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EVOLVE-MS-1 study: ALKS 8700 shows promise for RRMS
LOS ANGELES – ALKS 8700, a novel prodrug of monomethyl fumarate, looks promising as an oral, disease-modifying treatment for relapsing forms of multiple sclerosis, according to interim findings from the phase 3 EVOLVE-MS-1 study.
The annualized relapse rate at a median follow-up of 0.93 patient-years (total, 497.1 patient-years) in 578 patients enrolled to date in the 2-year, open-label study was just 0.16, Robert T. Naismith, MD, reported during an emerging science session at the annual meeting of the American Academy of Neurology.
Further, a statistically significant 80% reduction from baseline was seen in the number of gadolinium-enhancing lesions in 374 patients who completed a 1-year MRI assessment (from a mean of 1.5 to 0.3), said Dr. Naismith of Washington University, St. Louis.
Patients enrolled in the ongoing study are adults aged 18-65 years (mean, 41 years) with confirmed relapsing-remitting MS (RRMS), Expanded Disability Status Scale score of 6.0 or less (mean, 2.7), and no evidence of relapse within 30 days prior to starting ALKS 8700. Those with progressive forms of MS are excluded, as are patients who are pregnant or breastfeeding, patients with a history of other clinically significant conditions, and those with clinically significant abnormal laboratory tests at screening or absolute lymphocyte counts less than 0.9 x 103/mcL.
Of those enrolled so far, 72.5% received prior MS therapies, and their mean time since onset and diagnosis of MS was 9.7 and 7.6 years, respectively. The mean number of relapses in the prior year was 0.8.
ALKS 8700, also known as BIIB098, is given at a dose of 462 mg twice daily for up to 96 weeks; planned enrollment in EVOLVE-MS-1 is approximately 900 patients, Dr. Naismith said.
The preliminary findings from EVOLE-MS-1, which is limited by its single-arm, open-label design, “lend credence to ALKS 8700 as an oral treatment for patients with relapsing-remitting MS,” he said.
In addition to continued evaluation for long-term safety and tolerability in the current study, ALKS 8700 is also being evaluated in combination with 240 mg of twice daily dimethyl fumarate (DMF; Tecfidera) in the 5-week, randomized, double-blind EVOLVE-MS-2 study, which is looking at the gastrointestinal tolerability of the combination in patients with RRMS.
Oral DMF is approved for RRMS, and has been shown to significantly reduce clinical and MRI disease activity, but is commonly associated with GI events. Monomethyl fumarate is the active metabolite of DMF, and as a prodrug of monomethyl fumarate, ALKS 8700 is being developed to work in a manner similar to that of DMF, but with improved GI tolerability, Dr. Naismith explained.
EVOLE-MS-1 is funded by Alkermes. Dr. Naismith has served as a consultant and/or speaker for Alkermes, as well as for Acorda, Bayer, Biogen, Genentech, Genzyme, EMD Serono, Novartis, and Teva. He has received research support from the National Institutes of Health and the National Multiple Sclerosis Society.
SOURCE: Naismith R et al. AAN 2018 Emerging Science Abstract 006.
LOS ANGELES – ALKS 8700, a novel prodrug of monomethyl fumarate, looks promising as an oral, disease-modifying treatment for relapsing forms of multiple sclerosis, according to interim findings from the phase 3 EVOLVE-MS-1 study.
The annualized relapse rate at a median follow-up of 0.93 patient-years (total, 497.1 patient-years) in 578 patients enrolled to date in the 2-year, open-label study was just 0.16, Robert T. Naismith, MD, reported during an emerging science session at the annual meeting of the American Academy of Neurology.
Further, a statistically significant 80% reduction from baseline was seen in the number of gadolinium-enhancing lesions in 374 patients who completed a 1-year MRI assessment (from a mean of 1.5 to 0.3), said Dr. Naismith of Washington University, St. Louis.
Patients enrolled in the ongoing study are adults aged 18-65 years (mean, 41 years) with confirmed relapsing-remitting MS (RRMS), Expanded Disability Status Scale score of 6.0 or less (mean, 2.7), and no evidence of relapse within 30 days prior to starting ALKS 8700. Those with progressive forms of MS are excluded, as are patients who are pregnant or breastfeeding, patients with a history of other clinically significant conditions, and those with clinically significant abnormal laboratory tests at screening or absolute lymphocyte counts less than 0.9 x 103/mcL.
Of those enrolled so far, 72.5% received prior MS therapies, and their mean time since onset and diagnosis of MS was 9.7 and 7.6 years, respectively. The mean number of relapses in the prior year was 0.8.
ALKS 8700, also known as BIIB098, is given at a dose of 462 mg twice daily for up to 96 weeks; planned enrollment in EVOLVE-MS-1 is approximately 900 patients, Dr. Naismith said.
The preliminary findings from EVOLE-MS-1, which is limited by its single-arm, open-label design, “lend credence to ALKS 8700 as an oral treatment for patients with relapsing-remitting MS,” he said.
In addition to continued evaluation for long-term safety and tolerability in the current study, ALKS 8700 is also being evaluated in combination with 240 mg of twice daily dimethyl fumarate (DMF; Tecfidera) in the 5-week, randomized, double-blind EVOLVE-MS-2 study, which is looking at the gastrointestinal tolerability of the combination in patients with RRMS.
Oral DMF is approved for RRMS, and has been shown to significantly reduce clinical and MRI disease activity, but is commonly associated with GI events. Monomethyl fumarate is the active metabolite of DMF, and as a prodrug of monomethyl fumarate, ALKS 8700 is being developed to work in a manner similar to that of DMF, but with improved GI tolerability, Dr. Naismith explained.
EVOLE-MS-1 is funded by Alkermes. Dr. Naismith has served as a consultant and/or speaker for Alkermes, as well as for Acorda, Bayer, Biogen, Genentech, Genzyme, EMD Serono, Novartis, and Teva. He has received research support from the National Institutes of Health and the National Multiple Sclerosis Society.
SOURCE: Naismith R et al. AAN 2018 Emerging Science Abstract 006.
LOS ANGELES – ALKS 8700, a novel prodrug of monomethyl fumarate, looks promising as an oral, disease-modifying treatment for relapsing forms of multiple sclerosis, according to interim findings from the phase 3 EVOLVE-MS-1 study.
The annualized relapse rate at a median follow-up of 0.93 patient-years (total, 497.1 patient-years) in 578 patients enrolled to date in the 2-year, open-label study was just 0.16, Robert T. Naismith, MD, reported during an emerging science session at the annual meeting of the American Academy of Neurology.
Further, a statistically significant 80% reduction from baseline was seen in the number of gadolinium-enhancing lesions in 374 patients who completed a 1-year MRI assessment (from a mean of 1.5 to 0.3), said Dr. Naismith of Washington University, St. Louis.
Patients enrolled in the ongoing study are adults aged 18-65 years (mean, 41 years) with confirmed relapsing-remitting MS (RRMS), Expanded Disability Status Scale score of 6.0 or less (mean, 2.7), and no evidence of relapse within 30 days prior to starting ALKS 8700. Those with progressive forms of MS are excluded, as are patients who are pregnant or breastfeeding, patients with a history of other clinically significant conditions, and those with clinically significant abnormal laboratory tests at screening or absolute lymphocyte counts less than 0.9 x 103/mcL.
Of those enrolled so far, 72.5% received prior MS therapies, and their mean time since onset and diagnosis of MS was 9.7 and 7.6 years, respectively. The mean number of relapses in the prior year was 0.8.
ALKS 8700, also known as BIIB098, is given at a dose of 462 mg twice daily for up to 96 weeks; planned enrollment in EVOLVE-MS-1 is approximately 900 patients, Dr. Naismith said.
The preliminary findings from EVOLE-MS-1, which is limited by its single-arm, open-label design, “lend credence to ALKS 8700 as an oral treatment for patients with relapsing-remitting MS,” he said.
In addition to continued evaluation for long-term safety and tolerability in the current study, ALKS 8700 is also being evaluated in combination with 240 mg of twice daily dimethyl fumarate (DMF; Tecfidera) in the 5-week, randomized, double-blind EVOLVE-MS-2 study, which is looking at the gastrointestinal tolerability of the combination in patients with RRMS.
Oral DMF is approved for RRMS, and has been shown to significantly reduce clinical and MRI disease activity, but is commonly associated with GI events. Monomethyl fumarate is the active metabolite of DMF, and as a prodrug of monomethyl fumarate, ALKS 8700 is being developed to work in a manner similar to that of DMF, but with improved GI tolerability, Dr. Naismith explained.
EVOLE-MS-1 is funded by Alkermes. Dr. Naismith has served as a consultant and/or speaker for Alkermes, as well as for Acorda, Bayer, Biogen, Genentech, Genzyme, EMD Serono, Novartis, and Teva. He has received research support from the National Institutes of Health and the National Multiple Sclerosis Society.
SOURCE: Naismith R et al. AAN 2018 Emerging Science Abstract 006.
Key clinical point:
Major finding: The annualized relapse rate at 1 year was just 0.16 vs. 0.8 in the prior year.
Study details: One-year results from 578 patients in an ongoing phase 3, open-label study.
Disclosures: EVOLE-MS-1 is funded by Alkermes. Dr. Naismith has served as a consultant and/or speaker for Alkermes, as well as for Acorda, Bayer, Biogen, Genentech, Genzyme, EMD Serono, Novartis, and Teva. He has received research support from the National Institutes of Health and the National Multiple Sclerosis Society.
Source: Naismith R et al. AAN 2018 Emerging Science Abstract 006.
Deep Gray Matter Volume Loss May Drive Disability Worsening in MS
Deep gray matter volume loss drives disability accumulation in multiple sclerosis (MS), according to a multicenter, longitudinal study published in the February issue of Annals of Neurology.
The results “suggest that the development of deep gray matter atrophy may drive disability accumulation irrespective of clinical phenotypes, thereby becoming a useful outcome measure in neuroprotective clinical trials,” said Arman Eshaghi, MD, of the Queen Square MS Centre at the University College London Institute of Neurology, and colleagues. 
Gray matter atrophy occurs in all MS phenotypes. To investigate whether a spatiotemporal pattern of gray matter atrophy is associated with faster disability accumulation in MS, the investigators analyzed 3,604 high-resolution T1-weighted MRI brain scans from 1,417 participants. The investigators retrospectively collected the scans from seven European centers in the MRI in MS (MAGNIMS) network.
The study included 253 patients with clinically isolated syndrome (CIS), 708 patients with relapsing-remitting MS, 128 patients with secondary progressive MS and 125 patients with primary progressive MS with an average follow-up of 2.41 years, as well as 203 healthy controls with an average follow-up of 1.83 years. The researchers assessed disability using the Expanded Disability Status Scale (EDSS). They obtained volumes of deep gray matter; temporal, frontal, parietal, occipital, and cerebellar gray matter; brainstem; and cerebral white matter. Hierarchical mixed models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time to EDSS progression.
Of all baseline regional volumes, only deep gray matter predicted time to EDSS progression. For every standard deviation decrease in baseline deep gray matter volume, the risk of having a shorter time to EDSS worsening during follow-up increased by 27%. Of all longitudinal measures, deep gray matter had the fastest annual rate of atrophy. This rate
—Jake Remaly
Suggested Reading
Eshaghi A, Prados F, Brownlee WJ, et al. Deep gray matter volume loss drives disability worsening in multiple sclerosis. Ann Neurol. 2018;83(2):210-222.
Deep gray matter volume loss drives disability accumulation in multiple sclerosis (MS), according to a multicenter, longitudinal study published in the February issue of Annals of Neurology.
The results “suggest that the development of deep gray matter atrophy may drive disability accumulation irrespective of clinical phenotypes, thereby becoming a useful outcome measure in neuroprotective clinical trials,” said Arman Eshaghi, MD, of the Queen Square MS Centre at the University College London Institute of Neurology, and colleagues.
Gray matter atrophy occurs in all MS phenotypes. To investigate whether a spatiotemporal pattern of gray matter atrophy is associated with faster disability accumulation in MS, the investigators analyzed 3,604 high-resolution T1-weighted MRI brain scans from 1,417 participants. The investigators retrospectively collected the scans from seven European centers in the MRI in MS (MAGNIMS) network.
The study included 253 patients with clinically isolated syndrome (CIS), 708 patients with relapsing-remitting MS, 128 patients with secondary progressive MS and 125 patients with primary progressive MS with an average follow-up of 2.41 years, as well as 203 healthy controls with an average follow-up of 1.83 years. The researchers assessed disability using the Expanded Disability Status Scale (EDSS). They obtained volumes of deep gray matter; temporal, frontal, parietal, occipital, and cerebellar gray matter; brainstem; and cerebral white matter. Hierarchical mixed models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time to EDSS progression.
Of all baseline regional volumes, only deep gray matter predicted time to EDSS progression. For every standard deviation decrease in baseline deep gray matter volume, the risk of having a shorter time to EDSS worsening during follow-up increased by 27%. Of all longitudinal measures, deep gray matter had the fastest annual rate of atrophy. This rate
—Jake Remaly
Suggested Reading
Eshaghi A, Prados F, Brownlee WJ, et al. Deep gray matter volume loss drives disability worsening in multiple sclerosis. Ann Neurol. 2018;83(2):210-222.
Deep gray matter volume loss drives disability accumulation in multiple sclerosis (MS), according to a multicenter, longitudinal study published in the February issue of Annals of Neurology.
The results “suggest that the development of deep gray matter atrophy may drive disability accumulation irrespective of clinical phenotypes, thereby becoming a useful outcome measure in neuroprotective clinical trials,” said Arman Eshaghi, MD, of the Queen Square MS Centre at the University College London Institute of Neurology, and colleagues.
Gray matter atrophy occurs in all MS phenotypes. To investigate whether a spatiotemporal pattern of gray matter atrophy is associated with faster disability accumulation in MS, the investigators analyzed 3,604 high-resolution T1-weighted MRI brain scans from 1,417 participants. The investigators retrospectively collected the scans from seven European centers in the MRI in MS (MAGNIMS) network.
The study included 253 patients with clinically isolated syndrome (CIS), 708 patients with relapsing-remitting MS, 128 patients with secondary progressive MS and 125 patients with primary progressive MS with an average follow-up of 2.41 years, as well as 203 healthy controls with an average follow-up of 1.83 years. The researchers assessed disability using the Expanded Disability Status Scale (EDSS). They obtained volumes of deep gray matter; temporal, frontal, parietal, occipital, and cerebellar gray matter; brainstem; and cerebral white matter. Hierarchical mixed models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time to EDSS progression.
Of all baseline regional volumes, only deep gray matter predicted time to EDSS progression. For every standard deviation decrease in baseline deep gray matter volume, the risk of having a shorter time to EDSS worsening during follow-up increased by 27%. Of all longitudinal measures, deep gray matter had the fastest annual rate of atrophy. This rate
—Jake Remaly
Suggested Reading
Eshaghi A, Prados F, Brownlee WJ, et al. Deep gray matter volume loss drives disability worsening in multiple sclerosis. Ann Neurol. 2018;83(2):210-222.
MRI May Reveal PML in Patients With Undetectable JCV
Patients with multiple sclerosis (MS) who are treated with natalizumab can have small progressive multifocal leukoencephalopathy (PML) lesions on MRI, yet have undetectable JC virus (JCV) DNA in their CSF, according to a cross-sectional, retrospective study published online ahead of print March 12 in JAMA Neurology.
The findings show that for some people with MS, PML diagnosis could be delayed if CSF sampling is negative and patients are asymptomatic, potentially resulting in worse functional outcomes and survival rates, according to Martijn T. Wijburg, MD, a neurologist at the MS Center at VU University Medical Center in Amsterdam, and colleagues.
The study also described a potential correlation between PML lesion volume and JCV copy numbers. “To our knowledge, this is the first study that shows an association between total PML lesion volume measured by brain MRI and CSF JCV polymerase chain reaction [PCR] results in patients with [natalizumab-associated PML]. This finding may have considerable implications for patient care,” said the authors.
A Retrospective Study
PML, a lytic infection of glial and neuronal cells by the JCV, can be diagnosed when a patient exhibits clinical symptoms, when JCV DNA is detected in CSF by PCR, and when specific brain lesions are seen on MRI, according to a consensus statement from the Neuroinfectious Disease section of the American Academy of Neurology.
Dr. Wijburg and his coinvestigators reviewed data from Dutch and Belgian patients considered to have natalizumab-associated PML between January 2007 and December 2014. Patients were required to meet one of the following criteria:
- Definite or probable PML, based on positive PCR and MRI findings suggestive of PML, with or without PML symptoms.
- In the absence of a positive PCR, the presence of all four of the following features: high risk of PML development, such as positive anti-JCV serostatus and natalizumab treatment duration greater than 12 months; no MS disease activity prior to PML suspicion; MRI lesions highly suggestive of PML, with lesion characteristics as previously reported and absence of lesion characteristics suggestive of other diseases, as judged by an experienced neuroradiologist; and a lesion evolution on follow-up MRI scans suggestive of PML, including development of immune reconstitution inflammatory syndrome.
In the study of 56 patients (37 women), nine patients (16.1%) had undetectable JCV DNA in CSF, and 14 (25%) were asymptomatic for PML. At the time of PML diagnosis, the median age was 45, and the median natalizumab treatment duration was 43 months. Patients with a positive PCR had larger total PML lesion volumes than did those with undetectable JCV DNA (median volume, 22.9 mL vs 6.7 mL). Logistic regression showed that a smaller PML lesion volume significantly increased the probability for undetectable JCV DNA.
The research team also observed a positive correlation between PML lesion volume and JCV copy numbers. PML lesion volume was greater in patients with PML symptoms and in patients with more widespread lesion dissemination. But no association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms.
Results Suggest Need for Pharmacovigilance
The findings suggest that patients with a smaller PML lesion volume were more likely to have a negative test result for JCV, which may lead to a delayed diagnosis of PML. Patients with smaller lesion volume were also more likely to be asymptomatic, which may further delay diagnosis.
“This [finding] can result in a therapeutic dilemma. Unjustly excluding PML may have serious consequences (eg, when switching from [natalizumab] to even more potent immunosuppressive treatments, such as alemtuzumab),” said the authors.
“In patients with [natalizumab-associated PML], both the probability for a positive CSF JCV PCR result and the JCV viral load are associated with the total PML lesion volume.... As a consequence, patients with smaller PML lesion volumes are more likely to have undetectable JCV DNA, and PML can thus not reliably be excluded based on a negative PCR.”
Strict pharmacovigilance by MRI “will lead to identification of smaller [PML] lesions that associate with a higher likelihood of negative PCR results, which hampers a formal diagnosis of [PML] and may complicate patient treatment,” said the authors.
Meticulous clinical and MRI follow-up, in combination with repeated CSF JCV PCR testing, was warranted in these patients, they added. Complementary PML diagnostic approaches, such as assessing intrathecal antibody synthesis to JCV by determining the CSF JCV antibody index, may also be of additional value.
“Furthermore, undetectable JCV DNA does not completely preclude the presence of JCV DNA. Further development and improvement of ultrasensitive PCR assays may improve the diagnostic accuracy in the future.”
MRI Alone Cannot Yet Support Diagnosis
“Dr. Wijburg and colleagues raise an important point in our understanding of the development of PML by showing that small brain lesions may be present at what may be the start of JCV infection when the virus is still undetectable in CSF,” said Eugene O. Major, PhD, a consultant in the Division of Neuroimmunology and Neurovirology at NINDS in Bethesda, Maryland, in an accompanying editorial. “However, it is not yet clear how well the relationship between viral load in CSF and MRI brain lesions approximates the stages of the disease and the processes with which it affects its target brain cells.”
Repeat testing may be worthwhile when CSF testing is negative, because some patients test positive weeks after testing negative, he added. “Suspicion for PML may be increased when MRI shows signs of PML despite negative CSF testing, but it is too early to rely on MRI alone for diagnosis.”
Dr. Major has received consulting fees while serving on independent adjudication committees for Takeda/Millennium, Roche/Genentech, and GlaxoSmithKline.He has patent rights at the NIH as coinventor of the Ultrasensitive Quantitative PCR Multiplex assay for the detection of JCV DNA–distinguishing viral variants.
—Nicola Garrett
Suggested Reading
Major EO. Progressive multifocal leukoencephalopathy lesions and JC virus: the limits and value of imaging. JAMA Neurol. 2018 Mar 12 [Epub ahead of print].
Wijburg MT, Kleerekooper I, Lissenberg-Witte BI, et al. Association of progressive multifocal leukoencephalopathy lesion volume with JC virus polymerase chain reaction results in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis. JAMA Neurol. 2018 Mar 12 [Epub ahead of print].
Patients with multiple sclerosis (MS) who are treated with natalizumab can have small progressive multifocal leukoencephalopathy (PML) lesions on MRI, yet have undetectable JC virus (JCV) DNA in their CSF, according to a cross-sectional, retrospective study published online ahead of print March 12 in JAMA Neurology.
The findings show that for some people with MS, PML diagnosis could be delayed if CSF sampling is negative and patients are asymptomatic, potentially resulting in worse functional outcomes and survival rates, according to Martijn T. Wijburg, MD, a neurologist at the MS Center at VU University Medical Center in Amsterdam, and colleagues.
The study also described a potential correlation between PML lesion volume and JCV copy numbers. “To our knowledge, this is the first study that shows an association between total PML lesion volume measured by brain MRI and CSF JCV polymerase chain reaction [PCR] results in patients with [natalizumab-associated PML]. This finding may have considerable implications for patient care,” said the authors.
A Retrospective Study
PML, a lytic infection of glial and neuronal cells by the JCV, can be diagnosed when a patient exhibits clinical symptoms, when JCV DNA is detected in CSF by PCR, and when specific brain lesions are seen on MRI, according to a consensus statement from the Neuroinfectious Disease section of the American Academy of Neurology.
Dr. Wijburg and his coinvestigators reviewed data from Dutch and Belgian patients considered to have natalizumab-associated PML between January 2007 and December 2014. Patients were required to meet one of the following criteria:
- Definite or probable PML, based on positive PCR and MRI findings suggestive of PML, with or without PML symptoms.
- In the absence of a positive PCR, the presence of all four of the following features: high risk of PML development, such as positive anti-JCV serostatus and natalizumab treatment duration greater than 12 months; no MS disease activity prior to PML suspicion; MRI lesions highly suggestive of PML, with lesion characteristics as previously reported and absence of lesion characteristics suggestive of other diseases, as judged by an experienced neuroradiologist; and a lesion evolution on follow-up MRI scans suggestive of PML, including development of immune reconstitution inflammatory syndrome.
In the study of 56 patients (37 women), nine patients (16.1%) had undetectable JCV DNA in CSF, and 14 (25%) were asymptomatic for PML. At the time of PML diagnosis, the median age was 45, and the median natalizumab treatment duration was 43 months. Patients with a positive PCR had larger total PML lesion volumes than did those with undetectable JCV DNA (median volume, 22.9 mL vs 6.7 mL). Logistic regression showed that a smaller PML lesion volume significantly increased the probability for undetectable JCV DNA.
The research team also observed a positive correlation between PML lesion volume and JCV copy numbers. PML lesion volume was greater in patients with PML symptoms and in patients with more widespread lesion dissemination. But no association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms.
Results Suggest Need for Pharmacovigilance
The findings suggest that patients with a smaller PML lesion volume were more likely to have a negative test result for JCV, which may lead to a delayed diagnosis of PML. Patients with smaller lesion volume were also more likely to be asymptomatic, which may further delay diagnosis.
“This [finding] can result in a therapeutic dilemma. Unjustly excluding PML may have serious consequences (eg, when switching from [natalizumab] to even more potent immunosuppressive treatments, such as alemtuzumab),” said the authors.
“In patients with [natalizumab-associated PML], both the probability for a positive CSF JCV PCR result and the JCV viral load are associated with the total PML lesion volume.... As a consequence, patients with smaller PML lesion volumes are more likely to have undetectable JCV DNA, and PML can thus not reliably be excluded based on a negative PCR.”
Strict pharmacovigilance by MRI “will lead to identification of smaller [PML] lesions that associate with a higher likelihood of negative PCR results, which hampers a formal diagnosis of [PML] and may complicate patient treatment,” said the authors.
Meticulous clinical and MRI follow-up, in combination with repeated CSF JCV PCR testing, was warranted in these patients, they added. Complementary PML diagnostic approaches, such as assessing intrathecal antibody synthesis to JCV by determining the CSF JCV antibody index, may also be of additional value.
“Furthermore, undetectable JCV DNA does not completely preclude the presence of JCV DNA. Further development and improvement of ultrasensitive PCR assays may improve the diagnostic accuracy in the future.”
MRI Alone Cannot Yet Support Diagnosis
“Dr. Wijburg and colleagues raise an important point in our understanding of the development of PML by showing that small brain lesions may be present at what may be the start of JCV infection when the virus is still undetectable in CSF,” said Eugene O. Major, PhD, a consultant in the Division of Neuroimmunology and Neurovirology at NINDS in Bethesda, Maryland, in an accompanying editorial. “However, it is not yet clear how well the relationship between viral load in CSF and MRI brain lesions approximates the stages of the disease and the processes with which it affects its target brain cells.”
Repeat testing may be worthwhile when CSF testing is negative, because some patients test positive weeks after testing negative, he added. “Suspicion for PML may be increased when MRI shows signs of PML despite negative CSF testing, but it is too early to rely on MRI alone for diagnosis.”
Dr. Major has received consulting fees while serving on independent adjudication committees for Takeda/Millennium, Roche/Genentech, and GlaxoSmithKline.He has patent rights at the NIH as coinventor of the Ultrasensitive Quantitative PCR Multiplex assay for the detection of JCV DNA–distinguishing viral variants.
—Nicola Garrett
Suggested Reading
Major EO. Progressive multifocal leukoencephalopathy lesions and JC virus: the limits and value of imaging. JAMA Neurol. 2018 Mar 12 [Epub ahead of print].
Wijburg MT, Kleerekooper I, Lissenberg-Witte BI, et al. Association of progressive multifocal leukoencephalopathy lesion volume with JC virus polymerase chain reaction results in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis. JAMA Neurol. 2018 Mar 12 [Epub ahead of print].
Patients with multiple sclerosis (MS) who are treated with natalizumab can have small progressive multifocal leukoencephalopathy (PML) lesions on MRI, yet have undetectable JC virus (JCV) DNA in their CSF, according to a cross-sectional, retrospective study published online ahead of print March 12 in JAMA Neurology.
The findings show that for some people with MS, PML diagnosis could be delayed if CSF sampling is negative and patients are asymptomatic, potentially resulting in worse functional outcomes and survival rates, according to Martijn T. Wijburg, MD, a neurologist at the MS Center at VU University Medical Center in Amsterdam, and colleagues.
The study also described a potential correlation between PML lesion volume and JCV copy numbers. “To our knowledge, this is the first study that shows an association between total PML lesion volume measured by brain MRI and CSF JCV polymerase chain reaction [PCR] results in patients with [natalizumab-associated PML]. This finding may have considerable implications for patient care,” said the authors.
A Retrospective Study
PML, a lytic infection of glial and neuronal cells by the JCV, can be diagnosed when a patient exhibits clinical symptoms, when JCV DNA is detected in CSF by PCR, and when specific brain lesions are seen on MRI, according to a consensus statement from the Neuroinfectious Disease section of the American Academy of Neurology.
Dr. Wijburg and his coinvestigators reviewed data from Dutch and Belgian patients considered to have natalizumab-associated PML between January 2007 and December 2014. Patients were required to meet one of the following criteria:
- Definite or probable PML, based on positive PCR and MRI findings suggestive of PML, with or without PML symptoms.
- In the absence of a positive PCR, the presence of all four of the following features: high risk of PML development, such as positive anti-JCV serostatus and natalizumab treatment duration greater than 12 months; no MS disease activity prior to PML suspicion; MRI lesions highly suggestive of PML, with lesion characteristics as previously reported and absence of lesion characteristics suggestive of other diseases, as judged by an experienced neuroradiologist; and a lesion evolution on follow-up MRI scans suggestive of PML, including development of immune reconstitution inflammatory syndrome.
In the study of 56 patients (37 women), nine patients (16.1%) had undetectable JCV DNA in CSF, and 14 (25%) were asymptomatic for PML. At the time of PML diagnosis, the median age was 45, and the median natalizumab treatment duration was 43 months. Patients with a positive PCR had larger total PML lesion volumes than did those with undetectable JCV DNA (median volume, 22.9 mL vs 6.7 mL). Logistic regression showed that a smaller PML lesion volume significantly increased the probability for undetectable JCV DNA.
The research team also observed a positive correlation between PML lesion volume and JCV copy numbers. PML lesion volume was greater in patients with PML symptoms and in patients with more widespread lesion dissemination. But no association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms.
Results Suggest Need for Pharmacovigilance
The findings suggest that patients with a smaller PML lesion volume were more likely to have a negative test result for JCV, which may lead to a delayed diagnosis of PML. Patients with smaller lesion volume were also more likely to be asymptomatic, which may further delay diagnosis.
“This [finding] can result in a therapeutic dilemma. Unjustly excluding PML may have serious consequences (eg, when switching from [natalizumab] to even more potent immunosuppressive treatments, such as alemtuzumab),” said the authors.
“In patients with [natalizumab-associated PML], both the probability for a positive CSF JCV PCR result and the JCV viral load are associated with the total PML lesion volume.... As a consequence, patients with smaller PML lesion volumes are more likely to have undetectable JCV DNA, and PML can thus not reliably be excluded based on a negative PCR.”
Strict pharmacovigilance by MRI “will lead to identification of smaller [PML] lesions that associate with a higher likelihood of negative PCR results, which hampers a formal diagnosis of [PML] and may complicate patient treatment,” said the authors.
Meticulous clinical and MRI follow-up, in combination with repeated CSF JCV PCR testing, was warranted in these patients, they added. Complementary PML diagnostic approaches, such as assessing intrathecal antibody synthesis to JCV by determining the CSF JCV antibody index, may also be of additional value.
“Furthermore, undetectable JCV DNA does not completely preclude the presence of JCV DNA. Further development and improvement of ultrasensitive PCR assays may improve the diagnostic accuracy in the future.”
MRI Alone Cannot Yet Support Diagnosis
“Dr. Wijburg and colleagues raise an important point in our understanding of the development of PML by showing that small brain lesions may be present at what may be the start of JCV infection when the virus is still undetectable in CSF,” said Eugene O. Major, PhD, a consultant in the Division of Neuroimmunology and Neurovirology at NINDS in Bethesda, Maryland, in an accompanying editorial. “However, it is not yet clear how well the relationship between viral load in CSF and MRI brain lesions approximates the stages of the disease and the processes with which it affects its target brain cells.”
Repeat testing may be worthwhile when CSF testing is negative, because some patients test positive weeks after testing negative, he added. “Suspicion for PML may be increased when MRI shows signs of PML despite negative CSF testing, but it is too early to rely on MRI alone for diagnosis.”
Dr. Major has received consulting fees while serving on independent adjudication committees for Takeda/Millennium, Roche/Genentech, and GlaxoSmithKline.He has patent rights at the NIH as coinventor of the Ultrasensitive Quantitative PCR Multiplex assay for the detection of JCV DNA–distinguishing viral variants.
—Nicola Garrett
Suggested Reading
Major EO. Progressive multifocal leukoencephalopathy lesions and JC virus: the limits and value of imaging. JAMA Neurol. 2018 Mar 12 [Epub ahead of print].
Wijburg MT, Kleerekooper I, Lissenberg-Witte BI, et al. Association of progressive multifocal leukoencephalopathy lesion volume with JC virus polymerase chain reaction results in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis. JAMA Neurol. 2018 Mar 12 [Epub ahead of print].
Siponimod May Benefit Patients With Secondary Progressive MS
Among patients with secondary progressive multiple sclerosis (MS), siponimod appears to decrease the risk of disability progression, according to data published online ahead of print March 22 in Lancet. The drug’s safety profile is similar to those of other sphingosine-1-phosphate receptor modulators, and siponimod “might be a useful treatment for patients with secondary progressive MS,” according to the authors.
To date, no molecule has slowed disability progression consistently in clinical trials of patients with secondary progressive MS. Preclinical data indicate that siponimod might prevent synaptic neurodegeneration and promote remyelination. The drug reduced the number of active brain lesions and the annualized relapse rate in a phase II study.
Patients Received 2 mg/day of Oral Siponimod
Ludwig Kappos, MD, Professor of Neurology at the University of Basel in Switzerland, and colleagues conducted a double-blind, phase III trial to assess siponimod’s efficacy and safety in patients with secondary progressive MS. They enrolled 1,651 patients at 292 hospitals and MS centers in 31 countries. Eligible participants were between ages 18 and 60, had an Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5, a history of relapsing-remitting MS, EDSS progression in the previous two years, and no evidence of relapse in the three months before randomization. 
The investigators randomized patients 2:1 to once-daily oral siponimod (2 mg) or matching placebo. A trained assessor performed a full neurologic examination every three months. Participants underwent MRI scans at baseline, 12 months, 24 months, 36 months, and the end of the controlled treatment phase. Patients with six-month confirmed disability progression during the double-blind phase were given the opportunity to continue double-blind treatment, switch to open-label siponimod, or stop study treatment and remain untreated or receive another therapy.
The study’s primary end point was time to three-month confirmed disability progression, which was defined as a one-point increase in EDSS for patients with a baseline score of 3.0 to 5.0, or a 0.5-point increase for patients with a baseline score of 5.5 to 6.5. The key secondary end points were time to three-month confirmed worsening of at least 20% from baseline on the Timed 25-Foot Walk (T25FW) and change from baseline in T2 lesion volume.
Treatment Did Not Affect the T25FW
Dr. Kappos and colleagues randomized 1,105 patients to siponimod and 546 patients to placebo. Baseline characteristics were similar between the two study arms. Mean age was 48, and about 60% of patients were women. Participants’ median time in the study was 21 months, and median exposure to study drug was 18 months. Approximately 82% of the siponimod group and 78% of controls completed the study.
The rate of three-month confirmed disability progression was 26% in the siponimod group and 32% in the placebo group. Siponimod thus reduced the risk of this outcome by 21%. The researchers did not observe a significant difference between groups in time to three-month confirmed worsening of at least 20% on the T25FW. The mean increase in T2 lesion volume from baseline was 183.9 mm3 in the siponimod group and 879.2 mm3 among controls.
Siponimod reduced the risk of six-month confirmed disability progression by 26%, compared with placebo. It also was associated with a lower annualized relapse rate and a longer time to confirmed first relapse, compared with placebo.
The rate of adverse events was 89% in the siponimod group and 82% among controls. The rate of serious adverse events was 18% in the siponimod group and 15% among controls. The most frequent adverse events were headache, nasopharyngitis, urinary tract infection, and falls. Serious adverse events included increased liver transaminase concentrations, basal cell carcinoma, concussion, depression, urinary tract infection, suicide attempt, gait disturbance, MS relapse, and paraparesis. The rate of discontinuation because of adverse events was 8% for siponimod and 5% for placebo.
Subgroup analyses suggested that the treatment effect of siponimod decreased with increasing age, disability, baseline disease duration, and diminishing signs of disease activity. One interpretation of this finding “is that siponimod exerts its effect on both aspects of the pathogenesis of secondary progressive disease, albeit not equally,” according to the authors.
The study was funded by Novartis Pharma, which helped design and conduct the study; collect, manage, analyze, and interpret the data; and write the study report.
Drug Might Affect Inflammatory Activity
“The reduction in the proportion of participants reaching the primary end point of only 6% and the absence of a significant difference for the key secondary clinical outcome are disappointing results and do not suggest that siponimod is an effective treatment for secondary progressive MS,” said Luanne M. Metz, MD, Professor of Medicine, and Wei-Qiao Liu, MD, a doctoral student, both at the University of Calgary, Alberta, in an accompanying editorial.
Although siponimod had a “small benefit” on the primary end point, it did not reduce the time to three-month confirmed worsening of the T25FW, said the authors. “Worsening of the T25FW by 20%, as required in this trial, is a reliable measure of change and suggests clinical significance.”
The significant differences between the siponimod group and controls on the other secondary outcomes “might all reflect an effect on the inflammatory disease activity that characterizes relapsing-remitting MS, and this trial does not, in our opinion, provide convincing evidence that we have found a treatment that exerts its clinical effect through other mechanisms,” said Drs. Metz and Liu.
“Confidence in the treatment benefit of siponimod in progressive MS will … require confirmation in a second trial,” they continued. “Trials of other novel treatments that target noninflammatory mechanisms are still needed.”
—Erik Greb
Suggested Reading
Kappos L, Bar-Or A, Cree BAC, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018 Mar 22 [Epub ahead of print].
Metz LM, Liu WQ. Effective treatment of progressive MS remains elusive. Lancet. 2018 Mar 22 [Epub ahead of print].
Among patients with secondary progressive multiple sclerosis (MS), siponimod appears to decrease the risk of disability progression, according to data published online ahead of print March 22 in Lancet. The drug’s safety profile is similar to those of other sphingosine-1-phosphate receptor modulators, and siponimod “might be a useful treatment for patients with secondary progressive MS,” according to the authors.
To date, no molecule has slowed disability progression consistently in clinical trials of patients with secondary progressive MS. Preclinical data indicate that siponimod might prevent synaptic neurodegeneration and promote remyelination. The drug reduced the number of active brain lesions and the annualized relapse rate in a phase II study.
Patients Received 2 mg/day of Oral Siponimod
Ludwig Kappos, MD, Professor of Neurology at the University of Basel in Switzerland, and colleagues conducted a double-blind, phase III trial to assess siponimod’s efficacy and safety in patients with secondary progressive MS. They enrolled 1,651 patients at 292 hospitals and MS centers in 31 countries. Eligible participants were between ages 18 and 60, had an Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5, a history of relapsing-remitting MS, EDSS progression in the previous two years, and no evidence of relapse in the three months before randomization.
The investigators randomized patients 2:1 to once-daily oral siponimod (2 mg) or matching placebo. A trained assessor performed a full neurologic examination every three months. Participants underwent MRI scans at baseline, 12 months, 24 months, 36 months, and the end of the controlled treatment phase. Patients with six-month confirmed disability progression during the double-blind phase were given the opportunity to continue double-blind treatment, switch to open-label siponimod, or stop study treatment and remain untreated or receive another therapy.
The study’s primary end point was time to three-month confirmed disability progression, which was defined as a one-point increase in EDSS for patients with a baseline score of 3.0 to 5.0, or a 0.5-point increase for patients with a baseline score of 5.5 to 6.5. The key secondary end points were time to three-month confirmed worsening of at least 20% from baseline on the Timed 25-Foot Walk (T25FW) and change from baseline in T2 lesion volume.
Treatment Did Not Affect the T25FW
Dr. Kappos and colleagues randomized 1,105 patients to siponimod and 546 patients to placebo. Baseline characteristics were similar between the two study arms. Mean age was 48, and about 60% of patients were women. Participants’ median time in the study was 21 months, and median exposure to study drug was 18 months. Approximately 82% of the siponimod group and 78% of controls completed the study.
The rate of three-month confirmed disability progression was 26% in the siponimod group and 32% in the placebo group. Siponimod thus reduced the risk of this outcome by 21%. The researchers did not observe a significant difference between groups in time to three-month confirmed worsening of at least 20% on the T25FW. The mean increase in T2 lesion volume from baseline was 183.9 mm3 in the siponimod group and 879.2 mm3 among controls.
Siponimod reduced the risk of six-month confirmed disability progression by 26%, compared with placebo. It also was associated with a lower annualized relapse rate and a longer time to confirmed first relapse, compared with placebo.
The rate of adverse events was 89% in the siponimod group and 82% among controls. The rate of serious adverse events was 18% in the siponimod group and 15% among controls. The most frequent adverse events were headache, nasopharyngitis, urinary tract infection, and falls. Serious adverse events included increased liver transaminase concentrations, basal cell carcinoma, concussion, depression, urinary tract infection, suicide attempt, gait disturbance, MS relapse, and paraparesis. The rate of discontinuation because of adverse events was 8% for siponimod and 5% for placebo.
Subgroup analyses suggested that the treatment effect of siponimod decreased with increasing age, disability, baseline disease duration, and diminishing signs of disease activity. One interpretation of this finding “is that siponimod exerts its effect on both aspects of the pathogenesis of secondary progressive disease, albeit not equally,” according to the authors.
The study was funded by Novartis Pharma, which helped design and conduct the study; collect, manage, analyze, and interpret the data; and write the study report.
Drug Might Affect Inflammatory Activity
“The reduction in the proportion of participants reaching the primary end point of only 6% and the absence of a significant difference for the key secondary clinical outcome are disappointing results and do not suggest that siponimod is an effective treatment for secondary progressive MS,” said Luanne M. Metz, MD, Professor of Medicine, and Wei-Qiao Liu, MD, a doctoral student, both at the University of Calgary, Alberta, in an accompanying editorial.
Although siponimod had a “small benefit” on the primary end point, it did not reduce the time to three-month confirmed worsening of the T25FW, said the authors. “Worsening of the T25FW by 20%, as required in this trial, is a reliable measure of change and suggests clinical significance.”
The significant differences between the siponimod group and controls on the other secondary outcomes “might all reflect an effect on the inflammatory disease activity that characterizes relapsing-remitting MS, and this trial does not, in our opinion, provide convincing evidence that we have found a treatment that exerts its clinical effect through other mechanisms,” said Drs. Metz and Liu.
“Confidence in the treatment benefit of siponimod in progressive MS will … require confirmation in a second trial,” they continued. “Trials of other novel treatments that target noninflammatory mechanisms are still needed.”
—Erik Greb
Suggested Reading
Kappos L, Bar-Or A, Cree BAC, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018 Mar 22 [Epub ahead of print].
Metz LM, Liu WQ. Effective treatment of progressive MS remains elusive. Lancet. 2018 Mar 22 [Epub ahead of print].
Among patients with secondary progressive multiple sclerosis (MS), siponimod appears to decrease the risk of disability progression, according to data published online ahead of print March 22 in Lancet. The drug’s safety profile is similar to those of other sphingosine-1-phosphate receptor modulators, and siponimod “might be a useful treatment for patients with secondary progressive MS,” according to the authors.
To date, no molecule has slowed disability progression consistently in clinical trials of patients with secondary progressive MS. Preclinical data indicate that siponimod might prevent synaptic neurodegeneration and promote remyelination. The drug reduced the number of active brain lesions and the annualized relapse rate in a phase II study.
Patients Received 2 mg/day of Oral Siponimod
Ludwig Kappos, MD, Professor of Neurology at the University of Basel in Switzerland, and colleagues conducted a double-blind, phase III trial to assess siponimod’s efficacy and safety in patients with secondary progressive MS. They enrolled 1,651 patients at 292 hospitals and MS centers in 31 countries. Eligible participants were between ages 18 and 60, had an Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5, a history of relapsing-remitting MS, EDSS progression in the previous two years, and no evidence of relapse in the three months before randomization.
The investigators randomized patients 2:1 to once-daily oral siponimod (2 mg) or matching placebo. A trained assessor performed a full neurologic examination every three months. Participants underwent MRI scans at baseline, 12 months, 24 months, 36 months, and the end of the controlled treatment phase. Patients with six-month confirmed disability progression during the double-blind phase were given the opportunity to continue double-blind treatment, switch to open-label siponimod, or stop study treatment and remain untreated or receive another therapy.
The study’s primary end point was time to three-month confirmed disability progression, which was defined as a one-point increase in EDSS for patients with a baseline score of 3.0 to 5.0, or a 0.5-point increase for patients with a baseline score of 5.5 to 6.5. The key secondary end points were time to three-month confirmed worsening of at least 20% from baseline on the Timed 25-Foot Walk (T25FW) and change from baseline in T2 lesion volume.
Treatment Did Not Affect the T25FW
Dr. Kappos and colleagues randomized 1,105 patients to siponimod and 546 patients to placebo. Baseline characteristics were similar between the two study arms. Mean age was 48, and about 60% of patients were women. Participants’ median time in the study was 21 months, and median exposure to study drug was 18 months. Approximately 82% of the siponimod group and 78% of controls completed the study.
The rate of three-month confirmed disability progression was 26% in the siponimod group and 32% in the placebo group. Siponimod thus reduced the risk of this outcome by 21%. The researchers did not observe a significant difference between groups in time to three-month confirmed worsening of at least 20% on the T25FW. The mean increase in T2 lesion volume from baseline was 183.9 mm3 in the siponimod group and 879.2 mm3 among controls.
Siponimod reduced the risk of six-month confirmed disability progression by 26%, compared with placebo. It also was associated with a lower annualized relapse rate and a longer time to confirmed first relapse, compared with placebo.
The rate of adverse events was 89% in the siponimod group and 82% among controls. The rate of serious adverse events was 18% in the siponimod group and 15% among controls. The most frequent adverse events were headache, nasopharyngitis, urinary tract infection, and falls. Serious adverse events included increased liver transaminase concentrations, basal cell carcinoma, concussion, depression, urinary tract infection, suicide attempt, gait disturbance, MS relapse, and paraparesis. The rate of discontinuation because of adverse events was 8% for siponimod and 5% for placebo.
Subgroup analyses suggested that the treatment effect of siponimod decreased with increasing age, disability, baseline disease duration, and diminishing signs of disease activity. One interpretation of this finding “is that siponimod exerts its effect on both aspects of the pathogenesis of secondary progressive disease, albeit not equally,” according to the authors.
The study was funded by Novartis Pharma, which helped design and conduct the study; collect, manage, analyze, and interpret the data; and write the study report.
Drug Might Affect Inflammatory Activity
“The reduction in the proportion of participants reaching the primary end point of only 6% and the absence of a significant difference for the key secondary clinical outcome are disappointing results and do not suggest that siponimod is an effective treatment for secondary progressive MS,” said Luanne M. Metz, MD, Professor of Medicine, and Wei-Qiao Liu, MD, a doctoral student, both at the University of Calgary, Alberta, in an accompanying editorial.
Although siponimod had a “small benefit” on the primary end point, it did not reduce the time to three-month confirmed worsening of the T25FW, said the authors. “Worsening of the T25FW by 20%, as required in this trial, is a reliable measure of change and suggests clinical significance.”
The significant differences between the siponimod group and controls on the other secondary outcomes “might all reflect an effect on the inflammatory disease activity that characterizes relapsing-remitting MS, and this trial does not, in our opinion, provide convincing evidence that we have found a treatment that exerts its clinical effect through other mechanisms,” said Drs. Metz and Liu.
“Confidence in the treatment benefit of siponimod in progressive MS will … require confirmation in a second trial,” they continued. “Trials of other novel treatments that target noninflammatory mechanisms are still needed.”
—Erik Greb
Suggested Reading
Kappos L, Bar-Or A, Cree BAC, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018 Mar 22 [Epub ahead of print].
Metz LM, Liu WQ. Effective treatment of progressive MS remains elusive. Lancet. 2018 Mar 22 [Epub ahead of print].
MRI Techniques Could Help Distinguish Between MS and Migraine
STOWE, VT—Some patients with migraine receive an inappropriate diagnosis of multiple sclerosis (MS). The two disorders share certain clinical and radiologic features, and misdiagnosis is a significant problem. Using MRI scanners widely available to clinicians, researchers are developing several imaging techniques that can provide an objective basis for distinguishing between MS and migraine, according to an overview provided at the Headache Cooperative of New England’s 28th Annual Stowe Headache Symposium. 
The imaging techniques evaluate different aspects of MS pathology, said Andrew J. Solomon, MD, Associate Professor of Neurological Sciences at the University of Vermont College of Medicine in Burlington. The techniques have been automated to a large extent, which reduces the need for human interpretation of data. The incorporation of machine learning could further aid differential diagnosis.
Grounds for Confusion
Various similarities between migraine and MS increase the likelihood of misdiagnosis. The two disorders are chronic and entail attacks and remissions. Both are associated with changes in brain structure and white matter abnormalities that may be subclinical.
In a study of patients with migraine by Liu et al, between 25% and 35% of participants met MRI criteria for dissemination in space for MS, depending on how lesions were defined. The first report of natalizumab-associated progressive multifocal leukoencephalopathy occurred in a patient who, on autopsy, was found not to have had MS. In a 1988 study, Engell and colleagues found that of 518 consecutive patients who had died with a diagnosis of clinically definite MS, the diagnosis was incorrect for 6%.
In 2005, Carmosino and colleagues evaluated 281 patients who had been referred to an MS center and found that 67% of them did not have MS. The investigators identified 37 alternative diagnoses, of which migraine was the second most common. About 10% of participants had a final diagnosis of migraine.
In a recent survey, Dr. Solomon and colleagues asked more than 100 MS specialists whether they had seen patients who had had a diagnosis of MS for more than one year, but, on evaluation, determined that they did not have MS. Approximately 95% of respondents answered affirmatively. About 40% of respondents reported having seen three to five such patients in the previous year.
The current diagnostic criteria for MS rely on clinicians to interpret clinical and radiologic data and contain many caveats regarding their application, said Dr. Solomon. The criteria “were not developed to differentiate MS from other disorders,” but to predict which patients with an initial neurologic syndrome typical for MS will subsequently develop MS, he added. Physicians who are unfamiliar with the diagnostic criteria may misapply them and make an incorrect diagnosis.
The Central Vein Sign
Autopsy studies have indicated that MS lesions generally center around veins. Researchers have recently been able to visualize these veins within MS lesions using 7-T MRI. This finding, which investigators have called the central vein sign, could be a way to distinguish MS from other disorders. But 7-T MRI generally is not available to clinical neurologists. In 2012, scientists at the NIH developed a method that combines T2* imaging, which helps visualize veins, and fluid-attenuated inversion recovery (FLAIR) imaging that visualizes MS lesions. This method visualizes veins within lesions, or central vein sign, using 3-T MRI, which is more commonly available to clinical neurologists. The researchers called this sequence FLAIR*, and numerous studies have suggested that it may differentiate MS from other diagnoses.
Dr. Solomon and collaborators tested this technique on a group of 10 patients with MS who had no other comorbidities for white matter disease and 10 patients with migraine and white matter abnormalities who also had no other comorbidities for white matter disease. The mean percentage of lesions with central vessels per participant was 80% in patients with MS and 34% in migraineurs. The patients with migraine had fewer juxtacortical, periventricular, and infratentorial lesions, compared with patients with MS.
Because researchers have used various definitions of the central vein sign, Dr. Solomon and colleagues published a consensus statement to improve the interpretation of the imaging findings. They recommended that neurologists disregard periventricular lesions and concentrate on subcortical and white matter lesions that are visible from two perspectives.
Another limitation of this diagnostic imaging technique is that it “requires evaluation of every single lesion to determine if a central vein was present,” said Dr. Solomon. He and his colleagues developed a simplified algorithm that required the examination of three lesions. To test this algorithm, they examined their original cohort plus 10 patients with MS and comorbidities for white matter disease (eg, migraine or hypertension) and 10 patients who had been misdiagnosed with MS (most of whom had migraine). Three blinded raters examined three lesions chosen at random from each MRI. This method had a 0.98 specificity for MS and a sensitivity of 0.52. The study demonstrated problems with inter-rater reliability, however.
Dr. Solomon later collaborated with researchers at the University of Pennsylvania to develop a machine learning technique that could identify the central vein sign. When they applied the technique to the expanded cohort of 40 patients, it identified the sign accurately with an area under the curve of about 0.86. The central vein sign may be a good biomarker for MS, and using this automated technique to assess 3-T MRI images appears to be clinically applicable, said Dr. Solomon.
Thalamic Volume
Thalamic atrophy is common in the early stages of relapsing-remitting MS. The thalamus also is implicated in migraine. Although studies have examined volumetric brain changes in migraine, none has examined thalamic volume specifically, said Dr. Solomon.
He and his colleagues used an automatic segmentation method to analyze thalamic volume in their cohort of 40 patients. Analysis of variance indicated that thalamic volume was significantly smaller in patients with MS, compared with patients without MS. When the researchers used a thalamic volume less than 0.0077 as a cutoff, the technique’s sensitivity and specificity for the diagnosis of MS were 0.75.
Recent data suggest that thalamic atrophy in MS does not result from thalamic lesions, but from diffuse white matter abnormalities. Like the central vein sign, thalamic atrophy may reflect MS pathophysiology and could be incorporated into MS diagnostic criteria, said Dr. Solomon.
Cortical Lesions
Autopsy and MRI studies have shown that cortical lesions are characteristic of MS, but MRI studies have suggested that migraineurs generally do not have cortical lesions. Although neurologists can see these lesions in vivo on 7-T MRI, 3-T MRI is not as sensitive and makes cortical lesion detection challenging.
In 2017, Nakamura and colleagues found that ratio maps of T1- and T2-weighted 3-T MRI, images that are acquired in routine clinical care for MS, could identify areas of cortical demyelination. Dr. Solomon and colleagues tested whether this method could distinguish MS from migraine. They defined a z score of less than 3 as an indication of low myelin density. When they examined the cohort of 40 patients, they were able to correlate areas with z scores below the cutoff with cortical lesions that were visible on conventional imaging. The technique accurately distinguished patients with MS from patients with migraine.
None of these emerging imaging techniques is 100% accurate. In the future, however, combining several of these techniques in conjunction with tests of blood biomarkers such as microRNA could accurately distinguish between MS and other disorders with high specificity and sensitivity, Dr. Solomon concluded.
—Erik Greb
Carmosino MJ, Brousseau KM, Arciniegas DB, Corboy JR. Initial evaluations for multiple sclerosis in a university multiple sclerosis center: outcomes and role of magnetic resonance imaging in referral. Arch Neurol. 2005;62(4):585-590.
Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol Scand. 1988;78(1):39-44.
Liu S, Kullnat J, Bourdette D, et al. Prevalence of brain magnetic resonance imaging meeting Barkhof and McDonald criteria for dissemination in space among headache patients. Mult Scler. 2013;19(8):1101-1105.
Nakamura K, Chen JT, Ontaneda D, et al. T1-/T2-weighted ratio differs in demyelinated cortex in multiple sclerosis. Ann Neurol. 2017;82(4):635-639.
Sati P, Oh J, Constable RT, et al. The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative. Nat Rev Neurol. 2016;12(12):714-722.
Solomon AJ, Klein EP, Bourdette D. “Undiagnosing” multiple sclerosis: the challenge of misdiagnosis in MS. Neurology. 2012;78(24):1986-1991.
Solomon AJ, Schindler MK, Howard DB, et al. “Central vessel sign” on 3T FLAIR* MRI for the differentiation of multiple sclerosis from migraine. Ann Clin Transl Neurol. 2015;3(2):82-87.
Solomon AJ, Watts R, Dewey BE, Reich DS. MRI evaluation of thalamic volume differentiates MS from common mimics. Neurol Neuroimmunol Neuroinflamm. 2017;4(5):e387.
STOWE, VT—Some patients with migraine receive an inappropriate diagnosis of multiple sclerosis (MS). The two disorders share certain clinical and radiologic features, and misdiagnosis is a significant problem. Using MRI scanners widely available to clinicians, researchers are developing several imaging techniques that can provide an objective basis for distinguishing between MS and migraine, according to an overview provided at the Headache Cooperative of New England’s 28th Annual Stowe Headache Symposium.
The imaging techniques evaluate different aspects of MS pathology, said Andrew J. Solomon, MD, Associate Professor of Neurological Sciences at the University of Vermont College of Medicine in Burlington. The techniques have been automated to a large extent, which reduces the need for human interpretation of data. The incorporation of machine learning could further aid differential diagnosis.
Grounds for Confusion
Various similarities between migraine and MS increase the likelihood of misdiagnosis. The two disorders are chronic and entail attacks and remissions. Both are associated with changes in brain structure and white matter abnormalities that may be subclinical.
In a study of patients with migraine by Liu et al, between 25% and 35% of participants met MRI criteria for dissemination in space for MS, depending on how lesions were defined. The first report of natalizumab-associated progressive multifocal leukoencephalopathy occurred in a patient who, on autopsy, was found not to have had MS. In a 1988 study, Engell and colleagues found that of 518 consecutive patients who had died with a diagnosis of clinically definite MS, the diagnosis was incorrect for 6%.
In 2005, Carmosino and colleagues evaluated 281 patients who had been referred to an MS center and found that 67% of them did not have MS. The investigators identified 37 alternative diagnoses, of which migraine was the second most common. About 10% of participants had a final diagnosis of migraine.
In a recent survey, Dr. Solomon and colleagues asked more than 100 MS specialists whether they had seen patients who had had a diagnosis of MS for more than one year, but, on evaluation, determined that they did not have MS. Approximately 95% of respondents answered affirmatively. About 40% of respondents reported having seen three to five such patients in the previous year.
The current diagnostic criteria for MS rely on clinicians to interpret clinical and radiologic data and contain many caveats regarding their application, said Dr. Solomon. The criteria “were not developed to differentiate MS from other disorders,” but to predict which patients with an initial neurologic syndrome typical for MS will subsequently develop MS, he added. Physicians who are unfamiliar with the diagnostic criteria may misapply them and make an incorrect diagnosis.
The Central Vein Sign
Autopsy studies have indicated that MS lesions generally center around veins. Researchers have recently been able to visualize these veins within MS lesions using 7-T MRI. This finding, which investigators have called the central vein sign, could be a way to distinguish MS from other disorders. But 7-T MRI generally is not available to clinical neurologists. In 2012, scientists at the NIH developed a method that combines T2* imaging, which helps visualize veins, and fluid-attenuated inversion recovery (FLAIR) imaging that visualizes MS lesions. This method visualizes veins within lesions, or central vein sign, using 3-T MRI, which is more commonly available to clinical neurologists. The researchers called this sequence FLAIR*, and numerous studies have suggested that it may differentiate MS from other diagnoses.
Dr. Solomon and collaborators tested this technique on a group of 10 patients with MS who had no other comorbidities for white matter disease and 10 patients with migraine and white matter abnormalities who also had no other comorbidities for white matter disease. The mean percentage of lesions with central vessels per participant was 80% in patients with MS and 34% in migraineurs. The patients with migraine had fewer juxtacortical, periventricular, and infratentorial lesions, compared with patients with MS.
Because researchers have used various definitions of the central vein sign, Dr. Solomon and colleagues published a consensus statement to improve the interpretation of the imaging findings. They recommended that neurologists disregard periventricular lesions and concentrate on subcortical and white matter lesions that are visible from two perspectives.
Another limitation of this diagnostic imaging technique is that it “requires evaluation of every single lesion to determine if a central vein was present,” said Dr. Solomon. He and his colleagues developed a simplified algorithm that required the examination of three lesions. To test this algorithm, they examined their original cohort plus 10 patients with MS and comorbidities for white matter disease (eg, migraine or hypertension) and 10 patients who had been misdiagnosed with MS (most of whom had migraine). Three blinded raters examined three lesions chosen at random from each MRI. This method had a 0.98 specificity for MS and a sensitivity of 0.52. The study demonstrated problems with inter-rater reliability, however.
Dr. Solomon later collaborated with researchers at the University of Pennsylvania to develop a machine learning technique that could identify the central vein sign. When they applied the technique to the expanded cohort of 40 patients, it identified the sign accurately with an area under the curve of about 0.86. The central vein sign may be a good biomarker for MS, and using this automated technique to assess 3-T MRI images appears to be clinically applicable, said Dr. Solomon.
Thalamic Volume
Thalamic atrophy is common in the early stages of relapsing-remitting MS. The thalamus also is implicated in migraine. Although studies have examined volumetric brain changes in migraine, none has examined thalamic volume specifically, said Dr. Solomon.
He and his colleagues used an automatic segmentation method to analyze thalamic volume in their cohort of 40 patients. Analysis of variance indicated that thalamic volume was significantly smaller in patients with MS, compared with patients without MS. When the researchers used a thalamic volume less than 0.0077 as a cutoff, the technique’s sensitivity and specificity for the diagnosis of MS were 0.75.
Recent data suggest that thalamic atrophy in MS does not result from thalamic lesions, but from diffuse white matter abnormalities. Like the central vein sign, thalamic atrophy may reflect MS pathophysiology and could be incorporated into MS diagnostic criteria, said Dr. Solomon.
Cortical Lesions
Autopsy and MRI studies have shown that cortical lesions are characteristic of MS, but MRI studies have suggested that migraineurs generally do not have cortical lesions. Although neurologists can see these lesions in vivo on 7-T MRI, 3-T MRI is not as sensitive and makes cortical lesion detection challenging.
In 2017, Nakamura and colleagues found that ratio maps of T1- and T2-weighted 3-T MRI, images that are acquired in routine clinical care for MS, could identify areas of cortical demyelination. Dr. Solomon and colleagues tested whether this method could distinguish MS from migraine. They defined a z score of less than 3 as an indication of low myelin density. When they examined the cohort of 40 patients, they were able to correlate areas with z scores below the cutoff with cortical lesions that were visible on conventional imaging. The technique accurately distinguished patients with MS from patients with migraine.
None of these emerging imaging techniques is 100% accurate. In the future, however, combining several of these techniques in conjunction with tests of blood biomarkers such as microRNA could accurately distinguish between MS and other disorders with high specificity and sensitivity, Dr. Solomon concluded.
—Erik Greb
Carmosino MJ, Brousseau KM, Arciniegas DB, Corboy JR. Initial evaluations for multiple sclerosis in a university multiple sclerosis center: outcomes and role of magnetic resonance imaging in referral. Arch Neurol. 2005;62(4):585-590.
Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol Scand. 1988;78(1):39-44.
Liu S, Kullnat J, Bourdette D, et al. Prevalence of brain magnetic resonance imaging meeting Barkhof and McDonald criteria for dissemination in space among headache patients. Mult Scler. 2013;19(8):1101-1105.
Nakamura K, Chen JT, Ontaneda D, et al. T1-/T2-weighted ratio differs in demyelinated cortex in multiple sclerosis. Ann Neurol. 2017;82(4):635-639.
Sati P, Oh J, Constable RT, et al. The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative. Nat Rev Neurol. 2016;12(12):714-722.
Solomon AJ, Klein EP, Bourdette D. “Undiagnosing” multiple sclerosis: the challenge of misdiagnosis in MS. Neurology. 2012;78(24):1986-1991.
Solomon AJ, Schindler MK, Howard DB, et al. “Central vessel sign” on 3T FLAIR* MRI for the differentiation of multiple sclerosis from migraine. Ann Clin Transl Neurol. 2015;3(2):82-87.
Solomon AJ, Watts R, Dewey BE, Reich DS. MRI evaluation of thalamic volume differentiates MS from common mimics. Neurol Neuroimmunol Neuroinflamm. 2017;4(5):e387.
STOWE, VT—Some patients with migraine receive an inappropriate diagnosis of multiple sclerosis (MS). The two disorders share certain clinical and radiologic features, and misdiagnosis is a significant problem. Using MRI scanners widely available to clinicians, researchers are developing several imaging techniques that can provide an objective basis for distinguishing between MS and migraine, according to an overview provided at the Headache Cooperative of New England’s 28th Annual Stowe Headache Symposium.
The imaging techniques evaluate different aspects of MS pathology, said Andrew J. Solomon, MD, Associate Professor of Neurological Sciences at the University of Vermont College of Medicine in Burlington. The techniques have been automated to a large extent, which reduces the need for human interpretation of data. The incorporation of machine learning could further aid differential diagnosis.
Grounds for Confusion
Various similarities between migraine and MS increase the likelihood of misdiagnosis. The two disorders are chronic and entail attacks and remissions. Both are associated with changes in brain structure and white matter abnormalities that may be subclinical.
In a study of patients with migraine by Liu et al, between 25% and 35% of participants met MRI criteria for dissemination in space for MS, depending on how lesions were defined. The first report of natalizumab-associated progressive multifocal leukoencephalopathy occurred in a patient who, on autopsy, was found not to have had MS. In a 1988 study, Engell and colleagues found that of 518 consecutive patients who had died with a diagnosis of clinically definite MS, the diagnosis was incorrect for 6%.
In 2005, Carmosino and colleagues evaluated 281 patients who had been referred to an MS center and found that 67% of them did not have MS. The investigators identified 37 alternative diagnoses, of which migraine was the second most common. About 10% of participants had a final diagnosis of migraine.
In a recent survey, Dr. Solomon and colleagues asked more than 100 MS specialists whether they had seen patients who had had a diagnosis of MS for more than one year, but, on evaluation, determined that they did not have MS. Approximately 95% of respondents answered affirmatively. About 40% of respondents reported having seen three to five such patients in the previous year.
The current diagnostic criteria for MS rely on clinicians to interpret clinical and radiologic data and contain many caveats regarding their application, said Dr. Solomon. The criteria “were not developed to differentiate MS from other disorders,” but to predict which patients with an initial neurologic syndrome typical for MS will subsequently develop MS, he added. Physicians who are unfamiliar with the diagnostic criteria may misapply them and make an incorrect diagnosis.
The Central Vein Sign
Autopsy studies have indicated that MS lesions generally center around veins. Researchers have recently been able to visualize these veins within MS lesions using 7-T MRI. This finding, which investigators have called the central vein sign, could be a way to distinguish MS from other disorders. But 7-T MRI generally is not available to clinical neurologists. In 2012, scientists at the NIH developed a method that combines T2* imaging, which helps visualize veins, and fluid-attenuated inversion recovery (FLAIR) imaging that visualizes MS lesions. This method visualizes veins within lesions, or central vein sign, using 3-T MRI, which is more commonly available to clinical neurologists. The researchers called this sequence FLAIR*, and numerous studies have suggested that it may differentiate MS from other diagnoses.
Dr. Solomon and collaborators tested this technique on a group of 10 patients with MS who had no other comorbidities for white matter disease and 10 patients with migraine and white matter abnormalities who also had no other comorbidities for white matter disease. The mean percentage of lesions with central vessels per participant was 80% in patients with MS and 34% in migraineurs. The patients with migraine had fewer juxtacortical, periventricular, and infratentorial lesions, compared with patients with MS.
Because researchers have used various definitions of the central vein sign, Dr. Solomon and colleagues published a consensus statement to improve the interpretation of the imaging findings. They recommended that neurologists disregard periventricular lesions and concentrate on subcortical and white matter lesions that are visible from two perspectives.
Another limitation of this diagnostic imaging technique is that it “requires evaluation of every single lesion to determine if a central vein was present,” said Dr. Solomon. He and his colleagues developed a simplified algorithm that required the examination of three lesions. To test this algorithm, they examined their original cohort plus 10 patients with MS and comorbidities for white matter disease (eg, migraine or hypertension) and 10 patients who had been misdiagnosed with MS (most of whom had migraine). Three blinded raters examined three lesions chosen at random from each MRI. This method had a 0.98 specificity for MS and a sensitivity of 0.52. The study demonstrated problems with inter-rater reliability, however.
Dr. Solomon later collaborated with researchers at the University of Pennsylvania to develop a machine learning technique that could identify the central vein sign. When they applied the technique to the expanded cohort of 40 patients, it identified the sign accurately with an area under the curve of about 0.86. The central vein sign may be a good biomarker for MS, and using this automated technique to assess 3-T MRI images appears to be clinically applicable, said Dr. Solomon.
Thalamic Volume
Thalamic atrophy is common in the early stages of relapsing-remitting MS. The thalamus also is implicated in migraine. Although studies have examined volumetric brain changes in migraine, none has examined thalamic volume specifically, said Dr. Solomon.
He and his colleagues used an automatic segmentation method to analyze thalamic volume in their cohort of 40 patients. Analysis of variance indicated that thalamic volume was significantly smaller in patients with MS, compared with patients without MS. When the researchers used a thalamic volume less than 0.0077 as a cutoff, the technique’s sensitivity and specificity for the diagnosis of MS were 0.75.
Recent data suggest that thalamic atrophy in MS does not result from thalamic lesions, but from diffuse white matter abnormalities. Like the central vein sign, thalamic atrophy may reflect MS pathophysiology and could be incorporated into MS diagnostic criteria, said Dr. Solomon.
Cortical Lesions
Autopsy and MRI studies have shown that cortical lesions are characteristic of MS, but MRI studies have suggested that migraineurs generally do not have cortical lesions. Although neurologists can see these lesions in vivo on 7-T MRI, 3-T MRI is not as sensitive and makes cortical lesion detection challenging.
In 2017, Nakamura and colleagues found that ratio maps of T1- and T2-weighted 3-T MRI, images that are acquired in routine clinical care for MS, could identify areas of cortical demyelination. Dr. Solomon and colleagues tested whether this method could distinguish MS from migraine. They defined a z score of less than 3 as an indication of low myelin density. When they examined the cohort of 40 patients, they were able to correlate areas with z scores below the cutoff with cortical lesions that were visible on conventional imaging. The technique accurately distinguished patients with MS from patients with migraine.
None of these emerging imaging techniques is 100% accurate. In the future, however, combining several of these techniques in conjunction with tests of blood biomarkers such as microRNA could accurately distinguish between MS and other disorders with high specificity and sensitivity, Dr. Solomon concluded.
—Erik Greb
Carmosino MJ, Brousseau KM, Arciniegas DB, Corboy JR. Initial evaluations for multiple sclerosis in a university multiple sclerosis center: outcomes and role of magnetic resonance imaging in referral. Arch Neurol. 2005;62(4):585-590.
Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol Scand. 1988;78(1):39-44.
Liu S, Kullnat J, Bourdette D, et al. Prevalence of brain magnetic resonance imaging meeting Barkhof and McDonald criteria for dissemination in space among headache patients. Mult Scler. 2013;19(8):1101-1105.
Nakamura K, Chen JT, Ontaneda D, et al. T1-/T2-weighted ratio differs in demyelinated cortex in multiple sclerosis. Ann Neurol. 2017;82(4):635-639.
Sati P, Oh J, Constable RT, et al. The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative. Nat Rev Neurol. 2016;12(12):714-722.
Solomon AJ, Klein EP, Bourdette D. “Undiagnosing” multiple sclerosis: the challenge of misdiagnosis in MS. Neurology. 2012;78(24):1986-1991.
Solomon AJ, Schindler MK, Howard DB, et al. “Central vessel sign” on 3T FLAIR* MRI for the differentiation of multiple sclerosis from migraine. Ann Clin Transl Neurol. 2015;3(2):82-87.
Solomon AJ, Watts R, Dewey BE, Reich DS. MRI evaluation of thalamic volume differentiates MS from common mimics. Neurol Neuroimmunol Neuroinflamm. 2017;4(5):e387.
MS drugs in Medicare Part D: Higher tiers, less coverage, more prior authorizations
LOS ANGELES – Under Medicare Part D, private prescription drug plans and those bundled with Medicare Advantage plans have steadily raised injectable and oral disease-modifying therapies for multiple sclerosis to higher tiers with higher cost sharing, reduced coverage of particular drugs, and increased prior authorizations during the 10-year period of 2007-2016, according to an analysis conducted by Oregon State University researchers.
At the annual meeting of the American Academy of Neurology, Daniel Hartung, PharmD, of Oregon Health and Science University, Portland, and his colleagues reported that the proportion of plans with disease-modifying therapies (DMTs) in the highest tiers, generally tier 5 and above, rose from 11% in 2007 to 95% in 2016.
The scope of drugs covered by the plans declined marginally. Over the 10-year period, plans covering at least three DMTs declined from 98% to 95%, but plans that covered interferon beta-1b, intramuscular or subcutaneous interferon beta-1a, or glatiramer acetate declined from 85%-100% of plans to 60%-81%.
Plans with prior authorizations for DMTs rose across the board. The percentage of plans with at least one DMT not needing prior authorization dropped from 40% to 27%, while plans that covered interferon beta-1b, intramuscular or subcutaneous interferon beta-1a, or glatiramer acetate rose from 62%-65% to 77%-80%.
Based on 2016 coverage characteristics, Dr. Hartung and his associates estimated that the expected annual out-of-pocket costs for patients in 2019 would be over $5,000 for all drugs in the analysis, after accounting for the Bipartisan Budget Act’s closing the Part D coverage gap in 2019.
Part D covers noninfusible DMTs, which in this analysis included glatiramer acetate 20 and 40 mg (Copaxone 20 and Copaxone 40), generic glatiramer acetate 20 mg (Glatopa), interferon beta-1a intramuscular (Avonex), interferon beta-1a subcutaneous (Rebif), interferon beta-1b (Extavia and Betaseron), peginterferon beta-1a (Plegridy), fingolimod (Gilenya), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera). The infusible drugs natalizumab (Tysabri), alemtuzumab (Lemtrada), and ocrelizumab (Ocrevus) fall under Medicare Part B.
The study was supported by the National Multiple Sclerosis Society. None of the authors had anything to disclose.
SOURCE: Hartung D et al. AAN 2018. Abstract P3.161
LOS ANGELES – Under Medicare Part D, private prescription drug plans and those bundled with Medicare Advantage plans have steadily raised injectable and oral disease-modifying therapies for multiple sclerosis to higher tiers with higher cost sharing, reduced coverage of particular drugs, and increased prior authorizations during the 10-year period of 2007-2016, according to an analysis conducted by Oregon State University researchers.
At the annual meeting of the American Academy of Neurology, Daniel Hartung, PharmD, of Oregon Health and Science University, Portland, and his colleagues reported that the proportion of plans with disease-modifying therapies (DMTs) in the highest tiers, generally tier 5 and above, rose from 11% in 2007 to 95% in 2016.
The scope of drugs covered by the plans declined marginally. Over the 10-year period, plans covering at least three DMTs declined from 98% to 95%, but plans that covered interferon beta-1b, intramuscular or subcutaneous interferon beta-1a, or glatiramer acetate declined from 85%-100% of plans to 60%-81%.
Plans with prior authorizations for DMTs rose across the board. The percentage of plans with at least one DMT not needing prior authorization dropped from 40% to 27%, while plans that covered interferon beta-1b, intramuscular or subcutaneous interferon beta-1a, or glatiramer acetate rose from 62%-65% to 77%-80%.
Based on 2016 coverage characteristics, Dr. Hartung and his associates estimated that the expected annual out-of-pocket costs for patients in 2019 would be over $5,000 for all drugs in the analysis, after accounting for the Bipartisan Budget Act’s closing the Part D coverage gap in 2019.
Part D covers noninfusible DMTs, which in this analysis included glatiramer acetate 20 and 40 mg (Copaxone 20 and Copaxone 40), generic glatiramer acetate 20 mg (Glatopa), interferon beta-1a intramuscular (Avonex), interferon beta-1a subcutaneous (Rebif), interferon beta-1b (Extavia and Betaseron), peginterferon beta-1a (Plegridy), fingolimod (Gilenya), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera). The infusible drugs natalizumab (Tysabri), alemtuzumab (Lemtrada), and ocrelizumab (Ocrevus) fall under Medicare Part B.
The study was supported by the National Multiple Sclerosis Society. None of the authors had anything to disclose.
SOURCE: Hartung D et al. AAN 2018. Abstract P3.161
LOS ANGELES – Under Medicare Part D, private prescription drug plans and those bundled with Medicare Advantage plans have steadily raised injectable and oral disease-modifying therapies for multiple sclerosis to higher tiers with higher cost sharing, reduced coverage of particular drugs, and increased prior authorizations during the 10-year period of 2007-2016, according to an analysis conducted by Oregon State University researchers.
At the annual meeting of the American Academy of Neurology, Daniel Hartung, PharmD, of Oregon Health and Science University, Portland, and his colleagues reported that the proportion of plans with disease-modifying therapies (DMTs) in the highest tiers, generally tier 5 and above, rose from 11% in 2007 to 95% in 2016.
The scope of drugs covered by the plans declined marginally. Over the 10-year period, plans covering at least three DMTs declined from 98% to 95%, but plans that covered interferon beta-1b, intramuscular or subcutaneous interferon beta-1a, or glatiramer acetate declined from 85%-100% of plans to 60%-81%.
Plans with prior authorizations for DMTs rose across the board. The percentage of plans with at least one DMT not needing prior authorization dropped from 40% to 27%, while plans that covered interferon beta-1b, intramuscular or subcutaneous interferon beta-1a, or glatiramer acetate rose from 62%-65% to 77%-80%.
Based on 2016 coverage characteristics, Dr. Hartung and his associates estimated that the expected annual out-of-pocket costs for patients in 2019 would be over $5,000 for all drugs in the analysis, after accounting for the Bipartisan Budget Act’s closing the Part D coverage gap in 2019.
Part D covers noninfusible DMTs, which in this analysis included glatiramer acetate 20 and 40 mg (Copaxone 20 and Copaxone 40), generic glatiramer acetate 20 mg (Glatopa), interferon beta-1a intramuscular (Avonex), interferon beta-1a subcutaneous (Rebif), interferon beta-1b (Extavia and Betaseron), peginterferon beta-1a (Plegridy), fingolimod (Gilenya), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera). The infusible drugs natalizumab (Tysabri), alemtuzumab (Lemtrada), and ocrelizumab (Ocrevus) fall under Medicare Part B.
The study was supported by the National Multiple Sclerosis Society. None of the authors had anything to disclose.
SOURCE: Hartung D et al. AAN 2018. Abstract P3.161
REPORTING FROM AAN 2018
VIDEO: AAN MS guidelines aim to help clinicians weigh expanding drug choices
LOS ANGELES – A new clinical guideline for adults with multiple sclerosis is designed to help clinicians navigate an increasingly complex landscape of treatment options, its authors say.
The new American Academy of Neurology (AAN) guideline includes some 30 recommendations related to starting a disease-modifying therapy (DMT), switching therapies, or stopping treatment. The guideline, presented April 23 at the AAN annual meeting and published online simultaneously in Neurology, is the first full MS practice guideline issued by AAN since 2002, when only a handful of medications were licensed for use in MS.
The new guideline does not present a hierarchy of DMTs to start but instead weighs evidence for 21 medications or formulations, including 8 used off label, with the idea that clinicians will tailor their choices by considering patient needs, preferences, potential adverse affects, cost of medicines, comorbidities (including depression), and likelihood of adherence, among other factors addressed.
“It’s a dramatically different landscape of the choices clinicians have,” guideline lead author Alexander Rae-Grant, MD, of the Cleveland Clinic, said at a press conference announcing the guideline.
The guideline encourages clinicians and patients “to have a detailed discussion of the risks and benefits of different therapies,” guideline coauthor Ruth Ann Marrie, MD, PhD, of the University of Manitoba, Winnipeg, said at the press conference. “You need to have that informed ... discussion to share decision making – the guideline provides information for each provider-patient dyad to make decisions specific to that patient.”
The guideline incorporates findings from nearly 50 randomized trials, although few of these were head-to-head comparisons of therapies. The authors graded evidence for each DMT as compared with placebo or other DMTs in lowering relapse rate, taking into consideration study design and size. The guideline reflects changes to diagnostic criteria made in 2010, and a classification scheme issued in 2014 for MS subtypes, both of which have complicated the extension of clinical trial findings to some patient groups. It stresses early treatment, recommending that clinicians start DMTs in people with a single clinical demyelinating event and two or more brain lesions characteristic of MS.
Several drugs used off label in MS, including azathioprine and cladribine, were included in the evidence review, with cladribine described as a cost-effective option for patients without the resources to obtain approved agents.
Patients with a new diagnosis of MS should be counseled on starting DMTs not at the time of diagnosis but in a dedicated follow-up visit, the guideline says. Dr. Rae-Grant said that there’s a reasonable amount of “literature to suggest that at the time of diagnosis, what people hear after diagnosis is zero – and that deciding what medication to use is such a weighty decision, we did feel it was important to do that at a different time.”
Dr. Marrie said the AAN guideline “shares some strong similarities” with guidelines released in 2017 by the European Academy of Neurology, including recommendations for early initiation of therapy, for maintaining therapies, and for switching DMTs in individuals not responding or who have breakthrough relapses or changes on MRI.
Dr. Marrie disclosed no conflicts of interest related to her work on the guidelines. Dr. Rae-Grant disclosed income from textbooks on neurology and MS, and no other financial conflicts of interest.
SOURCE: Rae-Grant A et al. Neurology. 2018;90:777-88.
LOS ANGELES – A new clinical guideline for adults with multiple sclerosis is designed to help clinicians navigate an increasingly complex landscape of treatment options, its authors say.
The new American Academy of Neurology (AAN) guideline includes some 30 recommendations related to starting a disease-modifying therapy (DMT), switching therapies, or stopping treatment. The guideline, presented April 23 at the AAN annual meeting and published online simultaneously in Neurology, is the first full MS practice guideline issued by AAN since 2002, when only a handful of medications were licensed for use in MS.
The new guideline does not present a hierarchy of DMTs to start but instead weighs evidence for 21 medications or formulations, including 8 used off label, with the idea that clinicians will tailor their choices by considering patient needs, preferences, potential adverse affects, cost of medicines, comorbidities (including depression), and likelihood of adherence, among other factors addressed.
“It’s a dramatically different landscape of the choices clinicians have,” guideline lead author Alexander Rae-Grant, MD, of the Cleveland Clinic, said at a press conference announcing the guideline.
The guideline encourages clinicians and patients “to have a detailed discussion of the risks and benefits of different therapies,” guideline coauthor Ruth Ann Marrie, MD, PhD, of the University of Manitoba, Winnipeg, said at the press conference. “You need to have that informed ... discussion to share decision making – the guideline provides information for each provider-patient dyad to make decisions specific to that patient.”
The guideline incorporates findings from nearly 50 randomized trials, although few of these were head-to-head comparisons of therapies. The authors graded evidence for each DMT as compared with placebo or other DMTs in lowering relapse rate, taking into consideration study design and size. The guideline reflects changes to diagnostic criteria made in 2010, and a classification scheme issued in 2014 for MS subtypes, both of which have complicated the extension of clinical trial findings to some patient groups. It stresses early treatment, recommending that clinicians start DMTs in people with a single clinical demyelinating event and two or more brain lesions characteristic of MS.
Several drugs used off label in MS, including azathioprine and cladribine, were included in the evidence review, with cladribine described as a cost-effective option for patients without the resources to obtain approved agents.
Patients with a new diagnosis of MS should be counseled on starting DMTs not at the time of diagnosis but in a dedicated follow-up visit, the guideline says. Dr. Rae-Grant said that there’s a reasonable amount of “literature to suggest that at the time of diagnosis, what people hear after diagnosis is zero – and that deciding what medication to use is such a weighty decision, we did feel it was important to do that at a different time.”
Dr. Marrie said the AAN guideline “shares some strong similarities” with guidelines released in 2017 by the European Academy of Neurology, including recommendations for early initiation of therapy, for maintaining therapies, and for switching DMTs in individuals not responding or who have breakthrough relapses or changes on MRI.
Dr. Marrie disclosed no conflicts of interest related to her work on the guidelines. Dr. Rae-Grant disclosed income from textbooks on neurology and MS, and no other financial conflicts of interest.
SOURCE: Rae-Grant A et al. Neurology. 2018;90:777-88.
LOS ANGELES – A new clinical guideline for adults with multiple sclerosis is designed to help clinicians navigate an increasingly complex landscape of treatment options, its authors say.
The new American Academy of Neurology (AAN) guideline includes some 30 recommendations related to starting a disease-modifying therapy (DMT), switching therapies, or stopping treatment. The guideline, presented April 23 at the AAN annual meeting and published online simultaneously in Neurology, is the first full MS practice guideline issued by AAN since 2002, when only a handful of medications were licensed for use in MS.
The new guideline does not present a hierarchy of DMTs to start but instead weighs evidence for 21 medications or formulations, including 8 used off label, with the idea that clinicians will tailor their choices by considering patient needs, preferences, potential adverse affects, cost of medicines, comorbidities (including depression), and likelihood of adherence, among other factors addressed.
“It’s a dramatically different landscape of the choices clinicians have,” guideline lead author Alexander Rae-Grant, MD, of the Cleveland Clinic, said at a press conference announcing the guideline.
The guideline encourages clinicians and patients “to have a detailed discussion of the risks and benefits of different therapies,” guideline coauthor Ruth Ann Marrie, MD, PhD, of the University of Manitoba, Winnipeg, said at the press conference. “You need to have that informed ... discussion to share decision making – the guideline provides information for each provider-patient dyad to make decisions specific to that patient.”
The guideline incorporates findings from nearly 50 randomized trials, although few of these were head-to-head comparisons of therapies. The authors graded evidence for each DMT as compared with placebo or other DMTs in lowering relapse rate, taking into consideration study design and size. The guideline reflects changes to diagnostic criteria made in 2010, and a classification scheme issued in 2014 for MS subtypes, both of which have complicated the extension of clinical trial findings to some patient groups. It stresses early treatment, recommending that clinicians start DMTs in people with a single clinical demyelinating event and two or more brain lesions characteristic of MS.
Several drugs used off label in MS, including azathioprine and cladribine, were included in the evidence review, with cladribine described as a cost-effective option for patients without the resources to obtain approved agents.
Patients with a new diagnosis of MS should be counseled on starting DMTs not at the time of diagnosis but in a dedicated follow-up visit, the guideline says. Dr. Rae-Grant said that there’s a reasonable amount of “literature to suggest that at the time of diagnosis, what people hear after diagnosis is zero – and that deciding what medication to use is such a weighty decision, we did feel it was important to do that at a different time.”
Dr. Marrie said the AAN guideline “shares some strong similarities” with guidelines released in 2017 by the European Academy of Neurology, including recommendations for early initiation of therapy, for maintaining therapies, and for switching DMTs in individuals not responding or who have breakthrough relapses or changes on MRI.
Dr. Marrie disclosed no conflicts of interest related to her work on the guidelines. Dr. Rae-Grant disclosed income from textbooks on neurology and MS, and no other financial conflicts of interest.
SOURCE: Rae-Grant A et al. Neurology. 2018;90:777-88.
REPORTING FROM AAN 2018
Eating Fish May Be Associated With a Reduced Risk of MS
LOS ANGELES—Eating fish at least once per week or eating fish one to three times per month, in addition to taking daily fish oil supplements, may be associated with a reduced risk of multiple sclerosis (MS), according to a preliminary study presented at the American Academy of Neurology’s 70th Annual Meeting. These findings suggest that the omega-3 fatty acids found in fish may be associated with lowering the risk of developing MS.
“Consuming fish that contain omega-3 fatty acids has been shown to have a variety of health benefits, so we wanted to see if this simple lifestyle modification, regularly eating fish and taking fish oil supplements, could reduce the risk of MS,” said lead study author Annette Langer-Gould, MD, PhD, Regional Lead for Clinical and Translational Neuroscience for the Southern California Permanente Medical Group in Pasadena, and Clinical Assistant Professor at the Keck School of Medicine of the University of Southern California in Los Angeles. 
For this study, researchers examined the diets of 1,153 people (average age 36) from the MS Sunshine Study, a multi-ethnic matched case-control study of incident MS or clinically isolated syndrome (CIS), recruited from Kaiser Permanente Southern California.
Researchers queried participants about how much fish they consumed regularly. Investigators also examined 13 single nucleotide polymorphisms (SNPs) in FADS1, FADS2, and ELOV2, which regulate fatty acid biosynthesis.
High fish intake was defined as either eating one serving of fish per week or eating one to three servings per month in addition to taking daily fish oil supplements. Low intake was defined as less than one serving of fish per month and no fish oil supplements.
High fish intake was associated with a 45% reduced risk of MS or CIS, when compared with those who ate fish less than once a month and did not take fish oil supplements. A total of 180 of participants with MS had high fish intake compared with 251 of the healthy controls.
In addition, two SNPs, rs174611 and rs174618, in FADS2 were independently associated with a lower risk of MS, even after accounting for high fish intake. This suggests that some people may have a genetic advantage when it comes to regulating fatty acid levels, the researchers noted.
While the study suggests that omega-3 fatty acids, and how they are processed by the body, may play an important role in reducing MS risk. Dr. Langer-Gould and colleagues emphasized that their findings show an association, and not cause and effect. More research is needed to confirm the findings and to examine how omega-3 fatty acids may affect inflammation, metabolism, and nerve function.
The study was supported by the National Institute of Neurological Disorders and Stroke.
LOS ANGELES—Eating fish at least once per week or eating fish one to three times per month, in addition to taking daily fish oil supplements, may be associated with a reduced risk of multiple sclerosis (MS), according to a preliminary study presented at the American Academy of Neurology’s 70th Annual Meeting. These findings suggest that the omega-3 fatty acids found in fish may be associated with lowering the risk of developing MS.
“Consuming fish that contain omega-3 fatty acids has been shown to have a variety of health benefits, so we wanted to see if this simple lifestyle modification, regularly eating fish and taking fish oil supplements, could reduce the risk of MS,” said lead study author Annette Langer-Gould, MD, PhD, Regional Lead for Clinical and Translational Neuroscience for the Southern California Permanente Medical Group in Pasadena, and Clinical Assistant Professor at the Keck School of Medicine of the University of Southern California in Los Angeles.
For this study, researchers examined the diets of 1,153 people (average age 36) from the MS Sunshine Study, a multi-ethnic matched case-control study of incident MS or clinically isolated syndrome (CIS), recruited from Kaiser Permanente Southern California.
Researchers queried participants about how much fish they consumed regularly. Investigators also examined 13 single nucleotide polymorphisms (SNPs) in FADS1, FADS2, and ELOV2, which regulate fatty acid biosynthesis.
High fish intake was defined as either eating one serving of fish per week or eating one to three servings per month in addition to taking daily fish oil supplements. Low intake was defined as less than one serving of fish per month and no fish oil supplements.
High fish intake was associated with a 45% reduced risk of MS or CIS, when compared with those who ate fish less than once a month and did not take fish oil supplements. A total of 180 of participants with MS had high fish intake compared with 251 of the healthy controls.
In addition, two SNPs, rs174611 and rs174618, in FADS2 were independently associated with a lower risk of MS, even after accounting for high fish intake. This suggests that some people may have a genetic advantage when it comes to regulating fatty acid levels, the researchers noted.
While the study suggests that omega-3 fatty acids, and how they are processed by the body, may play an important role in reducing MS risk. Dr. Langer-Gould and colleagues emphasized that their findings show an association, and not cause and effect. More research is needed to confirm the findings and to examine how omega-3 fatty acids may affect inflammation, metabolism, and nerve function.
The study was supported by the National Institute of Neurological Disorders and Stroke.
LOS ANGELES—Eating fish at least once per week or eating fish one to three times per month, in addition to taking daily fish oil supplements, may be associated with a reduced risk of multiple sclerosis (MS), according to a preliminary study presented at the American Academy of Neurology’s 70th Annual Meeting. These findings suggest that the omega-3 fatty acids found in fish may be associated with lowering the risk of developing MS.
“Consuming fish that contain omega-3 fatty acids has been shown to have a variety of health benefits, so we wanted to see if this simple lifestyle modification, regularly eating fish and taking fish oil supplements, could reduce the risk of MS,” said lead study author Annette Langer-Gould, MD, PhD, Regional Lead for Clinical and Translational Neuroscience for the Southern California Permanente Medical Group in Pasadena, and Clinical Assistant Professor at the Keck School of Medicine of the University of Southern California in Los Angeles.
For this study, researchers examined the diets of 1,153 people (average age 36) from the MS Sunshine Study, a multi-ethnic matched case-control study of incident MS or clinically isolated syndrome (CIS), recruited from Kaiser Permanente Southern California.
Researchers queried participants about how much fish they consumed regularly. Investigators also examined 13 single nucleotide polymorphisms (SNPs) in FADS1, FADS2, and ELOV2, which regulate fatty acid biosynthesis.
High fish intake was defined as either eating one serving of fish per week or eating one to three servings per month in addition to taking daily fish oil supplements. Low intake was defined as less than one serving of fish per month and no fish oil supplements.
High fish intake was associated with a 45% reduced risk of MS or CIS, when compared with those who ate fish less than once a month and did not take fish oil supplements. A total of 180 of participants with MS had high fish intake compared with 251 of the healthy controls.
In addition, two SNPs, rs174611 and rs174618, in FADS2 were independently associated with a lower risk of MS, even after accounting for high fish intake. This suggests that some people may have a genetic advantage when it comes to regulating fatty acid levels, the researchers noted.
While the study suggests that omega-3 fatty acids, and how they are processed by the body, may play an important role in reducing MS risk. Dr. Langer-Gould and colleagues emphasized that their findings show an association, and not cause and effect. More research is needed to confirm the findings and to examine how omega-3 fatty acids may affect inflammation, metabolism, and nerve function.
The study was supported by the National Institute of Neurological Disorders and Stroke.
Blood-brain barrier health may signal early loss of MS treatment response
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of blood-brain barrier permeability in patients with relapsing-remitting multiple sclerosis may serve as an early marker of suboptimal treatment response to natalizumab or fingolimod, Danish researchers reported in a prospective, observational study.
The imaging method, when applied at baseline and at 3 months and 6 months after starting treatment with either drug in 35 patients, yielded a predictive threshold for determining if patients at 2 years of treatment would fail to meet criteria used for no evidence of disease activity (NEDA). The method is believed to work for natalizumab (Tysabri) and fingolimod (Gilenya) by measuring their effect on the passage of lymphocytes through the blood-brain barrier (BBB) because even though the two drugs have different mechanisms of action, “their final effect is the same, i.e., a reduction of the absolute number of lymphocytes trafficking across the BBB,” wrote Stig P. Cramer, MD, PhD, of the Rigshospitalet, Copenhagen, and his colleagues. The report was published in Annals of Neurology.
The investigators used three disease activity domains to define NEDA status: no new neurologic symptoms or signs that lasted more than 24 hours in the absence of concurrent fever or illness; no sustained Expanded Disability Status Scale score increase of one or more points for 6 or more months; and no new T2 hyperintense lesions and T1 gadolinium-enhancing lesions. They disregarded disease activity occurring within the first 3 months after initiation of natalizumab or fingolimod when assessing NEDA status to allow for development of a full treatment effect.
“In summary, we find that a single DCE-MRI at 6 months after initiation of natalizumab or fingolimod treatment provides information on the state of health of the BBB that enables reliable stratification of treatment response. Thus, DCE-MRI can enable early detection of long-term suboptimal treatment response in [relapsing-remitting multiple sclerosis], and a personalized medicine approach to treatment, limitations being the long scan time (15 minutes). These results and the proposed thresholds require validation in larger studies,” the researchers said.
The research was supported by grants from the Research Foundation of the Capital Region of Denmark, the Foundation for Health Research, the Danish Council for Independent Research, Rigshospitalets forskningspuljer, the Danish Multiple Sclerosis Society, and Biogen. Several authors reported financial relationships with Biogen, which sells natalizumab. But the company had no influence on study setup, subject inclusion, data analysis, interpretation of results, or publishing decisions, and any intellectual rights belong to the authors alone, they said.
SOURCE: Cramer S et al. Ann Neurol. 2018 Mar 31. doi: 10.1002/ana.25219.
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of blood-brain barrier permeability in patients with relapsing-remitting multiple sclerosis may serve as an early marker of suboptimal treatment response to natalizumab or fingolimod, Danish researchers reported in a prospective, observational study.
The imaging method, when applied at baseline and at 3 months and 6 months after starting treatment with either drug in 35 patients, yielded a predictive threshold for determining if patients at 2 years of treatment would fail to meet criteria used for no evidence of disease activity (NEDA). The method is believed to work for natalizumab (Tysabri) and fingolimod (Gilenya) by measuring their effect on the passage of lymphocytes through the blood-brain barrier (BBB) because even though the two drugs have different mechanisms of action, “their final effect is the same, i.e., a reduction of the absolute number of lymphocytes trafficking across the BBB,” wrote Stig P. Cramer, MD, PhD, of the Rigshospitalet, Copenhagen, and his colleagues. The report was published in Annals of Neurology.
The investigators used three disease activity domains to define NEDA status: no new neurologic symptoms or signs that lasted more than 24 hours in the absence of concurrent fever or illness; no sustained Expanded Disability Status Scale score increase of one or more points for 6 or more months; and no new T2 hyperintense lesions and T1 gadolinium-enhancing lesions. They disregarded disease activity occurring within the first 3 months after initiation of natalizumab or fingolimod when assessing NEDA status to allow for development of a full treatment effect.
“In summary, we find that a single DCE-MRI at 6 months after initiation of natalizumab or fingolimod treatment provides information on the state of health of the BBB that enables reliable stratification of treatment response. Thus, DCE-MRI can enable early detection of long-term suboptimal treatment response in [relapsing-remitting multiple sclerosis], and a personalized medicine approach to treatment, limitations being the long scan time (15 minutes). These results and the proposed thresholds require validation in larger studies,” the researchers said.
The research was supported by grants from the Research Foundation of the Capital Region of Denmark, the Foundation for Health Research, the Danish Council for Independent Research, Rigshospitalets forskningspuljer, the Danish Multiple Sclerosis Society, and Biogen. Several authors reported financial relationships with Biogen, which sells natalizumab. But the company had no influence on study setup, subject inclusion, data analysis, interpretation of results, or publishing decisions, and any intellectual rights belong to the authors alone, they said.
SOURCE: Cramer S et al. Ann Neurol. 2018 Mar 31. doi: 10.1002/ana.25219.
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of blood-brain barrier permeability in patients with relapsing-remitting multiple sclerosis may serve as an early marker of suboptimal treatment response to natalizumab or fingolimod, Danish researchers reported in a prospective, observational study.
The imaging method, when applied at baseline and at 3 months and 6 months after starting treatment with either drug in 35 patients, yielded a predictive threshold for determining if patients at 2 years of treatment would fail to meet criteria used for no evidence of disease activity (NEDA). The method is believed to work for natalizumab (Tysabri) and fingolimod (Gilenya) by measuring their effect on the passage of lymphocytes through the blood-brain barrier (BBB) because even though the two drugs have different mechanisms of action, “their final effect is the same, i.e., a reduction of the absolute number of lymphocytes trafficking across the BBB,” wrote Stig P. Cramer, MD, PhD, of the Rigshospitalet, Copenhagen, and his colleagues. The report was published in Annals of Neurology.
The investigators used three disease activity domains to define NEDA status: no new neurologic symptoms or signs that lasted more than 24 hours in the absence of concurrent fever or illness; no sustained Expanded Disability Status Scale score increase of one or more points for 6 or more months; and no new T2 hyperintense lesions and T1 gadolinium-enhancing lesions. They disregarded disease activity occurring within the first 3 months after initiation of natalizumab or fingolimod when assessing NEDA status to allow for development of a full treatment effect.
“In summary, we find that a single DCE-MRI at 6 months after initiation of natalizumab or fingolimod treatment provides information on the state of health of the BBB that enables reliable stratification of treatment response. Thus, DCE-MRI can enable early detection of long-term suboptimal treatment response in [relapsing-remitting multiple sclerosis], and a personalized medicine approach to treatment, limitations being the long scan time (15 minutes). These results and the proposed thresholds require validation in larger studies,” the researchers said.
The research was supported by grants from the Research Foundation of the Capital Region of Denmark, the Foundation for Health Research, the Danish Council for Independent Research, Rigshospitalets forskningspuljer, the Danish Multiple Sclerosis Society, and Biogen. Several authors reported financial relationships with Biogen, which sells natalizumab. But the company had no influence on study setup, subject inclusion, data analysis, interpretation of results, or publishing decisions, and any intellectual rights belong to the authors alone, they said.
SOURCE: Cramer S et al. Ann Neurol. 2018 Mar 31. doi: 10.1002/ana.25219.
FROM ANNALS OF NEUROLOGY
Key clinical point:
Major finding: A DCE-MRI measure of blood-brain permeability 6 months after starting natalizumab or fingolimod could predict the loss of NEDA at 2 years with an area under the curve value of 0.84.
Study details: A prospective, observational study of 35 patients with relapsing-remitting MS who started taking natalizumab or fingolimod.
Disclosures: The research was supported by grants from the Research Foundation of the Capital Region of Denmark, the Foundation for Health Research, the Danish Council for Independent Research, Rigshospitalets forskningspuljer, the Danish Multiple Sclerosis Society, and Biogen. Several authors reported financial relationships with Biogen, which sells natalizumab. Biogen had no influence on study setup, subject inclusion, data analysis, interpretation of results, or publishing decisions, and any intellectual rights belong to the authors alone, they said.
Source: Cramer S et al. Ann Neurol. 2018 Mar 31. doi: 10.1002/ana.25219.
Rare, serious alemtuzumab adverse events emerge
according to three new case reports and series in Neurology.
The complications include acute coronary syndrome in one patient, hemophagocytic lymphohistiocytosis (HLH) in two patients, and acute acalculous cholecystitis in eight patients.
Postmarketing surveillance aims to identify rare and late adverse events that may not be discovered during clinical trials.
The cardiac arrest incident occurred in a 24-year old woman with spinal-onset relapsing-remitting multiple sclerosis (RRMS) during alemtuzumab infusion. She had experienced two clinical relapses and a significant increase in cerebral and spinal MRI lesion load, despite previous treatment with natalizumab (Tysabri). The only striking thing about her medical history was allergic asthma.
On the third day of treatment, she developed severe asymptomatic sinus bradycardia (HR, 38 beats per minute), which resolved with treatment, and clinicians continued the regimen. The following morning, she experienced acute coronary syndrome, which later resolved.
The authors recommend that clinicians treating RRMS patients with alemtuzumab consider a baseline preinfusion ECG and monitoring heart rate at least hourly while infusion is being carried out.
The HLH cases occurred in a man and a woman with RRMS, both in their 20s. The woman was switched from natalizumab to alemtuzumab because of a high anti-JC virus antibody index. Both cases presented in the time frame typical of secondary autoimmunity. The female patient had an acalculous gallbladder with thickened walls and pericholecystic fluid and responded to intravenous antibiotics, but 3 weeks later she developed thrombocytopenia, coagulopathy, and anemia with abnormal liver enzymes. Treatment failed and she succumbed to the condition.
The man received alemtuzumab as first-line therapy for RRMS during the Keratinocyte Growth Factor to Prevent Autoimmunity After Alemtuzumab Treatment of Multiple Sclerosis (CAM-THY) clinical trial. He received boluses of either placebo or palifermin (Kepivance) before and after each alemtuzumab dose in order to reduce secondary autoimmunity. At 30 months after his initial cycle of alemtuzumab, he was admitted to the hospital with HLH and also developed acquired factor VIII hemophilia. He responded positively to 4 months of corticosteroid treatment combined with two doses of rituximab (Rituxan) and ultimately returned to work. However, he experienced a relapse of acquired hemophilia during later doses of corticosteroids and rituximab.
A search of the Food and Drug Administration Adverse Event Reporting System (FAERS) revealed eight cases of acute acalculous cholecystitis (AAC) – four assessed as possibly caused by alemtuzumab, and four assessed as probable – that occurred in patients with RRMS. Seven of the cases involved presentation during treatment or soon afterward, which suggests that acute cytokine release syndrome (ACRS) may be the cause. The cases did not share all of the manifestations of typical ACRS, but the researchers noted that coadministration of methylprednisolone in the RRMS dosing schedule may have masked some of the features.
Unlike typical AAC, these cases occurred primarily in females (six of eight) and were not associated with concurrent critical illnesses. Other risk factors were not consistently present. Historically, AAC is associated with treatment of older male patients in the ICU. Three of the patients underwent surgical treatment, and five received conservative treatment of antibiotics or an unspecified treatment. Seven patients recovered. The outcome in the eighth patient was not reported.
Despite these good outcomes, the authors of the report note that longer-term outcomes in this AAC population are not yet understood.
The findings led to the addition of AAC to the Warnings and Precautions section of the alemtuzumab label in October 2017.
None of the reports received funding. Some of the authors had financial ties to the pharmaceutical industry.
SOURCES: Croteau D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005422. Saarela M et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005420. Ferraro D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005417.
Clinical trials find most adverse events for a new drug, but postmarketing surveillance is essential to find rare events, even though they may underestimate the frequency of these events because of underreporting.
Other reports suggest the emergence of uncommon infectious complications associated with alemtuzumab, especially Listeria meningitis. Listeria infection can occur within days of alemtuzumab treatment, and the use of preventive sulfamethoxazole-trimethoprim treatment is now advocated in the United Kingdom.
Overall, these adverse events remind clinicians that they must balance the benefits of alemtuzumab, which is highly effective, against its potential risks.
Paolo A. Muraro, MD, PhD is a professor of neurology, neuroimmunology, and immunotherapy at Imperial College London. Neil J. Scolding MD, PhD, is director of the Bristol Institute of Clinical Neurosciences at the University of Bristol (England). Robert J. Fox, MD, is a neurologist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio. All of the authors reported financial relationships with companies marketing MS drugs. Their comments are derived from an editorial accompanying the adverse event reports (Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005409).
Clinical trials find most adverse events for a new drug, but postmarketing surveillance is essential to find rare events, even though they may underestimate the frequency of these events because of underreporting.
Other reports suggest the emergence of uncommon infectious complications associated with alemtuzumab, especially Listeria meningitis. Listeria infection can occur within days of alemtuzumab treatment, and the use of preventive sulfamethoxazole-trimethoprim treatment is now advocated in the United Kingdom.
Overall, these adverse events remind clinicians that they must balance the benefits of alemtuzumab, which is highly effective, against its potential risks.
Paolo A. Muraro, MD, PhD is a professor of neurology, neuroimmunology, and immunotherapy at Imperial College London. Neil J. Scolding MD, PhD, is director of the Bristol Institute of Clinical Neurosciences at the University of Bristol (England). Robert J. Fox, MD, is a neurologist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio. All of the authors reported financial relationships with companies marketing MS drugs. Their comments are derived from an editorial accompanying the adverse event reports (Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005409).
Clinical trials find most adverse events for a new drug, but postmarketing surveillance is essential to find rare events, even though they may underestimate the frequency of these events because of underreporting.
Other reports suggest the emergence of uncommon infectious complications associated with alemtuzumab, especially Listeria meningitis. Listeria infection can occur within days of alemtuzumab treatment, and the use of preventive sulfamethoxazole-trimethoprim treatment is now advocated in the United Kingdom.
Overall, these adverse events remind clinicians that they must balance the benefits of alemtuzumab, which is highly effective, against its potential risks.
Paolo A. Muraro, MD, PhD is a professor of neurology, neuroimmunology, and immunotherapy at Imperial College London. Neil J. Scolding MD, PhD, is director of the Bristol Institute of Clinical Neurosciences at the University of Bristol (England). Robert J. Fox, MD, is a neurologist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio. All of the authors reported financial relationships with companies marketing MS drugs. Their comments are derived from an editorial accompanying the adverse event reports (Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005409).
according to three new case reports and series in Neurology.
The complications include acute coronary syndrome in one patient, hemophagocytic lymphohistiocytosis (HLH) in two patients, and acute acalculous cholecystitis in eight patients.
Postmarketing surveillance aims to identify rare and late adverse events that may not be discovered during clinical trials.
The cardiac arrest incident occurred in a 24-year old woman with spinal-onset relapsing-remitting multiple sclerosis (RRMS) during alemtuzumab infusion. She had experienced two clinical relapses and a significant increase in cerebral and spinal MRI lesion load, despite previous treatment with natalizumab (Tysabri). The only striking thing about her medical history was allergic asthma.
On the third day of treatment, she developed severe asymptomatic sinus bradycardia (HR, 38 beats per minute), which resolved with treatment, and clinicians continued the regimen. The following morning, she experienced acute coronary syndrome, which later resolved.
The authors recommend that clinicians treating RRMS patients with alemtuzumab consider a baseline preinfusion ECG and monitoring heart rate at least hourly while infusion is being carried out.
The HLH cases occurred in a man and a woman with RRMS, both in their 20s. The woman was switched from natalizumab to alemtuzumab because of a high anti-JC virus antibody index. Both cases presented in the time frame typical of secondary autoimmunity. The female patient had an acalculous gallbladder with thickened walls and pericholecystic fluid and responded to intravenous antibiotics, but 3 weeks later she developed thrombocytopenia, coagulopathy, and anemia with abnormal liver enzymes. Treatment failed and she succumbed to the condition.
The man received alemtuzumab as first-line therapy for RRMS during the Keratinocyte Growth Factor to Prevent Autoimmunity After Alemtuzumab Treatment of Multiple Sclerosis (CAM-THY) clinical trial. He received boluses of either placebo or palifermin (Kepivance) before and after each alemtuzumab dose in order to reduce secondary autoimmunity. At 30 months after his initial cycle of alemtuzumab, he was admitted to the hospital with HLH and also developed acquired factor VIII hemophilia. He responded positively to 4 months of corticosteroid treatment combined with two doses of rituximab (Rituxan) and ultimately returned to work. However, he experienced a relapse of acquired hemophilia during later doses of corticosteroids and rituximab.
A search of the Food and Drug Administration Adverse Event Reporting System (FAERS) revealed eight cases of acute acalculous cholecystitis (AAC) – four assessed as possibly caused by alemtuzumab, and four assessed as probable – that occurred in patients with RRMS. Seven of the cases involved presentation during treatment or soon afterward, which suggests that acute cytokine release syndrome (ACRS) may be the cause. The cases did not share all of the manifestations of typical ACRS, but the researchers noted that coadministration of methylprednisolone in the RRMS dosing schedule may have masked some of the features.
Unlike typical AAC, these cases occurred primarily in females (six of eight) and were not associated with concurrent critical illnesses. Other risk factors were not consistently present. Historically, AAC is associated with treatment of older male patients in the ICU. Three of the patients underwent surgical treatment, and five received conservative treatment of antibiotics or an unspecified treatment. Seven patients recovered. The outcome in the eighth patient was not reported.
Despite these good outcomes, the authors of the report note that longer-term outcomes in this AAC population are not yet understood.
The findings led to the addition of AAC to the Warnings and Precautions section of the alemtuzumab label in October 2017.
None of the reports received funding. Some of the authors had financial ties to the pharmaceutical industry.
SOURCES: Croteau D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005422. Saarela M et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005420. Ferraro D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005417.
according to three new case reports and series in Neurology.
The complications include acute coronary syndrome in one patient, hemophagocytic lymphohistiocytosis (HLH) in two patients, and acute acalculous cholecystitis in eight patients.
Postmarketing surveillance aims to identify rare and late adverse events that may not be discovered during clinical trials.
The cardiac arrest incident occurred in a 24-year old woman with spinal-onset relapsing-remitting multiple sclerosis (RRMS) during alemtuzumab infusion. She had experienced two clinical relapses and a significant increase in cerebral and spinal MRI lesion load, despite previous treatment with natalizumab (Tysabri). The only striking thing about her medical history was allergic asthma.
On the third day of treatment, she developed severe asymptomatic sinus bradycardia (HR, 38 beats per minute), which resolved with treatment, and clinicians continued the regimen. The following morning, she experienced acute coronary syndrome, which later resolved.
The authors recommend that clinicians treating RRMS patients with alemtuzumab consider a baseline preinfusion ECG and monitoring heart rate at least hourly while infusion is being carried out.
The HLH cases occurred in a man and a woman with RRMS, both in their 20s. The woman was switched from natalizumab to alemtuzumab because of a high anti-JC virus antibody index. Both cases presented in the time frame typical of secondary autoimmunity. The female patient had an acalculous gallbladder with thickened walls and pericholecystic fluid and responded to intravenous antibiotics, but 3 weeks later she developed thrombocytopenia, coagulopathy, and anemia with abnormal liver enzymes. Treatment failed and she succumbed to the condition.
The man received alemtuzumab as first-line therapy for RRMS during the Keratinocyte Growth Factor to Prevent Autoimmunity After Alemtuzumab Treatment of Multiple Sclerosis (CAM-THY) clinical trial. He received boluses of either placebo or palifermin (Kepivance) before and after each alemtuzumab dose in order to reduce secondary autoimmunity. At 30 months after his initial cycle of alemtuzumab, he was admitted to the hospital with HLH and also developed acquired factor VIII hemophilia. He responded positively to 4 months of corticosteroid treatment combined with two doses of rituximab (Rituxan) and ultimately returned to work. However, he experienced a relapse of acquired hemophilia during later doses of corticosteroids and rituximab.
A search of the Food and Drug Administration Adverse Event Reporting System (FAERS) revealed eight cases of acute acalculous cholecystitis (AAC) – four assessed as possibly caused by alemtuzumab, and four assessed as probable – that occurred in patients with RRMS. Seven of the cases involved presentation during treatment or soon afterward, which suggests that acute cytokine release syndrome (ACRS) may be the cause. The cases did not share all of the manifestations of typical ACRS, but the researchers noted that coadministration of methylprednisolone in the RRMS dosing schedule may have masked some of the features.
Unlike typical AAC, these cases occurred primarily in females (six of eight) and were not associated with concurrent critical illnesses. Other risk factors were not consistently present. Historically, AAC is associated with treatment of older male patients in the ICU. Three of the patients underwent surgical treatment, and five received conservative treatment of antibiotics or an unspecified treatment. Seven patients recovered. The outcome in the eighth patient was not reported.
Despite these good outcomes, the authors of the report note that longer-term outcomes in this AAC population are not yet understood.
The findings led to the addition of AAC to the Warnings and Precautions section of the alemtuzumab label in October 2017.
None of the reports received funding. Some of the authors had financial ties to the pharmaceutical industry.
SOURCES: Croteau D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005422. Saarela M et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005420. Ferraro D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005417.
FROM NEUROLOGY
Key clinical point: Rare events associated with alemtuzumab are emerging that were not uncovered during clinical trials.
Major finding: Eight cases of acute acalculous cholecystitis formed the basis for its addition to the Warnings and Precautions section of the alemtuzumab label in October 2017.
Study details: Case reports of acute coronary syndrome in one patient, hemophagocytic lymphohistiocytosis in two patients, and acute acalculous cholecystitis in eight patients.
Disclosures: None of the reports received funding. Some of the authors had financial ties to the pharmaceutical industry.
Sources: Croteau D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005422; Saarela M et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005420; Ferraro D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005417.