS Research. Individual authors reported support for the research from the Charcot Foundation, the Hertie Foundation, and the National Institutes of Health. Several of the authors reported receiving consultancy fees from pharmaceutical companies.
SOURCE: Wijburg M et al. JAMA Neurol. 2018 Mar 12. doi: 10.1001/jamaneurol.2018.0094
Some multiple sclerosis patients who are treated with natalizumab can have small progressive multifocal leukoencephalopathy (PML) lesions seen on MRI yet have undetectable JC virus DNA in their cerebrospinal fluid, a cross-sectional, retrospective study has revealed.
The findings show that for some people with MS, PML diagnosis could be delayed if cerebrospinal fluid (CSF) sampling is negative and patients are asymptomatic, potentially resulting in worse functional outcomes and survival rates, according to the authors, led by Martijn T. Wijburg, MD, of the MS Center at VU University Medical Center in Amsterdam.
PML, a lytic infection of glial and neuronal cells by the JCV, can be diagnosed when a patient exhibits clinical symptoms, JC virus DNA is detected in CSF by PCR, and specific brain lesions are seen on MRI, according to a consensus statement from the Neuroinfectious Disease section of the American Academy of Neurology.
Dr. Wijburg and his coinvestigators reviewed data from Dutch and Belgian patients considered to have natalizumab (Tysabri)-associated PML during January 2007 and December 2014.
Patients were required to meet one of the following criteria:
• Definite or probable PML, based a positive PCR and MRI findings suggestive of PML, with or without PML symptoms.
• In the absence of a positive PCR, the presence of all four of the following features: high risk of PML development, such as positive anti-JCV serostatus and natalizumab treatment duration greater than 12 months; no MS disease activity prior to PML suspicion; MRI lesions highly suggestive of PML, with lesion characteristics as previously reported and absence of lesion characteristics suggestive of other diseases, as judged by an experienced neuroradiologist; and a lesion evolution on follow-up MRI scans suggestive of PML, including development of immune reconstitution inflammatory syndrome.
In the study of 56 patients (37 women), 9 patients (16.1%) had undetectable JCV DNA in CSF and 14 (25%) were asymptomatic for PML. At the time of PML diagnosis, the median age was 45 years, and the median natalizumab treatment duration was 43 months. Results showed that patients with a positive PCR had larger total PML lesion volumes than did those with undetectable JCV DNA (median volume, 22.9 mL vs. 6.7 mL; P = .008). Logistic regression showed that a lower PML lesion volume significantly increased the probability for undetectable JCV DNA.
The research team also observed a positive correlation between PML lesion volume and JCV copy numbers (Spearman’s rho, 0.32; P = .03). PML lesion volume was also higher in patients with PML symptoms and in patients with more widespread lesion dissemination. But no association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms.
The findings appear to show that patients with a smaller PML lesion volume were more likely to have a negative test result for JCV, which may lead to a delayed diagnosis of PML. Patients with smaller lesion volume were also more likely to be asymptomatic, which may further delay a diagnosis.
“This can result in a therapeutic dilemma. Unjustly excluding PML may have serious consequences (e.g., when switching from [natalizumab] to even more potent immunosuppressive treatments, such as alemtuzumab),” they wrote.
“In patients with [natalizumab-associated PML], both the probability for a positive CSF JCV PCR result and the JCV viral load are associated with the total PML lesion volume ... as a consequence, patients with smaller PML lesion volumes are more likely to have undetectable JCV DNA, and PML can thus not reliably be excluded based on a negative PCR,” they concluded.
They warned that strict pharmacovigilance by MRI “will lead to identification of smaller [PML] lesions that associate with a higher likelihood of negative polymerase chain reaction results, which hampers a formal diagnosis of [PML] and may complicate patient treatment.”
Meticulous clinical and MRI follow-up in combination with repeated CSF JCV PCR testing was warranted in these patients, the researchers advised.
They suggested that complementary PML diagnostic approaches, such as assessing intrathecal antibody synthesis to JCV by determining the CSF JCV antibody index, may also be of additional value.
“Furthermore, undetectable JCV DNA does not completely preclude the presence of JCV DNA. Further development and improvement of ultrasensitive PCR assays may improve the diagnostic accuracy in the future,” they added.
The study was supported by the Dutch Foundation for MS Research. Individual authors reported support for the research from the Charcot Foundation, the Hertie Foundation, and the National Institutes of Health. Several of the authors reported receiving consultancy fees from pharmaceutical companies.
SOURCE: Wijburg M et al. JAMA Neurol. 2018 Mar 12. doi: 10.1001/jamaneurol.2018.0094
FROM JAMA NEUROLOGY
Key clinical point: Meticulous clinical and MRI follow-up in combination with repeated CSF JCV PCR testing may be warranted in natalizumab-treated MS patients with small progressive multifocal leukoencephalopathy (PML) lesions seen on MRI but with undetectable JC virus DNA in their cerebrospinal fluid.
Major finding: of PML.
Study details: Retrospective cross-sectional study of 56 patients with natalizumab-associated PML.
Disclosures: The Dutch Foundation for MS Research supported the study. Individual authors reported support for the research from the Charcot Foundation, the Hertie Foundation, and the National Institutes of Health. Several of the authors reported receiving consultancy fees from pharmaceutical companies.
Source: Wijburg M et al. JAMA Neurol. 2018 Mar 12. doi: 10.1001/jamaneurol.2018.0094.
The case for being open-minded about medical marijuana
LAS VEGAS – Even if you do not believe in medical cannabis, be open to patients who ask you if it might benefit them, Kevin P. Hill, MD, advised.
“Being willing to talk to your patient about it is important,” said Dr. Hill, of the division of addiction psychiatry at Beth Israel Deaconess Medical Center, Boston, said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “Because what will happen is, they’ll say, ‘Look. I need medical marijuana to treat my anxiety.’ Then you can say, ‘Well, I have treatments that work for anxiety that we haven’t tried.’ Maybe you can get them into treatment because of that conversation.”
In his opinion, the appropriate candidate for medical cannabis is someone with a debilitating condition who has failed multiple first- and second-line treatments. “,” he noted. “It’s not a good place to be, but now the question becomes: How do we give people what they want while addressing the risks? I think we need to do a better job of that. We can provide a service to patients and colleagues by being informed and thoughtful on the topic.”
Food and Drug Administration–approved cannabinoids to date are dronabinol (Marinol) and nabilone (Cesamet). These agents are approved for nausea and vomiting associated with chemotherapy and for appetite stimulation in wasting illnesses such as AIDS. “Your patients may come to you and say, ‘I think I need medical cannabis for condition X,’ ” said Dr. Hill, who authored the book “Marijuana: The Unbiased Truth About the World’s Most Popular Weed” (Center City, Minn.: Hazelden Publishing, 2015). “Maybe the cannabis plant can outperform the two approved agents that we have. I think we have to be open to that possibility. Maybe they offer some things that dronabinol and nabilone don’t.”
Medical indications for cannabis in various states include 53 conditions, he said, such as cancer, glaucoma, AIDS, hepatitis C, amyotrophic lateral sclerosis, Crohn’s disease, Parkinson’s disease, and multiple sclerosis. However, data suggest that most people with medical cannabis cards do not have one of those conditions. More than 50 trials of cannabinoids, including cannabis, have been conducted, “and we definitely need a lot more,” Dr. Hill continued. “About half of the studies show positive effects for chronic pain, neuropathic pain, and spasticity associated with MS.”
Resources Dr. Hill recommended for clinicians include a review that he published in JAMA (2015;313[24]:2474-83), and a review of cannabis and pain that he coauthored that was published in the journal Cannabis and Cannabinoid Research (2017;2[1]:96-104), and a free downloadable publication from he National Academies Press entitled “Health Effects of Cannabis and Cannabinoid Research: The Current State of Evidence and Recommendations for Research.” One passage from that document reads as follows: “Despite the extensive changes in policy at the state level and the rapid rise in the use of cannabis both for medical purposes and for recreational use, conclusive evidence regarding the short- and long-term health effects (harms and benefits) of cannabis use remains elusive. A lack of scientific research has resulted in a lack of information on the health implications of cannabis use, which is a significant public health concern for vulnerable populations such as pregnant women and adolescents. Unlike other substances whose use may confer risk, such as alcohol or tobacco, no accepted standards exist to help guide individuals as they make choices regarding the issues of if, when, where, and how to use cannabis safely and, in regard to therapeutic uses, effectively.”
Dr. Hill disclosed that he has received research grants from National Institute on Drug Abuse, the Brain and Behavior Research Foundation, the American Lung Association, the Greater Boston Council on Alcoholism, and the Peter G. Dodge Foundation. He also receives book royalties from Hazelden Publishing.
dbrunk@frontlinemedcom.com
LAS VEGAS – Even if you do not believe in medical cannabis, be open to patients who ask you if it might benefit them, Kevin P. Hill, MD, advised.
“Being willing to talk to your patient about it is important,” said Dr. Hill, of the division of addiction psychiatry at Beth Israel Deaconess Medical Center, Boston, said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “Because what will happen is, they’ll say, ‘Look. I need medical marijuana to treat my anxiety.’ Then you can say, ‘Well, I have treatments that work for anxiety that we haven’t tried.’ Maybe you can get them into treatment because of that conversation.”
In his opinion, the appropriate candidate for medical cannabis is someone with a debilitating condition who has failed multiple first- and second-line treatments. “,” he noted. “It’s not a good place to be, but now the question becomes: How do we give people what they want while addressing the risks? I think we need to do a better job of that. We can provide a service to patients and colleagues by being informed and thoughtful on the topic.”
Food and Drug Administration–approved cannabinoids to date are dronabinol (Marinol) and nabilone (Cesamet). These agents are approved for nausea and vomiting associated with chemotherapy and for appetite stimulation in wasting illnesses such as AIDS. “Your patients may come to you and say, ‘I think I need medical cannabis for condition X,’ ” said Dr. Hill, who authored the book “Marijuana: The Unbiased Truth About the World’s Most Popular Weed” (Center City, Minn.: Hazelden Publishing, 2015). “Maybe the cannabis plant can outperform the two approved agents that we have. I think we have to be open to that possibility. Maybe they offer some things that dronabinol and nabilone don’t.”
Medical indications for cannabis in various states include 53 conditions, he said, such as cancer, glaucoma, AIDS, hepatitis C, amyotrophic lateral sclerosis, Crohn’s disease, Parkinson’s disease, and multiple sclerosis. However, data suggest that most people with medical cannabis cards do not have one of those conditions. More than 50 trials of cannabinoids, including cannabis, have been conducted, “and we definitely need a lot more,” Dr. Hill continued. “About half of the studies show positive effects for chronic pain, neuropathic pain, and spasticity associated with MS.”
Resources Dr. Hill recommended for clinicians include a review that he published in JAMA (2015;313[24]:2474-83), and a review of cannabis and pain that he coauthored that was published in the journal Cannabis and Cannabinoid Research (2017;2[1]:96-104), and a free downloadable publication from he National Academies Press entitled “Health Effects of Cannabis and Cannabinoid Research: The Current State of Evidence and Recommendations for Research.” One passage from that document reads as follows: “Despite the extensive changes in policy at the state level and the rapid rise in the use of cannabis both for medical purposes and for recreational use, conclusive evidence regarding the short- and long-term health effects (harms and benefits) of cannabis use remains elusive. A lack of scientific research has resulted in a lack of information on the health implications of cannabis use, which is a significant public health concern for vulnerable populations such as pregnant women and adolescents. Unlike other substances whose use may confer risk, such as alcohol or tobacco, no accepted standards exist to help guide individuals as they make choices regarding the issues of if, when, where, and how to use cannabis safely and, in regard to therapeutic uses, effectively.”
Dr. Hill disclosed that he has received research grants from National Institute on Drug Abuse, the Brain and Behavior Research Foundation, the American Lung Association, the Greater Boston Council on Alcoholism, and the Peter G. Dodge Foundation. He also receives book royalties from Hazelden Publishing.
dbrunk@frontlinemedcom.com
LAS VEGAS – Even if you do not believe in medical cannabis, be open to patients who ask you if it might benefit them, Kevin P. Hill, MD, advised.
“Being willing to talk to your patient about it is important,” said Dr. Hill, of the division of addiction psychiatry at Beth Israel Deaconess Medical Center, Boston, said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “Because what will happen is, they’ll say, ‘Look. I need medical marijuana to treat my anxiety.’ Then you can say, ‘Well, I have treatments that work for anxiety that we haven’t tried.’ Maybe you can get them into treatment because of that conversation.”
In his opinion, the appropriate candidate for medical cannabis is someone with a debilitating condition who has failed multiple first- and second-line treatments. “,” he noted. “It’s not a good place to be, but now the question becomes: How do we give people what they want while addressing the risks? I think we need to do a better job of that. We can provide a service to patients and colleagues by being informed and thoughtful on the topic.”
Food and Drug Administration–approved cannabinoids to date are dronabinol (Marinol) and nabilone (Cesamet). These agents are approved for nausea and vomiting associated with chemotherapy and for appetite stimulation in wasting illnesses such as AIDS. “Your patients may come to you and say, ‘I think I need medical cannabis for condition X,’ ” said Dr. Hill, who authored the book “Marijuana: The Unbiased Truth About the World’s Most Popular Weed” (Center City, Minn.: Hazelden Publishing, 2015). “Maybe the cannabis plant can outperform the two approved agents that we have. I think we have to be open to that possibility. Maybe they offer some things that dronabinol and nabilone don’t.”
Medical indications for cannabis in various states include 53 conditions, he said, such as cancer, glaucoma, AIDS, hepatitis C, amyotrophic lateral sclerosis, Crohn’s disease, Parkinson’s disease, and multiple sclerosis. However, data suggest that most people with medical cannabis cards do not have one of those conditions. More than 50 trials of cannabinoids, including cannabis, have been conducted, “and we definitely need a lot more,” Dr. Hill continued. “About half of the studies show positive effects for chronic pain, neuropathic pain, and spasticity associated with MS.”
Resources Dr. Hill recommended for clinicians include a review that he published in JAMA (2015;313[24]:2474-83), and a review of cannabis and pain that he coauthored that was published in the journal Cannabis and Cannabinoid Research (2017;2[1]:96-104), and a free downloadable publication from he National Academies Press entitled “Health Effects of Cannabis and Cannabinoid Research: The Current State of Evidence and Recommendations for Research.” One passage from that document reads as follows: “Despite the extensive changes in policy at the state level and the rapid rise in the use of cannabis both for medical purposes and for recreational use, conclusive evidence regarding the short- and long-term health effects (harms and benefits) of cannabis use remains elusive. A lack of scientific research has resulted in a lack of information on the health implications of cannabis use, which is a significant public health concern for vulnerable populations such as pregnant women and adolescents. Unlike other substances whose use may confer risk, such as alcohol or tobacco, no accepted standards exist to help guide individuals as they make choices regarding the issues of if, when, where, and how to use cannabis safely and, in regard to therapeutic uses, effectively.”
Dr. Hill disclosed that he has received research grants from National Institute on Drug Abuse, the Brain and Behavior Research Foundation, the American Lung Association, the Greater Boston Council on Alcoholism, and the Peter G. Dodge Foundation. He also receives book royalties from Hazelden Publishing.
dbrunk@frontlinemedcom.com
REPORTING FROM NPA 2018
MS Medication Withdrawn Because of Safety Concerns
Citing concerns about safety, Biogen and AbbVie announced March 2 that they will be withdrawing daclizumab (Zinbryta) from worldwide markets. Daclizumab has known risks, so it was usually prescribed only for people with relapsing multiple sclerosis who had tried two or more other medications that hadn’t worked well enough.
Reports of inflammatory encephalitis and meningoencephalitis led the European Medicines Agency to initiate an Article 20 referral procedure. In such referrals, a medicine or class of medicines are scientifically assessed because of concerns over safety or quality.
However, Biogen and AbbVie concluded that, because of the complex nature of these reports and how few patients were taking daclizumab, it would be difficult to characterize the nature of the medication’s harms and benefits, so the companies instead have decided to withdraw the medication from the market.
Patients taking daclizumab should contact their health care providers. More information can be found in the press release.
—Christopher Palmer
Citing concerns about safety, Biogen and AbbVie announced March 2 that they will be withdrawing daclizumab (Zinbryta) from worldwide markets. Daclizumab has known risks, so it was usually prescribed only for people with relapsing multiple sclerosis who had tried two or more other medications that hadn’t worked well enough.
Reports of inflammatory encephalitis and meningoencephalitis led the European Medicines Agency to initiate an Article 20 referral procedure. In such referrals, a medicine or class of medicines are scientifically assessed because of concerns over safety or quality.
However, Biogen and AbbVie concluded that, because of the complex nature of these reports and how few patients were taking daclizumab, it would be difficult to characterize the nature of the medication’s harms and benefits, so the companies instead have decided to withdraw the medication from the market.
Patients taking daclizumab should contact their health care providers. More information can be found in the press release.
—Christopher Palmer
Citing concerns about safety, Biogen and AbbVie announced March 2 that they will be withdrawing daclizumab (Zinbryta) from worldwide markets. Daclizumab has known risks, so it was usually prescribed only for people with relapsing multiple sclerosis who had tried two or more other medications that hadn’t worked well enough.
Reports of inflammatory encephalitis and meningoencephalitis led the European Medicines Agency to initiate an Article 20 referral procedure. In such referrals, a medicine or class of medicines are scientifically assessed because of concerns over safety or quality.
However, Biogen and AbbVie concluded that, because of the complex nature of these reports and how few patients were taking daclizumab, it would be difficult to characterize the nature of the medication’s harms and benefits, so the companies instead have decided to withdraw the medication from the market.
Patients taking daclizumab should contact their health care providers. More information can be found in the press release.
—Christopher Palmer
Alemtuzumab-induced autoimmunity: getting closer to answers
SAN DIEGO – The monoclonal antibody alemtuzumab can be an effective treatment for people living with multiple sclerosis, but there’s a catch — the agent is also associated with an increased risk for developing other autoimmune diseases, leaving clinicians with a conundrum.
“This is an efficacious treatment in multiple sclerosis” that can slow the rate of brain atrophy over the long-term, Alasdair Coles, MD, said at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “But 1 or 2 years after each cycle of alemtuzumab [Lemtrada], patients are at very high risk of autoimmune diseases. This is the not-too-worrying thyroid disease, but there are some very troubling and potentially highly threatening complications at lower frequency.”
Subsequent autoimmune thyroid disease can affect up to 40% of patients treated with alemtuzumab, but immune thrombocytopenia (3%) and autoimmune renal disease (0.1%) are also reported. About 1 in 10 people treated with the monoclonal antibody for MS can also develop de novo asymptomatic autoantibodies (10%).
“People ask: ‘Why doesn’t MS come back as part of this generic mechanism?’ and I don’t know the answer to that,” Dr. Coles said.
In the United States, alemtuzumab is indicated for treatment of relapsing multiple sclerosis in adults who have failed to respond adequately to two or more previous therapies. In contrast, “this has become a first-line treatment in the U.K.,” said Dr. Coles, a professor in the department of clinical neurosciences at the University of Cambridge (England).
“Unfortunately, we can offer no proven treatment to prevent this autoimmunity.”
Considering the prospects for different proposed mechanisms
Dr. Coles shared some encouraging news at ACTRIMS Forum 2018. His team and other researchers are getting closer to understanding the cellular mechanism underlying the paradoxical autoimmunity associated with alemtuzumab. Published reports in the literature from others suggest faulty immune B cells could be the culprit, pointing to a similar reconstitution of B cells after bone marrow transplantation. However, he said, “There is no difference in this reconstitution pattern between those who do and don’t get autoimmunity. So we do not think that autoimmunity after alemtuzumab is primarily a B cell problem.”
Other investigators have pointed to possible depletion of a key immune regulatory cell associated with alemtuzumab, such as alterations in CD52-positive T cells that cause depletion in T cells as part of an autoimmune cascade that involve CD52-high expressing cells and sialic acid-binding immunoglobulin-like lectin 10. “I’m not going to describe why we don’t believe any of this,” Dr. Coles said, but added, “We cannot replicate the data in type 1 diabetes or MS about the depletion of T cells.”
Along with his colleague Joanne Jones, PhD, a clinical fellow in the same department at the University of Cambridge, Dr. Coles and his team instead propose that autoimmunity after alemtuzumab therapy is associated with a homeostatic proliferation of T cells in the context of a defective thymus. “We see thymic function reduced after alemtuzumab for a few months. We don’t know if alemtuzumab is having a direct impact on the thymus or if it’s an indirect effect though a cytokine storm at the time of administering alemtuzumab.”
In addition, in contrast to B cells, both CD4-positive and CD8-positive T cells are clonally restricted after alemtuzumab treatment, Dr. Coles explained.
“These are the only changes that distinguish patients who do and do not develop autoimmunity,” he said. “Those who develop autoimmunity have reduced clonality and have impaired thymic function compared to those who don’t.”
As the theory goes, the limited clonal repertoire leads to expansion of the T cells, preferentially expanding autoreactive T cells, leading to B-cell- and antibody-mediated autoimmunity.
The bigger picture
The autoimmune phenomenon is not unique to alemtuzumab or multiple sclerosis. “This turns out to be one of a family of clinical situations where the reconstitution of the depleted lymphocyte repertoire leads to autoimmunity,” Dr. Coles said. A similar effect was seen years ago when very lymphopenic HIV patients were given antiviral therapy, he added, affecting about 10% of treated patients. About 10% of bone marrow transplant patients may experience similar autoimmune concerns.
“What we do think is true is we’ve tapped into a classical expression of autoimmunity,” Dr. Coles said. “Alemtuzumab is a fantastic opportunity to study the mechanisms underlying lymphopenia-associated autoimmunity.”
A ‘tantalizing prospect’
“It’s a tantalizing prospect that susceptible individuals might be identified in the future prior to treatment,” Dr. Coles said. One promising lead, he added, is “we also looked at IL-21. We showed that after treatment, and perhaps more interestingly, before treatment with alemtuzumab, serum IL-21 is greater in those who subsequently develop autoimmune disease. This suggests some individuals are prone to develop autoimmune disease, and could be identified potentially prior to treatment with alemtuzumab.”
More work is needed, including the development of more sensitive IL-21 assays for use in this population, Dr. Coles said. “Please do not attempt to predict the risk of autoimmunity after alemtuzumab using the current commercial assays. This is a source of some frustration for me.”
A potential route of lymphocyte repertoire reconstitution after alemtuzumab is thymic reconstitution, leading to a more diverse immune repertoire, Dr. Coles said. “The obvious corollary of this is if we can direct reconstitution through the thymic reconstitution, we should be able to prevent autoimmunity.”
Dr. Coles disclosed that he receives honoraria for travel and speaking from Sanofi Genzyme, which markets alemtuzumab.
SAN DIEGO – The monoclonal antibody alemtuzumab can be an effective treatment for people living with multiple sclerosis, but there’s a catch — the agent is also associated with an increased risk for developing other autoimmune diseases, leaving clinicians with a conundrum.
“This is an efficacious treatment in multiple sclerosis” that can slow the rate of brain atrophy over the long-term, Alasdair Coles, MD, said at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “But 1 or 2 years after each cycle of alemtuzumab [Lemtrada], patients are at very high risk of autoimmune diseases. This is the not-too-worrying thyroid disease, but there are some very troubling and potentially highly threatening complications at lower frequency.”
Subsequent autoimmune thyroid disease can affect up to 40% of patients treated with alemtuzumab, but immune thrombocytopenia (3%) and autoimmune renal disease (0.1%) are also reported. About 1 in 10 people treated with the monoclonal antibody for MS can also develop de novo asymptomatic autoantibodies (10%).
“People ask: ‘Why doesn’t MS come back as part of this generic mechanism?’ and I don’t know the answer to that,” Dr. Coles said.
In the United States, alemtuzumab is indicated for treatment of relapsing multiple sclerosis in adults who have failed to respond adequately to two or more previous therapies. In contrast, “this has become a first-line treatment in the U.K.,” said Dr. Coles, a professor in the department of clinical neurosciences at the University of Cambridge (England).
“Unfortunately, we can offer no proven treatment to prevent this autoimmunity.”
Considering the prospects for different proposed mechanisms
Dr. Coles shared some encouraging news at ACTRIMS Forum 2018. His team and other researchers are getting closer to understanding the cellular mechanism underlying the paradoxical autoimmunity associated with alemtuzumab. Published reports in the literature from others suggest faulty immune B cells could be the culprit, pointing to a similar reconstitution of B cells after bone marrow transplantation. However, he said, “There is no difference in this reconstitution pattern between those who do and don’t get autoimmunity. So we do not think that autoimmunity after alemtuzumab is primarily a B cell problem.”
Other investigators have pointed to possible depletion of a key immune regulatory cell associated with alemtuzumab, such as alterations in CD52-positive T cells that cause depletion in T cells as part of an autoimmune cascade that involve CD52-high expressing cells and sialic acid-binding immunoglobulin-like lectin 10. “I’m not going to describe why we don’t believe any of this,” Dr. Coles said, but added, “We cannot replicate the data in type 1 diabetes or MS about the depletion of T cells.”
Along with his colleague Joanne Jones, PhD, a clinical fellow in the same department at the University of Cambridge, Dr. Coles and his team instead propose that autoimmunity after alemtuzumab therapy is associated with a homeostatic proliferation of T cells in the context of a defective thymus. “We see thymic function reduced after alemtuzumab for a few months. We don’t know if alemtuzumab is having a direct impact on the thymus or if it’s an indirect effect though a cytokine storm at the time of administering alemtuzumab.”
In addition, in contrast to B cells, both CD4-positive and CD8-positive T cells are clonally restricted after alemtuzumab treatment, Dr. Coles explained.
“These are the only changes that distinguish patients who do and do not develop autoimmunity,” he said. “Those who develop autoimmunity have reduced clonality and have impaired thymic function compared to those who don’t.”
As the theory goes, the limited clonal repertoire leads to expansion of the T cells, preferentially expanding autoreactive T cells, leading to B-cell- and antibody-mediated autoimmunity.
The bigger picture
The autoimmune phenomenon is not unique to alemtuzumab or multiple sclerosis. “This turns out to be one of a family of clinical situations where the reconstitution of the depleted lymphocyte repertoire leads to autoimmunity,” Dr. Coles said. A similar effect was seen years ago when very lymphopenic HIV patients were given antiviral therapy, he added, affecting about 10% of treated patients. About 10% of bone marrow transplant patients may experience similar autoimmune concerns.
“What we do think is true is we’ve tapped into a classical expression of autoimmunity,” Dr. Coles said. “Alemtuzumab is a fantastic opportunity to study the mechanisms underlying lymphopenia-associated autoimmunity.”
A ‘tantalizing prospect’
“It’s a tantalizing prospect that susceptible individuals might be identified in the future prior to treatment,” Dr. Coles said. One promising lead, he added, is “we also looked at IL-21. We showed that after treatment, and perhaps more interestingly, before treatment with alemtuzumab, serum IL-21 is greater in those who subsequently develop autoimmune disease. This suggests some individuals are prone to develop autoimmune disease, and could be identified potentially prior to treatment with alemtuzumab.”
More work is needed, including the development of more sensitive IL-21 assays for use in this population, Dr. Coles said. “Please do not attempt to predict the risk of autoimmunity after alemtuzumab using the current commercial assays. This is a source of some frustration for me.”
A potential route of lymphocyte repertoire reconstitution after alemtuzumab is thymic reconstitution, leading to a more diverse immune repertoire, Dr. Coles said. “The obvious corollary of this is if we can direct reconstitution through the thymic reconstitution, we should be able to prevent autoimmunity.”
Dr. Coles disclosed that he receives honoraria for travel and speaking from Sanofi Genzyme, which markets alemtuzumab.
SAN DIEGO – The monoclonal antibody alemtuzumab can be an effective treatment for people living with multiple sclerosis, but there’s a catch — the agent is also associated with an increased risk for developing other autoimmune diseases, leaving clinicians with a conundrum.
“This is an efficacious treatment in multiple sclerosis” that can slow the rate of brain atrophy over the long-term, Alasdair Coles, MD, said at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “But 1 or 2 years after each cycle of alemtuzumab [Lemtrada], patients are at very high risk of autoimmune diseases. This is the not-too-worrying thyroid disease, but there are some very troubling and potentially highly threatening complications at lower frequency.”
Subsequent autoimmune thyroid disease can affect up to 40% of patients treated with alemtuzumab, but immune thrombocytopenia (3%) and autoimmune renal disease (0.1%) are also reported. About 1 in 10 people treated with the monoclonal antibody for MS can also develop de novo asymptomatic autoantibodies (10%).
“People ask: ‘Why doesn’t MS come back as part of this generic mechanism?’ and I don’t know the answer to that,” Dr. Coles said.
In the United States, alemtuzumab is indicated for treatment of relapsing multiple sclerosis in adults who have failed to respond adequately to two or more previous therapies. In contrast, “this has become a first-line treatment in the U.K.,” said Dr. Coles, a professor in the department of clinical neurosciences at the University of Cambridge (England).
“Unfortunately, we can offer no proven treatment to prevent this autoimmunity.”
Considering the prospects for different proposed mechanisms
Dr. Coles shared some encouraging news at ACTRIMS Forum 2018. His team and other researchers are getting closer to understanding the cellular mechanism underlying the paradoxical autoimmunity associated with alemtuzumab. Published reports in the literature from others suggest faulty immune B cells could be the culprit, pointing to a similar reconstitution of B cells after bone marrow transplantation. However, he said, “There is no difference in this reconstitution pattern between those who do and don’t get autoimmunity. So we do not think that autoimmunity after alemtuzumab is primarily a B cell problem.”
Other investigators have pointed to possible depletion of a key immune regulatory cell associated with alemtuzumab, such as alterations in CD52-positive T cells that cause depletion in T cells as part of an autoimmune cascade that involve CD52-high expressing cells and sialic acid-binding immunoglobulin-like lectin 10. “I’m not going to describe why we don’t believe any of this,” Dr. Coles said, but added, “We cannot replicate the data in type 1 diabetes or MS about the depletion of T cells.”
Along with his colleague Joanne Jones, PhD, a clinical fellow in the same department at the University of Cambridge, Dr. Coles and his team instead propose that autoimmunity after alemtuzumab therapy is associated with a homeostatic proliferation of T cells in the context of a defective thymus. “We see thymic function reduced after alemtuzumab for a few months. We don’t know if alemtuzumab is having a direct impact on the thymus or if it’s an indirect effect though a cytokine storm at the time of administering alemtuzumab.”
In addition, in contrast to B cells, both CD4-positive and CD8-positive T cells are clonally restricted after alemtuzumab treatment, Dr. Coles explained.
“These are the only changes that distinguish patients who do and do not develop autoimmunity,” he said. “Those who develop autoimmunity have reduced clonality and have impaired thymic function compared to those who don’t.”
As the theory goes, the limited clonal repertoire leads to expansion of the T cells, preferentially expanding autoreactive T cells, leading to B-cell- and antibody-mediated autoimmunity.
The bigger picture
The autoimmune phenomenon is not unique to alemtuzumab or multiple sclerosis. “This turns out to be one of a family of clinical situations where the reconstitution of the depleted lymphocyte repertoire leads to autoimmunity,” Dr. Coles said. A similar effect was seen years ago when very lymphopenic HIV patients were given antiviral therapy, he added, affecting about 10% of treated patients. About 10% of bone marrow transplant patients may experience similar autoimmune concerns.
“What we do think is true is we’ve tapped into a classical expression of autoimmunity,” Dr. Coles said. “Alemtuzumab is a fantastic opportunity to study the mechanisms underlying lymphopenia-associated autoimmunity.”
A ‘tantalizing prospect’
“It’s a tantalizing prospect that susceptible individuals might be identified in the future prior to treatment,” Dr. Coles said. One promising lead, he added, is “we also looked at IL-21. We showed that after treatment, and perhaps more interestingly, before treatment with alemtuzumab, serum IL-21 is greater in those who subsequently develop autoimmune disease. This suggests some individuals are prone to develop autoimmune disease, and could be identified potentially prior to treatment with alemtuzumab.”
More work is needed, including the development of more sensitive IL-21 assays for use in this population, Dr. Coles said. “Please do not attempt to predict the risk of autoimmunity after alemtuzumab using the current commercial assays. This is a source of some frustration for me.”
A potential route of lymphocyte repertoire reconstitution after alemtuzumab is thymic reconstitution, leading to a more diverse immune repertoire, Dr. Coles said. “The obvious corollary of this is if we can direct reconstitution through the thymic reconstitution, we should be able to prevent autoimmunity.”
Dr. Coles disclosed that he receives honoraria for travel and speaking from Sanofi Genzyme, which markets alemtuzumab.
EXPERT ANALYSIS FROM ACTRIMS FORUM 2018
MS medication withdrawn because of safety concerns
Citing concerns about safety, Biogen and AbbVie announced March 2 that they will be withdrawing daclizumab (Zinbryta) from worldwide markets. Daclizumab has known risks, so it was usually prescribed only for people with relapsing multiple sclerosis who had tried two or more other medications that hadn’t worked well enough.
Reports of inflammatory encephalitis and meningoencephalitis led the European Medicines Agency to initiate an Article 20 referral procedure. In such referrals, a medicine or class of medicines are scientifically assessed because of concerns over safety or quality.
However, Biogen and AbbVie concluded that, because of the complex nature of these reports and how few patients were taking daclizumab, it would be difficult to characterize the nature of the medication’s harms and benefits, so the companies instead have decided to withdraw the medication from the market.
On March 14, the Food and Drug Administration announced that it is conducting a review of similar adverse event reports it has received.
The drug will continue to be available to patients until April 30, 2018. Patients taking daclizumab should not stop taking the drug without talking to their doctor and should contact their doctor if they have any new or unexplained symptoms, the FDA said. More information can be found in the press release.
**Story updated 3/14/2018.
Citing concerns about safety, Biogen and AbbVie announced March 2 that they will be withdrawing daclizumab (Zinbryta) from worldwide markets. Daclizumab has known risks, so it was usually prescribed only for people with relapsing multiple sclerosis who had tried two or more other medications that hadn’t worked well enough.
Reports of inflammatory encephalitis and meningoencephalitis led the European Medicines Agency to initiate an Article 20 referral procedure. In such referrals, a medicine or class of medicines are scientifically assessed because of concerns over safety or quality.
However, Biogen and AbbVie concluded that, because of the complex nature of these reports and how few patients were taking daclizumab, it would be difficult to characterize the nature of the medication’s harms and benefits, so the companies instead have decided to withdraw the medication from the market.
On March 14, the Food and Drug Administration announced that it is conducting a review of similar adverse event reports it has received.
The drug will continue to be available to patients until April 30, 2018. Patients taking daclizumab should not stop taking the drug without talking to their doctor and should contact their doctor if they have any new or unexplained symptoms, the FDA said. More information can be found in the press release.
**Story updated 3/14/2018.
Citing concerns about safety, Biogen and AbbVie announced March 2 that they will be withdrawing daclizumab (Zinbryta) from worldwide markets. Daclizumab has known risks, so it was usually prescribed only for people with relapsing multiple sclerosis who had tried two or more other medications that hadn’t worked well enough.
Reports of inflammatory encephalitis and meningoencephalitis led the European Medicines Agency to initiate an Article 20 referral procedure. In such referrals, a medicine or class of medicines are scientifically assessed because of concerns over safety or quality.
However, Biogen and AbbVie concluded that, because of the complex nature of these reports and how few patients were taking daclizumab, it would be difficult to characterize the nature of the medication’s harms and benefits, so the companies instead have decided to withdraw the medication from the market.
On March 14, the Food and Drug Administration announced that it is conducting a review of similar adverse event reports it has received.
The drug will continue to be available to patients until April 30, 2018. Patients taking daclizumab should not stop taking the drug without talking to their doctor and should contact their doctor if they have any new or unexplained symptoms, the FDA said. More information can be found in the press release.
**Story updated 3/14/2018.
Does Vitamin D Level Affect Progressive MS?
SAN DIEGO—Vitamin D levels may be associated with brain imaging measures in patients with progressive multiple sclerosis (MS), according to an analysis presented at the ACTRIMS 2018 Forum. The association appears to be similar in primary progressive MS and secondary progressive MS and may reflect vitamin D’s protective effect on myelin in gray matter.
Research has identified vitamin D deficiency as a risk factor for MS. Low levels of the vitamin are associated with increased risk of brain lesions, relapses, and early progression of disability. Much of the literature focuses on relapsing-remitting MS. Less is known about the part that vitamin D plays in progressive MS, particularly with respect to clinical and imaging findings.
An Analysis of Phase II Data
Justin Abbatemarco, MD, a neurologist at Cleveland Clinic, and colleagues studied results from the phase II clinical trial of ibudilast to examine the association between vitamin D levels and clinical and MRI features in progressive MS. In the trial, investigators measured participants’ serum 25 OH vitamin D levels. At baseline, they collected demographic information such as age, gender, race, disease duration, duration of progression, prior treatment history, Expanded Disability Status Scale score, MS Functional Composite, and neurocognitive testing. Baseline MRI information included brain parenchymal fraction, diffusion tensor imaging (DTI), and magnetization transfer ratio (MTR).
Dr. Abbatemarco and colleagues used Spearman correlation to evaluate the associations between total vitamin D and vitamin D3 levels and clinical or imaging characteristics. They created a linear regression model to predict clinical and imaging outcome variables.
Vitamin D Was Associated With Whole Brain MTR
The analysis included 267 patients (47.2% male) with a mean age of 55.6. In all, 137 participants had primary progressive MS, and 130 participants had secondary progressive MS. Mean disease duration was 16.4 years. The population’s mean vitamin D3 level was 40.7 ng/mL, and mean total vitamin D level was 43.8 ng/mL. Mean brain parenchymal fraction was 0.8, mean T2 lesion volume was 10.3 mL, and mean whole brain MTR was 0.1.
The investigators did not observe a significant difference in mean vitamin D levels between patients with secondary progressive MS (44.7 ng/mL) and those with primary progressive MS (42.9 ng/mL). They did find positive associations between vitamin D3 and whole brain MTR, normal appearing brain tissue MTR, and normal appearing gray matter MTR. Dr. Abbatemarco’s group found no significant associations between vitamin D levels and brain parenchymal fraction, T1 or T2 lesion volume, or DTI metrics. The associations between vitamin D3 and MRI features were similar in patients with primary progressive MS and those with secondary progressive MS.
In a multivariate analysis that controlled for age, gender, disease duration, the time that vitamin D level was obtained, and latitude of study site, associations between vitamin D3 level and whole brain MTR remained significant. Every 10-ng/mL increase in vitamin D3 was associated with a 2.1% unit increase in whole brain MTR. The investigators found no association between vitamin D3 and brain parenchymal fraction, T2 lesion volume, T1 lesion volume, and clinical scores.
Dr. Abbatemarco and colleagues plan to test the effect of longitudinal changes on clinical and MRI measures once data become available.
—Erik Greb
Suggested Reading
Smolders J, Menheere P, Kessels A, et al. Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis. Mult Scler. 2008;14(9):1220-1224.
SAN DIEGO—Vitamin D levels may be associated with brain imaging measures in patients with progressive multiple sclerosis (MS), according to an analysis presented at the ACTRIMS 2018 Forum. The association appears to be similar in primary progressive MS and secondary progressive MS and may reflect vitamin D’s protective effect on myelin in gray matter.
Research has identified vitamin D deficiency as a risk factor for MS. Low levels of the vitamin are associated with increased risk of brain lesions, relapses, and early progression of disability. Much of the literature focuses on relapsing-remitting MS. Less is known about the part that vitamin D plays in progressive MS, particularly with respect to clinical and imaging findings.
An Analysis of Phase II Data
Justin Abbatemarco, MD, a neurologist at Cleveland Clinic, and colleagues studied results from the phase II clinical trial of ibudilast to examine the association between vitamin D levels and clinical and MRI features in progressive MS. In the trial, investigators measured participants’ serum 25 OH vitamin D levels. At baseline, they collected demographic information such as age, gender, race, disease duration, duration of progression, prior treatment history, Expanded Disability Status Scale score, MS Functional Composite, and neurocognitive testing. Baseline MRI information included brain parenchymal fraction, diffusion tensor imaging (DTI), and magnetization transfer ratio (MTR).
Dr. Abbatemarco and colleagues used Spearman correlation to evaluate the associations between total vitamin D and vitamin D3 levels and clinical or imaging characteristics. They created a linear regression model to predict clinical and imaging outcome variables.
Vitamin D Was Associated With Whole Brain MTR
The analysis included 267 patients (47.2% male) with a mean age of 55.6. In all, 137 participants had primary progressive MS, and 130 participants had secondary progressive MS. Mean disease duration was 16.4 years. The population’s mean vitamin D3 level was 40.7 ng/mL, and mean total vitamin D level was 43.8 ng/mL. Mean brain parenchymal fraction was 0.8, mean T2 lesion volume was 10.3 mL, and mean whole brain MTR was 0.1.
The investigators did not observe a significant difference in mean vitamin D levels between patients with secondary progressive MS (44.7 ng/mL) and those with primary progressive MS (42.9 ng/mL). They did find positive associations between vitamin D3 and whole brain MTR, normal appearing brain tissue MTR, and normal appearing gray matter MTR. Dr. Abbatemarco’s group found no significant associations between vitamin D levels and brain parenchymal fraction, T1 or T2 lesion volume, or DTI metrics. The associations between vitamin D3 and MRI features were similar in patients with primary progressive MS and those with secondary progressive MS.
In a multivariate analysis that controlled for age, gender, disease duration, the time that vitamin D level was obtained, and latitude of study site, associations between vitamin D3 level and whole brain MTR remained significant. Every 10-ng/mL increase in vitamin D3 was associated with a 2.1% unit increase in whole brain MTR. The investigators found no association between vitamin D3 and brain parenchymal fraction, T2 lesion volume, T1 lesion volume, and clinical scores.
Dr. Abbatemarco and colleagues plan to test the effect of longitudinal changes on clinical and MRI measures once data become available.
—Erik Greb
Suggested Reading
Smolders J, Menheere P, Kessels A, et al. Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis. Mult Scler. 2008;14(9):1220-1224.
SAN DIEGO—Vitamin D levels may be associated with brain imaging measures in patients with progressive multiple sclerosis (MS), according to an analysis presented at the ACTRIMS 2018 Forum. The association appears to be similar in primary progressive MS and secondary progressive MS and may reflect vitamin D’s protective effect on myelin in gray matter.
Research has identified vitamin D deficiency as a risk factor for MS. Low levels of the vitamin are associated with increased risk of brain lesions, relapses, and early progression of disability. Much of the literature focuses on relapsing-remitting MS. Less is known about the part that vitamin D plays in progressive MS, particularly with respect to clinical and imaging findings.
An Analysis of Phase II Data
Justin Abbatemarco, MD, a neurologist at Cleveland Clinic, and colleagues studied results from the phase II clinical trial of ibudilast to examine the association between vitamin D levels and clinical and MRI features in progressive MS. In the trial, investigators measured participants’ serum 25 OH vitamin D levels. At baseline, they collected demographic information such as age, gender, race, disease duration, duration of progression, prior treatment history, Expanded Disability Status Scale score, MS Functional Composite, and neurocognitive testing. Baseline MRI information included brain parenchymal fraction, diffusion tensor imaging (DTI), and magnetization transfer ratio (MTR).
Dr. Abbatemarco and colleagues used Spearman correlation to evaluate the associations between total vitamin D and vitamin D3 levels and clinical or imaging characteristics. They created a linear regression model to predict clinical and imaging outcome variables.
Vitamin D Was Associated With Whole Brain MTR
The analysis included 267 patients (47.2% male) with a mean age of 55.6. In all, 137 participants had primary progressive MS, and 130 participants had secondary progressive MS. Mean disease duration was 16.4 years. The population’s mean vitamin D3 level was 40.7 ng/mL, and mean total vitamin D level was 43.8 ng/mL. Mean brain parenchymal fraction was 0.8, mean T2 lesion volume was 10.3 mL, and mean whole brain MTR was 0.1.
The investigators did not observe a significant difference in mean vitamin D levels between patients with secondary progressive MS (44.7 ng/mL) and those with primary progressive MS (42.9 ng/mL). They did find positive associations between vitamin D3 and whole brain MTR, normal appearing brain tissue MTR, and normal appearing gray matter MTR. Dr. Abbatemarco’s group found no significant associations between vitamin D levels and brain parenchymal fraction, T1 or T2 lesion volume, or DTI metrics. The associations between vitamin D3 and MRI features were similar in patients with primary progressive MS and those with secondary progressive MS.
In a multivariate analysis that controlled for age, gender, disease duration, the time that vitamin D level was obtained, and latitude of study site, associations between vitamin D3 level and whole brain MTR remained significant. Every 10-ng/mL increase in vitamin D3 was associated with a 2.1% unit increase in whole brain MTR. The investigators found no association between vitamin D3 and brain parenchymal fraction, T2 lesion volume, T1 lesion volume, and clinical scores.
Dr. Abbatemarco and colleagues plan to test the effect of longitudinal changes on clinical and MRI measures once data become available.
—Erik Greb
Suggested Reading
Smolders J, Menheere P, Kessels A, et al. Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis. Mult Scler. 2008;14(9):1220-1224.