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New report highlights gaps in knowledge on marijuana use
A new report by the National Academies of Sciences, Engineering and Medicine shines a light on what the existing literature says about the perceived health benefits and dangers of using cannabis and cannabinoids.
“What little we know for certain about the effects of marijuana on human health — and all that we have reason to suspect — justifies serious national concern,” wrote the authors of the report, the evidence and research review of which was chaired by Marie McCormick, MD, of Harvard University in Boston. “The committee’s major recommendation called for an intensification and more comprehensive research effort into the effects of marijuana on the health of the American people.”
The authors concluded current literature shows substantial evidence stating that cannabis is effective at managing chronic pain in adults, while oral cannabinoid use is effective in mitigating nausea or vomiting induced by chemotherapy and improving patient-reported spasticity in patients with multiple sclerosis. Additionally, cannabinoids – specifically, nabiximols – are moderately effective in the short term for improving sleep disturbances brought on by obstructive sleep apnea syndrome, fibromyalgia, chronic pain, and multiple sclerosis.
However, there is limited evidence to support cannabis or cannabinoid use for reducing weight loss or inducing appetite in HIV/AIDS patients, improving clinician-measured spasicity or Tourette syndrome symptoms, reducing anxiety, improving symptoms brought on by post-traumatic stress, and improving outcomes in patients who have suffered traumatic brain injury or intracranial hemorrhage.
Additionally, there is no evidence to support the use of cannabis or cannabinoids in treating cancers or cancer-related anorexia, irritable bowel syndrome symptoms, epilepsy, spinal cord-related spasticity, symptoms of amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, schizophrenia, and dystonia.
“Present data on drug use progression neither support nor refute the suggestion that medical availability would increase drug abuse,” the authors noted. “However, this question is beyond the issues normally considered for medical uses of drugs and should not be a factor in evaluating the therapeutic potential of marijuana or cannabinoids.”
From a mental health standpoint, suicidal thoughts were found to be more likely in individuals who frequently used cannabis or cannabinoids. Symptoms like depression and anxiety are also more likely in those who smoke marijuana and have bipolar disorder. There is also “limited evidence of a statistical association between sustained abstinence from cannabis use [and] impairments in the cognitive domains of learning, memory, and attention.”
Among the other significant findings of the report, children who live in states where marijuana has been legalized are significantly more likely to ingest cannabis or cannabinoids; so far, marijuana use in some form – either recreational or medical – has been approved in 28 states and Washington, DC. Furthermore, adolescents who use marijuana are more likely to experience difficulties in social and educational development. And individuals of any age who smoke marijuana and drive are more likely to be involved in a car accident.
Also noteworthy is the lack of evidence pointing to marijuana use causing cancer. While chronic marijuana smoking was found to be linked to bronchitis, it was not found to cause cancers that are most commonly associated with chronic smoking of tobacco.
“This report highlights that there are critical gaps in our understanding of the health effects of cannabis,” explained John H. Krystal, MD, of Yale University in New Haven, Connecticut.
A reviewer of the report, Dr. Krystal elaborated on the gaps that exist in the current literature, saying “One reason for these gaps has been regulatory and practical challenges facing those who attempted to conduct this research. For example, what supply of cannabis should they use? Where, in the typical hospital settings where research is conducted, should patients participating in research be permitted to smoke cannabis? What standards should the institutional review committees employ when evaluating studies that involve the administration of cannabis or other cannabinoids?”
Ultimately, Dr. Krystal stated, “what should be evident from this summary is that only a few of the many publicized clinical applications for cannabis are adequately supported by acceptable research standards for determining safety or efficacy.” Specifically, states that have approved cannabis use for managing PTSD symptoms are doing so based off “meager” evidence, and in some cases, are circumventing FDA regulatory processes in a way. This could not only compromise patient care, but muddy the waters for physicians who want to treat their patients safely while also following legal avenues.
“Physicians may face a tension between their roles as physicians [and] their wish to provide a legal path for access to cannabinoids for their patients,” Dr. Krystal said, adding that “the endorsement of particular cannabis prescription practices by the states, even for clinical indications where cannabis has not been shown to be safe and effective, may create pressure for physicians to engage in ineffective or unsafe cannabis prescription practices.”
Ultimately, the report underlines areas of need in terms of understanding and effectively using cannabis and cannabinoid in treating patients. Calling the report a “call to arms” for those in the health care – and, specifically, the public health – arena, Dr. Krystal added that he hopes the findings of the report will be used for educating “legislators, physicians, and consumers [about the] potential benefits and risks of cannabis and thereby help to guide both legislation, clinical practice, and perhaps recreational use.”
A new report by the National Academies of Sciences, Engineering and Medicine shines a light on what the existing literature says about the perceived health benefits and dangers of using cannabis and cannabinoids.
“What little we know for certain about the effects of marijuana on human health — and all that we have reason to suspect — justifies serious national concern,” wrote the authors of the report, the evidence and research review of which was chaired by Marie McCormick, MD, of Harvard University in Boston. “The committee’s major recommendation called for an intensification and more comprehensive research effort into the effects of marijuana on the health of the American people.”
The authors concluded current literature shows substantial evidence stating that cannabis is effective at managing chronic pain in adults, while oral cannabinoid use is effective in mitigating nausea or vomiting induced by chemotherapy and improving patient-reported spasticity in patients with multiple sclerosis. Additionally, cannabinoids – specifically, nabiximols – are moderately effective in the short term for improving sleep disturbances brought on by obstructive sleep apnea syndrome, fibromyalgia, chronic pain, and multiple sclerosis.
However, there is limited evidence to support cannabis or cannabinoid use for reducing weight loss or inducing appetite in HIV/AIDS patients, improving clinician-measured spasicity or Tourette syndrome symptoms, reducing anxiety, improving symptoms brought on by post-traumatic stress, and improving outcomes in patients who have suffered traumatic brain injury or intracranial hemorrhage.
Additionally, there is no evidence to support the use of cannabis or cannabinoids in treating cancers or cancer-related anorexia, irritable bowel syndrome symptoms, epilepsy, spinal cord-related spasticity, symptoms of amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, schizophrenia, and dystonia.
“Present data on drug use progression neither support nor refute the suggestion that medical availability would increase drug abuse,” the authors noted. “However, this question is beyond the issues normally considered for medical uses of drugs and should not be a factor in evaluating the therapeutic potential of marijuana or cannabinoids.”
From a mental health standpoint, suicidal thoughts were found to be more likely in individuals who frequently used cannabis or cannabinoids. Symptoms like depression and anxiety are also more likely in those who smoke marijuana and have bipolar disorder. There is also “limited evidence of a statistical association between sustained abstinence from cannabis use [and] impairments in the cognitive domains of learning, memory, and attention.”
Among the other significant findings of the report, children who live in states where marijuana has been legalized are significantly more likely to ingest cannabis or cannabinoids; so far, marijuana use in some form – either recreational or medical – has been approved in 28 states and Washington, DC. Furthermore, adolescents who use marijuana are more likely to experience difficulties in social and educational development. And individuals of any age who smoke marijuana and drive are more likely to be involved in a car accident.
Also noteworthy is the lack of evidence pointing to marijuana use causing cancer. While chronic marijuana smoking was found to be linked to bronchitis, it was not found to cause cancers that are most commonly associated with chronic smoking of tobacco.
“This report highlights that there are critical gaps in our understanding of the health effects of cannabis,” explained John H. Krystal, MD, of Yale University in New Haven, Connecticut.
A reviewer of the report, Dr. Krystal elaborated on the gaps that exist in the current literature, saying “One reason for these gaps has been regulatory and practical challenges facing those who attempted to conduct this research. For example, what supply of cannabis should they use? Where, in the typical hospital settings where research is conducted, should patients participating in research be permitted to smoke cannabis? What standards should the institutional review committees employ when evaluating studies that involve the administration of cannabis or other cannabinoids?”
Ultimately, Dr. Krystal stated, “what should be evident from this summary is that only a few of the many publicized clinical applications for cannabis are adequately supported by acceptable research standards for determining safety or efficacy.” Specifically, states that have approved cannabis use for managing PTSD symptoms are doing so based off “meager” evidence, and in some cases, are circumventing FDA regulatory processes in a way. This could not only compromise patient care, but muddy the waters for physicians who want to treat their patients safely while also following legal avenues.
“Physicians may face a tension between their roles as physicians [and] their wish to provide a legal path for access to cannabinoids for their patients,” Dr. Krystal said, adding that “the endorsement of particular cannabis prescription practices by the states, even for clinical indications where cannabis has not been shown to be safe and effective, may create pressure for physicians to engage in ineffective or unsafe cannabis prescription practices.”
Ultimately, the report underlines areas of need in terms of understanding and effectively using cannabis and cannabinoid in treating patients. Calling the report a “call to arms” for those in the health care – and, specifically, the public health – arena, Dr. Krystal added that he hopes the findings of the report will be used for educating “legislators, physicians, and consumers [about the] potential benefits and risks of cannabis and thereby help to guide both legislation, clinical practice, and perhaps recreational use.”
A new report by the National Academies of Sciences, Engineering and Medicine shines a light on what the existing literature says about the perceived health benefits and dangers of using cannabis and cannabinoids.
“What little we know for certain about the effects of marijuana on human health — and all that we have reason to suspect — justifies serious national concern,” wrote the authors of the report, the evidence and research review of which was chaired by Marie McCormick, MD, of Harvard University in Boston. “The committee’s major recommendation called for an intensification and more comprehensive research effort into the effects of marijuana on the health of the American people.”
The authors concluded current literature shows substantial evidence stating that cannabis is effective at managing chronic pain in adults, while oral cannabinoid use is effective in mitigating nausea or vomiting induced by chemotherapy and improving patient-reported spasticity in patients with multiple sclerosis. Additionally, cannabinoids – specifically, nabiximols – are moderately effective in the short term for improving sleep disturbances brought on by obstructive sleep apnea syndrome, fibromyalgia, chronic pain, and multiple sclerosis.
However, there is limited evidence to support cannabis or cannabinoid use for reducing weight loss or inducing appetite in HIV/AIDS patients, improving clinician-measured spasicity or Tourette syndrome symptoms, reducing anxiety, improving symptoms brought on by post-traumatic stress, and improving outcomes in patients who have suffered traumatic brain injury or intracranial hemorrhage.
Additionally, there is no evidence to support the use of cannabis or cannabinoids in treating cancers or cancer-related anorexia, irritable bowel syndrome symptoms, epilepsy, spinal cord-related spasticity, symptoms of amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, schizophrenia, and dystonia.
“Present data on drug use progression neither support nor refute the suggestion that medical availability would increase drug abuse,” the authors noted. “However, this question is beyond the issues normally considered for medical uses of drugs and should not be a factor in evaluating the therapeutic potential of marijuana or cannabinoids.”
From a mental health standpoint, suicidal thoughts were found to be more likely in individuals who frequently used cannabis or cannabinoids. Symptoms like depression and anxiety are also more likely in those who smoke marijuana and have bipolar disorder. There is also “limited evidence of a statistical association between sustained abstinence from cannabis use [and] impairments in the cognitive domains of learning, memory, and attention.”
Among the other significant findings of the report, children who live in states where marijuana has been legalized are significantly more likely to ingest cannabis or cannabinoids; so far, marijuana use in some form – either recreational or medical – has been approved in 28 states and Washington, DC. Furthermore, adolescents who use marijuana are more likely to experience difficulties in social and educational development. And individuals of any age who smoke marijuana and drive are more likely to be involved in a car accident.
Also noteworthy is the lack of evidence pointing to marijuana use causing cancer. While chronic marijuana smoking was found to be linked to bronchitis, it was not found to cause cancers that are most commonly associated with chronic smoking of tobacco.
“This report highlights that there are critical gaps in our understanding of the health effects of cannabis,” explained John H. Krystal, MD, of Yale University in New Haven, Connecticut.
A reviewer of the report, Dr. Krystal elaborated on the gaps that exist in the current literature, saying “One reason for these gaps has been regulatory and practical challenges facing those who attempted to conduct this research. For example, what supply of cannabis should they use? Where, in the typical hospital settings where research is conducted, should patients participating in research be permitted to smoke cannabis? What standards should the institutional review committees employ when evaluating studies that involve the administration of cannabis or other cannabinoids?”
Ultimately, Dr. Krystal stated, “what should be evident from this summary is that only a few of the many publicized clinical applications for cannabis are adequately supported by acceptable research standards for determining safety or efficacy.” Specifically, states that have approved cannabis use for managing PTSD symptoms are doing so based off “meager” evidence, and in some cases, are circumventing FDA regulatory processes in a way. This could not only compromise patient care, but muddy the waters for physicians who want to treat their patients safely while also following legal avenues.
“Physicians may face a tension between their roles as physicians [and] their wish to provide a legal path for access to cannabinoids for their patients,” Dr. Krystal said, adding that “the endorsement of particular cannabis prescription practices by the states, even for clinical indications where cannabis has not been shown to be safe and effective, may create pressure for physicians to engage in ineffective or unsafe cannabis prescription practices.”
Ultimately, the report underlines areas of need in terms of understanding and effectively using cannabis and cannabinoid in treating patients. Calling the report a “call to arms” for those in the health care – and, specifically, the public health – arena, Dr. Krystal added that he hopes the findings of the report will be used for educating “legislators, physicians, and consumers [about the] potential benefits and risks of cannabis and thereby help to guide both legislation, clinical practice, and perhaps recreational use.”
FROM THE NATIONAL ACADEMIES OF SCIENCES, ENGINEERING AND MEDICINE
Switch from fingolimod to alemtuzumab might trigger MS relapse
Nine relapsing multiple sclerosis patients had significant and unexpected disease activity within 12 months of switching from fingolimod to alemtuzumab, according to a report from six European neuroscience centers.
The centers treated 174 patients with alemtuzumab (Lemtrada); 36 had been on fingolimod (Gilenya) beforehand. “Therefore, these nine patients ... represent 25% of the fingolimod-alemtuzumab cohort,” said investigators led by Mark Willis, MBBCh, a clinical research fellow at Cardiff University, Wales (Neurol Neuroimmunol Neuroinflamm. 2017 Jan 10. doi: 10.1212/NXI.0000000000000320).
“Careful consideration needs to be given to mode of action of individual therapies and sequential treatment effects,” the team concluded.
The nine patients were on fingolimod for 5-33 months, but it wasn’t working well so they were started on alemtuzumab following a median fingolimod washout period of 6 weeks. Eight patients had at least one clinical relapse within 12 months of the first alemtuzumab infusion cycle; the median time to relapse following alemtuzumab induction was 4.5 months. All nine patients had radiologic evidence of new disease activity.
Five patients had lymphocyte counts below normal when started on alemtuzumab.
Fingolimod has a half-life of 6-9 days, so “lymphocytes would be expected to normalize 2-4 weeks after discontinuation. However, there are case reports of prolonged lymphopenia following prolonged drug exposure, up to 37 months after discontinuation.” It has “been suggested that patients continue on an alternative [disease-modifying treatment] after fingolimod discontinuation, preferably until peripheral lymphocyte counts have normalized.” However, “there is currently no consensus as to which subsequent therapeutic agent is optimal,” the investigators said.
Despite the presence of disease activity in the first 12 months, all nine patients went on to the second planned infusion of alemtuzumab; eight were relapse free during a mean follow-up of 6 months after the second treatment cycle. Four of seven were radiologically stable, but three had new T2 lesions and one with a single new gadolinium-enhancing lesion.
Even so, the findings offers “some support to the hypothesis that, after a period, sequestrated lymphocytes eventually become available for depletion by alemtuzumab,” the researchers noted.
The mean age of the patients when diagnosed with MS was 21 years. The median disease duration to alemtuzumab treatment was 94 months.
There was no external funding. Dr. Willis had no disclosures. Other researchers reported ties to a number of companies, including Genzyme, maker of alemtuzumab, and Novartis, fingolimod’s maker.
Nine relapsing multiple sclerosis patients had significant and unexpected disease activity within 12 months of switching from fingolimod to alemtuzumab, according to a report from six European neuroscience centers.
The centers treated 174 patients with alemtuzumab (Lemtrada); 36 had been on fingolimod (Gilenya) beforehand. “Therefore, these nine patients ... represent 25% of the fingolimod-alemtuzumab cohort,” said investigators led by Mark Willis, MBBCh, a clinical research fellow at Cardiff University, Wales (Neurol Neuroimmunol Neuroinflamm. 2017 Jan 10. doi: 10.1212/NXI.0000000000000320).
“Careful consideration needs to be given to mode of action of individual therapies and sequential treatment effects,” the team concluded.
The nine patients were on fingolimod for 5-33 months, but it wasn’t working well so they were started on alemtuzumab following a median fingolimod washout period of 6 weeks. Eight patients had at least one clinical relapse within 12 months of the first alemtuzumab infusion cycle; the median time to relapse following alemtuzumab induction was 4.5 months. All nine patients had radiologic evidence of new disease activity.
Five patients had lymphocyte counts below normal when started on alemtuzumab.
Fingolimod has a half-life of 6-9 days, so “lymphocytes would be expected to normalize 2-4 weeks after discontinuation. However, there are case reports of prolonged lymphopenia following prolonged drug exposure, up to 37 months after discontinuation.” It has “been suggested that patients continue on an alternative [disease-modifying treatment] after fingolimod discontinuation, preferably until peripheral lymphocyte counts have normalized.” However, “there is currently no consensus as to which subsequent therapeutic agent is optimal,” the investigators said.
Despite the presence of disease activity in the first 12 months, all nine patients went on to the second planned infusion of alemtuzumab; eight were relapse free during a mean follow-up of 6 months after the second treatment cycle. Four of seven were radiologically stable, but three had new T2 lesions and one with a single new gadolinium-enhancing lesion.
Even so, the findings offers “some support to the hypothesis that, after a period, sequestrated lymphocytes eventually become available for depletion by alemtuzumab,” the researchers noted.
The mean age of the patients when diagnosed with MS was 21 years. The median disease duration to alemtuzumab treatment was 94 months.
There was no external funding. Dr. Willis had no disclosures. Other researchers reported ties to a number of companies, including Genzyme, maker of alemtuzumab, and Novartis, fingolimod’s maker.
Nine relapsing multiple sclerosis patients had significant and unexpected disease activity within 12 months of switching from fingolimod to alemtuzumab, according to a report from six European neuroscience centers.
The centers treated 174 patients with alemtuzumab (Lemtrada); 36 had been on fingolimod (Gilenya) beforehand. “Therefore, these nine patients ... represent 25% of the fingolimod-alemtuzumab cohort,” said investigators led by Mark Willis, MBBCh, a clinical research fellow at Cardiff University, Wales (Neurol Neuroimmunol Neuroinflamm. 2017 Jan 10. doi: 10.1212/NXI.0000000000000320).
“Careful consideration needs to be given to mode of action of individual therapies and sequential treatment effects,” the team concluded.
The nine patients were on fingolimod for 5-33 months, but it wasn’t working well so they were started on alemtuzumab following a median fingolimod washout period of 6 weeks. Eight patients had at least one clinical relapse within 12 months of the first alemtuzumab infusion cycle; the median time to relapse following alemtuzumab induction was 4.5 months. All nine patients had radiologic evidence of new disease activity.
Five patients had lymphocyte counts below normal when started on alemtuzumab.
Fingolimod has a half-life of 6-9 days, so “lymphocytes would be expected to normalize 2-4 weeks after discontinuation. However, there are case reports of prolonged lymphopenia following prolonged drug exposure, up to 37 months after discontinuation.” It has “been suggested that patients continue on an alternative [disease-modifying treatment] after fingolimod discontinuation, preferably until peripheral lymphocyte counts have normalized.” However, “there is currently no consensus as to which subsequent therapeutic agent is optimal,” the investigators said.
Despite the presence of disease activity in the first 12 months, all nine patients went on to the second planned infusion of alemtuzumab; eight were relapse free during a mean follow-up of 6 months after the second treatment cycle. Four of seven were radiologically stable, but three had new T2 lesions and one with a single new gadolinium-enhancing lesion.
Even so, the findings offers “some support to the hypothesis that, after a period, sequestrated lymphocytes eventually become available for depletion by alemtuzumab,” the researchers noted.
The mean age of the patients when diagnosed with MS was 21 years. The median disease duration to alemtuzumab treatment was 94 months.
There was no external funding. Dr. Willis had no disclosures. Other researchers reported ties to a number of companies, including Genzyme, maker of alemtuzumab, and Novartis, fingolimod’s maker.
FROM NEUROLOGY: NEUROIMMUNOLOGY AND NEUROINFLAMMATION
High-risk relatives of MS patients show early signs of disease
Asymptomatic first-degree relatives of multiple sclerosis patients at high risk for developing the disease were significantly more likely to show subclinical signs of MS than were family members at lower risk, in the Genes and Environment in Multiple Sclerosis prospective cohort study. The findings were published online on Jan. 17 in JAMA Neurology.
The Genes and Environment in Multiple Sclerosis (GEMS) project is the first prospective study of populations at risk for MS and is the first detailed cross-sectional examination of higher-risk and lower-risk family members to date, according to investigators led by Zongqi Xia, MD, PhD, of Brigham and Women’s Hospital, Boston. Although the totality of evidence put together through neuroimaging and numerous clinical tests in the study indicate that individuals with the highest risk for MS have higher risk for the disease than do those with the lowest risk, simple vibration threshold testing gave the best results, Dr. Xia and his colleagues reported.
The study involved 100 neurologically asymptomatic adults aged 18-50 years who were first-degree relatives of people with MS who participated in the GEMS project during August 2012 to July 2015. These 100 comprised 41 high-risk participants from the top 10% of a Genetic and Environmental Risk Score (GERS) and 59 low-risk participants from the bottom 10% on the GERS. The GERS included genetic risk factors (HLA alleles and several MS-associated non-HLA genetic variants) and environmental factors, such as smoking status, body mass index, history of infectious mononucleosis and migraine, and vitamin D levels.
However, because 40 of the 41 high-risk individuals were female and 25 of the 59 low-risk individuals were female, the investigators limited the study to the 65 female participants to avoid “attributing any potential difference primarily to the role of sex.”
To help in identifying early signs of MS, the researchers used brain MRI and optical coherence tomography and other measures of neurological function, including the Expanded Disability Status Scale, timed 25-foot walk, Nine-Hole Peg Test, Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Timed Up and Go, and high-contrast and low-contrast visual acuity (JAMA Neurol. 2017 Jan 17. doi: 10.1001/jamaneurol.2016.5056).
Overall, high-risk women showed more subclinical signs of MS than did low-risk women based on an omnibus test that globally assessed the burden of neurological dysfunction by comparing the overall differences between the two groups when considering all of the measured outcomes (P = .01). However, impaired vibration perception yielded a stronger result; of 47 women (27 high-risk and 20 low-risk) tested in this manner, high-risk women showed significantly reduced vibration perception in the distal lower extremities (P = .008).
One individual in the high-risk group converted to clinically definite MS during the study. Four of the high-risk women had T2-weighted hyperintense lesions that met the 2010 McDonald MRI criteria for dissemination in space, compared with one low-risk woman. The 2016 proposed consensus MRI criteria for MS diagnosis were met by two high-risk women and one low-risk woman. Radiological isolated syndrome occurred in one woman of each group, and there was a single foci of leptominengeal enhancement in three high-risk women and one low-risk woman.
The findings were limited by several factors including the small size, lack of male participants, cross-sectional nature of the study, and the fact that vibration sensitivity thresholds were in the normal range for high-risk and low-risk individuals. However, the researchers wrote that they “plan to confirm the finding of change in vibration sensitivity with a follow-up study,” and they noted that the “study highlights the important need to develop and test more sensitive measures, particularly with biometric devices, to detect subtle subclinical changes early in the disease process.”
The National Institutes of Health and the National Multiple Sclerosis Society supported the study. Some of the authors reported receiving awards from the National Multiple Sclerosis Society, the American Academy of Neurology, and the National Institute of Neurological Disorders and Stroke.
The GEMS study represents the most ambitious effort yet to identify presymptomatic individuals who are at increased risk for MS, and it is a valuable first step toward targeted screening. Even if we cannot yet intervene therapeutically using currently available disease-modifying treatments in presymptomatic stages of MS, the ability to better define high-risk individuals is likely to make active surveillance programs more cost effective. It also provides important information to counsel individuals about lifestyle changes, such as quitting smoking.
The GERS also can likely be further refined with more up-to-date data on the interaction between specific genetic and environmental factors.
Fredrik Piehl, MD, PhD, is a member of the department of neurology at the Karolinska Institutet and Karolinska University Hospital, Stockholm. His comments are derived from an editorial accompanying the report by Dr. Xia and colleagues (JAMA Neurol. 2017 Jan 17. doi: 10.1001/jamaneurol.2016.5126). He disclosed research support, travel grants, and other relationships with Biogen, Genzyme, Novartis, Merck, Roche, Serono, and Teva.
The GEMS study represents the most ambitious effort yet to identify presymptomatic individuals who are at increased risk for MS, and it is a valuable first step toward targeted screening. Even if we cannot yet intervene therapeutically using currently available disease-modifying treatments in presymptomatic stages of MS, the ability to better define high-risk individuals is likely to make active surveillance programs more cost effective. It also provides important information to counsel individuals about lifestyle changes, such as quitting smoking.
The GERS also can likely be further refined with more up-to-date data on the interaction between specific genetic and environmental factors.
Fredrik Piehl, MD, PhD, is a member of the department of neurology at the Karolinska Institutet and Karolinska University Hospital, Stockholm. His comments are derived from an editorial accompanying the report by Dr. Xia and colleagues (JAMA Neurol. 2017 Jan 17. doi: 10.1001/jamaneurol.2016.5126). He disclosed research support, travel grants, and other relationships with Biogen, Genzyme, Novartis, Merck, Roche, Serono, and Teva.
The GEMS study represents the most ambitious effort yet to identify presymptomatic individuals who are at increased risk for MS, and it is a valuable first step toward targeted screening. Even if we cannot yet intervene therapeutically using currently available disease-modifying treatments in presymptomatic stages of MS, the ability to better define high-risk individuals is likely to make active surveillance programs more cost effective. It also provides important information to counsel individuals about lifestyle changes, such as quitting smoking.
The GERS also can likely be further refined with more up-to-date data on the interaction between specific genetic and environmental factors.
Fredrik Piehl, MD, PhD, is a member of the department of neurology at the Karolinska Institutet and Karolinska University Hospital, Stockholm. His comments are derived from an editorial accompanying the report by Dr. Xia and colleagues (JAMA Neurol. 2017 Jan 17. doi: 10.1001/jamaneurol.2016.5126). He disclosed research support, travel grants, and other relationships with Biogen, Genzyme, Novartis, Merck, Roche, Serono, and Teva.
Asymptomatic first-degree relatives of multiple sclerosis patients at high risk for developing the disease were significantly more likely to show subclinical signs of MS than were family members at lower risk, in the Genes and Environment in Multiple Sclerosis prospective cohort study. The findings were published online on Jan. 17 in JAMA Neurology.
The Genes and Environment in Multiple Sclerosis (GEMS) project is the first prospective study of populations at risk for MS and is the first detailed cross-sectional examination of higher-risk and lower-risk family members to date, according to investigators led by Zongqi Xia, MD, PhD, of Brigham and Women’s Hospital, Boston. Although the totality of evidence put together through neuroimaging and numerous clinical tests in the study indicate that individuals with the highest risk for MS have higher risk for the disease than do those with the lowest risk, simple vibration threshold testing gave the best results, Dr. Xia and his colleagues reported.
The study involved 100 neurologically asymptomatic adults aged 18-50 years who were first-degree relatives of people with MS who participated in the GEMS project during August 2012 to July 2015. These 100 comprised 41 high-risk participants from the top 10% of a Genetic and Environmental Risk Score (GERS) and 59 low-risk participants from the bottom 10% on the GERS. The GERS included genetic risk factors (HLA alleles and several MS-associated non-HLA genetic variants) and environmental factors, such as smoking status, body mass index, history of infectious mononucleosis and migraine, and vitamin D levels.
However, because 40 of the 41 high-risk individuals were female and 25 of the 59 low-risk individuals were female, the investigators limited the study to the 65 female participants to avoid “attributing any potential difference primarily to the role of sex.”
To help in identifying early signs of MS, the researchers used brain MRI and optical coherence tomography and other measures of neurological function, including the Expanded Disability Status Scale, timed 25-foot walk, Nine-Hole Peg Test, Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Timed Up and Go, and high-contrast and low-contrast visual acuity (JAMA Neurol. 2017 Jan 17. doi: 10.1001/jamaneurol.2016.5056).
Overall, high-risk women showed more subclinical signs of MS than did low-risk women based on an omnibus test that globally assessed the burden of neurological dysfunction by comparing the overall differences between the two groups when considering all of the measured outcomes (P = .01). However, impaired vibration perception yielded a stronger result; of 47 women (27 high-risk and 20 low-risk) tested in this manner, high-risk women showed significantly reduced vibration perception in the distal lower extremities (P = .008).
One individual in the high-risk group converted to clinically definite MS during the study. Four of the high-risk women had T2-weighted hyperintense lesions that met the 2010 McDonald MRI criteria for dissemination in space, compared with one low-risk woman. The 2016 proposed consensus MRI criteria for MS diagnosis were met by two high-risk women and one low-risk woman. Radiological isolated syndrome occurred in one woman of each group, and there was a single foci of leptominengeal enhancement in three high-risk women and one low-risk woman.
The findings were limited by several factors including the small size, lack of male participants, cross-sectional nature of the study, and the fact that vibration sensitivity thresholds were in the normal range for high-risk and low-risk individuals. However, the researchers wrote that they “plan to confirm the finding of change in vibration sensitivity with a follow-up study,” and they noted that the “study highlights the important need to develop and test more sensitive measures, particularly with biometric devices, to detect subtle subclinical changes early in the disease process.”
The National Institutes of Health and the National Multiple Sclerosis Society supported the study. Some of the authors reported receiving awards from the National Multiple Sclerosis Society, the American Academy of Neurology, and the National Institute of Neurological Disorders and Stroke.
Asymptomatic first-degree relatives of multiple sclerosis patients at high risk for developing the disease were significantly more likely to show subclinical signs of MS than were family members at lower risk, in the Genes and Environment in Multiple Sclerosis prospective cohort study. The findings were published online on Jan. 17 in JAMA Neurology.
The Genes and Environment in Multiple Sclerosis (GEMS) project is the first prospective study of populations at risk for MS and is the first detailed cross-sectional examination of higher-risk and lower-risk family members to date, according to investigators led by Zongqi Xia, MD, PhD, of Brigham and Women’s Hospital, Boston. Although the totality of evidence put together through neuroimaging and numerous clinical tests in the study indicate that individuals with the highest risk for MS have higher risk for the disease than do those with the lowest risk, simple vibration threshold testing gave the best results, Dr. Xia and his colleagues reported.
The study involved 100 neurologically asymptomatic adults aged 18-50 years who were first-degree relatives of people with MS who participated in the GEMS project during August 2012 to July 2015. These 100 comprised 41 high-risk participants from the top 10% of a Genetic and Environmental Risk Score (GERS) and 59 low-risk participants from the bottom 10% on the GERS. The GERS included genetic risk factors (HLA alleles and several MS-associated non-HLA genetic variants) and environmental factors, such as smoking status, body mass index, history of infectious mononucleosis and migraine, and vitamin D levels.
However, because 40 of the 41 high-risk individuals were female and 25 of the 59 low-risk individuals were female, the investigators limited the study to the 65 female participants to avoid “attributing any potential difference primarily to the role of sex.”
To help in identifying early signs of MS, the researchers used brain MRI and optical coherence tomography and other measures of neurological function, including the Expanded Disability Status Scale, timed 25-foot walk, Nine-Hole Peg Test, Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Timed Up and Go, and high-contrast and low-contrast visual acuity (JAMA Neurol. 2017 Jan 17. doi: 10.1001/jamaneurol.2016.5056).
Overall, high-risk women showed more subclinical signs of MS than did low-risk women based on an omnibus test that globally assessed the burden of neurological dysfunction by comparing the overall differences between the two groups when considering all of the measured outcomes (P = .01). However, impaired vibration perception yielded a stronger result; of 47 women (27 high-risk and 20 low-risk) tested in this manner, high-risk women showed significantly reduced vibration perception in the distal lower extremities (P = .008).
One individual in the high-risk group converted to clinically definite MS during the study. Four of the high-risk women had T2-weighted hyperintense lesions that met the 2010 McDonald MRI criteria for dissemination in space, compared with one low-risk woman. The 2016 proposed consensus MRI criteria for MS diagnosis were met by two high-risk women and one low-risk woman. Radiological isolated syndrome occurred in one woman of each group, and there was a single foci of leptominengeal enhancement in three high-risk women and one low-risk woman.
The findings were limited by several factors including the small size, lack of male participants, cross-sectional nature of the study, and the fact that vibration sensitivity thresholds were in the normal range for high-risk and low-risk individuals. However, the researchers wrote that they “plan to confirm the finding of change in vibration sensitivity with a follow-up study,” and they noted that the “study highlights the important need to develop and test more sensitive measures, particularly with biometric devices, to detect subtle subclinical changes early in the disease process.”
The National Institutes of Health and the National Multiple Sclerosis Society supported the study. Some of the authors reported receiving awards from the National Multiple Sclerosis Society, the American Academy of Neurology, and the National Institute of Neurological Disorders and Stroke.
FROM JAMA NEUROLOGY
Key clinical point: Higher-risk asymptomatic female family relatives of patients with MS are more likely to have early subclinical manifestations of the disease and deserve further monitoring.
Major finding: Women at high risk for MS scored significantly higher on a composite of measured outcomes (P = .01) and on a vibration sensitivity test (P = .008), compared with lower-risk women.
Data source: A prospective, cross-sectional, cohort study of 65 adult women at risk for MS.
Disclosures: The National Institutes of Health and the National Multiple Sclerosis Society supported the study. Some of the authors reported receiving awards from the National Multiple Sclerosis Society, the American Academy of Neurology, and the National Institute of Neurological Disorders and Stroke.
Rituximab May Have Advantages Over Fingolimod and Natalizumab in MS
LONDON—As a first- or second-line agent for relapsing-remitting multiple sclerosis (MS), rituximab demonstrates superior drug survival (ie, the proportion of patients remaining on a
Rituximab Is Not Indicated for MS
Rituximab, a chimeric mouse–human anti-CD20 monoclonal antibody, is not approved as an MS treatment, but researchers have studied it for this indication. Naismith et al found that rituximab effectively treated breakthrough disease in patients with relapsing-remitting MS.
In a retrospective, observational study, Fredrik Piehl, MD, Professor of Neuroimmunology at Karolinska Institutet in Stockholm, and colleagues examined outcomes in patients with MS who switched from natalizumab to rituximab or fingolimod as part of a risk-management strategy. Compared with patients who switched to fingolimod, patients who switched to rituximab had lower risks of clinical relapses and adverse events.
These results prompted Dr. Piehl and colleagues to conduct a study to compare the baseline characteristics and outcomes of patients with relapsing-remitting MS starting rituximab, fingolimod, or natalizumab. The investigators used data from the Swedish Neuroregistry, which contains information on approximately 80% of all Swedish patients with MS. They included 4,244 patients in their final analysis and examined only the first period for each therapy and patient.
Rituximab Reduced Likelihood of Relapse
Approximately 14% of Swedish patients with relapsing-remitting MS received natalizumab, 10% received fingolimod, and 29% received rituximab. Patients who initiated therapy with natalizumab tended to be younger, have a higher Expanded Disability Status Scale (EDSS) score, and have more active disease at baseline, compared with the other participants.
Drug survival was greater among all patients who ever received rituximab, compared with all patients who ever received fingolimod or natalizumab. When the researchers examined the drugs as first-line agents, drug survival was greater with rituximab than with the other therapies. They found the same result when they analyzed the treatments as second-line agents. Among patients who switched from natalizumab, drug survival was greater in patients who initiated rituximab, compared with those who initiated fingolimod.
Relapse-free survival was most likely among patients receiving rituximab, compared with patients receiving fingolimod or natalizumab. When the researchers analyzed the drugs as first-line agents, they found that relapse-free survival was more likely with rituximab than with the other therapies, but the difference was small. The difference in relapse-free survival was greater, however, when the researchers analyzed the three drugs as second-line therapies.
“The strengths of this study are that it is nationwide and [that] it is a real-world population, including patients with various comorbidities,” said Dr. Piehl. The study results were susceptible to hidden confounding by indication, however. Another weakness of the study was its retrospective, observational design, said Dr. Piehl.
—Erik Greb
Suggested Reading
Naismith RT, Piccio L, Lyons JA, et al. Rituximab add-on therapy for breakthrough relapsing multiple sclerosis: a 52-week phase II trial. Neurology. 2010;74(23):1860-1867.
Salzer J, Svenningsson R, Alping P, et al. Rituximab in multiple sclerosis: A retrospective observational study on safety and efficacy. Neurology. 2016 Oct 19 [Epub ahead of print].
LONDON—As a first- or second-line agent for relapsing-remitting multiple sclerosis (MS), rituximab demonstrates superior drug survival (ie, the proportion of patients remaining on a
Rituximab Is Not Indicated for MS
Rituximab, a chimeric mouse–human anti-CD20 monoclonal antibody, is not approved as an MS treatment, but researchers have studied it for this indication. Naismith et al found that rituximab effectively treated breakthrough disease in patients with relapsing-remitting MS.
In a retrospective, observational study, Fredrik Piehl, MD, Professor of Neuroimmunology at Karolinska Institutet in Stockholm, and colleagues examined outcomes in patients with MS who switched from natalizumab to rituximab or fingolimod as part of a risk-management strategy. Compared with patients who switched to fingolimod, patients who switched to rituximab had lower risks of clinical relapses and adverse events.
These results prompted Dr. Piehl and colleagues to conduct a study to compare the baseline characteristics and outcomes of patients with relapsing-remitting MS starting rituximab, fingolimod, or natalizumab. The investigators used data from the Swedish Neuroregistry, which contains information on approximately 80% of all Swedish patients with MS. They included 4,244 patients in their final analysis and examined only the first period for each therapy and patient.
Rituximab Reduced Likelihood of Relapse
Approximately 14% of Swedish patients with relapsing-remitting MS received natalizumab, 10% received fingolimod, and 29% received rituximab. Patients who initiated therapy with natalizumab tended to be younger, have a higher Expanded Disability Status Scale (EDSS) score, and have more active disease at baseline, compared with the other participants.
Drug survival was greater among all patients who ever received rituximab, compared with all patients who ever received fingolimod or natalizumab. When the researchers examined the drugs as first-line agents, drug survival was greater with rituximab than with the other therapies. They found the same result when they analyzed the treatments as second-line agents. Among patients who switched from natalizumab, drug survival was greater in patients who initiated rituximab, compared with those who initiated fingolimod.
Relapse-free survival was most likely among patients receiving rituximab, compared with patients receiving fingolimod or natalizumab. When the researchers analyzed the drugs as first-line agents, they found that relapse-free survival was more likely with rituximab than with the other therapies, but the difference was small. The difference in relapse-free survival was greater, however, when the researchers analyzed the three drugs as second-line therapies.
“The strengths of this study are that it is nationwide and [that] it is a real-world population, including patients with various comorbidities,” said Dr. Piehl. The study results were susceptible to hidden confounding by indication, however. Another weakness of the study was its retrospective, observational design, said Dr. Piehl.
—Erik Greb
Suggested Reading
Naismith RT, Piccio L, Lyons JA, et al. Rituximab add-on therapy for breakthrough relapsing multiple sclerosis: a 52-week phase II trial. Neurology. 2010;74(23):1860-1867.
Salzer J, Svenningsson R, Alping P, et al. Rituximab in multiple sclerosis: A retrospective observational study on safety and efficacy. Neurology. 2016 Oct 19 [Epub ahead of print].
LONDON—As a first- or second-line agent for relapsing-remitting multiple sclerosis (MS), rituximab demonstrates superior drug survival (ie, the proportion of patients remaining on a
Rituximab Is Not Indicated for MS
Rituximab, a chimeric mouse–human anti-CD20 monoclonal antibody, is not approved as an MS treatment, but researchers have studied it for this indication. Naismith et al found that rituximab effectively treated breakthrough disease in patients with relapsing-remitting MS.
In a retrospective, observational study, Fredrik Piehl, MD, Professor of Neuroimmunology at Karolinska Institutet in Stockholm, and colleagues examined outcomes in patients with MS who switched from natalizumab to rituximab or fingolimod as part of a risk-management strategy. Compared with patients who switched to fingolimod, patients who switched to rituximab had lower risks of clinical relapses and adverse events.
These results prompted Dr. Piehl and colleagues to conduct a study to compare the baseline characteristics and outcomes of patients with relapsing-remitting MS starting rituximab, fingolimod, or natalizumab. The investigators used data from the Swedish Neuroregistry, which contains information on approximately 80% of all Swedish patients with MS. They included 4,244 patients in their final analysis and examined only the first period for each therapy and patient.
Rituximab Reduced Likelihood of Relapse
Approximately 14% of Swedish patients with relapsing-remitting MS received natalizumab, 10% received fingolimod, and 29% received rituximab. Patients who initiated therapy with natalizumab tended to be younger, have a higher Expanded Disability Status Scale (EDSS) score, and have more active disease at baseline, compared with the other participants.
Drug survival was greater among all patients who ever received rituximab, compared with all patients who ever received fingolimod or natalizumab. When the researchers examined the drugs as first-line agents, drug survival was greater with rituximab than with the other therapies. They found the same result when they analyzed the treatments as second-line agents. Among patients who switched from natalizumab, drug survival was greater in patients who initiated rituximab, compared with those who initiated fingolimod.
Relapse-free survival was most likely among patients receiving rituximab, compared with patients receiving fingolimod or natalizumab. When the researchers analyzed the drugs as first-line agents, they found that relapse-free survival was more likely with rituximab than with the other therapies, but the difference was small. The difference in relapse-free survival was greater, however, when the researchers analyzed the three drugs as second-line therapies.
“The strengths of this study are that it is nationwide and [that] it is a real-world population, including patients with various comorbidities,” said Dr. Piehl. The study results were susceptible to hidden confounding by indication, however. Another weakness of the study was its retrospective, observational design, said Dr. Piehl.
—Erik Greb
Suggested Reading
Naismith RT, Piccio L, Lyons JA, et al. Rituximab add-on therapy for breakthrough relapsing multiple sclerosis: a 52-week phase II trial. Neurology. 2010;74(23):1860-1867.
Salzer J, Svenningsson R, Alping P, et al. Rituximab in multiple sclerosis: A retrospective observational study on safety and efficacy. Neurology. 2016 Oct 19 [Epub ahead of print].
What Are the Best Treatments for Bladder Dysfunction in MS?
LONDON—Many patients with multiple sclerosis (MS) suffer from bladder dysfunction, however, few of these patients have their symptoms managed, according to an overview presented at the 32nd Congress of the European Committee for Treatment and Research in MS.
If a patient reports bladder symptoms, most often those bladder symptoms will persist and increase, said Jalesh Panicker, MD, DM, Consultant Neurologist and Clinical Lead in Uroneurology at the University College London Institute of Neurology in Queen Square, London. Symptoms of urinary frequency, urgency, incontinence, and nocturia, which are collectively called overactive bladder syndrome, increase with increased duration of MS and tend to correlate with the neurologic disability, especially lower limb parameter weakness.
In a large survey of 3,000 patients with MS, 90% rated bladder complications as one of the top five common symptomatic problems. Seventy percent of the group reported that bladder issues had a moderate or high impact on them. Only one-third of patients surveyed reported improvement after starting disease-modifying therapies.
Bladder symptoms in MS occur, on average, six years into the illness. Lower urinary tract symptoms are present in 10% of patients at first diagnosis. To help address this issue, the Actionable eight-item questionnaire was developed to help make it easier for doctors to assess bladder problems, said Dr. Panicker.
Lesion location plays a significant role in urinary tract dysfunction. Patients with suprapontine lesions present predominantly with overactive bladder, whereas patients with spinal lesions tend to report voiding symptoms such as hesitancy and poor stream. Plaques in the cerebral cord can also alter the pattern of lower urinary tract dysfunction.
Measuring post-void residue is critical for bladder dysfunction management. Unlike in urgency and incontinence, patients tend to have difficulties expressing voiding and voiding dysfunction symptoms. A high post-void residue can cause urinary tract infections and lead to devastating effects on patients, Dr. Panicker said. Using a bladder scanner to detect high post-void residuals may help reduce urinary tract infections.
Oral Agents
The three most commonly used treatments for bladder dysfunction in patients with MS are oral agents, botulinum toxin, and neuromodulation. Oral antimuscarinics work through the muscarinic receptors of the bladder, reducing bladder sensation and intrusive pressures, inhibiting detrusor overactivity, and improving bladder capacity. Oxybutynin, for example, can cause dry mouth and dry eyes, whereas newer antimuscarinics such as tolteradine, solifenancin, or fesoteradine are less likely to cause dry eyes, dry mouth, or constipation, Dr. Panicker noted.
Anticholinergic burden refers to the cumulative effect of multiple medications with anticholinergic properties. The higher the anticholinergic burden, the greater the risk of cognitive impairment, impaired functional performance, mortality, and brain atrophy. The Anticholinergic Burden Scale (ACB) grades medications according to their anticholinergic burden—mild (ACB1), moderate (ACB2), and severe (ACB3). Total ACB score is the sum of each medication the patient is on; any ACB score over 3 is considered clinically relevant.
Beta 3 agonists are another class of oral agents used to control bladder symptoms. Beta 3 agonists inhibit intrusive muscle contractions and increase relaxation by acting on the beta 3 receptors present on the wall of the bladder. Unlike antimuscarinics, beta 3 agonists are devoid of side effects like dry mouth, dry eyes, and constipation; however, these oral agents are associated with cardiovascular side effects. Currently, there are pivotal phase III studies on the efficacy of mirabegron in the UK, however, there is limited evidence from neurologic patients and there is a need for more long-term data, Dr. Panicker said.
Botulinum Toxin
Botulinum toxin is effective for bladder management. Evidence shows that patients with MS experienced significant improvement in urinary incontinence, frequency, and urgency as early as four weeks after injections, and this beneficial effect is not lost with repeated injections. Three pivotal phase III studies have demonstrated the efficacy of onabotulinumtoxinA for improving incontinence. Studies suggest that onabotulinumtoxinA significantly improved incontinence at week 12. The median duration of retreatment was 42 weeks.
Neuromodulation
Stimulating the tibial nerve is beneficial in managing overactive bladder symptoms such as urinary frequency and incontinence. Percutaneous tibial nerve stimulation is one of the few treatments that does not tend to worsen voiding dysfunction. It is also potentially a treatment for patients who are retaining urine or experiencing incomplete bladder emptying.
“With several disease-modifying therapies over the last few years, it is clear that the number of MS relapses in patients is coming down. There is evidence to suggest that the neurologic disability that accumulates is also either halted or possibly even reversed. Whether the nonmotor symptoms of MS, such as urinary tract dysfunction, also would get halted or reversed with these treatments is an area for further research,” said Dr. Panicker.
—Erica Tricarico
Suggested Reading
Ginsberg D, Gousse A, Keppenne V, et al. Phase 3 efficacy and tolerability study of onabotulinumtoxinA for urinary incontinence from neurogenic detrusor overactivity. J Urol. 2012;187(6):2131-2139.
Jongen PJ, Blok BF, Heesakkers JP, et al. Simplified scoring of the Actionable 8-item screening questionnaire for neurogenic bladder overactivity in multiple sclerosis: a comparative analysis of test performance at different cut-off points. BMC Urol. 2015;15:106.
Wintner A, Kim MM, Bechis SK, Kreydin El. Voiding dysfunction in multiple sclerosis. Semin Neurol. 2016;36(1):34-40.
LONDON—Many patients with multiple sclerosis (MS) suffer from bladder dysfunction, however, few of these patients have their symptoms managed, according to an overview presented at the 32nd Congress of the European Committee for Treatment and Research in MS.
If a patient reports bladder symptoms, most often those bladder symptoms will persist and increase, said Jalesh Panicker, MD, DM, Consultant Neurologist and Clinical Lead in Uroneurology at the University College London Institute of Neurology in Queen Square, London. Symptoms of urinary frequency, urgency, incontinence, and nocturia, which are collectively called overactive bladder syndrome, increase with increased duration of MS and tend to correlate with the neurologic disability, especially lower limb parameter weakness.
In a large survey of 3,000 patients with MS, 90% rated bladder complications as one of the top five common symptomatic problems. Seventy percent of the group reported that bladder issues had a moderate or high impact on them. Only one-third of patients surveyed reported improvement after starting disease-modifying therapies.
Bladder symptoms in MS occur, on average, six years into the illness. Lower urinary tract symptoms are present in 10% of patients at first diagnosis. To help address this issue, the Actionable eight-item questionnaire was developed to help make it easier for doctors to assess bladder problems, said Dr. Panicker.
Lesion location plays a significant role in urinary tract dysfunction. Patients with suprapontine lesions present predominantly with overactive bladder, whereas patients with spinal lesions tend to report voiding symptoms such as hesitancy and poor stream. Plaques in the cerebral cord can also alter the pattern of lower urinary tract dysfunction.
Measuring post-void residue is critical for bladder dysfunction management. Unlike in urgency and incontinence, patients tend to have difficulties expressing voiding and voiding dysfunction symptoms. A high post-void residue can cause urinary tract infections and lead to devastating effects on patients, Dr. Panicker said. Using a bladder scanner to detect high post-void residuals may help reduce urinary tract infections.
Oral Agents
The three most commonly used treatments for bladder dysfunction in patients with MS are oral agents, botulinum toxin, and neuromodulation. Oral antimuscarinics work through the muscarinic receptors of the bladder, reducing bladder sensation and intrusive pressures, inhibiting detrusor overactivity, and improving bladder capacity. Oxybutynin, for example, can cause dry mouth and dry eyes, whereas newer antimuscarinics such as tolteradine, solifenancin, or fesoteradine are less likely to cause dry eyes, dry mouth, or constipation, Dr. Panicker noted.
Anticholinergic burden refers to the cumulative effect of multiple medications with anticholinergic properties. The higher the anticholinergic burden, the greater the risk of cognitive impairment, impaired functional performance, mortality, and brain atrophy. The Anticholinergic Burden Scale (ACB) grades medications according to their anticholinergic burden—mild (ACB1), moderate (ACB2), and severe (ACB3). Total ACB score is the sum of each medication the patient is on; any ACB score over 3 is considered clinically relevant.
Beta 3 agonists are another class of oral agents used to control bladder symptoms. Beta 3 agonists inhibit intrusive muscle contractions and increase relaxation by acting on the beta 3 receptors present on the wall of the bladder. Unlike antimuscarinics, beta 3 agonists are devoid of side effects like dry mouth, dry eyes, and constipation; however, these oral agents are associated with cardiovascular side effects. Currently, there are pivotal phase III studies on the efficacy of mirabegron in the UK, however, there is limited evidence from neurologic patients and there is a need for more long-term data, Dr. Panicker said.
Botulinum Toxin
Botulinum toxin is effective for bladder management. Evidence shows that patients with MS experienced significant improvement in urinary incontinence, frequency, and urgency as early as four weeks after injections, and this beneficial effect is not lost with repeated injections. Three pivotal phase III studies have demonstrated the efficacy of onabotulinumtoxinA for improving incontinence. Studies suggest that onabotulinumtoxinA significantly improved incontinence at week 12. The median duration of retreatment was 42 weeks.
Neuromodulation
Stimulating the tibial nerve is beneficial in managing overactive bladder symptoms such as urinary frequency and incontinence. Percutaneous tibial nerve stimulation is one of the few treatments that does not tend to worsen voiding dysfunction. It is also potentially a treatment for patients who are retaining urine or experiencing incomplete bladder emptying.
“With several disease-modifying therapies over the last few years, it is clear that the number of MS relapses in patients is coming down. There is evidence to suggest that the neurologic disability that accumulates is also either halted or possibly even reversed. Whether the nonmotor symptoms of MS, such as urinary tract dysfunction, also would get halted or reversed with these treatments is an area for further research,” said Dr. Panicker.
—Erica Tricarico
Suggested Reading
Ginsberg D, Gousse A, Keppenne V, et al. Phase 3 efficacy and tolerability study of onabotulinumtoxinA for urinary incontinence from neurogenic detrusor overactivity. J Urol. 2012;187(6):2131-2139.
Jongen PJ, Blok BF, Heesakkers JP, et al. Simplified scoring of the Actionable 8-item screening questionnaire for neurogenic bladder overactivity in multiple sclerosis: a comparative analysis of test performance at different cut-off points. BMC Urol. 2015;15:106.
Wintner A, Kim MM, Bechis SK, Kreydin El. Voiding dysfunction in multiple sclerosis. Semin Neurol. 2016;36(1):34-40.
LONDON—Many patients with multiple sclerosis (MS) suffer from bladder dysfunction, however, few of these patients have their symptoms managed, according to an overview presented at the 32nd Congress of the European Committee for Treatment and Research in MS.
If a patient reports bladder symptoms, most often those bladder symptoms will persist and increase, said Jalesh Panicker, MD, DM, Consultant Neurologist and Clinical Lead in Uroneurology at the University College London Institute of Neurology in Queen Square, London. Symptoms of urinary frequency, urgency, incontinence, and nocturia, which are collectively called overactive bladder syndrome, increase with increased duration of MS and tend to correlate with the neurologic disability, especially lower limb parameter weakness.
In a large survey of 3,000 patients with MS, 90% rated bladder complications as one of the top five common symptomatic problems. Seventy percent of the group reported that bladder issues had a moderate or high impact on them. Only one-third of patients surveyed reported improvement after starting disease-modifying therapies.
Bladder symptoms in MS occur, on average, six years into the illness. Lower urinary tract symptoms are present in 10% of patients at first diagnosis. To help address this issue, the Actionable eight-item questionnaire was developed to help make it easier for doctors to assess bladder problems, said Dr. Panicker.
Lesion location plays a significant role in urinary tract dysfunction. Patients with suprapontine lesions present predominantly with overactive bladder, whereas patients with spinal lesions tend to report voiding symptoms such as hesitancy and poor stream. Plaques in the cerebral cord can also alter the pattern of lower urinary tract dysfunction.
Measuring post-void residue is critical for bladder dysfunction management. Unlike in urgency and incontinence, patients tend to have difficulties expressing voiding and voiding dysfunction symptoms. A high post-void residue can cause urinary tract infections and lead to devastating effects on patients, Dr. Panicker said. Using a bladder scanner to detect high post-void residuals may help reduce urinary tract infections.
Oral Agents
The three most commonly used treatments for bladder dysfunction in patients with MS are oral agents, botulinum toxin, and neuromodulation. Oral antimuscarinics work through the muscarinic receptors of the bladder, reducing bladder sensation and intrusive pressures, inhibiting detrusor overactivity, and improving bladder capacity. Oxybutynin, for example, can cause dry mouth and dry eyes, whereas newer antimuscarinics such as tolteradine, solifenancin, or fesoteradine are less likely to cause dry eyes, dry mouth, or constipation, Dr. Panicker noted.
Anticholinergic burden refers to the cumulative effect of multiple medications with anticholinergic properties. The higher the anticholinergic burden, the greater the risk of cognitive impairment, impaired functional performance, mortality, and brain atrophy. The Anticholinergic Burden Scale (ACB) grades medications according to their anticholinergic burden—mild (ACB1), moderate (ACB2), and severe (ACB3). Total ACB score is the sum of each medication the patient is on; any ACB score over 3 is considered clinically relevant.
Beta 3 agonists are another class of oral agents used to control bladder symptoms. Beta 3 agonists inhibit intrusive muscle contractions and increase relaxation by acting on the beta 3 receptors present on the wall of the bladder. Unlike antimuscarinics, beta 3 agonists are devoid of side effects like dry mouth, dry eyes, and constipation; however, these oral agents are associated with cardiovascular side effects. Currently, there are pivotal phase III studies on the efficacy of mirabegron in the UK, however, there is limited evidence from neurologic patients and there is a need for more long-term data, Dr. Panicker said.
Botulinum Toxin
Botulinum toxin is effective for bladder management. Evidence shows that patients with MS experienced significant improvement in urinary incontinence, frequency, and urgency as early as four weeks after injections, and this beneficial effect is not lost with repeated injections. Three pivotal phase III studies have demonstrated the efficacy of onabotulinumtoxinA for improving incontinence. Studies suggest that onabotulinumtoxinA significantly improved incontinence at week 12. The median duration of retreatment was 42 weeks.
Neuromodulation
Stimulating the tibial nerve is beneficial in managing overactive bladder symptoms such as urinary frequency and incontinence. Percutaneous tibial nerve stimulation is one of the few treatments that does not tend to worsen voiding dysfunction. It is also potentially a treatment for patients who are retaining urine or experiencing incomplete bladder emptying.
“With several disease-modifying therapies over the last few years, it is clear that the number of MS relapses in patients is coming down. There is evidence to suggest that the neurologic disability that accumulates is also either halted or possibly even reversed. Whether the nonmotor symptoms of MS, such as urinary tract dysfunction, also would get halted or reversed with these treatments is an area for further research,” said Dr. Panicker.
—Erica Tricarico
Suggested Reading
Ginsberg D, Gousse A, Keppenne V, et al. Phase 3 efficacy and tolerability study of onabotulinumtoxinA for urinary incontinence from neurogenic detrusor overactivity. J Urol. 2012;187(6):2131-2139.
Jongen PJ, Blok BF, Heesakkers JP, et al. Simplified scoring of the Actionable 8-item screening questionnaire for neurogenic bladder overactivity in multiple sclerosis: a comparative analysis of test performance at different cut-off points. BMC Urol. 2015;15:106.
Wintner A, Kim MM, Bechis SK, Kreydin El. Voiding dysfunction in multiple sclerosis. Semin Neurol. 2016;36(1):34-40.
Lack of natalizumab concentration increase before PML argues against extending dosing interval
Serum concentrations of natalizumab do not appear to rise before patients with relapsing-remitting multiple sclerosis are diagnosed with progressive multifocal leukoencephalopathy, contradicting the hypothesis that exposure to elevated concentrations of the drug is a risk factor for the disease, according to findings from a prospective, observational cohort study.
Zoé L.E. van Kempen, MD, and her colleagues at VU Medical Center Amsterdam noted that a small but increasing number of “neurologists are extending dose intervals of natalizumab [Tysabri] with the primary aim of reducing the risk of PML [progressive multifocal leukoencephalopathy] by lowering the natalizumab exposure per patient,” which also potentially has the benefit of decreasing drug costs, as well as clinic or hospital visits. However, there have been no prospective studies that confirm that extending natalizumab dose intervals does not affect efficacy.
Dr. van Kempen and her coinvestigators investigated this hypothesis by comparing serum concentrations of natalizumab in 5 patients with PML and 10 age- and sex-matched controls from a cohort of 219 relapsing-remitting multiple sclerosis patients taking natalizumab who had blood samples routinely drawn every 12 weeks before the infusion of natalizumab (Mult Scler. 2016 Dec 13. doi: 10.1177/1352458516684023). These 10 controls had a mean concentration of 23.8 mcg/mL, which was in the same range as the 18.9 mcg/mL level observed before the diagnosis of PML in the 5 cases from the cohort. The five cases also did not show a rise in concentration before the diagnosis of PML and did not have concentrations fluctuate more than 11 mcg/mL during treatment. The patients with PML received a mean of 43 infusions, whereas controls received an average of 106 infusions. A median number of 5 pre-PML samples underwent testing, compared with yearly concentration measurements in the 10 controls who had at least 7 years’ treatment duration.
The increased risk of PML that has been documented in other studies with more than 24 months of natalizumab treatment also was not explained in this study by a rise in serum concentration over long-term follow-up.
“Although this cohort is too small to draw definite conclusions, our results do not support the hypothesis of high serum concentrations as a risk factor for developing PML,” the investigators wrote.
“With our small cohort in mind and insufficient data on this subject so far, neurologists should be careful in extending dose intervals and not overstate a possible decrease in the risk of developing PML. Obviously, if neurologists choose to extend dosing intervals of natalizumab in [John Cunningham virus]–positive patients, these patients should still receive stringent PML monitoring according to current recommendations,” they advised.
The study received support from the Brain Foundation Netherlands. Five of the authors reported financial ties to various pharmaceutical companies that market MS drugs, including Biogen, which markets natalizumab.
Serum concentrations of natalizumab do not appear to rise before patients with relapsing-remitting multiple sclerosis are diagnosed with progressive multifocal leukoencephalopathy, contradicting the hypothesis that exposure to elevated concentrations of the drug is a risk factor for the disease, according to findings from a prospective, observational cohort study.
Zoé L.E. van Kempen, MD, and her colleagues at VU Medical Center Amsterdam noted that a small but increasing number of “neurologists are extending dose intervals of natalizumab [Tysabri] with the primary aim of reducing the risk of PML [progressive multifocal leukoencephalopathy] by lowering the natalizumab exposure per patient,” which also potentially has the benefit of decreasing drug costs, as well as clinic or hospital visits. However, there have been no prospective studies that confirm that extending natalizumab dose intervals does not affect efficacy.
Dr. van Kempen and her coinvestigators investigated this hypothesis by comparing serum concentrations of natalizumab in 5 patients with PML and 10 age- and sex-matched controls from a cohort of 219 relapsing-remitting multiple sclerosis patients taking natalizumab who had blood samples routinely drawn every 12 weeks before the infusion of natalizumab (Mult Scler. 2016 Dec 13. doi: 10.1177/1352458516684023). These 10 controls had a mean concentration of 23.8 mcg/mL, which was in the same range as the 18.9 mcg/mL level observed before the diagnosis of PML in the 5 cases from the cohort. The five cases also did not show a rise in concentration before the diagnosis of PML and did not have concentrations fluctuate more than 11 mcg/mL during treatment. The patients with PML received a mean of 43 infusions, whereas controls received an average of 106 infusions. A median number of 5 pre-PML samples underwent testing, compared with yearly concentration measurements in the 10 controls who had at least 7 years’ treatment duration.
The increased risk of PML that has been documented in other studies with more than 24 months of natalizumab treatment also was not explained in this study by a rise in serum concentration over long-term follow-up.
“Although this cohort is too small to draw definite conclusions, our results do not support the hypothesis of high serum concentrations as a risk factor for developing PML,” the investigators wrote.
“With our small cohort in mind and insufficient data on this subject so far, neurologists should be careful in extending dose intervals and not overstate a possible decrease in the risk of developing PML. Obviously, if neurologists choose to extend dosing intervals of natalizumab in [John Cunningham virus]–positive patients, these patients should still receive stringent PML monitoring according to current recommendations,” they advised.
The study received support from the Brain Foundation Netherlands. Five of the authors reported financial ties to various pharmaceutical companies that market MS drugs, including Biogen, which markets natalizumab.
Serum concentrations of natalizumab do not appear to rise before patients with relapsing-remitting multiple sclerosis are diagnosed with progressive multifocal leukoencephalopathy, contradicting the hypothesis that exposure to elevated concentrations of the drug is a risk factor for the disease, according to findings from a prospective, observational cohort study.
Zoé L.E. van Kempen, MD, and her colleagues at VU Medical Center Amsterdam noted that a small but increasing number of “neurologists are extending dose intervals of natalizumab [Tysabri] with the primary aim of reducing the risk of PML [progressive multifocal leukoencephalopathy] by lowering the natalizumab exposure per patient,” which also potentially has the benefit of decreasing drug costs, as well as clinic or hospital visits. However, there have been no prospective studies that confirm that extending natalizumab dose intervals does not affect efficacy.
Dr. van Kempen and her coinvestigators investigated this hypothesis by comparing serum concentrations of natalizumab in 5 patients with PML and 10 age- and sex-matched controls from a cohort of 219 relapsing-remitting multiple sclerosis patients taking natalizumab who had blood samples routinely drawn every 12 weeks before the infusion of natalizumab (Mult Scler. 2016 Dec 13. doi: 10.1177/1352458516684023). These 10 controls had a mean concentration of 23.8 mcg/mL, which was in the same range as the 18.9 mcg/mL level observed before the diagnosis of PML in the 5 cases from the cohort. The five cases also did not show a rise in concentration before the diagnosis of PML and did not have concentrations fluctuate more than 11 mcg/mL during treatment. The patients with PML received a mean of 43 infusions, whereas controls received an average of 106 infusions. A median number of 5 pre-PML samples underwent testing, compared with yearly concentration measurements in the 10 controls who had at least 7 years’ treatment duration.
The increased risk of PML that has been documented in other studies with more than 24 months of natalizumab treatment also was not explained in this study by a rise in serum concentration over long-term follow-up.
“Although this cohort is too small to draw definite conclusions, our results do not support the hypothesis of high serum concentrations as a risk factor for developing PML,” the investigators wrote.
“With our small cohort in mind and insufficient data on this subject so far, neurologists should be careful in extending dose intervals and not overstate a possible decrease in the risk of developing PML. Obviously, if neurologists choose to extend dosing intervals of natalizumab in [John Cunningham virus]–positive patients, these patients should still receive stringent PML monitoring according to current recommendations,” they advised.
The study received support from the Brain Foundation Netherlands. Five of the authors reported financial ties to various pharmaceutical companies that market MS drugs, including Biogen, which markets natalizumab.
FROM MULTIPLE SCLEROSIS JOURNAL
Key clinical point:
Major finding: A total of 10 control patients had a mean natalizumab serum concentration of 23.8 mcg/mL, which was in the same range as the 18.9 mcg/mL level observed in 5 patients before a diagnosis of PML.
Data source: A comparison of 5 patients with PML and 10 age- and sex-matched controls from a prospective cohort of 219 patients with relapsing-remitting MS who were treated with natalizumab at one center.
Disclosures: The study received support from the Brain Foundation Netherlands. Five of the authors reported financial ties to various pharmaceutical companies that market MS drugs, including Biogen, which markets natalizumab.
Nomogram predicts conversion of first demyelinating event to definite MS
Baseline and follow-up data from a prospective, multinational cohort of more than 3,000 patients with clinically isolated events allowed researchers to develop an accurate prognostic nomogram to calculate an individual’s risk for conversion to clinically definite multiple sclerosis at 12 months.
“Identification of patient, disease, and examination factors associated with higher probability of second attack in clinical practice may enable clinicians to flag patients that could benefit from more intensive follow-up and consideration of early DMD [disease-modifying drug] treatment intervention, facilitating more favorable patient outcomes,” wrote Tim Spelman, PhD, and his associates.
Risk of relapse was decreased when clinically isolated syndrome was diagnosed later, with an adjusted hazard ratio of 0.9 for every 5 additional years of age. Other risk factors for earlier relapse include higher Expanded Disability Status Scale score at the onset of the first demyelinating event, DMD exposure prior to the first attack, multiple brain and spinal MRI criteria, and oligoclonal bands.
“These results corroborate and extend prior, albeit smaller, studies observing similar sets of predictors of clinical conversion probability,” Dr. Spelman and his coauthors wrote.
The predictive nomogram had a concordance index of 0.81 between the 12-month estimated and observed conversion probabilities.
“While our own internal validation suggested good performance, both an additional training-validation approach and an external validation through the application of the nomogram to a separate MS data set or population are required to confirm the generalizability of the nomogram,” they wrote.
Read the full study in Multiple Sclerosis Journal (2016 Nov 24. doi: 10.1177/1352458516679893).
Baseline and follow-up data from a prospective, multinational cohort of more than 3,000 patients with clinically isolated events allowed researchers to develop an accurate prognostic nomogram to calculate an individual’s risk for conversion to clinically definite multiple sclerosis at 12 months.
“Identification of patient, disease, and examination factors associated with higher probability of second attack in clinical practice may enable clinicians to flag patients that could benefit from more intensive follow-up and consideration of early DMD [disease-modifying drug] treatment intervention, facilitating more favorable patient outcomes,” wrote Tim Spelman, PhD, and his associates.
Risk of relapse was decreased when clinically isolated syndrome was diagnosed later, with an adjusted hazard ratio of 0.9 for every 5 additional years of age. Other risk factors for earlier relapse include higher Expanded Disability Status Scale score at the onset of the first demyelinating event, DMD exposure prior to the first attack, multiple brain and spinal MRI criteria, and oligoclonal bands.
“These results corroborate and extend prior, albeit smaller, studies observing similar sets of predictors of clinical conversion probability,” Dr. Spelman and his coauthors wrote.
The predictive nomogram had a concordance index of 0.81 between the 12-month estimated and observed conversion probabilities.
“While our own internal validation suggested good performance, both an additional training-validation approach and an external validation through the application of the nomogram to a separate MS data set or population are required to confirm the generalizability of the nomogram,” they wrote.
Read the full study in Multiple Sclerosis Journal (2016 Nov 24. doi: 10.1177/1352458516679893).
Baseline and follow-up data from a prospective, multinational cohort of more than 3,000 patients with clinically isolated events allowed researchers to develop an accurate prognostic nomogram to calculate an individual’s risk for conversion to clinically definite multiple sclerosis at 12 months.
“Identification of patient, disease, and examination factors associated with higher probability of second attack in clinical practice may enable clinicians to flag patients that could benefit from more intensive follow-up and consideration of early DMD [disease-modifying drug] treatment intervention, facilitating more favorable patient outcomes,” wrote Tim Spelman, PhD, and his associates.
Risk of relapse was decreased when clinically isolated syndrome was diagnosed later, with an adjusted hazard ratio of 0.9 for every 5 additional years of age. Other risk factors for earlier relapse include higher Expanded Disability Status Scale score at the onset of the first demyelinating event, DMD exposure prior to the first attack, multiple brain and spinal MRI criteria, and oligoclonal bands.
“These results corroborate and extend prior, albeit smaller, studies observing similar sets of predictors of clinical conversion probability,” Dr. Spelman and his coauthors wrote.
The predictive nomogram had a concordance index of 0.81 between the 12-month estimated and observed conversion probabilities.
“While our own internal validation suggested good performance, both an additional training-validation approach and an external validation through the application of the nomogram to a separate MS data set or population are required to confirm the generalizability of the nomogram,” they wrote.
Read the full study in Multiple Sclerosis Journal (2016 Nov 24. doi: 10.1177/1352458516679893).
FROM MULTIPLE SCLEROSIS JOURNAL
What Do We Know About Pediatric MS?
BALTIMORE—Lack of evidence for disease-modifying therapies (DMTs) in children presents a significant challenge in pediatric multiple sclerosis (MS). Forty percent of children with pediatric MS discontinue DMTs for inefficacy or side effects, according to an overview presented at the 141st Annual Meeting of the American Neurological Association.
“We need to keep working on clinical trials in kids and not shy away from investigating the stronger agents,” said Jennifer Graves, MD, PhD, Assistant Professor of Neurology at the University of California, San Francisco School of Medicine. Future studies should incorporate comprehensive outcomes that include measures of cognition, brain volume, and retinal integrity, she added. National and international collaborations currently under way may help achieve sample sizes that could provide conclusive evidence.
Pediatric MS Has Distinctive Features
Nearly 5% of patients with MS have pediatric onset of symptoms; 20%–30% of these patients have onset before age 11. The mean age of onset for pediatric MS is 13. In several ways, the course of MS is different in children than in adults. Children typically have higher relapse rates than adults and are less likely to develop primary or secondary progressive MS in their childhood. Neurologists are concerned, however, about the possibility that these children will develop secondary progression in their 20s or 30s.
“A lot of these kids drop off the map between seeing us in pediatric centers and moving to adult MS centers. Often, these are the people that show up at [age] 30 with significant disability and high lesion burdens because they dropped out of care when they left their parents’ homes,” said Dr. Graves.
Unlike in adult MS, the gender ratio is approximately equal in prepubertal pediatric MS. There is a near 1:1 ratio of females to males in children who present before age 11, but the ratio increases over time to 2:1 or 3:1 in adolescents and adults. Postpubertal and adult patients with MS have similar features, but prepubertal patients have features distinct from those of adult MS. For example, prepubertal patients have a lower prevalence of oligoclonal bands. Their MRI lesions tend to be larger and less distinct and sometimes resolve completely. In addition, children tend to have better motor, visual, and cerebellar recovery from relapses than adults.
A study published in the July issue of Pediatrics described the demographic and clinical characteristics of patients with pediatric MS in the United States. Of the 490 children and adolescents enrolled, 28% developed symptoms before age 12. Sixty-seven percent of participants identified as white, 21% as African-American, and 70% as non-Hispanic. Thirty-nine percent of patients had one or two foreign-born parents. Approximately 31% of patients had a prodrome (often infectious), which occurred mostly in children under age 12. Researchers observed a difference in the type of relapses in children under 12, compared with adolescents and adults. Young children tended to have more cerebellar symptoms, encephalopathy, and greater lesion burden in the posterior fossa.
Perinatal Risk Factors in Pediatric MS
In work from the US Network of Pediatric MS Centers presented at the 68th Annual Meeting of the American Academy of Neurology, Cesarean section (C-section) was associated with a 60% reduced odds of having pediatric-onset MS. The association remained statistically significant after the researchers adjusted for socioeconomic status and other maternal variables such as BMI, age, gestational diabetes, pre-eclampsia, and birth complications. While the mechanism of the association remains unknown, it is of interest in light of the new insights regarding the microbiome and MS. Children born by C-section typically have different gut flora for at least the first year of life, said Dr. Graves. When the data were adjusted for C-section result, maternal illness was independently associated with a twofold increase in the risk of pediatric MS.
The mechanism of maternal illness effects on MS risk have yet to be elucidated, but in animal models of MS, exposure during pregnancy to certain bacterial antigens can result in a proinflammatory Th17 phenotype and may cause long-term effects in offspring. An exploratory analysis in this perinatal risk factor study revealed that variables associated with agricultural work by the parent and home use of pesticides and insecticides were associated with a twofold increased risk of pediatric MS.
Diet, BMI, and Exercise
Diets high in salt have been associated with high relapse rate in adults. This association has not been found in pediatric MS, however. High fat intake is associated with high relapse rate in children with MS, according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS. Diets rich in fruits and vegetables are linked to a lower relapse rate, even after adjusting for fat intake.
In addition, data indicate that BMI is directly proportional to the risk for pediatric MS. Vigorous activity, however, is associated with decreased risk of pediatric MS, a decreased number of T2 lesions, and a decreased relapse rate, according to a Canadian study.
Role of Risk Genes and Genetic Ancestry in Pediatric MS
Genetics may play a key role in the development of early-onset pediatric MS. Researchers are analyzing data in the United States for people of multiple genetic ancestries. Of 110 nonhuman leukocyte antigen (HLA) risk variants for adult MS, 36 may increase the risk of pediatric MS, either at the level of single-nucleotide polymorphisms (SNPs) or as an aggregate genetic risk factor. The effect size of each SNP is greater in children than in adults; each SNP may increase the risk of MS by twofold or more.
Imaging Efforts
Imaging could improve understanding of pediatric MS. National and international efforts to standardize protocols for 3-T imaging, volumetric scans, and diffusion tensor imaging (DTI) are under way. DTI already has revealed abnormal fractional anisotropy in pediatric MS, and this abnormality is associated with cognitive difficulty. MRI and optical coherence tomography (OCT) help to distinguish between MS, neuromyelitis optica (NMO), and acute disseminated encephalomyelitis (ADEM).
OCT imaging in children indicates similar levels of neuronal and axonal injury as in adults, despite better visual recovery in children. In a study published in the Multiple Sclerosis Journal, boys with pediatric MS were found to have greater axonal loss than girls with pediatric MS.
Testing DMTs’ Efficacy
Several studies of DMTs in pediatric MS are under way. PARADIGMS is an ongoing, 24-month, double-blind, double-randomized trial investigating the effect of fingolimod on relapse rate in pediatric MS. The control group is receiving
Observational registries are studying the safety and clinical experience with disease modifying agents in children. Investigators recently published data for 100 children in an Italian registry of patients with MS treated with natalizumab. The treatment decreased relapse rate to 0.1. Approximately 28% of the population had no evidence of disease activity. The drug appeared to be well tolerated in children and to be efficacious.
—Erica Tricarico
Suggested Reading
Belman AL, Krupp LB, Olsen CS, et al. Characteristics of children and adolescents with multiple sclerosis. Pediatrics. 2016;138(1).
BALTIMORE—Lack of evidence for disease-modifying therapies (DMTs) in children presents a significant challenge in pediatric multiple sclerosis (MS). Forty percent of children with pediatric MS discontinue DMTs for inefficacy or side effects, according to an overview presented at the 141st Annual Meeting of the American Neurological Association.
“We need to keep working on clinical trials in kids and not shy away from investigating the stronger agents,” said Jennifer Graves, MD, PhD, Assistant Professor of Neurology at the University of California, San Francisco School of Medicine. Future studies should incorporate comprehensive outcomes that include measures of cognition, brain volume, and retinal integrity, she added. National and international collaborations currently under way may help achieve sample sizes that could provide conclusive evidence.
Pediatric MS Has Distinctive Features
Nearly 5% of patients with MS have pediatric onset of symptoms; 20%–30% of these patients have onset before age 11. The mean age of onset for pediatric MS is 13. In several ways, the course of MS is different in children than in adults. Children typically have higher relapse rates than adults and are less likely to develop primary or secondary progressive MS in their childhood. Neurologists are concerned, however, about the possibility that these children will develop secondary progression in their 20s or 30s.
“A lot of these kids drop off the map between seeing us in pediatric centers and moving to adult MS centers. Often, these are the people that show up at [age] 30 with significant disability and high lesion burdens because they dropped out of care when they left their parents’ homes,” said Dr. Graves.
Unlike in adult MS, the gender ratio is approximately equal in prepubertal pediatric MS. There is a near 1:1 ratio of females to males in children who present before age 11, but the ratio increases over time to 2:1 or 3:1 in adolescents and adults. Postpubertal and adult patients with MS have similar features, but prepubertal patients have features distinct from those of adult MS. For example, prepubertal patients have a lower prevalence of oligoclonal bands. Their MRI lesions tend to be larger and less distinct and sometimes resolve completely. In addition, children tend to have better motor, visual, and cerebellar recovery from relapses than adults.
A study published in the July issue of Pediatrics described the demographic and clinical characteristics of patients with pediatric MS in the United States. Of the 490 children and adolescents enrolled, 28% developed symptoms before age 12. Sixty-seven percent of participants identified as white, 21% as African-American, and 70% as non-Hispanic. Thirty-nine percent of patients had one or two foreign-born parents. Approximately 31% of patients had a prodrome (often infectious), which occurred mostly in children under age 12. Researchers observed a difference in the type of relapses in children under 12, compared with adolescents and adults. Young children tended to have more cerebellar symptoms, encephalopathy, and greater lesion burden in the posterior fossa.
Perinatal Risk Factors in Pediatric MS
In work from the US Network of Pediatric MS Centers presented at the 68th Annual Meeting of the American Academy of Neurology, Cesarean section (C-section) was associated with a 60% reduced odds of having pediatric-onset MS. The association remained statistically significant after the researchers adjusted for socioeconomic status and other maternal variables such as BMI, age, gestational diabetes, pre-eclampsia, and birth complications. While the mechanism of the association remains unknown, it is of interest in light of the new insights regarding the microbiome and MS. Children born by C-section typically have different gut flora for at least the first year of life, said Dr. Graves. When the data were adjusted for C-section result, maternal illness was independently associated with a twofold increase in the risk of pediatric MS.
The mechanism of maternal illness effects on MS risk have yet to be elucidated, but in animal models of MS, exposure during pregnancy to certain bacterial antigens can result in a proinflammatory Th17 phenotype and may cause long-term effects in offspring. An exploratory analysis in this perinatal risk factor study revealed that variables associated with agricultural work by the parent and home use of pesticides and insecticides were associated with a twofold increased risk of pediatric MS.
Diet, BMI, and Exercise
Diets high in salt have been associated with high relapse rate in adults. This association has not been found in pediatric MS, however. High fat intake is associated with high relapse rate in children with MS, according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS. Diets rich in fruits and vegetables are linked to a lower relapse rate, even after adjusting for fat intake.
In addition, data indicate that BMI is directly proportional to the risk for pediatric MS. Vigorous activity, however, is associated with decreased risk of pediatric MS, a decreased number of T2 lesions, and a decreased relapse rate, according to a Canadian study.
Role of Risk Genes and Genetic Ancestry in Pediatric MS
Genetics may play a key role in the development of early-onset pediatric MS. Researchers are analyzing data in the United States for people of multiple genetic ancestries. Of 110 nonhuman leukocyte antigen (HLA) risk variants for adult MS, 36 may increase the risk of pediatric MS, either at the level of single-nucleotide polymorphisms (SNPs) or as an aggregate genetic risk factor. The effect size of each SNP is greater in children than in adults; each SNP may increase the risk of MS by twofold or more.
Imaging Efforts
Imaging could improve understanding of pediatric MS. National and international efforts to standardize protocols for 3-T imaging, volumetric scans, and diffusion tensor imaging (DTI) are under way. DTI already has revealed abnormal fractional anisotropy in pediatric MS, and this abnormality is associated with cognitive difficulty. MRI and optical coherence tomography (OCT) help to distinguish between MS, neuromyelitis optica (NMO), and acute disseminated encephalomyelitis (ADEM).
OCT imaging in children indicates similar levels of neuronal and axonal injury as in adults, despite better visual recovery in children. In a study published in the Multiple Sclerosis Journal, boys with pediatric MS were found to have greater axonal loss than girls with pediatric MS.
Testing DMTs’ Efficacy
Several studies of DMTs in pediatric MS are under way. PARADIGMS is an ongoing, 24-month, double-blind, double-randomized trial investigating the effect of fingolimod on relapse rate in pediatric MS. The control group is receiving
Observational registries are studying the safety and clinical experience with disease modifying agents in children. Investigators recently published data for 100 children in an Italian registry of patients with MS treated with natalizumab. The treatment decreased relapse rate to 0.1. Approximately 28% of the population had no evidence of disease activity. The drug appeared to be well tolerated in children and to be efficacious.
—Erica Tricarico
Suggested Reading
Belman AL, Krupp LB, Olsen CS, et al. Characteristics of children and adolescents with multiple sclerosis. Pediatrics. 2016;138(1).
BALTIMORE—Lack of evidence for disease-modifying therapies (DMTs) in children presents a significant challenge in pediatric multiple sclerosis (MS). Forty percent of children with pediatric MS discontinue DMTs for inefficacy or side effects, according to an overview presented at the 141st Annual Meeting of the American Neurological Association.
“We need to keep working on clinical trials in kids and not shy away from investigating the stronger agents,” said Jennifer Graves, MD, PhD, Assistant Professor of Neurology at the University of California, San Francisco School of Medicine. Future studies should incorporate comprehensive outcomes that include measures of cognition, brain volume, and retinal integrity, she added. National and international collaborations currently under way may help achieve sample sizes that could provide conclusive evidence.
Pediatric MS Has Distinctive Features
Nearly 5% of patients with MS have pediatric onset of symptoms; 20%–30% of these patients have onset before age 11. The mean age of onset for pediatric MS is 13. In several ways, the course of MS is different in children than in adults. Children typically have higher relapse rates than adults and are less likely to develop primary or secondary progressive MS in their childhood. Neurologists are concerned, however, about the possibility that these children will develop secondary progression in their 20s or 30s.
“A lot of these kids drop off the map between seeing us in pediatric centers and moving to adult MS centers. Often, these are the people that show up at [age] 30 with significant disability and high lesion burdens because they dropped out of care when they left their parents’ homes,” said Dr. Graves.
Unlike in adult MS, the gender ratio is approximately equal in prepubertal pediatric MS. There is a near 1:1 ratio of females to males in children who present before age 11, but the ratio increases over time to 2:1 or 3:1 in adolescents and adults. Postpubertal and adult patients with MS have similar features, but prepubertal patients have features distinct from those of adult MS. For example, prepubertal patients have a lower prevalence of oligoclonal bands. Their MRI lesions tend to be larger and less distinct and sometimes resolve completely. In addition, children tend to have better motor, visual, and cerebellar recovery from relapses than adults.
A study published in the July issue of Pediatrics described the demographic and clinical characteristics of patients with pediatric MS in the United States. Of the 490 children and adolescents enrolled, 28% developed symptoms before age 12. Sixty-seven percent of participants identified as white, 21% as African-American, and 70% as non-Hispanic. Thirty-nine percent of patients had one or two foreign-born parents. Approximately 31% of patients had a prodrome (often infectious), which occurred mostly in children under age 12. Researchers observed a difference in the type of relapses in children under 12, compared with adolescents and adults. Young children tended to have more cerebellar symptoms, encephalopathy, and greater lesion burden in the posterior fossa.
Perinatal Risk Factors in Pediatric MS
In work from the US Network of Pediatric MS Centers presented at the 68th Annual Meeting of the American Academy of Neurology, Cesarean section (C-section) was associated with a 60% reduced odds of having pediatric-onset MS. The association remained statistically significant after the researchers adjusted for socioeconomic status and other maternal variables such as BMI, age, gestational diabetes, pre-eclampsia, and birth complications. While the mechanism of the association remains unknown, it is of interest in light of the new insights regarding the microbiome and MS. Children born by C-section typically have different gut flora for at least the first year of life, said Dr. Graves. When the data were adjusted for C-section result, maternal illness was independently associated with a twofold increase in the risk of pediatric MS.
The mechanism of maternal illness effects on MS risk have yet to be elucidated, but in animal models of MS, exposure during pregnancy to certain bacterial antigens can result in a proinflammatory Th17 phenotype and may cause long-term effects in offspring. An exploratory analysis in this perinatal risk factor study revealed that variables associated with agricultural work by the parent and home use of pesticides and insecticides were associated with a twofold increased risk of pediatric MS.
Diet, BMI, and Exercise
Diets high in salt have been associated with high relapse rate in adults. This association has not been found in pediatric MS, however. High fat intake is associated with high relapse rate in children with MS, according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS. Diets rich in fruits and vegetables are linked to a lower relapse rate, even after adjusting for fat intake.
In addition, data indicate that BMI is directly proportional to the risk for pediatric MS. Vigorous activity, however, is associated with decreased risk of pediatric MS, a decreased number of T2 lesions, and a decreased relapse rate, according to a Canadian study.
Role of Risk Genes and Genetic Ancestry in Pediatric MS
Genetics may play a key role in the development of early-onset pediatric MS. Researchers are analyzing data in the United States for people of multiple genetic ancestries. Of 110 nonhuman leukocyte antigen (HLA) risk variants for adult MS, 36 may increase the risk of pediatric MS, either at the level of single-nucleotide polymorphisms (SNPs) or as an aggregate genetic risk factor. The effect size of each SNP is greater in children than in adults; each SNP may increase the risk of MS by twofold or more.
Imaging Efforts
Imaging could improve understanding of pediatric MS. National and international efforts to standardize protocols for 3-T imaging, volumetric scans, and diffusion tensor imaging (DTI) are under way. DTI already has revealed abnormal fractional anisotropy in pediatric MS, and this abnormality is associated with cognitive difficulty. MRI and optical coherence tomography (OCT) help to distinguish between MS, neuromyelitis optica (NMO), and acute disseminated encephalomyelitis (ADEM).
OCT imaging in children indicates similar levels of neuronal and axonal injury as in adults, despite better visual recovery in children. In a study published in the Multiple Sclerosis Journal, boys with pediatric MS were found to have greater axonal loss than girls with pediatric MS.
Testing DMTs’ Efficacy
Several studies of DMTs in pediatric MS are under way. PARADIGMS is an ongoing, 24-month, double-blind, double-randomized trial investigating the effect of fingolimod on relapse rate in pediatric MS. The control group is receiving
Observational registries are studying the safety and clinical experience with disease modifying agents in children. Investigators recently published data for 100 children in an Italian registry of patients with MS treated with natalizumab. The treatment decreased relapse rate to 0.1. Approximately 28% of the population had no evidence of disease activity. The drug appeared to be well tolerated in children and to be efficacious.
—Erica Tricarico
Suggested Reading
Belman AL, Krupp LB, Olsen CS, et al. Characteristics of children and adolescents with multiple sclerosis. Pediatrics. 2016;138(1).
Higher Latitude Is Associated With Earlier Age of MS Onset
Among patients of European descent, higher latitude regions are associated with an earlier age at onset of multiple sclerosis (MS), according to data published online ahead of print November 3 in the Journal of Neurology, Neurosurgery and Psychiatry. Age at MS onset also is lower among people with less exposure to ultraviolet radiation.
Bruce V. Taylor, MBBS, Professorial Research Fellow at the University of Tasmania, Australia, and his collaborators examined data for 22,162 eligible patients participating in the international MSBase Registry. Eligible participants had MS, were age 16 or older, and came from centers of largely European descent. The investigators defined age at onset as the year of the first symptom suggestive of inflammatory CNS demyelination. They evaluated predictors of age at onset using linear regression.
Most patients in the sample were women (70.4%) and had relapsing-remitting MS (91.5%). In addition, most participants were from the northern hemisphere (81.4%), particularly Europe (67.2%), and a large proportion (15.7%) were from Australia. The sample’s mean age at MS onset was 32.3.
In the univariable analysis, latitude as a continuous linear factor was significantly negatively associated with age at onset. Every 10° increment of latitude was associated with a 0.3-year earlier onset. After adjustment for relevant covariates, patients of the highest latitude stratum had MS onset nearly 1.9 years earlier than patients of the lowest latitude stratum. In an evaluation of latitude as a continuous variable in the multivariable analysis, a 10° increase in latitude was associated with a 0.82-year earlier onset.
A similar pattern emerged for exposure to ultraviolet light. After adjustment for confounders, the investigators found a dose-dependent association between ultraviolet B and age at MS onset. In the multivariable analysis, people with the lowest ultraviolet B exposure had MS onset nearly two years earlier than people with the highest ultraviolet B exposure.
After adjustment for variables, age at MS onset was 0.43 years lower among women than among men. The latitudinal gradient of age at onset was not significantly different between men and women. Birth dates were evenly distributed in all four seasons, and the researchers found no association between season of birth and age at onset.
—Erik Greb
Suggested Reading
Tao C, Simpson S Jr, van der Mei I, et al. Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016 Nov 3 [Epub ahead of print].
Among patients of European descent, higher latitude regions are associated with an earlier age at onset of multiple sclerosis (MS), according to data published online ahead of print November 3 in the Journal of Neurology, Neurosurgery and Psychiatry. Age at MS onset also is lower among people with less exposure to ultraviolet radiation.
Bruce V. Taylor, MBBS, Professorial Research Fellow at the University of Tasmania, Australia, and his collaborators examined data for 22,162 eligible patients participating in the international MSBase Registry. Eligible participants had MS, were age 16 or older, and came from centers of largely European descent. The investigators defined age at onset as the year of the first symptom suggestive of inflammatory CNS demyelination. They evaluated predictors of age at onset using linear regression.
Most patients in the sample were women (70.4%) and had relapsing-remitting MS (91.5%). In addition, most participants were from the northern hemisphere (81.4%), particularly Europe (67.2%), and a large proportion (15.7%) were from Australia. The sample’s mean age at MS onset was 32.3.
In the univariable analysis, latitude as a continuous linear factor was significantly negatively associated with age at onset. Every 10° increment of latitude was associated with a 0.3-year earlier onset. After adjustment for relevant covariates, patients of the highest latitude stratum had MS onset nearly 1.9 years earlier than patients of the lowest latitude stratum. In an evaluation of latitude as a continuous variable in the multivariable analysis, a 10° increase in latitude was associated with a 0.82-year earlier onset.
A similar pattern emerged for exposure to ultraviolet light. After adjustment for confounders, the investigators found a dose-dependent association between ultraviolet B and age at MS onset. In the multivariable analysis, people with the lowest ultraviolet B exposure had MS onset nearly two years earlier than people with the highest ultraviolet B exposure.
After adjustment for variables, age at MS onset was 0.43 years lower among women than among men. The latitudinal gradient of age at onset was not significantly different between men and women. Birth dates were evenly distributed in all four seasons, and the researchers found no association between season of birth and age at onset.
—Erik Greb
Suggested Reading
Tao C, Simpson S Jr, van der Mei I, et al. Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016 Nov 3 [Epub ahead of print].
Among patients of European descent, higher latitude regions are associated with an earlier age at onset of multiple sclerosis (MS), according to data published online ahead of print November 3 in the Journal of Neurology, Neurosurgery and Psychiatry. Age at MS onset also is lower among people with less exposure to ultraviolet radiation.
Bruce V. Taylor, MBBS, Professorial Research Fellow at the University of Tasmania, Australia, and his collaborators examined data for 22,162 eligible patients participating in the international MSBase Registry. Eligible participants had MS, were age 16 or older, and came from centers of largely European descent. The investigators defined age at onset as the year of the first symptom suggestive of inflammatory CNS demyelination. They evaluated predictors of age at onset using linear regression.
Most patients in the sample were women (70.4%) and had relapsing-remitting MS (91.5%). In addition, most participants were from the northern hemisphere (81.4%), particularly Europe (67.2%), and a large proportion (15.7%) were from Australia. The sample’s mean age at MS onset was 32.3.
In the univariable analysis, latitude as a continuous linear factor was significantly negatively associated with age at onset. Every 10° increment of latitude was associated with a 0.3-year earlier onset. After adjustment for relevant covariates, patients of the highest latitude stratum had MS onset nearly 1.9 years earlier than patients of the lowest latitude stratum. In an evaluation of latitude as a continuous variable in the multivariable analysis, a 10° increase in latitude was associated with a 0.82-year earlier onset.
A similar pattern emerged for exposure to ultraviolet light. After adjustment for confounders, the investigators found a dose-dependent association between ultraviolet B and age at MS onset. In the multivariable analysis, people with the lowest ultraviolet B exposure had MS onset nearly two years earlier than people with the highest ultraviolet B exposure.
After adjustment for variables, age at MS onset was 0.43 years lower among women than among men. The latitudinal gradient of age at onset was not significantly different between men and women. Birth dates were evenly distributed in all four seasons, and the researchers found no association between season of birth and age at onset.
—Erik Greb
Suggested Reading
Tao C, Simpson S Jr, van der Mei I, et al. Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016 Nov 3 [Epub ahead of print].
Opicinumab May Benefit Patients With Relapsing-Remitting MS
LONDON—Opicinumab, an investigational remyelinating agent, may promote clinical improvement in patients with multiple sclerosis (MS) who are receiving interferon beta-1a, according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS. The monoclonal antibody appears not to have a linear dose response; the high and low doses are associated with less improvement than the moderate doses.
In a phase IIb study, patients with relapsing-remitting MS, shorter disease duration, and less severe damage to the brain had a stronger response to opicinumab. “These biological markers are, we believe, valuable to inform all future steps,” said Diego Cadavid, MD, Senior Director at Biogen in Cambridge, Massachusetts. Opicinumab was generally well tolerated. The main adverse events were hypersensitivity reactions that occurred at a dose of 100 mg/kg.
Testing Effects on Pre-Existing Disability
Dr. Cadavid and colleagues conducted the SYNERGY trial to assess the efficacy of four doses of opicinumab versus placebo in patients with MS, pre-existing disability, and recent active relapse. Of the 418 patients enrolled, 80% had relapsing-remitting MS and 20% had secondary progressive MS. All participants were receiving intramuscular interferon beta-1a.
The investigators randomized patients to placebo or one of four doses of opicinumab (ie, 3 mg/kg, 10 mg/kg, 30 mg/kg, and 100 mg/kg). A total of 418 participants were randomized and dosed; 334 completed the study. The treatment period was 72 weeks, and a final safety and efficacy analysis occurred at 84 weeks. The primary end point was confirmed improvement on Expanded Disability Status Scale (EDSS) score, Timed 25-Foot Walk (T25FW), Nine-Hole Peg Test (9HPT), or 3-second Paced Auditory Serial Addition Test (PASAT-3).
The majority of participants were female, and mean age at baseline was approximately 40. Average disease duration was approximately 10 years. The median EDSS score was 3.5. Mean T25FW score was approximately 8 seconds. Mean 9HPT score was 25 seconds. Mean PASAT-3 score was 49. Randomization resulted in well-balanced treatment groups.
Moderate Doses Brought Most Benefit
Increasing doses of opicinumab did not lead to increases in the percentage of patients experiencing improvement of pre-existing disability. The estimated percentage of improvement responders was 52% for placebo, 51% for the 3-mg/kg dose, 66% for the 10-mg/kg dose, 69% for the 30-mg/kg dose, and 41% for the 100-mg/kg dose.
“We have observed an inverted-U dose response for the improvement of pre-existing disability with opicinumab,” said Dr. Cadavid. The odds ratios for improvement on the EDSS and the 9HPT were greatest for the 10-mg/kg dose. The odds ratio for improvement on the T25FW was greatest for the 3-mg dose. The odds ratio for improvement on PASAT-3 was greatest for the 30-mg/kg dose. The study, however, was not powered for any individual component.
Participants with better whole brain multispectral thermal imaging, greater whole brain radial diffusivity on diffusion tensor imaging (DTI RD), and greater normalized whole brain volume responded better to opicinumab. The strongest odds ratios in this univariable analysis were observed on the DTI RD at 10 mg/kg.
“Further work is clearly needed to understand what explains the behavior of opicinumab at the highest dose,” said Dr. Cadavid. “We have identified an appropriate patient population, a dose and exposure, and end points to inform the next study, and [we] are in the process of evaluating the optimized study design.”
—Erik Greb
LONDON—Opicinumab, an investigational remyelinating agent, may promote clinical improvement in patients with multiple sclerosis (MS) who are receiving interferon beta-1a, according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS. The monoclonal antibody appears not to have a linear dose response; the high and low doses are associated with less improvement than the moderate doses.
In a phase IIb study, patients with relapsing-remitting MS, shorter disease duration, and less severe damage to the brain had a stronger response to opicinumab. “These biological markers are, we believe, valuable to inform all future steps,” said Diego Cadavid, MD, Senior Director at Biogen in Cambridge, Massachusetts. Opicinumab was generally well tolerated. The main adverse events were hypersensitivity reactions that occurred at a dose of 100 mg/kg.
Testing Effects on Pre-Existing Disability
Dr. Cadavid and colleagues conducted the SYNERGY trial to assess the efficacy of four doses of opicinumab versus placebo in patients with MS, pre-existing disability, and recent active relapse. Of the 418 patients enrolled, 80% had relapsing-remitting MS and 20% had secondary progressive MS. All participants were receiving intramuscular interferon beta-1a.
The investigators randomized patients to placebo or one of four doses of opicinumab (ie, 3 mg/kg, 10 mg/kg, 30 mg/kg, and 100 mg/kg). A total of 418 participants were randomized and dosed; 334 completed the study. The treatment period was 72 weeks, and a final safety and efficacy analysis occurred at 84 weeks. The primary end point was confirmed improvement on Expanded Disability Status Scale (EDSS) score, Timed 25-Foot Walk (T25FW), Nine-Hole Peg Test (9HPT), or 3-second Paced Auditory Serial Addition Test (PASAT-3).
The majority of participants were female, and mean age at baseline was approximately 40. Average disease duration was approximately 10 years. The median EDSS score was 3.5. Mean T25FW score was approximately 8 seconds. Mean 9HPT score was 25 seconds. Mean PASAT-3 score was 49. Randomization resulted in well-balanced treatment groups.
Moderate Doses Brought Most Benefit
Increasing doses of opicinumab did not lead to increases in the percentage of patients experiencing improvement of pre-existing disability. The estimated percentage of improvement responders was 52% for placebo, 51% for the 3-mg/kg dose, 66% for the 10-mg/kg dose, 69% for the 30-mg/kg dose, and 41% for the 100-mg/kg dose.
“We have observed an inverted-U dose response for the improvement of pre-existing disability with opicinumab,” said Dr. Cadavid. The odds ratios for improvement on the EDSS and the 9HPT were greatest for the 10-mg/kg dose. The odds ratio for improvement on the T25FW was greatest for the 3-mg dose. The odds ratio for improvement on PASAT-3 was greatest for the 30-mg/kg dose. The study, however, was not powered for any individual component.
Participants with better whole brain multispectral thermal imaging, greater whole brain radial diffusivity on diffusion tensor imaging (DTI RD), and greater normalized whole brain volume responded better to opicinumab. The strongest odds ratios in this univariable analysis were observed on the DTI RD at 10 mg/kg.
“Further work is clearly needed to understand what explains the behavior of opicinumab at the highest dose,” said Dr. Cadavid. “We have identified an appropriate patient population, a dose and exposure, and end points to inform the next study, and [we] are in the process of evaluating the optimized study design.”
—Erik Greb
LONDON—Opicinumab, an investigational remyelinating agent, may promote clinical improvement in patients with multiple sclerosis (MS) who are receiving interferon beta-1a, according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS. The monoclonal antibody appears not to have a linear dose response; the high and low doses are associated with less improvement than the moderate doses.
In a phase IIb study, patients with relapsing-remitting MS, shorter disease duration, and less severe damage to the brain had a stronger response to opicinumab. “These biological markers are, we believe, valuable to inform all future steps,” said Diego Cadavid, MD, Senior Director at Biogen in Cambridge, Massachusetts. Opicinumab was generally well tolerated. The main adverse events were hypersensitivity reactions that occurred at a dose of 100 mg/kg.
Testing Effects on Pre-Existing Disability
Dr. Cadavid and colleagues conducted the SYNERGY trial to assess the efficacy of four doses of opicinumab versus placebo in patients with MS, pre-existing disability, and recent active relapse. Of the 418 patients enrolled, 80% had relapsing-remitting MS and 20% had secondary progressive MS. All participants were receiving intramuscular interferon beta-1a.
The investigators randomized patients to placebo or one of four doses of opicinumab (ie, 3 mg/kg, 10 mg/kg, 30 mg/kg, and 100 mg/kg). A total of 418 participants were randomized and dosed; 334 completed the study. The treatment period was 72 weeks, and a final safety and efficacy analysis occurred at 84 weeks. The primary end point was confirmed improvement on Expanded Disability Status Scale (EDSS) score, Timed 25-Foot Walk (T25FW), Nine-Hole Peg Test (9HPT), or 3-second Paced Auditory Serial Addition Test (PASAT-3).
The majority of participants were female, and mean age at baseline was approximately 40. Average disease duration was approximately 10 years. The median EDSS score was 3.5. Mean T25FW score was approximately 8 seconds. Mean 9HPT score was 25 seconds. Mean PASAT-3 score was 49. Randomization resulted in well-balanced treatment groups.
Moderate Doses Brought Most Benefit
Increasing doses of opicinumab did not lead to increases in the percentage of patients experiencing improvement of pre-existing disability. The estimated percentage of improvement responders was 52% for placebo, 51% for the 3-mg/kg dose, 66% for the 10-mg/kg dose, 69% for the 30-mg/kg dose, and 41% for the 100-mg/kg dose.
“We have observed an inverted-U dose response for the improvement of pre-existing disability with opicinumab,” said Dr. Cadavid. The odds ratios for improvement on the EDSS and the 9HPT were greatest for the 10-mg/kg dose. The odds ratio for improvement on the T25FW was greatest for the 3-mg dose. The odds ratio for improvement on PASAT-3 was greatest for the 30-mg/kg dose. The study, however, was not powered for any individual component.
Participants with better whole brain multispectral thermal imaging, greater whole brain radial diffusivity on diffusion tensor imaging (DTI RD), and greater normalized whole brain volume responded better to opicinumab. The strongest odds ratios in this univariable analysis were observed on the DTI RD at 10 mg/kg.
“Further work is clearly needed to understand what explains the behavior of opicinumab at the highest dose,” said Dr. Cadavid. “We have identified an appropriate patient population, a dose and exposure, and end points to inform the next study, and [we] are in the process of evaluating the optimized study design.”
—Erik Greb
