User login
BTK inhibitor reduces MS enhancing lesions
. However, there was no difference between the 25-mg once daily, 75-mg once daily, 75-mg twice daily, and placebo-treated groups in Expanded Disability Status Scale scores, according to a double-blind, randomized, phase 2 trial published in the New England Journal of Medicine (2019 May 10. doi: 10.1056/NEJMoa1901981).
We first reported on the results of this trial when they were presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Find our coverage at the link below.
. However, there was no difference between the 25-mg once daily, 75-mg once daily, 75-mg twice daily, and placebo-treated groups in Expanded Disability Status Scale scores, according to a double-blind, randomized, phase 2 trial published in the New England Journal of Medicine (2019 May 10. doi: 10.1056/NEJMoa1901981).
We first reported on the results of this trial when they were presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Find our coverage at the link below.
. However, there was no difference between the 25-mg once daily, 75-mg once daily, 75-mg twice daily, and placebo-treated groups in Expanded Disability Status Scale scores, according to a double-blind, randomized, phase 2 trial published in the New England Journal of Medicine (2019 May 10. doi: 10.1056/NEJMoa1901981).
We first reported on the results of this trial when they were presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Find our coverage at the link below.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Interview with Stephen Krieger, MD, on the topographical model of multiple sclerosis
We interviewed Dr. Stephen Krieger to discuss his research in the implementation of the topographical model of Multiple Sclerosis.
What is the concept behind the topographical model of multiple sclerosis (MS)?
DR. KRIEGER: MS is an incredibly heterogeneous, and in many ways, unpredictable disease. Some people with MS will have a relapsing course, others will take a progressive course of disease, and many will have a disease course that spans both a relapsing phase and a progressive phase.
We have traditionally divided MS into phenotypes like relapsing-remitting MS (RRMS), secondary-progressive MS (SPMS), or primary-progressive MS (PPMS), and these phenotypes have been foundational in our field and used to define clinical trial cohorts and outcomes. They also have been used for the approval of our medicines. In practice, however, it sometimes can be difficult to know precisely what kind of MS, what phenotypes of MS, that an individual patient has.
The topographical model, which was proposed four years ago, tries to unify our concepts of MS in a way that spans across those phenotypes and animates the disease course in a more dynamic way to bridge from one phenotype to another.
As an individual patient, for example, develops clinically isolated syndrome (CIS) or first attack, and then RRMS, and then later SPMS, that gets depicted in a dynamic visualization through the topographical model. The model also makes use of the idea that where an MS lesion is in the central nervous system (CNS) defines the clinical symptoms that it causes.
This is something that we have long known, and the art of localization in neurology has existed for at least a couple hundred years. But we have not used that in the way we have depicted MS clinical course in recent decades. The topographical model tries to bring this idea of mapping an individual patient’s disease topography back into the clinical picture.
In the topographical model, the lesions are shown as different topographical peaks, via the hills and valleys of areas of MS damage across different regions of the CNS [image]. They are compensated for by reserve, by the ability that the nervous system has to compensate and to keep a disease process from crossing the clinical threshold and causing symptoms. What the topographical model displays is that patients with MS lose reserve as time passes.
We know that there is brain atrophy, brain stem atrophy, spinal cord atrophy, and retinal nerve fiber layer thinning in this disease. The topographical model takes the concept that MS causes a loss of tissue across the CNS and applies it to where the lesions are in the CNS. The coming together of those two things brings about the clinical picture unmasking the deficit from those lesions over time. The short version is a depiction of disease course in MS. The way it looks has been likened to a leaking swimming pool, where there is a shallow end and a deep end, and as reserve drains over time more and more of that subclinical disease becomes unmasked.
In the Laitman article (2018), you applied the model to real patients. What were the main findings from that study?
DR. KRIEGER: Until now, the topographical model has been conceptual with a visual depiction, and I think it has been important as an educational tool and an aid to help shape our thinking about MS in a unified way.
The Laitman et al research, is the first time we have applied the concepts of the model to individual patients to confirm whether we could map individual patients’ MS histories in the topographical model and see if we could depict their clinical course this way. We found that we could.
One of the most important points that the topographical model makes is the idea that as progression occurs and reserve is lost, there is an unmasking of underlying disease. Meaning, all of the signs and symptoms that a patient has had during their relapse when they were accumulating lesions should be re-revealed or recapitulated when reserve is lost and progression occurs.
To confirm this, we mapped ten patients in the topographical model. We characterized their signs and symptoms of relapses during the relapsing phase and we found that the vast majority of these symptoms had redeclared themselves at the time that these patients developed SPMS. Furthermore, those symptoms were continuing to worsen in their pattern; that is in the pattern of their disease topography as the years have continued to pass since they developed SPMS.
This was the first empirical study in real patients to show that the principles of the topographical model held true. This recapitulation hypothesis of symptoms in progressive disease was borne out, and that can help to lay the groundwork for future empirical studies to see how this model can be used as a predictive tool.
How does this new theory of MS disease progression better inform treatment decisions than the disease course theories that currently exist?
DR. KRIEGER: We have had the clinical phenotypes for 20 years and it has been very helpful to us in the development of treatments that we have shown are effective for RRMS and in more recent years for PPMS. What we don’t really have is a way of personalizing and predicting the individual person’s disease trajectory.
Although we have prognostic factors that we know are important, such as age and MRI disease burden, there is still great uncertainty of the clinical course in the individual patient. If the topographical model can be further empirically validated using real world data, that could help us to predict what is going to happen to an individual patient. That can help us to make better treatment decisions for them because it could inform our treatment decisions in a more personalized way.
Is there any other recent research that supports these concepts?
DR. KRIEGER: We talk a lot about the need for biomarkers in MS to help us predict disease course and the topographical model makes the case that lesion location is a crucial biomarker. That is, the patient that has lesions in the spinal cord and the brain stem is more likely to have progressive signs and symptoms referable to those lesions.
A separate piece of work recently done by Keegan and colleagues that was published in Multiple Sclerosis Journal, looked at their own cohort of patients that had at least one critically located lesion, typically in the high cervical spinal cord or the lower brain stem, as being the crucial driver of the development of motor dysfunction and progressive disability.
In an editorial I wrote with my colleague, Fred Lublin, called “Location, location, location,” we point out that this is in some ways the best data in support of the concept of the topographical model that I have seen. It outlines a framework or a methodology where the importance of lesion location in defining the clinical picture and the risk of progression for an individual patient can be studied.
We interviewed Dr. Stephen Krieger to discuss his research in the implementation of the topographical model of Multiple Sclerosis.
What is the concept behind the topographical model of multiple sclerosis (MS)?
DR. KRIEGER: MS is an incredibly heterogeneous, and in many ways, unpredictable disease. Some people with MS will have a relapsing course, others will take a progressive course of disease, and many will have a disease course that spans both a relapsing phase and a progressive phase.
We have traditionally divided MS into phenotypes like relapsing-remitting MS (RRMS), secondary-progressive MS (SPMS), or primary-progressive MS (PPMS), and these phenotypes have been foundational in our field and used to define clinical trial cohorts and outcomes. They also have been used for the approval of our medicines. In practice, however, it sometimes can be difficult to know precisely what kind of MS, what phenotypes of MS, that an individual patient has.
The topographical model, which was proposed four years ago, tries to unify our concepts of MS in a way that spans across those phenotypes and animates the disease course in a more dynamic way to bridge from one phenotype to another.
As an individual patient, for example, develops clinically isolated syndrome (CIS) or first attack, and then RRMS, and then later SPMS, that gets depicted in a dynamic visualization through the topographical model. The model also makes use of the idea that where an MS lesion is in the central nervous system (CNS) defines the clinical symptoms that it causes.
This is something that we have long known, and the art of localization in neurology has existed for at least a couple hundred years. But we have not used that in the way we have depicted MS clinical course in recent decades. The topographical model tries to bring this idea of mapping an individual patient’s disease topography back into the clinical picture.
In the topographical model, the lesions are shown as different topographical peaks, via the hills and valleys of areas of MS damage across different regions of the CNS [image]. They are compensated for by reserve, by the ability that the nervous system has to compensate and to keep a disease process from crossing the clinical threshold and causing symptoms. What the topographical model displays is that patients with MS lose reserve as time passes.
We know that there is brain atrophy, brain stem atrophy, spinal cord atrophy, and retinal nerve fiber layer thinning in this disease. The topographical model takes the concept that MS causes a loss of tissue across the CNS and applies it to where the lesions are in the CNS. The coming together of those two things brings about the clinical picture unmasking the deficit from those lesions over time. The short version is a depiction of disease course in MS. The way it looks has been likened to a leaking swimming pool, where there is a shallow end and a deep end, and as reserve drains over time more and more of that subclinical disease becomes unmasked.
In the Laitman article (2018), you applied the model to real patients. What were the main findings from that study?
DR. KRIEGER: Until now, the topographical model has been conceptual with a visual depiction, and I think it has been important as an educational tool and an aid to help shape our thinking about MS in a unified way.
The Laitman et al research, is the first time we have applied the concepts of the model to individual patients to confirm whether we could map individual patients’ MS histories in the topographical model and see if we could depict their clinical course this way. We found that we could.
One of the most important points that the topographical model makes is the idea that as progression occurs and reserve is lost, there is an unmasking of underlying disease. Meaning, all of the signs and symptoms that a patient has had during their relapse when they were accumulating lesions should be re-revealed or recapitulated when reserve is lost and progression occurs.
To confirm this, we mapped ten patients in the topographical model. We characterized their signs and symptoms of relapses during the relapsing phase and we found that the vast majority of these symptoms had redeclared themselves at the time that these patients developed SPMS. Furthermore, those symptoms were continuing to worsen in their pattern; that is in the pattern of their disease topography as the years have continued to pass since they developed SPMS.
This was the first empirical study in real patients to show that the principles of the topographical model held true. This recapitulation hypothesis of symptoms in progressive disease was borne out, and that can help to lay the groundwork for future empirical studies to see how this model can be used as a predictive tool.
How does this new theory of MS disease progression better inform treatment decisions than the disease course theories that currently exist?
DR. KRIEGER: We have had the clinical phenotypes for 20 years and it has been very helpful to us in the development of treatments that we have shown are effective for RRMS and in more recent years for PPMS. What we don’t really have is a way of personalizing and predicting the individual person’s disease trajectory.
Although we have prognostic factors that we know are important, such as age and MRI disease burden, there is still great uncertainty of the clinical course in the individual patient. If the topographical model can be further empirically validated using real world data, that could help us to predict what is going to happen to an individual patient. That can help us to make better treatment decisions for them because it could inform our treatment decisions in a more personalized way.
Is there any other recent research that supports these concepts?
DR. KRIEGER: We talk a lot about the need for biomarkers in MS to help us predict disease course and the topographical model makes the case that lesion location is a crucial biomarker. That is, the patient that has lesions in the spinal cord and the brain stem is more likely to have progressive signs and symptoms referable to those lesions.
A separate piece of work recently done by Keegan and colleagues that was published in Multiple Sclerosis Journal, looked at their own cohort of patients that had at least one critically located lesion, typically in the high cervical spinal cord or the lower brain stem, as being the crucial driver of the development of motor dysfunction and progressive disability.
In an editorial I wrote with my colleague, Fred Lublin, called “Location, location, location,” we point out that this is in some ways the best data in support of the concept of the topographical model that I have seen. It outlines a framework or a methodology where the importance of lesion location in defining the clinical picture and the risk of progression for an individual patient can be studied.
We interviewed Dr. Stephen Krieger to discuss his research in the implementation of the topographical model of Multiple Sclerosis.
What is the concept behind the topographical model of multiple sclerosis (MS)?
DR. KRIEGER: MS is an incredibly heterogeneous, and in many ways, unpredictable disease. Some people with MS will have a relapsing course, others will take a progressive course of disease, and many will have a disease course that spans both a relapsing phase and a progressive phase.
We have traditionally divided MS into phenotypes like relapsing-remitting MS (RRMS), secondary-progressive MS (SPMS), or primary-progressive MS (PPMS), and these phenotypes have been foundational in our field and used to define clinical trial cohorts and outcomes. They also have been used for the approval of our medicines. In practice, however, it sometimes can be difficult to know precisely what kind of MS, what phenotypes of MS, that an individual patient has.
The topographical model, which was proposed four years ago, tries to unify our concepts of MS in a way that spans across those phenotypes and animates the disease course in a more dynamic way to bridge from one phenotype to another.
As an individual patient, for example, develops clinically isolated syndrome (CIS) or first attack, and then RRMS, and then later SPMS, that gets depicted in a dynamic visualization through the topographical model. The model also makes use of the idea that where an MS lesion is in the central nervous system (CNS) defines the clinical symptoms that it causes.
This is something that we have long known, and the art of localization in neurology has existed for at least a couple hundred years. But we have not used that in the way we have depicted MS clinical course in recent decades. The topographical model tries to bring this idea of mapping an individual patient’s disease topography back into the clinical picture.
In the topographical model, the lesions are shown as different topographical peaks, via the hills and valleys of areas of MS damage across different regions of the CNS [image]. They are compensated for by reserve, by the ability that the nervous system has to compensate and to keep a disease process from crossing the clinical threshold and causing symptoms. What the topographical model displays is that patients with MS lose reserve as time passes.
We know that there is brain atrophy, brain stem atrophy, spinal cord atrophy, and retinal nerve fiber layer thinning in this disease. The topographical model takes the concept that MS causes a loss of tissue across the CNS and applies it to where the lesions are in the CNS. The coming together of those two things brings about the clinical picture unmasking the deficit from those lesions over time. The short version is a depiction of disease course in MS. The way it looks has been likened to a leaking swimming pool, where there is a shallow end and a deep end, and as reserve drains over time more and more of that subclinical disease becomes unmasked.
In the Laitman article (2018), you applied the model to real patients. What were the main findings from that study?
DR. KRIEGER: Until now, the topographical model has been conceptual with a visual depiction, and I think it has been important as an educational tool and an aid to help shape our thinking about MS in a unified way.
The Laitman et al research, is the first time we have applied the concepts of the model to individual patients to confirm whether we could map individual patients’ MS histories in the topographical model and see if we could depict their clinical course this way. We found that we could.
One of the most important points that the topographical model makes is the idea that as progression occurs and reserve is lost, there is an unmasking of underlying disease. Meaning, all of the signs and symptoms that a patient has had during their relapse when they were accumulating lesions should be re-revealed or recapitulated when reserve is lost and progression occurs.
To confirm this, we mapped ten patients in the topographical model. We characterized their signs and symptoms of relapses during the relapsing phase and we found that the vast majority of these symptoms had redeclared themselves at the time that these patients developed SPMS. Furthermore, those symptoms were continuing to worsen in their pattern; that is in the pattern of their disease topography as the years have continued to pass since they developed SPMS.
This was the first empirical study in real patients to show that the principles of the topographical model held true. This recapitulation hypothesis of symptoms in progressive disease was borne out, and that can help to lay the groundwork for future empirical studies to see how this model can be used as a predictive tool.
How does this new theory of MS disease progression better inform treatment decisions than the disease course theories that currently exist?
DR. KRIEGER: We have had the clinical phenotypes for 20 years and it has been very helpful to us in the development of treatments that we have shown are effective for RRMS and in more recent years for PPMS. What we don’t really have is a way of personalizing and predicting the individual person’s disease trajectory.
Although we have prognostic factors that we know are important, such as age and MRI disease burden, there is still great uncertainty of the clinical course in the individual patient. If the topographical model can be further empirically validated using real world data, that could help us to predict what is going to happen to an individual patient. That can help us to make better treatment decisions for them because it could inform our treatment decisions in a more personalized way.
Is there any other recent research that supports these concepts?
DR. KRIEGER: We talk a lot about the need for biomarkers in MS to help us predict disease course and the topographical model makes the case that lesion location is a crucial biomarker. That is, the patient that has lesions in the spinal cord and the brain stem is more likely to have progressive signs and symptoms referable to those lesions.
A separate piece of work recently done by Keegan and colleagues that was published in Multiple Sclerosis Journal, looked at their own cohort of patients that had at least one critically located lesion, typically in the high cervical spinal cord or the lower brain stem, as being the crucial driver of the development of motor dysfunction and progressive disability.
In an editorial I wrote with my colleague, Fred Lublin, called “Location, location, location,” we point out that this is in some ways the best data in support of the concept of the topographical model that I have seen. It outlines a framework or a methodology where the importance of lesion location in defining the clinical picture and the risk of progression for an individual patient can be studied.
Changes in brain networks may predict MS worsening
PHILADELPHIA – (MS), according to a study described at the annual meeting of the American Academy of Neurology.
Neurologists do not have reliable biomarkers to predict disease evolution in the medium or long term for patients with MS. The ability to predict disease evolution accurately could aid in the choice of treatment.
Maria Assunta Rocca, MD, head of the Neuroimaging of CNS White Matter Unit, Department of Neurology, Institute of Experimental Neurology, Scientific Institute Ospedale, San Raffaele, Milan, Italy, and colleagues sought to evaluate structural and functional network MRI measures as predictors of clinical deterioration over 6.5 years. They obtained conventional, 3D, T1-weighted, diffusion-weighted MRI, and resting-state functional MRI images at baseline from 233 patients with MS and 77 healthy controls. Patients underwent a neurologic examination at baseline and after a median follow-up period of 6.5 years. At follow-up, the researchers classified patients as clinically stable or worsened, according to their change in Expanded Disability Status Scale (EDSS) score. They also evaluated conversion to secondary progressive MS among patients with relapsing remitting MS at baseline.
To identify the main large-scale resting state functional connectivity networks, Dr. Rocca and colleagues applied spatial independent component analysis to resting state functional MRI data. They applied the same technique to gray matter probability maps and fractional anisotropy maps to identify the corresponding structural gray matter and white matter networks.
At follow-up, 105 patients with MS (45%) had significant EDSS worsening. Of 157 patients with relapsing remitting MS, 26 (16%) converted to secondary progressive MS. The multivariable model, after adjustment for follow-up duration, identified baseline EDSS score (odds ratio, 1.59), normalized gray matter volume (OR, 0.99), and abnormally high baseline resting state functional connectivity of the left precentral gyrus in the sensorimotor network (OR, 1.67) as predictors of EDSS worsening. These variables remained significant after the researchers adjusted for treatment effect. Independent variables associated with conversion to secondary progressive MS included baseline EDSS score (OR, 2.8) and atrophy of gray matter networks associated with sensory (OR, 0.5) and motor (OR, 0.4) functions.
Dr. Rocca received personal compensation from Biogen Idec, Novartis, Genzyme, Sanofi-Aventis, Teva, Merck Serono, and Roche. Coauthors reported research support from Biogen, Merck Serono, Novartis, Teva, and Roche..
SOURCE: Filippi M et al. AAN 2019, Abstract S49.004.
PHILADELPHIA – (MS), according to a study described at the annual meeting of the American Academy of Neurology.
Neurologists do not have reliable biomarkers to predict disease evolution in the medium or long term for patients with MS. The ability to predict disease evolution accurately could aid in the choice of treatment.
Maria Assunta Rocca, MD, head of the Neuroimaging of CNS White Matter Unit, Department of Neurology, Institute of Experimental Neurology, Scientific Institute Ospedale, San Raffaele, Milan, Italy, and colleagues sought to evaluate structural and functional network MRI measures as predictors of clinical deterioration over 6.5 years. They obtained conventional, 3D, T1-weighted, diffusion-weighted MRI, and resting-state functional MRI images at baseline from 233 patients with MS and 77 healthy controls. Patients underwent a neurologic examination at baseline and after a median follow-up period of 6.5 years. At follow-up, the researchers classified patients as clinically stable or worsened, according to their change in Expanded Disability Status Scale (EDSS) score. They also evaluated conversion to secondary progressive MS among patients with relapsing remitting MS at baseline.
To identify the main large-scale resting state functional connectivity networks, Dr. Rocca and colleagues applied spatial independent component analysis to resting state functional MRI data. They applied the same technique to gray matter probability maps and fractional anisotropy maps to identify the corresponding structural gray matter and white matter networks.
At follow-up, 105 patients with MS (45%) had significant EDSS worsening. Of 157 patients with relapsing remitting MS, 26 (16%) converted to secondary progressive MS. The multivariable model, after adjustment for follow-up duration, identified baseline EDSS score (odds ratio, 1.59), normalized gray matter volume (OR, 0.99), and abnormally high baseline resting state functional connectivity of the left precentral gyrus in the sensorimotor network (OR, 1.67) as predictors of EDSS worsening. These variables remained significant after the researchers adjusted for treatment effect. Independent variables associated with conversion to secondary progressive MS included baseline EDSS score (OR, 2.8) and atrophy of gray matter networks associated with sensory (OR, 0.5) and motor (OR, 0.4) functions.
Dr. Rocca received personal compensation from Biogen Idec, Novartis, Genzyme, Sanofi-Aventis, Teva, Merck Serono, and Roche. Coauthors reported research support from Biogen, Merck Serono, Novartis, Teva, and Roche..
SOURCE: Filippi M et al. AAN 2019, Abstract S49.004.
PHILADELPHIA – (MS), according to a study described at the annual meeting of the American Academy of Neurology.
Neurologists do not have reliable biomarkers to predict disease evolution in the medium or long term for patients with MS. The ability to predict disease evolution accurately could aid in the choice of treatment.
Maria Assunta Rocca, MD, head of the Neuroimaging of CNS White Matter Unit, Department of Neurology, Institute of Experimental Neurology, Scientific Institute Ospedale, San Raffaele, Milan, Italy, and colleagues sought to evaluate structural and functional network MRI measures as predictors of clinical deterioration over 6.5 years. They obtained conventional, 3D, T1-weighted, diffusion-weighted MRI, and resting-state functional MRI images at baseline from 233 patients with MS and 77 healthy controls. Patients underwent a neurologic examination at baseline and after a median follow-up period of 6.5 years. At follow-up, the researchers classified patients as clinically stable or worsened, according to their change in Expanded Disability Status Scale (EDSS) score. They also evaluated conversion to secondary progressive MS among patients with relapsing remitting MS at baseline.
To identify the main large-scale resting state functional connectivity networks, Dr. Rocca and colleagues applied spatial independent component analysis to resting state functional MRI data. They applied the same technique to gray matter probability maps and fractional anisotropy maps to identify the corresponding structural gray matter and white matter networks.
At follow-up, 105 patients with MS (45%) had significant EDSS worsening. Of 157 patients with relapsing remitting MS, 26 (16%) converted to secondary progressive MS. The multivariable model, after adjustment for follow-up duration, identified baseline EDSS score (odds ratio, 1.59), normalized gray matter volume (OR, 0.99), and abnormally high baseline resting state functional connectivity of the left precentral gyrus in the sensorimotor network (OR, 1.67) as predictors of EDSS worsening. These variables remained significant after the researchers adjusted for treatment effect. Independent variables associated with conversion to secondary progressive MS included baseline EDSS score (OR, 2.8) and atrophy of gray matter networks associated with sensory (OR, 0.5) and motor (OR, 0.4) functions.
Dr. Rocca received personal compensation from Biogen Idec, Novartis, Genzyme, Sanofi-Aventis, Teva, Merck Serono, and Roche. Coauthors reported research support from Biogen, Merck Serono, Novartis, Teva, and Roche..
SOURCE: Filippi M et al. AAN 2019, Abstract S49.004.
REPORTING FROM AAN 2019
Key clinical point: Structural and functional network MRI measures predict long-term worsening in multiple sclerosis.
Major finding: The odds ratio of worsening for patients with abnormally high baseline resting state functional connectivity is 1.67.
Study details: A prospective imaging study of 233 patients with multiple sclerosis and 77 healthy controls.
Disclosures: Dr. Rocca received personal compensation from Biogen Idec, Novartis, Genzyme, Sanofi-Aventis, Teva, Merck Serono, and Roche. Coauthors reported research support from Biogen, Merck Serono, Novartis, Teva, and Roche.
Source: Filippi M et al. AAN 2019, Abstract S49.004.
Ibudilast’s efficacy differs in primary and secondary progressive MS
PHILADELPHIA – researchers reported at the annual meeting of the American Academy of Neurology.
The difference may be related to faster atrophy rates among patients with primary progressive MS who received placebo, compared with those with secondary progressive MS who received placebo.
The finding was surprising, said Andrew Goodman, MD, professor of neurology, chief of the neuroimmunology unit, and director of the multiple sclerosis center at the University of Rochester (N.Y.). “Going into the trial, it was my bias and expectation that both primary and secondary progressive MS would behave more similarly than different.”
The trial, SPRINT-MS, included more than 250 patients with progressive MS at 28 sites. Patients were aged 18-65 years and were followed for 96 weeks. Patients had primary progressive MS (n = 134) or secondary progressive MS (n = 121) and were randomized 1:1 to ibudilast or placebo.
Ibudilast is an orally administered small molecule that has been used in Japan for approximately 30 years for asthma and other indications, Dr. Goodman said. Preclinical models suggested that the drug may have neuroprotective effects.
The trial’s primary result – a 48% slowing in the rate of whole brain atrophy as measured by brain parenchymal fraction with ibudilast – was reported last year (N Engl J Med. 2018 Aug 30;379[9]:846-55).
The present study examined whether the treatment effect of ibudilast was similar by progressive disease type using a linear mixed model analytic approach.
The group with primary progressive MS included a smaller percentage of women. Patients with secondary progressive MS had longer disease duration and more brain atrophy at baseline.
“The overall benefit which we previously reported appears to be driven by subjects with primary progressive rather than secondary progressive MS,” Dr. Goodman said. Accounting for baseline covariates did not affect this result.
Among patients who received placebo, brain atrophy in those with secondary progressive MS was 57% slower than in those with primary progressive MS. The rate of atrophy for untreated patients with primary progressive MS “was roughly twice as fast as that in the secondary progressive MS group, which we think may explain in part the differential in efficacy,” Dr. Goodman said. “These findings may impact future trial design for progressive MS.”
The SPRINT-MS trial was funded by the National Institute of Neurological Disorders and Stroke. The National Multiple Sclerosis Society and MediciNova also supported the study. Dr. Goodman reported receiving research support from pharmaceutical companies, as well as personal compensation from companies for consulting, serving on a scientific advisory board, and speaking.
SOURCE: Goodman A et al. AAN 2019, Abstract S12.007.
PHILADELPHIA – researchers reported at the annual meeting of the American Academy of Neurology.
The difference may be related to faster atrophy rates among patients with primary progressive MS who received placebo, compared with those with secondary progressive MS who received placebo.
The finding was surprising, said Andrew Goodman, MD, professor of neurology, chief of the neuroimmunology unit, and director of the multiple sclerosis center at the University of Rochester (N.Y.). “Going into the trial, it was my bias and expectation that both primary and secondary progressive MS would behave more similarly than different.”
The trial, SPRINT-MS, included more than 250 patients with progressive MS at 28 sites. Patients were aged 18-65 years and were followed for 96 weeks. Patients had primary progressive MS (n = 134) or secondary progressive MS (n = 121) and were randomized 1:1 to ibudilast or placebo.
Ibudilast is an orally administered small molecule that has been used in Japan for approximately 30 years for asthma and other indications, Dr. Goodman said. Preclinical models suggested that the drug may have neuroprotective effects.
The trial’s primary result – a 48% slowing in the rate of whole brain atrophy as measured by brain parenchymal fraction with ibudilast – was reported last year (N Engl J Med. 2018 Aug 30;379[9]:846-55).
The present study examined whether the treatment effect of ibudilast was similar by progressive disease type using a linear mixed model analytic approach.
The group with primary progressive MS included a smaller percentage of women. Patients with secondary progressive MS had longer disease duration and more brain atrophy at baseline.
“The overall benefit which we previously reported appears to be driven by subjects with primary progressive rather than secondary progressive MS,” Dr. Goodman said. Accounting for baseline covariates did not affect this result.
Among patients who received placebo, brain atrophy in those with secondary progressive MS was 57% slower than in those with primary progressive MS. The rate of atrophy for untreated patients with primary progressive MS “was roughly twice as fast as that in the secondary progressive MS group, which we think may explain in part the differential in efficacy,” Dr. Goodman said. “These findings may impact future trial design for progressive MS.”
The SPRINT-MS trial was funded by the National Institute of Neurological Disorders and Stroke. The National Multiple Sclerosis Society and MediciNova also supported the study. Dr. Goodman reported receiving research support from pharmaceutical companies, as well as personal compensation from companies for consulting, serving on a scientific advisory board, and speaking.
SOURCE: Goodman A et al. AAN 2019, Abstract S12.007.
PHILADELPHIA – researchers reported at the annual meeting of the American Academy of Neurology.
The difference may be related to faster atrophy rates among patients with primary progressive MS who received placebo, compared with those with secondary progressive MS who received placebo.
The finding was surprising, said Andrew Goodman, MD, professor of neurology, chief of the neuroimmunology unit, and director of the multiple sclerosis center at the University of Rochester (N.Y.). “Going into the trial, it was my bias and expectation that both primary and secondary progressive MS would behave more similarly than different.”
The trial, SPRINT-MS, included more than 250 patients with progressive MS at 28 sites. Patients were aged 18-65 years and were followed for 96 weeks. Patients had primary progressive MS (n = 134) or secondary progressive MS (n = 121) and were randomized 1:1 to ibudilast or placebo.
Ibudilast is an orally administered small molecule that has been used in Japan for approximately 30 years for asthma and other indications, Dr. Goodman said. Preclinical models suggested that the drug may have neuroprotective effects.
The trial’s primary result – a 48% slowing in the rate of whole brain atrophy as measured by brain parenchymal fraction with ibudilast – was reported last year (N Engl J Med. 2018 Aug 30;379[9]:846-55).
The present study examined whether the treatment effect of ibudilast was similar by progressive disease type using a linear mixed model analytic approach.
The group with primary progressive MS included a smaller percentage of women. Patients with secondary progressive MS had longer disease duration and more brain atrophy at baseline.
“The overall benefit which we previously reported appears to be driven by subjects with primary progressive rather than secondary progressive MS,” Dr. Goodman said. Accounting for baseline covariates did not affect this result.
Among patients who received placebo, brain atrophy in those with secondary progressive MS was 57% slower than in those with primary progressive MS. The rate of atrophy for untreated patients with primary progressive MS “was roughly twice as fast as that in the secondary progressive MS group, which we think may explain in part the differential in efficacy,” Dr. Goodman said. “These findings may impact future trial design for progressive MS.”
The SPRINT-MS trial was funded by the National Institute of Neurological Disorders and Stroke. The National Multiple Sclerosis Society and MediciNova also supported the study. Dr. Goodman reported receiving research support from pharmaceutical companies, as well as personal compensation from companies for consulting, serving on a scientific advisory board, and speaking.
SOURCE: Goodman A et al. AAN 2019, Abstract S12.007.
REPORTING FROM AAN 2019
The art of selecting an MS therapy
DALLAS – , said Mark Freedman, MD, MSc, in a presentation at ACTRIMS Forum 2019, the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “Right now, we are probably dealing with more of an imprecise medicine,” said Dr. Freedman.
Information such as a patient’s ability to recover from relapses may indicate MS severity or the likelihood of disease progression, but selecting a therapy remains “an art of medicine,” said Dr. Freedman, professor of neurology at the University of Ottawa, director of the multiple sclerosis research unit at Ottawa Hospital, and senior scientist at the Ottawa Hospital Research Institute.
When prescribing a DMT, neurologists tend to consider three key elements: the disease, the treatment, and patient expectations. “Focus on these three aspects,” Dr. Freedman said.
It is no longer sufficient for neurologists to diagnose MS, hand the patient a drug, and “expect that things are going to go the way you want them to go,” he said.
Immunomodulating, anti–cell trafficking, or cell-depleting therapy?
Genetics, sex, types of relapses, recovery from relapses, response to therapy, MRI burden, and other biomarkers such as oligoclonal bands and neurofilaments may indicate which patients have severe disease and should receive aggressive treatment.
Determining the phase of the disease is a crucial first step “that is going to drive your choice of therapy,” he said.
Dr. Freedman likened the development of progressive MS to approaching the edge of a cliff. If patients appear to be nearing the progressive phase, “then your choice of therapy has to be an aggressive one – one that will hopefully hold them back from falling,” he said. In the earlier phases of MS, on the other hand, “you are looking at a long-term treatment that should probably be safe and still able to contain the disease,” such as an immunomodulator. If a patient is “about to fall off, you may want to go for temporary use of an antitrafficker to control things, and then eventually deplete the cells that are going to be causing the patient to fall off the cliff.”
Prognostic factors
Disease activity over time, and whether the disease is progressing faster or slower than would be expected, may be important prognostic factors. A patient’s sex also may be a factor because women tend to have more attacks and to have their attacks at a younger age, Dr. Freedman said.
The types of relapses and a patient’s ability to recover from them may provide important information. “Some attacks are quite mild. Others tend to build up disease,” Dr. Freedman said. “Some people are better healers than others. We have all seen people who have been quadriplegic in an ICU on a ventilator walk out of the hospital without even a numb toe. And other people who have a little bit of weakness in one leg seem to never be able to recover from that. Exactly what drives repair is still not clear.” Most patients do recover, however, “and the inability to recover early on is a bad omen,” Dr. Freedman said.
When researchers examined the relationship between functional components of the Expanded Disability Status Scale (EDSS) and disability progression, “not surprisingly ... pyramidal and spinal cord and cerebellar [functioning] are more associated with earlier progression” (Neuroepidemiology. 2015;44[1]:16-23).
A study by Lublin et al. found that patients with MS whose attacks left them with residual deficits had more EDSS accumulation over time (Neurology. 2003 Dec 9;61[11]:1528-32.).
Response to immunomodulators
“The inability to control the disease with an immunomodulator is a bad sign,” Dr. Freedman said. He pointed to data from a trial of teriflunomide that included patients who had had suboptimal responses to first-line therapy as well as patients who were treatment naive (Mult Scler. 2018 Apr;24[4]:535-9.). Some of the patients who had received prior MS therapy were randomized to placebo, which “is not something that would happen today,” he said.
“If you just focus on the [patients who received placebo] and look at the rate of attack in patients who had no prior DMT, at least one prior DMT, or two or more prior DMTs, the attack rates are much higher in those individuals who tried and failed first-line therapies,” Dr. Freedman said. These patients also had more EDSS progression. “The majority of people do respond [to first-line treatment], but those who do not you need to worry about a little bit more than those who do respond.”
MRI lesions and brain reserve
MRI activity over time tends to predict disease progression, and lesion location is important. One cohort study found that the likelihood of developing secondary progressive MS was lower among patients who did not develop new spinal cord or brainstem lesions in the first three years of the disease, compared with those who did.
In addition, patients who presented with more lesions were more likely to reach an EDSS score 3 or 6 over 10 years (Brain. 2008 Mar;131[Pt 3]:808-17.).
Brain reserve also may be important. Among 52 treatment-naive Serbian adults with MS, Sumowski et al. found that maximal lifetime brain growth as estimated with intracranial volume was associated with risk of disability progression over 5 years (Neurology. 2016 May 24;86[21]:2006-9.). “Those who had a greater reserve had a much lower risk of disease progression,” Dr. Freedman said. The results suggest that patients with more brain reserve may be better able to sustain damage as the disease progresses and they age, he said.
Comorbidities
In the past, neurologists may have left it up to general practitioners “to sort out the rest of the patient’s health,” Dr. Freedman said. “But we now recognize that having certain comorbidities already puts a higher burden onto the disease. And those patients who have more comorbidities ... are going to do worse. But not only are they going to do worse ... it turns out that patients who have more comorbidities are going to have less of a response to your various therapies.” Vascular comorbidities, in particular, may affect treatment response (Neurology. 2017 Nov 28;89[22]:2222-9.).
If hypertension or diabetes clinics can help control those conditions in patients with MS, “it will help us a lot in getting what we are expecting from the [MS] medications,” Dr. Freedman said.
Adherence, expectations, and symptomatic treatment
Ultimately, selecting an MS therapy is a decision that doctors share with their patients. “You’re going to have a discussion with them,” he said. “You can see what fits their lifestyle.” For example, a world traveler might not be a good candidate for a drug that requires regular monitoring. A patient’s risk averseness also may influence treatment choice.
If you involve patients in the selection process, it may improve medication adherence. In addition, patients need to understand what you aim to accomplish with a DMT, said Dr. Freedman. “That may sound like a trivial thing. But how many times has the patient come in and said, ‘The drug is not working. ... My eye is not better’” when that was not the goal of treatment to begin with. Let patients know that symptomatic treatments may address problems apart from MS DMT. This personalized but imprecise approach to treatment is “probably the best we can do for now,” Dr. Freedman said.
Dr. Freedman has received a research grant from Genzyme and is on the company’s speakers bureau. He has received honoraria and consulting fees from various pharmaceutical companies and serves on companies’ advisory boards.
SOURCE: Freedman MS. ACTRIMS Forum 2019, Session 2.
DALLAS – , said Mark Freedman, MD, MSc, in a presentation at ACTRIMS Forum 2019, the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “Right now, we are probably dealing with more of an imprecise medicine,” said Dr. Freedman.
Information such as a patient’s ability to recover from relapses may indicate MS severity or the likelihood of disease progression, but selecting a therapy remains “an art of medicine,” said Dr. Freedman, professor of neurology at the University of Ottawa, director of the multiple sclerosis research unit at Ottawa Hospital, and senior scientist at the Ottawa Hospital Research Institute.
When prescribing a DMT, neurologists tend to consider three key elements: the disease, the treatment, and patient expectations. “Focus on these three aspects,” Dr. Freedman said.
It is no longer sufficient for neurologists to diagnose MS, hand the patient a drug, and “expect that things are going to go the way you want them to go,” he said.
Immunomodulating, anti–cell trafficking, or cell-depleting therapy?
Genetics, sex, types of relapses, recovery from relapses, response to therapy, MRI burden, and other biomarkers such as oligoclonal bands and neurofilaments may indicate which patients have severe disease and should receive aggressive treatment.
Determining the phase of the disease is a crucial first step “that is going to drive your choice of therapy,” he said.
Dr. Freedman likened the development of progressive MS to approaching the edge of a cliff. If patients appear to be nearing the progressive phase, “then your choice of therapy has to be an aggressive one – one that will hopefully hold them back from falling,” he said. In the earlier phases of MS, on the other hand, “you are looking at a long-term treatment that should probably be safe and still able to contain the disease,” such as an immunomodulator. If a patient is “about to fall off, you may want to go for temporary use of an antitrafficker to control things, and then eventually deplete the cells that are going to be causing the patient to fall off the cliff.”
Prognostic factors
Disease activity over time, and whether the disease is progressing faster or slower than would be expected, may be important prognostic factors. A patient’s sex also may be a factor because women tend to have more attacks and to have their attacks at a younger age, Dr. Freedman said.
The types of relapses and a patient’s ability to recover from them may provide important information. “Some attacks are quite mild. Others tend to build up disease,” Dr. Freedman said. “Some people are better healers than others. We have all seen people who have been quadriplegic in an ICU on a ventilator walk out of the hospital without even a numb toe. And other people who have a little bit of weakness in one leg seem to never be able to recover from that. Exactly what drives repair is still not clear.” Most patients do recover, however, “and the inability to recover early on is a bad omen,” Dr. Freedman said.
When researchers examined the relationship between functional components of the Expanded Disability Status Scale (EDSS) and disability progression, “not surprisingly ... pyramidal and spinal cord and cerebellar [functioning] are more associated with earlier progression” (Neuroepidemiology. 2015;44[1]:16-23).
A study by Lublin et al. found that patients with MS whose attacks left them with residual deficits had more EDSS accumulation over time (Neurology. 2003 Dec 9;61[11]:1528-32.).
Response to immunomodulators
“The inability to control the disease with an immunomodulator is a bad sign,” Dr. Freedman said. He pointed to data from a trial of teriflunomide that included patients who had had suboptimal responses to first-line therapy as well as patients who were treatment naive (Mult Scler. 2018 Apr;24[4]:535-9.). Some of the patients who had received prior MS therapy were randomized to placebo, which “is not something that would happen today,” he said.
“If you just focus on the [patients who received placebo] and look at the rate of attack in patients who had no prior DMT, at least one prior DMT, or two or more prior DMTs, the attack rates are much higher in those individuals who tried and failed first-line therapies,” Dr. Freedman said. These patients also had more EDSS progression. “The majority of people do respond [to first-line treatment], but those who do not you need to worry about a little bit more than those who do respond.”
MRI lesions and brain reserve
MRI activity over time tends to predict disease progression, and lesion location is important. One cohort study found that the likelihood of developing secondary progressive MS was lower among patients who did not develop new spinal cord or brainstem lesions in the first three years of the disease, compared with those who did.
In addition, patients who presented with more lesions were more likely to reach an EDSS score 3 or 6 over 10 years (Brain. 2008 Mar;131[Pt 3]:808-17.).
Brain reserve also may be important. Among 52 treatment-naive Serbian adults with MS, Sumowski et al. found that maximal lifetime brain growth as estimated with intracranial volume was associated with risk of disability progression over 5 years (Neurology. 2016 May 24;86[21]:2006-9.). “Those who had a greater reserve had a much lower risk of disease progression,” Dr. Freedman said. The results suggest that patients with more brain reserve may be better able to sustain damage as the disease progresses and they age, he said.
Comorbidities
In the past, neurologists may have left it up to general practitioners “to sort out the rest of the patient’s health,” Dr. Freedman said. “But we now recognize that having certain comorbidities already puts a higher burden onto the disease. And those patients who have more comorbidities ... are going to do worse. But not only are they going to do worse ... it turns out that patients who have more comorbidities are going to have less of a response to your various therapies.” Vascular comorbidities, in particular, may affect treatment response (Neurology. 2017 Nov 28;89[22]:2222-9.).
If hypertension or diabetes clinics can help control those conditions in patients with MS, “it will help us a lot in getting what we are expecting from the [MS] medications,” Dr. Freedman said.
Adherence, expectations, and symptomatic treatment
Ultimately, selecting an MS therapy is a decision that doctors share with their patients. “You’re going to have a discussion with them,” he said. “You can see what fits their lifestyle.” For example, a world traveler might not be a good candidate for a drug that requires regular monitoring. A patient’s risk averseness also may influence treatment choice.
If you involve patients in the selection process, it may improve medication adherence. In addition, patients need to understand what you aim to accomplish with a DMT, said Dr. Freedman. “That may sound like a trivial thing. But how many times has the patient come in and said, ‘The drug is not working. ... My eye is not better’” when that was not the goal of treatment to begin with. Let patients know that symptomatic treatments may address problems apart from MS DMT. This personalized but imprecise approach to treatment is “probably the best we can do for now,” Dr. Freedman said.
Dr. Freedman has received a research grant from Genzyme and is on the company’s speakers bureau. He has received honoraria and consulting fees from various pharmaceutical companies and serves on companies’ advisory boards.
SOURCE: Freedman MS. ACTRIMS Forum 2019, Session 2.
DALLAS – , said Mark Freedman, MD, MSc, in a presentation at ACTRIMS Forum 2019, the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “Right now, we are probably dealing with more of an imprecise medicine,” said Dr. Freedman.
Information such as a patient’s ability to recover from relapses may indicate MS severity or the likelihood of disease progression, but selecting a therapy remains “an art of medicine,” said Dr. Freedman, professor of neurology at the University of Ottawa, director of the multiple sclerosis research unit at Ottawa Hospital, and senior scientist at the Ottawa Hospital Research Institute.
When prescribing a DMT, neurologists tend to consider three key elements: the disease, the treatment, and patient expectations. “Focus on these three aspects,” Dr. Freedman said.
It is no longer sufficient for neurologists to diagnose MS, hand the patient a drug, and “expect that things are going to go the way you want them to go,” he said.
Immunomodulating, anti–cell trafficking, or cell-depleting therapy?
Genetics, sex, types of relapses, recovery from relapses, response to therapy, MRI burden, and other biomarkers such as oligoclonal bands and neurofilaments may indicate which patients have severe disease and should receive aggressive treatment.
Determining the phase of the disease is a crucial first step “that is going to drive your choice of therapy,” he said.
Dr. Freedman likened the development of progressive MS to approaching the edge of a cliff. If patients appear to be nearing the progressive phase, “then your choice of therapy has to be an aggressive one – one that will hopefully hold them back from falling,” he said. In the earlier phases of MS, on the other hand, “you are looking at a long-term treatment that should probably be safe and still able to contain the disease,” such as an immunomodulator. If a patient is “about to fall off, you may want to go for temporary use of an antitrafficker to control things, and then eventually deplete the cells that are going to be causing the patient to fall off the cliff.”
Prognostic factors
Disease activity over time, and whether the disease is progressing faster or slower than would be expected, may be important prognostic factors. A patient’s sex also may be a factor because women tend to have more attacks and to have their attacks at a younger age, Dr. Freedman said.
The types of relapses and a patient’s ability to recover from them may provide important information. “Some attacks are quite mild. Others tend to build up disease,” Dr. Freedman said. “Some people are better healers than others. We have all seen people who have been quadriplegic in an ICU on a ventilator walk out of the hospital without even a numb toe. And other people who have a little bit of weakness in one leg seem to never be able to recover from that. Exactly what drives repair is still not clear.” Most patients do recover, however, “and the inability to recover early on is a bad omen,” Dr. Freedman said.
When researchers examined the relationship between functional components of the Expanded Disability Status Scale (EDSS) and disability progression, “not surprisingly ... pyramidal and spinal cord and cerebellar [functioning] are more associated with earlier progression” (Neuroepidemiology. 2015;44[1]:16-23).
A study by Lublin et al. found that patients with MS whose attacks left them with residual deficits had more EDSS accumulation over time (Neurology. 2003 Dec 9;61[11]:1528-32.).
Response to immunomodulators
“The inability to control the disease with an immunomodulator is a bad sign,” Dr. Freedman said. He pointed to data from a trial of teriflunomide that included patients who had had suboptimal responses to first-line therapy as well as patients who were treatment naive (Mult Scler. 2018 Apr;24[4]:535-9.). Some of the patients who had received prior MS therapy were randomized to placebo, which “is not something that would happen today,” he said.
“If you just focus on the [patients who received placebo] and look at the rate of attack in patients who had no prior DMT, at least one prior DMT, or two or more prior DMTs, the attack rates are much higher in those individuals who tried and failed first-line therapies,” Dr. Freedman said. These patients also had more EDSS progression. “The majority of people do respond [to first-line treatment], but those who do not you need to worry about a little bit more than those who do respond.”
MRI lesions and brain reserve
MRI activity over time tends to predict disease progression, and lesion location is important. One cohort study found that the likelihood of developing secondary progressive MS was lower among patients who did not develop new spinal cord or brainstem lesions in the first three years of the disease, compared with those who did.
In addition, patients who presented with more lesions were more likely to reach an EDSS score 3 or 6 over 10 years (Brain. 2008 Mar;131[Pt 3]:808-17.).
Brain reserve also may be important. Among 52 treatment-naive Serbian adults with MS, Sumowski et al. found that maximal lifetime brain growth as estimated with intracranial volume was associated with risk of disability progression over 5 years (Neurology. 2016 May 24;86[21]:2006-9.). “Those who had a greater reserve had a much lower risk of disease progression,” Dr. Freedman said. The results suggest that patients with more brain reserve may be better able to sustain damage as the disease progresses and they age, he said.
Comorbidities
In the past, neurologists may have left it up to general practitioners “to sort out the rest of the patient’s health,” Dr. Freedman said. “But we now recognize that having certain comorbidities already puts a higher burden onto the disease. And those patients who have more comorbidities ... are going to do worse. But not only are they going to do worse ... it turns out that patients who have more comorbidities are going to have less of a response to your various therapies.” Vascular comorbidities, in particular, may affect treatment response (Neurology. 2017 Nov 28;89[22]:2222-9.).
If hypertension or diabetes clinics can help control those conditions in patients with MS, “it will help us a lot in getting what we are expecting from the [MS] medications,” Dr. Freedman said.
Adherence, expectations, and symptomatic treatment
Ultimately, selecting an MS therapy is a decision that doctors share with their patients. “You’re going to have a discussion with them,” he said. “You can see what fits their lifestyle.” For example, a world traveler might not be a good candidate for a drug that requires regular monitoring. A patient’s risk averseness also may influence treatment choice.
If you involve patients in the selection process, it may improve medication adherence. In addition, patients need to understand what you aim to accomplish with a DMT, said Dr. Freedman. “That may sound like a trivial thing. But how many times has the patient come in and said, ‘The drug is not working. ... My eye is not better’” when that was not the goal of treatment to begin with. Let patients know that symptomatic treatments may address problems apart from MS DMT. This personalized but imprecise approach to treatment is “probably the best we can do for now,” Dr. Freedman said.
Dr. Freedman has received a research grant from Genzyme and is on the company’s speakers bureau. He has received honoraria and consulting fees from various pharmaceutical companies and serves on companies’ advisory boards.
SOURCE: Freedman MS. ACTRIMS Forum 2019, Session 2.
EXPERT ANALYSIS FROM ACTRIMS
Researchers examine vitamin D, skin pigmentation, and outcomes of pediatric MS
PHILADELPHIA – according to research described at the annual meeting of the American Academy of Neurology. Future research will be required to understand the interactions between dietary vitamin D ingestion, sun exposure, pigmentation of sun-exposed skin, seasonal vitamin D concentrations, and the genetic influences of vitamin D pathways with MS risk.
Race, vitamin D status, HLA-DRB1*15 genotype, and place of residence during childhood all affect the risk of MS. The place of residence also can affect exposure to ultraviolet radiation and, thus, dermal pigmentation.
Candice Dunn, a clinical research coordinator at the Children’s Hospital of Philadelphia, and colleagues conducted a prospective study to determine whether HLA-DRB1*15 status, 25-hydroxyvitamin D (25[OH]D) levels measured at baseline, and skin tone are associated with MS outcome in children with ADS. They enrolled 259 children with incident ADS in a multisite study in Toronto and Philadelphia (latitudes 43° to 51°). The investigators measured non–sun-exposed upper inner arm melanin content using the DSM II ColorMeter device. They measured 25(OH)D concentrations in serum obtained within 60 days of symptom onset and compared them with laboratory-reported normative values. Vitamin D insufficiency was defined as 25(OH)D less than 75 nmol/L. Ms. Dunn and colleagues quantified HLA-DRB1*15 alleles using allele-specific polymerase chain reaction amplification. Statistical analysis was performed using Spearman correlation models and Wilcoxon or Kruskal-Wallis tests as appropriate.
In all, 68 children were diagnosed with MS, 191 remained monophasic (monoADS). Approximately 46% of children with MS were HLA-DRB1*15-positive, compared with 29.9% of monoADS children. In addition, children with MS had significantly lower 25(OH)D levels (mean, 45.4 nmol/L) than monoADS children (mean, 61.9 nmol/L) at baseline. Non–sun-exposed skin tone measured in the upper inner arm did not differ between children diagnosed with MS (mean melanin index, 46.4) and monoADS (mean melanin index, 43.5). Furthermore, 25(OH)D levels correlated with upper inner arm melanin index in the MS group, but not in children with monoADS.
Ms. Dunn had nothing to disclose, but various coauthors have received compensation from companies such as Novartis, Merck, Teva, Celgene, and Genentech.
SOURCE: Dunn C et al. AAN 2019, Abstract S19.007.
PHILADELPHIA – according to research described at the annual meeting of the American Academy of Neurology. Future research will be required to understand the interactions between dietary vitamin D ingestion, sun exposure, pigmentation of sun-exposed skin, seasonal vitamin D concentrations, and the genetic influences of vitamin D pathways with MS risk.
Race, vitamin D status, HLA-DRB1*15 genotype, and place of residence during childhood all affect the risk of MS. The place of residence also can affect exposure to ultraviolet radiation and, thus, dermal pigmentation.
Candice Dunn, a clinical research coordinator at the Children’s Hospital of Philadelphia, and colleagues conducted a prospective study to determine whether HLA-DRB1*15 status, 25-hydroxyvitamin D (25[OH]D) levels measured at baseline, and skin tone are associated with MS outcome in children with ADS. They enrolled 259 children with incident ADS in a multisite study in Toronto and Philadelphia (latitudes 43° to 51°). The investigators measured non–sun-exposed upper inner arm melanin content using the DSM II ColorMeter device. They measured 25(OH)D concentrations in serum obtained within 60 days of symptom onset and compared them with laboratory-reported normative values. Vitamin D insufficiency was defined as 25(OH)D less than 75 nmol/L. Ms. Dunn and colleagues quantified HLA-DRB1*15 alleles using allele-specific polymerase chain reaction amplification. Statistical analysis was performed using Spearman correlation models and Wilcoxon or Kruskal-Wallis tests as appropriate.
In all, 68 children were diagnosed with MS, 191 remained monophasic (monoADS). Approximately 46% of children with MS were HLA-DRB1*15-positive, compared with 29.9% of monoADS children. In addition, children with MS had significantly lower 25(OH)D levels (mean, 45.4 nmol/L) than monoADS children (mean, 61.9 nmol/L) at baseline. Non–sun-exposed skin tone measured in the upper inner arm did not differ between children diagnosed with MS (mean melanin index, 46.4) and monoADS (mean melanin index, 43.5). Furthermore, 25(OH)D levels correlated with upper inner arm melanin index in the MS group, but not in children with monoADS.
Ms. Dunn had nothing to disclose, but various coauthors have received compensation from companies such as Novartis, Merck, Teva, Celgene, and Genentech.
SOURCE: Dunn C et al. AAN 2019, Abstract S19.007.
PHILADELPHIA – according to research described at the annual meeting of the American Academy of Neurology. Future research will be required to understand the interactions between dietary vitamin D ingestion, sun exposure, pigmentation of sun-exposed skin, seasonal vitamin D concentrations, and the genetic influences of vitamin D pathways with MS risk.
Race, vitamin D status, HLA-DRB1*15 genotype, and place of residence during childhood all affect the risk of MS. The place of residence also can affect exposure to ultraviolet radiation and, thus, dermal pigmentation.
Candice Dunn, a clinical research coordinator at the Children’s Hospital of Philadelphia, and colleagues conducted a prospective study to determine whether HLA-DRB1*15 status, 25-hydroxyvitamin D (25[OH]D) levels measured at baseline, and skin tone are associated with MS outcome in children with ADS. They enrolled 259 children with incident ADS in a multisite study in Toronto and Philadelphia (latitudes 43° to 51°). The investigators measured non–sun-exposed upper inner arm melanin content using the DSM II ColorMeter device. They measured 25(OH)D concentrations in serum obtained within 60 days of symptom onset and compared them with laboratory-reported normative values. Vitamin D insufficiency was defined as 25(OH)D less than 75 nmol/L. Ms. Dunn and colleagues quantified HLA-DRB1*15 alleles using allele-specific polymerase chain reaction amplification. Statistical analysis was performed using Spearman correlation models and Wilcoxon or Kruskal-Wallis tests as appropriate.
In all, 68 children were diagnosed with MS, 191 remained monophasic (monoADS). Approximately 46% of children with MS were HLA-DRB1*15-positive, compared with 29.9% of monoADS children. In addition, children with MS had significantly lower 25(OH)D levels (mean, 45.4 nmol/L) than monoADS children (mean, 61.9 nmol/L) at baseline. Non–sun-exposed skin tone measured in the upper inner arm did not differ between children diagnosed with MS (mean melanin index, 46.4) and monoADS (mean melanin index, 43.5). Furthermore, 25(OH)D levels correlated with upper inner arm melanin index in the MS group, but not in children with monoADS.
Ms. Dunn had nothing to disclose, but various coauthors have received compensation from companies such as Novartis, Merck, Teva, Celgene, and Genentech.
SOURCE: Dunn C et al. AAN 2019, Abstract S19.007.
REPORTING FROM AAN 2019
Key clinical point: The relationship between vitamin D status and MS outcome in children relates to skin pigmentation.
Major finding: About 46% of children with MS were HLA-DRB1*15 positive.
Study details: A multisite, prospective study of 259 children with MS.
Disclosures: Ms. Dunn had no disclosures, but various coauthors have received compensation from companies such as Novartis, Merck, Teva, Celgene, and Genentech.
Source: Dunn C et al. AAN 2019, Abstract S19.007.
Criterion based on the central vein sign distinguishes between MS and mimics
PHILADELPHIA – according to research presented at the annual meeting of the American Academy of Neurology. Using this criterion in clinical practice is feasible, the researchers added.
Several years ago, researchers proposed the central vein sign as a specific and sensitive imaging biomarker for distinguishing between multiple sclerosis (MS) and its imaging mimics. Recent studies have proposed criteria for this distinction that are based on the proportion of lesions with the central vein sign. Criteria that are based on the absolute numbers of lesions with the central vein sign, however, may be more applicable in clinical practice, said Tim Sinnecker, MD, research associate at the University of Basel (Switzerland).
Dr. Sinnecker and colleagues conducted a multicenter study to evaluate the sensitivity and specificity of criteria that are based on the absolute numbers of lesions with the central vein sign (CVS) in distinguishing MS from non-MS conditions on clinical 3T brain MRI. They analyzed 606 participants with clinically isolated syndrome (CIS; n = 117), relapsing remitting MS (RRMS; n = 236, of whom 108 had a disease duration shorter than 5 years), aquaporin 4 antibody–positive neuromyelitis optica spectrum disorder (n = 32), systemic lupus erythematosus (n = 25), migraine (n = 29), cluster headache (n = 5), diabetes mellitus (n = 20), or other types of small-vessel disease (n = 142). Raters blinded to clinical data and lesion distribution determined the occurrence of CVS on 3T T2*-weighted or susceptibility-weighted imaging. The researchers assessed the sensitivity and specificity of different CVS lesion criteria that were defined according to the absolute numbers of lesions with CVS.
In total, Dr. Sinnecker and colleagues analyzed 4,447 lesions. The “two-CVS-lesions criterion” (two or more lesions with CVS) had a sensitivity and specificity of 76.2% and 79.3%, respectively, in distinguishing between RRMS/CIS and non-MS. The “three-CVS-lesions criterion” (three or more lesions with CVS) had a sensitivity and specificity of 61.9% and 89.0%, respectively. The observed sensitivity and specificity values were consistent across all disease subgroups examined in the study, including CIS and early RRMS. These results indicate that positive criteria based on CVS could be used to support the diagnosis of MS, Dr. Sinnecker said.
Dr. Sinnecker reported receiving personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion.
SOURCE: Sinnecker T et al. AAN 2019, Abstract S6.002.
PHILADELPHIA – according to research presented at the annual meeting of the American Academy of Neurology. Using this criterion in clinical practice is feasible, the researchers added.
Several years ago, researchers proposed the central vein sign as a specific and sensitive imaging biomarker for distinguishing between multiple sclerosis (MS) and its imaging mimics. Recent studies have proposed criteria for this distinction that are based on the proportion of lesions with the central vein sign. Criteria that are based on the absolute numbers of lesions with the central vein sign, however, may be more applicable in clinical practice, said Tim Sinnecker, MD, research associate at the University of Basel (Switzerland).
Dr. Sinnecker and colleagues conducted a multicenter study to evaluate the sensitivity and specificity of criteria that are based on the absolute numbers of lesions with the central vein sign (CVS) in distinguishing MS from non-MS conditions on clinical 3T brain MRI. They analyzed 606 participants with clinically isolated syndrome (CIS; n = 117), relapsing remitting MS (RRMS; n = 236, of whom 108 had a disease duration shorter than 5 years), aquaporin 4 antibody–positive neuromyelitis optica spectrum disorder (n = 32), systemic lupus erythematosus (n = 25), migraine (n = 29), cluster headache (n = 5), diabetes mellitus (n = 20), or other types of small-vessel disease (n = 142). Raters blinded to clinical data and lesion distribution determined the occurrence of CVS on 3T T2*-weighted or susceptibility-weighted imaging. The researchers assessed the sensitivity and specificity of different CVS lesion criteria that were defined according to the absolute numbers of lesions with CVS.
In total, Dr. Sinnecker and colleagues analyzed 4,447 lesions. The “two-CVS-lesions criterion” (two or more lesions with CVS) had a sensitivity and specificity of 76.2% and 79.3%, respectively, in distinguishing between RRMS/CIS and non-MS. The “three-CVS-lesions criterion” (three or more lesions with CVS) had a sensitivity and specificity of 61.9% and 89.0%, respectively. The observed sensitivity and specificity values were consistent across all disease subgroups examined in the study, including CIS and early RRMS. These results indicate that positive criteria based on CVS could be used to support the diagnosis of MS, Dr. Sinnecker said.
Dr. Sinnecker reported receiving personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion.
SOURCE: Sinnecker T et al. AAN 2019, Abstract S6.002.
PHILADELPHIA – according to research presented at the annual meeting of the American Academy of Neurology. Using this criterion in clinical practice is feasible, the researchers added.
Several years ago, researchers proposed the central vein sign as a specific and sensitive imaging biomarker for distinguishing between multiple sclerosis (MS) and its imaging mimics. Recent studies have proposed criteria for this distinction that are based on the proportion of lesions with the central vein sign. Criteria that are based on the absolute numbers of lesions with the central vein sign, however, may be more applicable in clinical practice, said Tim Sinnecker, MD, research associate at the University of Basel (Switzerland).
Dr. Sinnecker and colleagues conducted a multicenter study to evaluate the sensitivity and specificity of criteria that are based on the absolute numbers of lesions with the central vein sign (CVS) in distinguishing MS from non-MS conditions on clinical 3T brain MRI. They analyzed 606 participants with clinically isolated syndrome (CIS; n = 117), relapsing remitting MS (RRMS; n = 236, of whom 108 had a disease duration shorter than 5 years), aquaporin 4 antibody–positive neuromyelitis optica spectrum disorder (n = 32), systemic lupus erythematosus (n = 25), migraine (n = 29), cluster headache (n = 5), diabetes mellitus (n = 20), or other types of small-vessel disease (n = 142). Raters blinded to clinical data and lesion distribution determined the occurrence of CVS on 3T T2*-weighted or susceptibility-weighted imaging. The researchers assessed the sensitivity and specificity of different CVS lesion criteria that were defined according to the absolute numbers of lesions with CVS.
In total, Dr. Sinnecker and colleagues analyzed 4,447 lesions. The “two-CVS-lesions criterion” (two or more lesions with CVS) had a sensitivity and specificity of 76.2% and 79.3%, respectively, in distinguishing between RRMS/CIS and non-MS. The “three-CVS-lesions criterion” (three or more lesions with CVS) had a sensitivity and specificity of 61.9% and 89.0%, respectively. The observed sensitivity and specificity values were consistent across all disease subgroups examined in the study, including CIS and early RRMS. These results indicate that positive criteria based on CVS could be used to support the diagnosis of MS, Dr. Sinnecker said.
Dr. Sinnecker reported receiving personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion.
SOURCE: Sinnecker T et al. AAN 2019, Abstract S6.002.
REPORTING FROM AAN 2019
Eculizumab cuts relapse risk in NMO spectrum disorder
PHILADELPHIA – Treatment with the monoclonal antibody eculizumab substantially reduced the risk of relapse versus placebo in patients with aquaporin-4 positive neuromyelitis optica (NMO) spectrum disorder, according to the results of a phase 3 trial reported at the annual meeting of the American Academy of Neurology. Nearly 98% of patients with this autoimmune inflammatory CNS disorder were relapse-free at 48 weeks in the PREVENT trial, according to principal investigator Sean J. Pittock, MD, director of the Mayo Clinic’s Center for Multiple Sclerosis and Autoimmune Neurology in Rochester, Minn.
“This was a dramatic result, I think, really showing a significant amount of hope for people with this disease,” Dr. Pittock said in a press conference.
Most cases of NMO are associated with aquaporin-4 antibodies and complement-mediated CNS damage, and eculizumab (Soliris) is an inhibitor of complement protein C5 shown to reduce relapse frequency in a previous, small open-label study, according to Dr. Pittock.
In the current global phase 3 trial, conducted at 70 centers in 18 countries, 143 adult patients with aquaporin-4 positive NMO spectrum disorder were randomized to eculizumab every 2 weeks or placebo. The trial allowed for supportive immunosuppressive therapy and excluded patients who had received rituximab in the past 3 months. A total of 124 patients completed the study, which was stopped after 23 adjudicated relapses had occurred.
Time to first adjudicated relapse on trial, the primary endpoint of the study, showed a significant effect (P less than .0001) in favor of monoclonal antibody treatment over placebo, with a 94.2% reduction in risk of relapse, according to Dr. Pittock and coinvestigators.
At 48 weeks, 97.9% of patients were relapse free in the eculizumab group, versus 63.2% in the placebo group, they added in their report, which was published May 3 online ahead of print in the New England Journal of Medicine (doi: 10.1056/NEJMoa1900866).
Longer-term follow-up showed that, at 144 weeks, 96% of eculizumab-treated patients remained relapse free, while 45% of the placebo group were relapse free, Dr. Pittock said in the press conference.
Most adverse events seen on treatment were mild to moderate, and no meningococcal infections were observed.
One death occurred in the study from pulmonary empyema in an eculizumab-treated patient, but the associated cultures yielded microorganisms not associated with complement deficiency, investigators said in their published report.
“The concept that you can discover a target, understand the immunopathology of a disease, identify a novel mechanism, then identify a precision drug that targets that mechanism, and essentially turn off, or switch off, the disease is very, very exciting,” Dr. Pittock said in the press conference.
The study was supported by Alexion Pharmaceuticals. Dr. Pittock provided disclosures related to Alexion Pharmaceuticals, MedImmune, and Grifols, along with patents related to administration of eculizumab and cancer markers in neuromyelitis optica.
SOURCE: Pittock SJ et al. AAN 2019, Emerging Science Abstract 009.
PHILADELPHIA – Treatment with the monoclonal antibody eculizumab substantially reduced the risk of relapse versus placebo in patients with aquaporin-4 positive neuromyelitis optica (NMO) spectrum disorder, according to the results of a phase 3 trial reported at the annual meeting of the American Academy of Neurology. Nearly 98% of patients with this autoimmune inflammatory CNS disorder were relapse-free at 48 weeks in the PREVENT trial, according to principal investigator Sean J. Pittock, MD, director of the Mayo Clinic’s Center for Multiple Sclerosis and Autoimmune Neurology in Rochester, Minn.
“This was a dramatic result, I think, really showing a significant amount of hope for people with this disease,” Dr. Pittock said in a press conference.
Most cases of NMO are associated with aquaporin-4 antibodies and complement-mediated CNS damage, and eculizumab (Soliris) is an inhibitor of complement protein C5 shown to reduce relapse frequency in a previous, small open-label study, according to Dr. Pittock.
In the current global phase 3 trial, conducted at 70 centers in 18 countries, 143 adult patients with aquaporin-4 positive NMO spectrum disorder were randomized to eculizumab every 2 weeks or placebo. The trial allowed for supportive immunosuppressive therapy and excluded patients who had received rituximab in the past 3 months. A total of 124 patients completed the study, which was stopped after 23 adjudicated relapses had occurred.
Time to first adjudicated relapse on trial, the primary endpoint of the study, showed a significant effect (P less than .0001) in favor of monoclonal antibody treatment over placebo, with a 94.2% reduction in risk of relapse, according to Dr. Pittock and coinvestigators.
At 48 weeks, 97.9% of patients were relapse free in the eculizumab group, versus 63.2% in the placebo group, they added in their report, which was published May 3 online ahead of print in the New England Journal of Medicine (doi: 10.1056/NEJMoa1900866).
Longer-term follow-up showed that, at 144 weeks, 96% of eculizumab-treated patients remained relapse free, while 45% of the placebo group were relapse free, Dr. Pittock said in the press conference.
Most adverse events seen on treatment were mild to moderate, and no meningococcal infections were observed.
One death occurred in the study from pulmonary empyema in an eculizumab-treated patient, but the associated cultures yielded microorganisms not associated with complement deficiency, investigators said in their published report.
“The concept that you can discover a target, understand the immunopathology of a disease, identify a novel mechanism, then identify a precision drug that targets that mechanism, and essentially turn off, or switch off, the disease is very, very exciting,” Dr. Pittock said in the press conference.
The study was supported by Alexion Pharmaceuticals. Dr. Pittock provided disclosures related to Alexion Pharmaceuticals, MedImmune, and Grifols, along with patents related to administration of eculizumab and cancer markers in neuromyelitis optica.
SOURCE: Pittock SJ et al. AAN 2019, Emerging Science Abstract 009.
PHILADELPHIA – Treatment with the monoclonal antibody eculizumab substantially reduced the risk of relapse versus placebo in patients with aquaporin-4 positive neuromyelitis optica (NMO) spectrum disorder, according to the results of a phase 3 trial reported at the annual meeting of the American Academy of Neurology. Nearly 98% of patients with this autoimmune inflammatory CNS disorder were relapse-free at 48 weeks in the PREVENT trial, according to principal investigator Sean J. Pittock, MD, director of the Mayo Clinic’s Center for Multiple Sclerosis and Autoimmune Neurology in Rochester, Minn.
“This was a dramatic result, I think, really showing a significant amount of hope for people with this disease,” Dr. Pittock said in a press conference.
Most cases of NMO are associated with aquaporin-4 antibodies and complement-mediated CNS damage, and eculizumab (Soliris) is an inhibitor of complement protein C5 shown to reduce relapse frequency in a previous, small open-label study, according to Dr. Pittock.
In the current global phase 3 trial, conducted at 70 centers in 18 countries, 143 adult patients with aquaporin-4 positive NMO spectrum disorder were randomized to eculizumab every 2 weeks or placebo. The trial allowed for supportive immunosuppressive therapy and excluded patients who had received rituximab in the past 3 months. A total of 124 patients completed the study, which was stopped after 23 adjudicated relapses had occurred.
Time to first adjudicated relapse on trial, the primary endpoint of the study, showed a significant effect (P less than .0001) in favor of monoclonal antibody treatment over placebo, with a 94.2% reduction in risk of relapse, according to Dr. Pittock and coinvestigators.
At 48 weeks, 97.9% of patients were relapse free in the eculizumab group, versus 63.2% in the placebo group, they added in their report, which was published May 3 online ahead of print in the New England Journal of Medicine (doi: 10.1056/NEJMoa1900866).
Longer-term follow-up showed that, at 144 weeks, 96% of eculizumab-treated patients remained relapse free, while 45% of the placebo group were relapse free, Dr. Pittock said in the press conference.
Most adverse events seen on treatment were mild to moderate, and no meningococcal infections were observed.
One death occurred in the study from pulmonary empyema in an eculizumab-treated patient, but the associated cultures yielded microorganisms not associated with complement deficiency, investigators said in their published report.
“The concept that you can discover a target, understand the immunopathology of a disease, identify a novel mechanism, then identify a precision drug that targets that mechanism, and essentially turn off, or switch off, the disease is very, very exciting,” Dr. Pittock said in the press conference.
The study was supported by Alexion Pharmaceuticals. Dr. Pittock provided disclosures related to Alexion Pharmaceuticals, MedImmune, and Grifols, along with patents related to administration of eculizumab and cancer markers in neuromyelitis optica.
SOURCE: Pittock SJ et al. AAN 2019, Emerging Science Abstract 009.
FROM AAN 2019
Key clinical point: Treatment with eculizumab substantially reduced risk of relapse versus placebo in patients with aquaporin-4 positive neuromyelitis optica spectrum disorder.
Major finding: Time to first adjudicated relapse on trial, the primary endpoint of the study, showed a significant (P less than .0001) effect in favor of monoclonal antibody treatment over placebo, with a 94.2% reduction in risk of relapse.
Study details: A phase 3, randomized, double-blind, placebo-controlled, multicenter trial (PREVENT) including 143 adult patients.
Disclosures: The study was supported by Alexion Pharmaceuticals. Dr. Pittock provided disclosures related to Alexion Pharmaceuticals, MedImmune, and Grifols, along with patents related to administration of eculizumab and cancer markers in neuromyelitis optica.
Source: Pittock SJ et al. AAN 2019, Emerging Science Abstract 009.
Immunotherapy induces improvements in PML
Philadelphia – Adoptive transfer of donor-derived T cells represents a potentially life-saving treatment of severely immunocompromised patients with progressive multifocal leukoencephalopathy (PML).
“We think this strategy has real potential to be one of the first effective treatments for PML,” Erin Beck, MD, PhD, said during a press conference at the annual meeting of the American Academy of Neurology.
In a pilot study including 12 patients with PML, the 7 who survived had substantial neurological improvement after treatment with this immunotherapeutic approach, said Dr. Beck of the National Institute of Neurological Disorders and Stroke.
“This was very encouraging to us because these patients were worsening at the time of their treatment and we did not expect them to do well,” she said.
There were no serious adverse events related to treatment, which suggests the approach is safe for patients with PML, according to Dr. Beck.
“This is a phenomenal breakthrough,” Natalia S. Rost, MD, MPH, chair of the meeting’s science committee, said at the press conference. “Giving a diagnosis of PML to a patient is basically giving them a death sentence, and it’s one of the most dreaded scenarios in our clinical practice.”
PML, an opportunistic infection of the central nervous system caused by JC polyomavirus, is usually fatal unless adaptive immunity to JC polyomavirus can be restored, Dr. Beck said.
Cases of PML surged in the 1980s and 1990s as a result of the HIV/AIDS epidemic, she said, and an increase in cases has been observed more recently related to new immunosuppressive treatments for cancer and autoimmune diseases.
The pilot study described by Dr. Beck included 12 patients with refractory PML who underwent adoptive transfer of polyomavirus-specific T cells (PyVSTs) that were generated from partially matched first-degree relatives of the patients. Up to three infusions were given at least 28 days apart.
Although five patients died of PML, the remaining seven patients stabilized and in some cases experienced significant neurological improvement, according to the investigators. Two of the seven died of PML a year after their final infusion.
No overt immune reconstitution inflammatory syndrome (IRIS) was observed in treated patients.
It’s not clear to date which PML patients may be most likely to benefit from this treatment approach because there were no differences in age, sex, baseline leukocyte count numbers, or time since their initial diagnosis between responders and nonresponders, Dr. Beck said.
However, patients who died tended to have much higher JC virus copy numbers in their spinal fluid, as did some patients who were enrolled but died before they could receive any treatment, she added.
“That high range, I think, is a very bad prognostic sign,” Dr. Beck said. “A number in the lower range doesn’t mean a good prognosis, but it means potentially that you could respond to a treatment such as this one.”
The study was funded by National Institute of Neurological Disorders and Stroke. The investigators disclosed no conflicts related to the study.
SOURCE: Cortese I et al. AAN 2019, Abstract Plen01.002.
Philadelphia – Adoptive transfer of donor-derived T cells represents a potentially life-saving treatment of severely immunocompromised patients with progressive multifocal leukoencephalopathy (PML).
“We think this strategy has real potential to be one of the first effective treatments for PML,” Erin Beck, MD, PhD, said during a press conference at the annual meeting of the American Academy of Neurology.
In a pilot study including 12 patients with PML, the 7 who survived had substantial neurological improvement after treatment with this immunotherapeutic approach, said Dr. Beck of the National Institute of Neurological Disorders and Stroke.
“This was very encouraging to us because these patients were worsening at the time of their treatment and we did not expect them to do well,” she said.
There were no serious adverse events related to treatment, which suggests the approach is safe for patients with PML, according to Dr. Beck.
“This is a phenomenal breakthrough,” Natalia S. Rost, MD, MPH, chair of the meeting’s science committee, said at the press conference. “Giving a diagnosis of PML to a patient is basically giving them a death sentence, and it’s one of the most dreaded scenarios in our clinical practice.”
PML, an opportunistic infection of the central nervous system caused by JC polyomavirus, is usually fatal unless adaptive immunity to JC polyomavirus can be restored, Dr. Beck said.
Cases of PML surged in the 1980s and 1990s as a result of the HIV/AIDS epidemic, she said, and an increase in cases has been observed more recently related to new immunosuppressive treatments for cancer and autoimmune diseases.
The pilot study described by Dr. Beck included 12 patients with refractory PML who underwent adoptive transfer of polyomavirus-specific T cells (PyVSTs) that were generated from partially matched first-degree relatives of the patients. Up to three infusions were given at least 28 days apart.
Although five patients died of PML, the remaining seven patients stabilized and in some cases experienced significant neurological improvement, according to the investigators. Two of the seven died of PML a year after their final infusion.
No overt immune reconstitution inflammatory syndrome (IRIS) was observed in treated patients.
It’s not clear to date which PML patients may be most likely to benefit from this treatment approach because there were no differences in age, sex, baseline leukocyte count numbers, or time since their initial diagnosis between responders and nonresponders, Dr. Beck said.
However, patients who died tended to have much higher JC virus copy numbers in their spinal fluid, as did some patients who were enrolled but died before they could receive any treatment, she added.
“That high range, I think, is a very bad prognostic sign,” Dr. Beck said. “A number in the lower range doesn’t mean a good prognosis, but it means potentially that you could respond to a treatment such as this one.”
The study was funded by National Institute of Neurological Disorders and Stroke. The investigators disclosed no conflicts related to the study.
SOURCE: Cortese I et al. AAN 2019, Abstract Plen01.002.
Philadelphia – Adoptive transfer of donor-derived T cells represents a potentially life-saving treatment of severely immunocompromised patients with progressive multifocal leukoencephalopathy (PML).
“We think this strategy has real potential to be one of the first effective treatments for PML,” Erin Beck, MD, PhD, said during a press conference at the annual meeting of the American Academy of Neurology.
In a pilot study including 12 patients with PML, the 7 who survived had substantial neurological improvement after treatment with this immunotherapeutic approach, said Dr. Beck of the National Institute of Neurological Disorders and Stroke.
“This was very encouraging to us because these patients were worsening at the time of their treatment and we did not expect them to do well,” she said.
There were no serious adverse events related to treatment, which suggests the approach is safe for patients with PML, according to Dr. Beck.
“This is a phenomenal breakthrough,” Natalia S. Rost, MD, MPH, chair of the meeting’s science committee, said at the press conference. “Giving a diagnosis of PML to a patient is basically giving them a death sentence, and it’s one of the most dreaded scenarios in our clinical practice.”
PML, an opportunistic infection of the central nervous system caused by JC polyomavirus, is usually fatal unless adaptive immunity to JC polyomavirus can be restored, Dr. Beck said.
Cases of PML surged in the 1980s and 1990s as a result of the HIV/AIDS epidemic, she said, and an increase in cases has been observed more recently related to new immunosuppressive treatments for cancer and autoimmune diseases.
The pilot study described by Dr. Beck included 12 patients with refractory PML who underwent adoptive transfer of polyomavirus-specific T cells (PyVSTs) that were generated from partially matched first-degree relatives of the patients. Up to three infusions were given at least 28 days apart.
Although five patients died of PML, the remaining seven patients stabilized and in some cases experienced significant neurological improvement, according to the investigators. Two of the seven died of PML a year after their final infusion.
No overt immune reconstitution inflammatory syndrome (IRIS) was observed in treated patients.
It’s not clear to date which PML patients may be most likely to benefit from this treatment approach because there were no differences in age, sex, baseline leukocyte count numbers, or time since their initial diagnosis between responders and nonresponders, Dr. Beck said.
However, patients who died tended to have much higher JC virus copy numbers in their spinal fluid, as did some patients who were enrolled but died before they could receive any treatment, she added.
“That high range, I think, is a very bad prognostic sign,” Dr. Beck said. “A number in the lower range doesn’t mean a good prognosis, but it means potentially that you could respond to a treatment such as this one.”
The study was funded by National Institute of Neurological Disorders and Stroke. The investigators disclosed no conflicts related to the study.
SOURCE: Cortese I et al. AAN 2019, Abstract Plen01.002.
FROM AAN 2019
Key clinical point: Adoptive transfer of donor-derived T cells represents a potentially life-saving strategy for patients with progressive multifocal leukoencephalopathy.
Major finding: Seven of 12 patients stabilized and in some cases experienced significant neurological improvement.
Study details: A pilot study including 12 patients with refractory PML.
Disclosures: The study was funded by NINDS. The investigators disclosed no conflicts related to the study.
Source: Cortese I et al. AAN 2019, Abstract Plen01.002.
Multiple sclerosis may not flare up after pregnancy
PHILADELPHIA – according to a study to be presented at the annual meeting of the American Academy of Neurology.
“We did not observe any rebound disease activity,” said Annette Langer-Gould, MD, PhD, and her research colleagues in their report.
The findings contrast with those of 20-year-old studies that first identified a lower risk of relapse during pregnancy but signficant rebound disease activity in the early postpartum period. The initial studies were conducted before disease-modifying treatments (DMTs) were available and before neurologists used MRI to help diagnose MS after one attack, noted Dr. Langer-Gould in a statement.
In the large, contemporary cohort of patients with MS, the annualized relapse rate was 0.39 pre-pregnancy, 0.07-0.14 during pregnancy, 0.27 in the first 3 months postpartum, and 0.37 at 4-6 months postpartum. Exclusive breastfeeding significantly reduced the risk of postpartum relapses by 42% (adjusted hazard ratio = 0.58). Women who supplemented breast milk with formula within 2 months of delivery had the same risk of relapse as women who did not breastfeed, however.
“These results are exciting, as MS is more common among women of childbearing age than in any other group,” said Dr. Langer-Gould, who is regional lead for clinical and translational neuroscience at Kaiser Permanente Southern California in Pasadena, in the statement. “This shows us that women with MS today can have children, breastfeed, and resume their treatment without experiencing an increased risk of relapses during the postpartum period.”
To describe the risk of postpartum relapses and identify potential risk factors for relapse the investigators analyzed prospectively collected data from 466 pregnancies among 375 women with MS from the complete electronic health record at Kaiser Permanente Southern and Northern California between 2008 and 2016. The researchers also used surveys to collect information about treatment history, breastfeeding, and relapses. They used multivariable models to account for intraclass clustering and disease severity.
In 38% of the pregnancies, the mother had not received treatment in the year before conception. In 14.6%, the mother had a clinically isolated syndrome; in 8.4%, the mother had a relapse during pregnancy.
Resuming modestly effective DMTs such as interferon-betas and glatiramer acetate did not affect relapse risk.
In the postpartum year, 26.4% of mothers relapsed, 87% breastfed, 35% breastfed exclusively, and 41.2% resumed using DMT.
The lack of rebound disease activity in this cohort could be related to the high rate of exclusive breastfeeding, as well as the inclusion of women from a population-based setting and the inclusion of women who had incorrectly been diagnosed with MS after a single relapse. Few patients in this cohort had been treated with natalizumab or fingolimod prior to pregnancy, so the study does not address the potential harms of stopping these drugs or the potential benefits of breastfeeding among patients treated with these drugs.
The study was supported by the National Multiple Sclerosis Society. The researchers had no disclosures.
SOURCE: Langer-Gould A et al. AAN 2019, Abstract S6.007.
PHILADELPHIA – according to a study to be presented at the annual meeting of the American Academy of Neurology.
“We did not observe any rebound disease activity,” said Annette Langer-Gould, MD, PhD, and her research colleagues in their report.
The findings contrast with those of 20-year-old studies that first identified a lower risk of relapse during pregnancy but signficant rebound disease activity in the early postpartum period. The initial studies were conducted before disease-modifying treatments (DMTs) were available and before neurologists used MRI to help diagnose MS after one attack, noted Dr. Langer-Gould in a statement.
In the large, contemporary cohort of patients with MS, the annualized relapse rate was 0.39 pre-pregnancy, 0.07-0.14 during pregnancy, 0.27 in the first 3 months postpartum, and 0.37 at 4-6 months postpartum. Exclusive breastfeeding significantly reduced the risk of postpartum relapses by 42% (adjusted hazard ratio = 0.58). Women who supplemented breast milk with formula within 2 months of delivery had the same risk of relapse as women who did not breastfeed, however.
“These results are exciting, as MS is more common among women of childbearing age than in any other group,” said Dr. Langer-Gould, who is regional lead for clinical and translational neuroscience at Kaiser Permanente Southern California in Pasadena, in the statement. “This shows us that women with MS today can have children, breastfeed, and resume their treatment without experiencing an increased risk of relapses during the postpartum period.”
To describe the risk of postpartum relapses and identify potential risk factors for relapse the investigators analyzed prospectively collected data from 466 pregnancies among 375 women with MS from the complete electronic health record at Kaiser Permanente Southern and Northern California between 2008 and 2016. The researchers also used surveys to collect information about treatment history, breastfeeding, and relapses. They used multivariable models to account for intraclass clustering and disease severity.
In 38% of the pregnancies, the mother had not received treatment in the year before conception. In 14.6%, the mother had a clinically isolated syndrome; in 8.4%, the mother had a relapse during pregnancy.
Resuming modestly effective DMTs such as interferon-betas and glatiramer acetate did not affect relapse risk.
In the postpartum year, 26.4% of mothers relapsed, 87% breastfed, 35% breastfed exclusively, and 41.2% resumed using DMT.
The lack of rebound disease activity in this cohort could be related to the high rate of exclusive breastfeeding, as well as the inclusion of women from a population-based setting and the inclusion of women who had incorrectly been diagnosed with MS after a single relapse. Few patients in this cohort had been treated with natalizumab or fingolimod prior to pregnancy, so the study does not address the potential harms of stopping these drugs or the potential benefits of breastfeeding among patients treated with these drugs.
The study was supported by the National Multiple Sclerosis Society. The researchers had no disclosures.
SOURCE: Langer-Gould A et al. AAN 2019, Abstract S6.007.
PHILADELPHIA – according to a study to be presented at the annual meeting of the American Academy of Neurology.
“We did not observe any rebound disease activity,” said Annette Langer-Gould, MD, PhD, and her research colleagues in their report.
The findings contrast with those of 20-year-old studies that first identified a lower risk of relapse during pregnancy but signficant rebound disease activity in the early postpartum period. The initial studies were conducted before disease-modifying treatments (DMTs) were available and before neurologists used MRI to help diagnose MS after one attack, noted Dr. Langer-Gould in a statement.
In the large, contemporary cohort of patients with MS, the annualized relapse rate was 0.39 pre-pregnancy, 0.07-0.14 during pregnancy, 0.27 in the first 3 months postpartum, and 0.37 at 4-6 months postpartum. Exclusive breastfeeding significantly reduced the risk of postpartum relapses by 42% (adjusted hazard ratio = 0.58). Women who supplemented breast milk with formula within 2 months of delivery had the same risk of relapse as women who did not breastfeed, however.
“These results are exciting, as MS is more common among women of childbearing age than in any other group,” said Dr. Langer-Gould, who is regional lead for clinical and translational neuroscience at Kaiser Permanente Southern California in Pasadena, in the statement. “This shows us that women with MS today can have children, breastfeed, and resume their treatment without experiencing an increased risk of relapses during the postpartum period.”
To describe the risk of postpartum relapses and identify potential risk factors for relapse the investigators analyzed prospectively collected data from 466 pregnancies among 375 women with MS from the complete electronic health record at Kaiser Permanente Southern and Northern California between 2008 and 2016. The researchers also used surveys to collect information about treatment history, breastfeeding, and relapses. They used multivariable models to account for intraclass clustering and disease severity.
In 38% of the pregnancies, the mother had not received treatment in the year before conception. In 14.6%, the mother had a clinically isolated syndrome; in 8.4%, the mother had a relapse during pregnancy.
Resuming modestly effective DMTs such as interferon-betas and glatiramer acetate did not affect relapse risk.
In the postpartum year, 26.4% of mothers relapsed, 87% breastfed, 35% breastfed exclusively, and 41.2% resumed using DMT.
The lack of rebound disease activity in this cohort could be related to the high rate of exclusive breastfeeding, as well as the inclusion of women from a population-based setting and the inclusion of women who had incorrectly been diagnosed with MS after a single relapse. Few patients in this cohort had been treated with natalizumab or fingolimod prior to pregnancy, so the study does not address the potential harms of stopping these drugs or the potential benefits of breastfeeding among patients treated with these drugs.
The study was supported by the National Multiple Sclerosis Society. The researchers had no disclosures.
SOURCE: Langer-Gould A et al. AAN 2019, Abstract S6.007.
FROM AAN 2019