User login
NfL blood biomarker captures suboptimal treatment response in MS
a new study has shown.
The study found that current serum NfL levels predicted relapses, disability worsening, and MRI activity in the following year independent of standard metrics for treatment monitoring, such as relapse rate, disability worsening, and MRI findings. The biomarker also detected subclinical disease activity in patients with no evidence of disease activity (NEDA3), as measured by absence of previous relapses, worsening score on the Expanded Disability Status Scale (EDSS), or brain lesion formation on MRI.
“Our data in this well-characterized large real-world cohort supports the value of serum NfL levels for treatment monitoring in MS clinical practice,” lead author Özgür Yaldizli, MD, concluded.
Dr. Yaldizli, who is a consultant neurologist at University Hospital Basel (Switzerland), presented the findings at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
“This is the first study to compare NfL simultaneously with other markers of disease progression, such as MRI lesions and relapse rate in treated patients. We show that NfL gives a unique signal that is not captured by other markers,” Dr. Yaldizli said.
“This is likely the largest study of NfL in MS to date, with more than 7,000 samples from well-characterized MS patients followed longitudinally for more than 5 years of sampling and including high quality data on MRI and clinical examinations. It is the first time all these factors have been combined so that we can see how NfL compares with other markers of disease progression in predicting clinical events and monitoring treatment efficacy,” said senior author Jens Kuhle, MD, PhD, also from University Hospital Basel.
Large normative database for reference
The researchers also reported a large normative database of NfL values with data from more than 8,000 healthy controls. “This is the largest normative database to date, that gives us reliable reference values for NfL across a range of ages and comorbidities,” Dr. Kuhle noted.
In his presentation, Dr. Yaldizli explained that NfL is a neuronal cytoskeletal protein released into the cerebrospinal fluid and blood following neuroaxonal injury. Although numerous studies have shown that serum NfL is associated with clinical and MRI disease activity and treatment response, it is not clear whether serum NfL under established disease-modifying therapy (DMT) can identify patients with suboptimal treatment response, compared with standard clinical and MRI activity measures.
This study addressed that question in the large real-world Swiss MS cohort.
The study involved 1,366 patients (88.8% with relapsing remitting MS [RRMS], 5.4% with secondary progressive MS, and 5.8% with primary progressive MS) receiving DMT for at least 3 months from seven MS centers. The median disease duration was 7.2 years. Serum NfL was measured every 6 or 12 months with NF-Light assay on the latest-generation HDX platform (blinded for clinical and MRI data). The median follow-up was 4.9 years. There was an average of five samples per patient, with a total of 7462 samples.
Results showed that NfL levels were higher in older patients (14.5% per 10 years), those with secondary progressive MS (12.4% vs. RRMS), those with primary progressive MS (14.4% vs. RRMS), and in those who had a relapse in the last 4 months (53.4%).
NfL levels were 13.4% lower in patients receiving oral DMT (vs. untreated patients) and 17.7% in patients receiving monoclonal antibodies (vs. untreated patients).
In the large cohort of healthy controls, NfL levels also increased with age, but levels in patients with MS were higher than in controls across the whole age spectrum.
To obtain a measure of deviation from normal, the authors converted NfL levels to z score, which express how much (in terms of number of standard deviations) a measurement differs from mean values found in healthy controls of the same age. Effects were more pronounced with use of z score derived from the normative database than with use of absolute NfL levels even after adjustment for age.
In the univariate analysis, serum NfL z score predicted relapse or EDSS worsening in the following year: The higher the z score, the higher the risk for relapse or EDSS worsening. Patients with an NfL z score greater than 1 had a 41% higher risk for relapse or EDSS worsening in the following year, compared with those whose z score was less than 1 (odds ratio, 1.41).
Patients with an NfL z score exceeding 1.5 had an 80% higher risk for relapse or EDSS worsening in the following year than did those whose score was below 1.5 (OR, 1.8).
Patients with an NfL z score greater than 2 had a 2.3 times higher risk for relapse or EDSS worsening in the following year versus those with a score below 2. (P < 0.001 for all comparisons.)
A screen for nervous system conditions?
Dr, Kuhle reported that NfL is being used on an individual basis in clinical practice at present – at certain MS centers. “One of the problems is not having reliable reference values, so this database of normative values will be very helpful in developing those,” he said. “We see an increase in NfL with age in healthy controls. In order to know what pathological levels are, we need to know what normal levels are in controls throughout the spectrum of ages and other comorbidities, which also play a role. If we normalize these, then we can work out the MS signal in a more efficient way.”
Dr. Kuhle believes that, in the future, NfL may be used to screen for nervous system disease. “NfL is a measure of neuronal health independent of MS. If we have increased levels, we should be worried.”
There is a “high level of energy in this field,” he added. “In future, it could be like having a cholesterol test at present – picking up that something is not right and indicating the need for more tests.”
Dr. Yaldizli suggested that NfL monitoring could also help to individualize and optimize use of MS treatments. “There is a huge unmet need in MS. While we have a plethora of treatment options, we are struggling to individualize and monitor treatments. If NfL levels increase, this is likely a strong indication to change treatment even if there are no other overt symptoms.”
Commenting on the current study, ACTRIMS president, Jeffrey Cohen, MD, Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, called it “an important study.”
“NfL clearly can detect disease activity and distinguish efficacy of DMT in groups of patients,” Dr. Cohen said.
“This study shows that NfL can be used to monitor DMT efficacy in individual patients and can detect suboptimal treatment response in patients with NEDA (i.e., who appear stable by the measures we typically employ in practice),” he added.
Dr. Yaldizli sits on advisory boards for Sanofi Genzyme, Novartis, Biogen, and Novartis. Dr. Kuhle reported no relevant disclosures.
This article first appeared on Medscape.com.
a new study has shown.
The study found that current serum NfL levels predicted relapses, disability worsening, and MRI activity in the following year independent of standard metrics for treatment monitoring, such as relapse rate, disability worsening, and MRI findings. The biomarker also detected subclinical disease activity in patients with no evidence of disease activity (NEDA3), as measured by absence of previous relapses, worsening score on the Expanded Disability Status Scale (EDSS), or brain lesion formation on MRI.
“Our data in this well-characterized large real-world cohort supports the value of serum NfL levels for treatment monitoring in MS clinical practice,” lead author Özgür Yaldizli, MD, concluded.
Dr. Yaldizli, who is a consultant neurologist at University Hospital Basel (Switzerland), presented the findings at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
“This is the first study to compare NfL simultaneously with other markers of disease progression, such as MRI lesions and relapse rate in treated patients. We show that NfL gives a unique signal that is not captured by other markers,” Dr. Yaldizli said.
“This is likely the largest study of NfL in MS to date, with more than 7,000 samples from well-characterized MS patients followed longitudinally for more than 5 years of sampling and including high quality data on MRI and clinical examinations. It is the first time all these factors have been combined so that we can see how NfL compares with other markers of disease progression in predicting clinical events and monitoring treatment efficacy,” said senior author Jens Kuhle, MD, PhD, also from University Hospital Basel.
Large normative database for reference
The researchers also reported a large normative database of NfL values with data from more than 8,000 healthy controls. “This is the largest normative database to date, that gives us reliable reference values for NfL across a range of ages and comorbidities,” Dr. Kuhle noted.
In his presentation, Dr. Yaldizli explained that NfL is a neuronal cytoskeletal protein released into the cerebrospinal fluid and blood following neuroaxonal injury. Although numerous studies have shown that serum NfL is associated with clinical and MRI disease activity and treatment response, it is not clear whether serum NfL under established disease-modifying therapy (DMT) can identify patients with suboptimal treatment response, compared with standard clinical and MRI activity measures.
This study addressed that question in the large real-world Swiss MS cohort.
The study involved 1,366 patients (88.8% with relapsing remitting MS [RRMS], 5.4% with secondary progressive MS, and 5.8% with primary progressive MS) receiving DMT for at least 3 months from seven MS centers. The median disease duration was 7.2 years. Serum NfL was measured every 6 or 12 months with NF-Light assay on the latest-generation HDX platform (blinded for clinical and MRI data). The median follow-up was 4.9 years. There was an average of five samples per patient, with a total of 7462 samples.
Results showed that NfL levels were higher in older patients (14.5% per 10 years), those with secondary progressive MS (12.4% vs. RRMS), those with primary progressive MS (14.4% vs. RRMS), and in those who had a relapse in the last 4 months (53.4%).
NfL levels were 13.4% lower in patients receiving oral DMT (vs. untreated patients) and 17.7% in patients receiving monoclonal antibodies (vs. untreated patients).
In the large cohort of healthy controls, NfL levels also increased with age, but levels in patients with MS were higher than in controls across the whole age spectrum.
To obtain a measure of deviation from normal, the authors converted NfL levels to z score, which express how much (in terms of number of standard deviations) a measurement differs from mean values found in healthy controls of the same age. Effects were more pronounced with use of z score derived from the normative database than with use of absolute NfL levels even after adjustment for age.
In the univariate analysis, serum NfL z score predicted relapse or EDSS worsening in the following year: The higher the z score, the higher the risk for relapse or EDSS worsening. Patients with an NfL z score greater than 1 had a 41% higher risk for relapse or EDSS worsening in the following year, compared with those whose z score was less than 1 (odds ratio, 1.41).
Patients with an NfL z score exceeding 1.5 had an 80% higher risk for relapse or EDSS worsening in the following year than did those whose score was below 1.5 (OR, 1.8).
Patients with an NfL z score greater than 2 had a 2.3 times higher risk for relapse or EDSS worsening in the following year versus those with a score below 2. (P < 0.001 for all comparisons.)
A screen for nervous system conditions?
Dr, Kuhle reported that NfL is being used on an individual basis in clinical practice at present – at certain MS centers. “One of the problems is not having reliable reference values, so this database of normative values will be very helpful in developing those,” he said. “We see an increase in NfL with age in healthy controls. In order to know what pathological levels are, we need to know what normal levels are in controls throughout the spectrum of ages and other comorbidities, which also play a role. If we normalize these, then we can work out the MS signal in a more efficient way.”
Dr. Kuhle believes that, in the future, NfL may be used to screen for nervous system disease. “NfL is a measure of neuronal health independent of MS. If we have increased levels, we should be worried.”
There is a “high level of energy in this field,” he added. “In future, it could be like having a cholesterol test at present – picking up that something is not right and indicating the need for more tests.”
Dr. Yaldizli suggested that NfL monitoring could also help to individualize and optimize use of MS treatments. “There is a huge unmet need in MS. While we have a plethora of treatment options, we are struggling to individualize and monitor treatments. If NfL levels increase, this is likely a strong indication to change treatment even if there are no other overt symptoms.”
Commenting on the current study, ACTRIMS president, Jeffrey Cohen, MD, Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, called it “an important study.”
“NfL clearly can detect disease activity and distinguish efficacy of DMT in groups of patients,” Dr. Cohen said.
“This study shows that NfL can be used to monitor DMT efficacy in individual patients and can detect suboptimal treatment response in patients with NEDA (i.e., who appear stable by the measures we typically employ in practice),” he added.
Dr. Yaldizli sits on advisory boards for Sanofi Genzyme, Novartis, Biogen, and Novartis. Dr. Kuhle reported no relevant disclosures.
This article first appeared on Medscape.com.
a new study has shown.
The study found that current serum NfL levels predicted relapses, disability worsening, and MRI activity in the following year independent of standard metrics for treatment monitoring, such as relapse rate, disability worsening, and MRI findings. The biomarker also detected subclinical disease activity in patients with no evidence of disease activity (NEDA3), as measured by absence of previous relapses, worsening score on the Expanded Disability Status Scale (EDSS), or brain lesion formation on MRI.
“Our data in this well-characterized large real-world cohort supports the value of serum NfL levels for treatment monitoring in MS clinical practice,” lead author Özgür Yaldizli, MD, concluded.
Dr. Yaldizli, who is a consultant neurologist at University Hospital Basel (Switzerland), presented the findings at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
“This is the first study to compare NfL simultaneously with other markers of disease progression, such as MRI lesions and relapse rate in treated patients. We show that NfL gives a unique signal that is not captured by other markers,” Dr. Yaldizli said.
“This is likely the largest study of NfL in MS to date, with more than 7,000 samples from well-characterized MS patients followed longitudinally for more than 5 years of sampling and including high quality data on MRI and clinical examinations. It is the first time all these factors have been combined so that we can see how NfL compares with other markers of disease progression in predicting clinical events and monitoring treatment efficacy,” said senior author Jens Kuhle, MD, PhD, also from University Hospital Basel.
Large normative database for reference
The researchers also reported a large normative database of NfL values with data from more than 8,000 healthy controls. “This is the largest normative database to date, that gives us reliable reference values for NfL across a range of ages and comorbidities,” Dr. Kuhle noted.
In his presentation, Dr. Yaldizli explained that NfL is a neuronal cytoskeletal protein released into the cerebrospinal fluid and blood following neuroaxonal injury. Although numerous studies have shown that serum NfL is associated with clinical and MRI disease activity and treatment response, it is not clear whether serum NfL under established disease-modifying therapy (DMT) can identify patients with suboptimal treatment response, compared with standard clinical and MRI activity measures.
This study addressed that question in the large real-world Swiss MS cohort.
The study involved 1,366 patients (88.8% with relapsing remitting MS [RRMS], 5.4% with secondary progressive MS, and 5.8% with primary progressive MS) receiving DMT for at least 3 months from seven MS centers. The median disease duration was 7.2 years. Serum NfL was measured every 6 or 12 months with NF-Light assay on the latest-generation HDX platform (blinded for clinical and MRI data). The median follow-up was 4.9 years. There was an average of five samples per patient, with a total of 7462 samples.
Results showed that NfL levels were higher in older patients (14.5% per 10 years), those with secondary progressive MS (12.4% vs. RRMS), those with primary progressive MS (14.4% vs. RRMS), and in those who had a relapse in the last 4 months (53.4%).
NfL levels were 13.4% lower in patients receiving oral DMT (vs. untreated patients) and 17.7% in patients receiving monoclonal antibodies (vs. untreated patients).
In the large cohort of healthy controls, NfL levels also increased with age, but levels in patients with MS were higher than in controls across the whole age spectrum.
To obtain a measure of deviation from normal, the authors converted NfL levels to z score, which express how much (in terms of number of standard deviations) a measurement differs from mean values found in healthy controls of the same age. Effects were more pronounced with use of z score derived from the normative database than with use of absolute NfL levels even after adjustment for age.
In the univariate analysis, serum NfL z score predicted relapse or EDSS worsening in the following year: The higher the z score, the higher the risk for relapse or EDSS worsening. Patients with an NfL z score greater than 1 had a 41% higher risk for relapse or EDSS worsening in the following year, compared with those whose z score was less than 1 (odds ratio, 1.41).
Patients with an NfL z score exceeding 1.5 had an 80% higher risk for relapse or EDSS worsening in the following year than did those whose score was below 1.5 (OR, 1.8).
Patients with an NfL z score greater than 2 had a 2.3 times higher risk for relapse or EDSS worsening in the following year versus those with a score below 2. (P < 0.001 for all comparisons.)
A screen for nervous system conditions?
Dr, Kuhle reported that NfL is being used on an individual basis in clinical practice at present – at certain MS centers. “One of the problems is not having reliable reference values, so this database of normative values will be very helpful in developing those,” he said. “We see an increase in NfL with age in healthy controls. In order to know what pathological levels are, we need to know what normal levels are in controls throughout the spectrum of ages and other comorbidities, which also play a role. If we normalize these, then we can work out the MS signal in a more efficient way.”
Dr. Kuhle believes that, in the future, NfL may be used to screen for nervous system disease. “NfL is a measure of neuronal health independent of MS. If we have increased levels, we should be worried.”
There is a “high level of energy in this field,” he added. “In future, it could be like having a cholesterol test at present – picking up that something is not right and indicating the need for more tests.”
Dr. Yaldizli suggested that NfL monitoring could also help to individualize and optimize use of MS treatments. “There is a huge unmet need in MS. While we have a plethora of treatment options, we are struggling to individualize and monitor treatments. If NfL levels increase, this is likely a strong indication to change treatment even if there are no other overt symptoms.”
Commenting on the current study, ACTRIMS president, Jeffrey Cohen, MD, Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, called it “an important study.”
“NfL clearly can detect disease activity and distinguish efficacy of DMT in groups of patients,” Dr. Cohen said.
“This study shows that NfL can be used to monitor DMT efficacy in individual patients and can detect suboptimal treatment response in patients with NEDA (i.e., who appear stable by the measures we typically employ in practice),” he added.
Dr. Yaldizli sits on advisory boards for Sanofi Genzyme, Novartis, Biogen, and Novartis. Dr. Kuhle reported no relevant disclosures.
This article first appeared on Medscape.com.
FROM MSVIRTUAL 2020
Neutrophil granulocyte markers may distinguish between demyelinating diseases
, researchers reported. If current findings are replicated, these biomarkers will help neurologists distinguish between these disorders in the future, even in cases that are negative for autoantibodies, they said.
The sensitivity and specificity profile of neutrophil granulocyte biomarkers is not as good as that for cell-based assays for AQP4 and anti-MOG antibodies when it comes to distinguishing between acute NMOSD or MOGAD versus acute relapsing-remitting MS, said David Leppert, MD, of University Hospital Basel (Switzerland) and the University of Basel. But the sensitivity and specificity of neutrophil granulocyte biomarkers are “even with” those of referring ELISA tests, he added. Furthermore, the evaluation of these biomarkers can be completed within hours, thus providing the potential for timely support for therapeutic decisions about patients with acute NMOSD.
It can be difficult to distinguish between NMOSD, MOGAD, and MS using a clinical examination and MRI scans alone. Assays for AQP4 and anti-MOG antibodies are the standard for refining the diagnosis, but obtaining the results of these assays takes 1-2 weeks. This time frame may delay the administration of urgently needed treatment.
Neutrophil granulocytes have various components that carry molecules that, although they are secreted to defend the host, also can damage tissue. These cells are common in brain tissue and CSF among patients with NMOSD. Patients with MOGAD often have neutrophil granulocytes as well, but the latter are rare in MS.
Biomarkers had high AUC
Dr. Leppert and colleagues conducted a study to evaluate whether these cells can distinguish NMOSD or MOGAD from MS. The investigators specifically examined the following neutrophil granule products: elastase, myeloperoxidase (MPO), matrix metalloproteinase-8 (MMP-8), and neutrophil gelatinase-associated lipocalin (NGAL). Dr. Leppert’s group evaluated CSF samples from 42 patients with NMOSD, 6 patients with MOGAD, and 41 patients with relapsing-remitting MS for these potential biomarkers. They also examined the samples for neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and S100B by conventional ELISA or single-molecule array assay. The investigators examined CSF samples from 25 healthy controls as a reference group.
Linear models allowed Dr. Leppert and colleagues to assess the association between biomarkers and disease groups. The investigators modeled the change of biomarker levels over time. They calculated receiver operating characteristic (ROC) curves and area under the curve (AUC) to estimate the potential to distinguish NMOSD and MOGAD from relapsing-remitting MS in acute disease phase (i.e., at 20 or fewer days after relapse), as well as between acute NMOSD and MOGAD. Finally, they assessed the association of biomarkers with Expanded Disability Status Scale (EDSS) score in acute NMOSD and relapsing-remitting MS using linear models and Spearman correlation.
Dr. Leppert and colleagues found that levels of NfL were increased among patients, compared with healthy controls. GFAP levels were increased in patients with NMOSD, compared with controls.
Among patients with NMOSD, all four neutrophil granulocyte markers were significantly increased, compared with healthy controls and patients with acute relapsing-remitting MS. Among patients with MOGAD, elastase, MPO, and MMP-8 were increased, compared with healthy controls and patients with acute relapsing-remitting MS. In ROC analyses comparing patients with acute NMOSD or MOGAD against those with acute RRMS, the AUC of elastase and NGAL was 0.91, the AUC of MPO was 0.82, and the AUC of MMP-8 was 0.81.
Levels of S100B were increased in 89% of patients with acute NMOSD (AUC = 0.82), and levels of GFAP were increased in 83% of patients with acute NMOSD (AUC = 0.80), compared with median values of MOGAD. Among patients with acute NMOSD, EDSS scores correlated with all four neutrophil granulocyte markers and GFAP, but not with NfL and S100B. The neutrophil granulocyte markers in acute NMOSD are likely drivers of tissue damage, said Dr. Leppert. “We may end up in the future with an algorithm that combines several markers into one score to optimize the differentiating power.” The next step will be to validate these findings in a larger sample set, he said at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
Biomarkers may predict attacks
Granulocyte markers may provide support for a diagnosis of NMOSD over MS even in the small subgroup of patients who are seronegative for AQP4-IgG and MOG-IgG, said Brian G. Weinshenker, MD, a neurology consultant at Mayo Clinic in Rochester, Minn. In the study by Leppert and colleagues, granulocyte markers did not appear able to distinguish patients with AQP4-IgG–associated NMOSD from those with MOG-IgG–associated NMOSD, although astrocyte markers did in previous studies. “Granulocyte markers are primarily effective when studied in the context of an acute attack, unlike the antibody biomarkers,” said Dr. Weinshenker.
“Perhaps the most promising aspect of these new biomarkers is the fact that they are biomarkers for important mediators of tissue toxicity and seemed to correlate with attack-related disability,” he added. “They may prove to be prognostic indicators of attacks, and might influence the aggressiveness of acute management of attacks, although, in practice, all patients with NMOSD attacks, especially those associated with AQP4-IgG, should be managed aggressively.”
The current results will need independent confirmation before these biomarkers can be integrated into clinical practice, said Dr. Weinshenker. Studies should include patients with other diseases that can cause inflammation in the spinal cord and optic nerve (e.g., acute disseminated encephalomyelitis, infectious myelitis, and parainfectious myelitis) as relevant controls to determine whether granulocyte markers can distinguish these conditions effectively.
In addition, patients with discrepant values for elevations of granulocyte markers and serological indicators of NMOSD should be followed to determine the markers’ significance in this population, as well as to understand the value that measuring neutrophil markers provides. “Further studies of how these markers might herald attacks and predict disability might render these tests useful in monitoring patients and potentially intervening early in the attack process before attacks are fully manifest clinically.”
Dr. Leppert did not report any disclosures or any outside funding for the study. Dr. Weinshenker receives royalties from RSR, Oxford University, Hospices Civil de Lyon, and MVZ Labor PD Dr. Volkmann und Kollegen for a patent on NMO-IgG as a diagnostic test for NMOSD. He has served on an adjudication committee for clinical trials in NMOSD being conducted by MedImmune/VielaBio and Alexion, and consulted for Chugai/Roche/Genentech and Mitsubishi-Tanabe regarding a clinical trial for NMOSD.
SOURCE: Leppert D et al. MSVirtual2020. Abstract LB01.03.
, researchers reported. If current findings are replicated, these biomarkers will help neurologists distinguish between these disorders in the future, even in cases that are negative for autoantibodies, they said.
The sensitivity and specificity profile of neutrophil granulocyte biomarkers is not as good as that for cell-based assays for AQP4 and anti-MOG antibodies when it comes to distinguishing between acute NMOSD or MOGAD versus acute relapsing-remitting MS, said David Leppert, MD, of University Hospital Basel (Switzerland) and the University of Basel. But the sensitivity and specificity of neutrophil granulocyte biomarkers are “even with” those of referring ELISA tests, he added. Furthermore, the evaluation of these biomarkers can be completed within hours, thus providing the potential for timely support for therapeutic decisions about patients with acute NMOSD.
It can be difficult to distinguish between NMOSD, MOGAD, and MS using a clinical examination and MRI scans alone. Assays for AQP4 and anti-MOG antibodies are the standard for refining the diagnosis, but obtaining the results of these assays takes 1-2 weeks. This time frame may delay the administration of urgently needed treatment.
Neutrophil granulocytes have various components that carry molecules that, although they are secreted to defend the host, also can damage tissue. These cells are common in brain tissue and CSF among patients with NMOSD. Patients with MOGAD often have neutrophil granulocytes as well, but the latter are rare in MS.
Biomarkers had high AUC
Dr. Leppert and colleagues conducted a study to evaluate whether these cells can distinguish NMOSD or MOGAD from MS. The investigators specifically examined the following neutrophil granule products: elastase, myeloperoxidase (MPO), matrix metalloproteinase-8 (MMP-8), and neutrophil gelatinase-associated lipocalin (NGAL). Dr. Leppert’s group evaluated CSF samples from 42 patients with NMOSD, 6 patients with MOGAD, and 41 patients with relapsing-remitting MS for these potential biomarkers. They also examined the samples for neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and S100B by conventional ELISA or single-molecule array assay. The investigators examined CSF samples from 25 healthy controls as a reference group.
Linear models allowed Dr. Leppert and colleagues to assess the association between biomarkers and disease groups. The investigators modeled the change of biomarker levels over time. They calculated receiver operating characteristic (ROC) curves and area under the curve (AUC) to estimate the potential to distinguish NMOSD and MOGAD from relapsing-remitting MS in acute disease phase (i.e., at 20 or fewer days after relapse), as well as between acute NMOSD and MOGAD. Finally, they assessed the association of biomarkers with Expanded Disability Status Scale (EDSS) score in acute NMOSD and relapsing-remitting MS using linear models and Spearman correlation.
Dr. Leppert and colleagues found that levels of NfL were increased among patients, compared with healthy controls. GFAP levels were increased in patients with NMOSD, compared with controls.
Among patients with NMOSD, all four neutrophil granulocyte markers were significantly increased, compared with healthy controls and patients with acute relapsing-remitting MS. Among patients with MOGAD, elastase, MPO, and MMP-8 were increased, compared with healthy controls and patients with acute relapsing-remitting MS. In ROC analyses comparing patients with acute NMOSD or MOGAD against those with acute RRMS, the AUC of elastase and NGAL was 0.91, the AUC of MPO was 0.82, and the AUC of MMP-8 was 0.81.
Levels of S100B were increased in 89% of patients with acute NMOSD (AUC = 0.82), and levels of GFAP were increased in 83% of patients with acute NMOSD (AUC = 0.80), compared with median values of MOGAD. Among patients with acute NMOSD, EDSS scores correlated with all four neutrophil granulocyte markers and GFAP, but not with NfL and S100B. The neutrophil granulocyte markers in acute NMOSD are likely drivers of tissue damage, said Dr. Leppert. “We may end up in the future with an algorithm that combines several markers into one score to optimize the differentiating power.” The next step will be to validate these findings in a larger sample set, he said at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
Biomarkers may predict attacks
Granulocyte markers may provide support for a diagnosis of NMOSD over MS even in the small subgroup of patients who are seronegative for AQP4-IgG and MOG-IgG, said Brian G. Weinshenker, MD, a neurology consultant at Mayo Clinic in Rochester, Minn. In the study by Leppert and colleagues, granulocyte markers did not appear able to distinguish patients with AQP4-IgG–associated NMOSD from those with MOG-IgG–associated NMOSD, although astrocyte markers did in previous studies. “Granulocyte markers are primarily effective when studied in the context of an acute attack, unlike the antibody biomarkers,” said Dr. Weinshenker.
“Perhaps the most promising aspect of these new biomarkers is the fact that they are biomarkers for important mediators of tissue toxicity and seemed to correlate with attack-related disability,” he added. “They may prove to be prognostic indicators of attacks, and might influence the aggressiveness of acute management of attacks, although, in practice, all patients with NMOSD attacks, especially those associated with AQP4-IgG, should be managed aggressively.”
The current results will need independent confirmation before these biomarkers can be integrated into clinical practice, said Dr. Weinshenker. Studies should include patients with other diseases that can cause inflammation in the spinal cord and optic nerve (e.g., acute disseminated encephalomyelitis, infectious myelitis, and parainfectious myelitis) as relevant controls to determine whether granulocyte markers can distinguish these conditions effectively.
In addition, patients with discrepant values for elevations of granulocyte markers and serological indicators of NMOSD should be followed to determine the markers’ significance in this population, as well as to understand the value that measuring neutrophil markers provides. “Further studies of how these markers might herald attacks and predict disability might render these tests useful in monitoring patients and potentially intervening early in the attack process before attacks are fully manifest clinically.”
Dr. Leppert did not report any disclosures or any outside funding for the study. Dr. Weinshenker receives royalties from RSR, Oxford University, Hospices Civil de Lyon, and MVZ Labor PD Dr. Volkmann und Kollegen for a patent on NMO-IgG as a diagnostic test for NMOSD. He has served on an adjudication committee for clinical trials in NMOSD being conducted by MedImmune/VielaBio and Alexion, and consulted for Chugai/Roche/Genentech and Mitsubishi-Tanabe regarding a clinical trial for NMOSD.
SOURCE: Leppert D et al. MSVirtual2020. Abstract LB01.03.
, researchers reported. If current findings are replicated, these biomarkers will help neurologists distinguish between these disorders in the future, even in cases that are negative for autoantibodies, they said.
The sensitivity and specificity profile of neutrophil granulocyte biomarkers is not as good as that for cell-based assays for AQP4 and anti-MOG antibodies when it comes to distinguishing between acute NMOSD or MOGAD versus acute relapsing-remitting MS, said David Leppert, MD, of University Hospital Basel (Switzerland) and the University of Basel. But the sensitivity and specificity of neutrophil granulocyte biomarkers are “even with” those of referring ELISA tests, he added. Furthermore, the evaluation of these biomarkers can be completed within hours, thus providing the potential for timely support for therapeutic decisions about patients with acute NMOSD.
It can be difficult to distinguish between NMOSD, MOGAD, and MS using a clinical examination and MRI scans alone. Assays for AQP4 and anti-MOG antibodies are the standard for refining the diagnosis, but obtaining the results of these assays takes 1-2 weeks. This time frame may delay the administration of urgently needed treatment.
Neutrophil granulocytes have various components that carry molecules that, although they are secreted to defend the host, also can damage tissue. These cells are common in brain tissue and CSF among patients with NMOSD. Patients with MOGAD often have neutrophil granulocytes as well, but the latter are rare in MS.
Biomarkers had high AUC
Dr. Leppert and colleagues conducted a study to evaluate whether these cells can distinguish NMOSD or MOGAD from MS. The investigators specifically examined the following neutrophil granule products: elastase, myeloperoxidase (MPO), matrix metalloproteinase-8 (MMP-8), and neutrophil gelatinase-associated lipocalin (NGAL). Dr. Leppert’s group evaluated CSF samples from 42 patients with NMOSD, 6 patients with MOGAD, and 41 patients with relapsing-remitting MS for these potential biomarkers. They also examined the samples for neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and S100B by conventional ELISA or single-molecule array assay. The investigators examined CSF samples from 25 healthy controls as a reference group.
Linear models allowed Dr. Leppert and colleagues to assess the association between biomarkers and disease groups. The investigators modeled the change of biomarker levels over time. They calculated receiver operating characteristic (ROC) curves and area under the curve (AUC) to estimate the potential to distinguish NMOSD and MOGAD from relapsing-remitting MS in acute disease phase (i.e., at 20 or fewer days after relapse), as well as between acute NMOSD and MOGAD. Finally, they assessed the association of biomarkers with Expanded Disability Status Scale (EDSS) score in acute NMOSD and relapsing-remitting MS using linear models and Spearman correlation.
Dr. Leppert and colleagues found that levels of NfL were increased among patients, compared with healthy controls. GFAP levels were increased in patients with NMOSD, compared with controls.
Among patients with NMOSD, all four neutrophil granulocyte markers were significantly increased, compared with healthy controls and patients with acute relapsing-remitting MS. Among patients with MOGAD, elastase, MPO, and MMP-8 were increased, compared with healthy controls and patients with acute relapsing-remitting MS. In ROC analyses comparing patients with acute NMOSD or MOGAD against those with acute RRMS, the AUC of elastase and NGAL was 0.91, the AUC of MPO was 0.82, and the AUC of MMP-8 was 0.81.
Levels of S100B were increased in 89% of patients with acute NMOSD (AUC = 0.82), and levels of GFAP were increased in 83% of patients with acute NMOSD (AUC = 0.80), compared with median values of MOGAD. Among patients with acute NMOSD, EDSS scores correlated with all four neutrophil granulocyte markers and GFAP, but not with NfL and S100B. The neutrophil granulocyte markers in acute NMOSD are likely drivers of tissue damage, said Dr. Leppert. “We may end up in the future with an algorithm that combines several markers into one score to optimize the differentiating power.” The next step will be to validate these findings in a larger sample set, he said at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
Biomarkers may predict attacks
Granulocyte markers may provide support for a diagnosis of NMOSD over MS even in the small subgroup of patients who are seronegative for AQP4-IgG and MOG-IgG, said Brian G. Weinshenker, MD, a neurology consultant at Mayo Clinic in Rochester, Minn. In the study by Leppert and colleagues, granulocyte markers did not appear able to distinguish patients with AQP4-IgG–associated NMOSD from those with MOG-IgG–associated NMOSD, although astrocyte markers did in previous studies. “Granulocyte markers are primarily effective when studied in the context of an acute attack, unlike the antibody biomarkers,” said Dr. Weinshenker.
“Perhaps the most promising aspect of these new biomarkers is the fact that they are biomarkers for important mediators of tissue toxicity and seemed to correlate with attack-related disability,” he added. “They may prove to be prognostic indicators of attacks, and might influence the aggressiveness of acute management of attacks, although, in practice, all patients with NMOSD attacks, especially those associated with AQP4-IgG, should be managed aggressively.”
The current results will need independent confirmation before these biomarkers can be integrated into clinical practice, said Dr. Weinshenker. Studies should include patients with other diseases that can cause inflammation in the spinal cord and optic nerve (e.g., acute disseminated encephalomyelitis, infectious myelitis, and parainfectious myelitis) as relevant controls to determine whether granulocyte markers can distinguish these conditions effectively.
In addition, patients with discrepant values for elevations of granulocyte markers and serological indicators of NMOSD should be followed to determine the markers’ significance in this population, as well as to understand the value that measuring neutrophil markers provides. “Further studies of how these markers might herald attacks and predict disability might render these tests useful in monitoring patients and potentially intervening early in the attack process before attacks are fully manifest clinically.”
Dr. Leppert did not report any disclosures or any outside funding for the study. Dr. Weinshenker receives royalties from RSR, Oxford University, Hospices Civil de Lyon, and MVZ Labor PD Dr. Volkmann und Kollegen for a patent on NMO-IgG as a diagnostic test for NMOSD. He has served on an adjudication committee for clinical trials in NMOSD being conducted by MedImmune/VielaBio and Alexion, and consulted for Chugai/Roche/Genentech and Mitsubishi-Tanabe regarding a clinical trial for NMOSD.
SOURCE: Leppert D et al. MSVirtual2020. Abstract LB01.03.
FROM MSVIRTUAL2020
Bacteria may be associated with risk of MS relapse
No broad differences in gut bacterial composition, however, are associated with risk of relapse, according to the investigators. The findings were presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
Previous research has found an association between Blautia stercoris and disease activity in other immune-mediated diseases such as systemic lupus. Although the current study is the largest in patients with MS that includes data about the microbiome and relapses, its findings require replication, said Mary Horton, a doctoral candidate in epidemiology at the University of California, Berkeley.
Gut microbes digest food, produce vitamins (for example, B12 and K), create a barrier against pathogens, and regulate the immune system, among other tasks. Most current knowledge about the gut microbiome in MS comes from studies of patients with adult-onset MS. In 2016, Tremlett et al. found an increase in Desulfovibrionaceae and a decrease in Lachnospiraceae and Ruminococcaceae in patients with pediatric-onset MS. They also found that a decrease in Fusobacteria was associated with risk of relapse in this population.
Advanced analytical methods
Using a larger sample size and newer analytical methods than in the study by Tremlett and colleagues, Ms. Horton’s group sought to determine whether features of the gut microbiome are associated with relapse. From 2014 to 2018, the investigators recruited 53 patients with pediatric-onset MS from the University of California, San Francisco, and six centers in the U.S. Network of Pediatric MS Centers. At baseline, they collected stool samples, blood samples, information about past relapses, medication records, demographics, and environmental factors. At each relapse, the investigators collected information about the patient’s current and past medication use and about relapses that the patient had had since the previous visit.
Ms. Horton and colleagues analyzed the stool samples using 16S rRNA sequencing of the V4 region. They identified amplicon sequence variants (ASVs), which are used to define species of bacteria, with the Divisive Amplicon Denoising Algorithm-2 (DADA2). Taxonomies were assigned using the naive Bayesian classifier method, and the read count was normalized using multiple rarefaction.
The investigators identified ASV clusters using weighted genetic correlation network analysis (WGCNA). To evaluate whether individual ASVs were associated with relapse, they used a Prentice, Williams, and Peterson (PWP) recurrent event model, an extension of the Cox proportional hazards model.
The role of methanogenesis
Ms. Horton and colleagues included 53 patients (72% girls) in their study. The population’s mean age was 14.3 years at disease onset and 15.5 years at stool sample collection. About 70% of patients were White, and about 36% were Hispanic. Mean disease duration was 1.3 years, and median Expanded Disability Status Scale score was 1.0.
Approximately 45% of participants had one relapse, and 30% had more than one relapse during the subsequent mean follow-up of 2.5 years. About 91% of patients used a disease-modifying therapy during follow-up.
Gut bacterial abundance was broadly similar between patients who relapsed during the study period and those who did not. Of 270 ASVs included in the analyses, 20 were nominally associated with risk of relapse. Blautia stercoris had the most significant association with relapse risk (hazard ratio, 2.50). Blautia massiliensis also was among the 20 ASVs associated with risk of relapse.
WGCNA identified six ASV clusters. Higher values of one cluster’s eigengene were significantly associated with higher relapse risk (HR, 1.23). The following four ASVs nominally associated with higher relapse risk were in this cluster: Blautia massiliensis, Dorea longicatena, Coprococcus comes, and an unknown species in genus Subdoligranulum.
When Ms. Horton and colleagues examined the pathways from these bacterial species, they found 10 that were significantly associated with the risk of relapse. Four of these 10 pathways are involved in methane production, which suggests the involvement of methanogenesis pathways in relapse.
Although the investigators used advanced techniques for genetic and statistical analysis, the study’s sample size is small, Ms. Horton acknowledged. In addition, the conclusions that can be drawn from observational data are limited.
These suggest several avenues for future research. “There is a big question about how the different treatments that people are on when they are experiencing relapses might impact the microbiome,” said Ms. Horton. “Is the microbiome impacting your treatment response, or is it the reverse?” Investigators also could examine why the methane production pathway is overrepresented among people with MS who have relapses. “Which specific archaea might be leading to that increase in methane is a ripe future study question. Just what that means for health is really unknown.”
The National MS Society and the National Institute of Neurological Disorders and Stroke provided funding for the study. Ms. Horton had no disclosures.
SOURCE: Horton M et al. MSVirtual2020, Abstract LB01.05.
No broad differences in gut bacterial composition, however, are associated with risk of relapse, according to the investigators. The findings were presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
Previous research has found an association between Blautia stercoris and disease activity in other immune-mediated diseases such as systemic lupus. Although the current study is the largest in patients with MS that includes data about the microbiome and relapses, its findings require replication, said Mary Horton, a doctoral candidate in epidemiology at the University of California, Berkeley.
Gut microbes digest food, produce vitamins (for example, B12 and K), create a barrier against pathogens, and regulate the immune system, among other tasks. Most current knowledge about the gut microbiome in MS comes from studies of patients with adult-onset MS. In 2016, Tremlett et al. found an increase in Desulfovibrionaceae and a decrease in Lachnospiraceae and Ruminococcaceae in patients with pediatric-onset MS. They also found that a decrease in Fusobacteria was associated with risk of relapse in this population.
Advanced analytical methods
Using a larger sample size and newer analytical methods than in the study by Tremlett and colleagues, Ms. Horton’s group sought to determine whether features of the gut microbiome are associated with relapse. From 2014 to 2018, the investigators recruited 53 patients with pediatric-onset MS from the University of California, San Francisco, and six centers in the U.S. Network of Pediatric MS Centers. At baseline, they collected stool samples, blood samples, information about past relapses, medication records, demographics, and environmental factors. At each relapse, the investigators collected information about the patient’s current and past medication use and about relapses that the patient had had since the previous visit.
Ms. Horton and colleagues analyzed the stool samples using 16S rRNA sequencing of the V4 region. They identified amplicon sequence variants (ASVs), which are used to define species of bacteria, with the Divisive Amplicon Denoising Algorithm-2 (DADA2). Taxonomies were assigned using the naive Bayesian classifier method, and the read count was normalized using multiple rarefaction.
The investigators identified ASV clusters using weighted genetic correlation network analysis (WGCNA). To evaluate whether individual ASVs were associated with relapse, they used a Prentice, Williams, and Peterson (PWP) recurrent event model, an extension of the Cox proportional hazards model.
The role of methanogenesis
Ms. Horton and colleagues included 53 patients (72% girls) in their study. The population’s mean age was 14.3 years at disease onset and 15.5 years at stool sample collection. About 70% of patients were White, and about 36% were Hispanic. Mean disease duration was 1.3 years, and median Expanded Disability Status Scale score was 1.0.
Approximately 45% of participants had one relapse, and 30% had more than one relapse during the subsequent mean follow-up of 2.5 years. About 91% of patients used a disease-modifying therapy during follow-up.
Gut bacterial abundance was broadly similar between patients who relapsed during the study period and those who did not. Of 270 ASVs included in the analyses, 20 were nominally associated with risk of relapse. Blautia stercoris had the most significant association with relapse risk (hazard ratio, 2.50). Blautia massiliensis also was among the 20 ASVs associated with risk of relapse.
WGCNA identified six ASV clusters. Higher values of one cluster’s eigengene were significantly associated with higher relapse risk (HR, 1.23). The following four ASVs nominally associated with higher relapse risk were in this cluster: Blautia massiliensis, Dorea longicatena, Coprococcus comes, and an unknown species in genus Subdoligranulum.
When Ms. Horton and colleagues examined the pathways from these bacterial species, they found 10 that were significantly associated with the risk of relapse. Four of these 10 pathways are involved in methane production, which suggests the involvement of methanogenesis pathways in relapse.
Although the investigators used advanced techniques for genetic and statistical analysis, the study’s sample size is small, Ms. Horton acknowledged. In addition, the conclusions that can be drawn from observational data are limited.
These suggest several avenues for future research. “There is a big question about how the different treatments that people are on when they are experiencing relapses might impact the microbiome,” said Ms. Horton. “Is the microbiome impacting your treatment response, or is it the reverse?” Investigators also could examine why the methane production pathway is overrepresented among people with MS who have relapses. “Which specific archaea might be leading to that increase in methane is a ripe future study question. Just what that means for health is really unknown.”
The National MS Society and the National Institute of Neurological Disorders and Stroke provided funding for the study. Ms. Horton had no disclosures.
SOURCE: Horton M et al. MSVirtual2020, Abstract LB01.05.
No broad differences in gut bacterial composition, however, are associated with risk of relapse, according to the investigators. The findings were presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
Previous research has found an association between Blautia stercoris and disease activity in other immune-mediated diseases such as systemic lupus. Although the current study is the largest in patients with MS that includes data about the microbiome and relapses, its findings require replication, said Mary Horton, a doctoral candidate in epidemiology at the University of California, Berkeley.
Gut microbes digest food, produce vitamins (for example, B12 and K), create a barrier against pathogens, and regulate the immune system, among other tasks. Most current knowledge about the gut microbiome in MS comes from studies of patients with adult-onset MS. In 2016, Tremlett et al. found an increase in Desulfovibrionaceae and a decrease in Lachnospiraceae and Ruminococcaceae in patients with pediatric-onset MS. They also found that a decrease in Fusobacteria was associated with risk of relapse in this population.
Advanced analytical methods
Using a larger sample size and newer analytical methods than in the study by Tremlett and colleagues, Ms. Horton’s group sought to determine whether features of the gut microbiome are associated with relapse. From 2014 to 2018, the investigators recruited 53 patients with pediatric-onset MS from the University of California, San Francisco, and six centers in the U.S. Network of Pediatric MS Centers. At baseline, they collected stool samples, blood samples, information about past relapses, medication records, demographics, and environmental factors. At each relapse, the investigators collected information about the patient’s current and past medication use and about relapses that the patient had had since the previous visit.
Ms. Horton and colleagues analyzed the stool samples using 16S rRNA sequencing of the V4 region. They identified amplicon sequence variants (ASVs), which are used to define species of bacteria, with the Divisive Amplicon Denoising Algorithm-2 (DADA2). Taxonomies were assigned using the naive Bayesian classifier method, and the read count was normalized using multiple rarefaction.
The investigators identified ASV clusters using weighted genetic correlation network analysis (WGCNA). To evaluate whether individual ASVs were associated with relapse, they used a Prentice, Williams, and Peterson (PWP) recurrent event model, an extension of the Cox proportional hazards model.
The role of methanogenesis
Ms. Horton and colleagues included 53 patients (72% girls) in their study. The population’s mean age was 14.3 years at disease onset and 15.5 years at stool sample collection. About 70% of patients were White, and about 36% were Hispanic. Mean disease duration was 1.3 years, and median Expanded Disability Status Scale score was 1.0.
Approximately 45% of participants had one relapse, and 30% had more than one relapse during the subsequent mean follow-up of 2.5 years. About 91% of patients used a disease-modifying therapy during follow-up.
Gut bacterial abundance was broadly similar between patients who relapsed during the study period and those who did not. Of 270 ASVs included in the analyses, 20 were nominally associated with risk of relapse. Blautia stercoris had the most significant association with relapse risk (hazard ratio, 2.50). Blautia massiliensis also was among the 20 ASVs associated with risk of relapse.
WGCNA identified six ASV clusters. Higher values of one cluster’s eigengene were significantly associated with higher relapse risk (HR, 1.23). The following four ASVs nominally associated with higher relapse risk were in this cluster: Blautia massiliensis, Dorea longicatena, Coprococcus comes, and an unknown species in genus Subdoligranulum.
When Ms. Horton and colleagues examined the pathways from these bacterial species, they found 10 that were significantly associated with the risk of relapse. Four of these 10 pathways are involved in methane production, which suggests the involvement of methanogenesis pathways in relapse.
Although the investigators used advanced techniques for genetic and statistical analysis, the study’s sample size is small, Ms. Horton acknowledged. In addition, the conclusions that can be drawn from observational data are limited.
These suggest several avenues for future research. “There is a big question about how the different treatments that people are on when they are experiencing relapses might impact the microbiome,” said Ms. Horton. “Is the microbiome impacting your treatment response, or is it the reverse?” Investigators also could examine why the methane production pathway is overrepresented among people with MS who have relapses. “Which specific archaea might be leading to that increase in methane is a ripe future study question. Just what that means for health is really unknown.”
The National MS Society and the National Institute of Neurological Disorders and Stroke provided funding for the study. Ms. Horton had no disclosures.
SOURCE: Horton M et al. MSVirtual2020, Abstract LB01.05.
From MSVirtual2020
COVID-19 risks are no higher in patients with multiple sclerosis
new U.S. data suggest. A separate study from the United Kingdom also found similar trends of rates of COVID-19 infection in patients with MS and the general population.
Both studies were presented Sept. 26 at a special session on multiple sclerosis and COVID-19 at a final “Encore” event as part of the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
The U.S. data appear consistent with studies from several other countries, in that worse COVID-19 outcomes increase with age and higher disability levels, both of which would be expected from findings in the general population.
The U.S. data also show a clear effect of race in MS, with higher rates of adverse COVID-19 outcomes in Black patients, again in line with what is seen in the general population.
“I would say the results from our study and in general do not suggest that MS itself is associated with higher risks of severe COVID-19 outcomes, compared with the general population,” said Amber Salter, PhD.
Dr. Salter, who is assistant professor of biostatistics at Washington University, St. Louis, presented data from the COViMS North American registry, set up for health care providers to report persons with MS who are infected with COVID-19.
The COViMS registry so far has information on 858 patients with MS who have COVID-19 (80% verified by a positive test), as reported from 150 different health care providers in the United States and Canada. The average age was 48 years, with average disease duration of 13.6 years. MS clinical course was reported as relapsing remitting in 78%, secondary progressive in 15%, and primary progressive in 5%. Most patients (72%) were fully ambulatory, 16% could walk with assistance, and 12% were nonambulatory.
Severe COVID-19 outcomes were classified as mortality (which occurred in 5.7% of the cohort), mortality/ICU admission (13.6%) and mortality/ICU admission/hospitalization (30.2%).
Results were adjusted for many different covariates, including sex, age, smoking, MS clinical course (relapsing, progressive), disease duration, ambulation, individual comorbidities (cardiovascular disease, cerebrovascular disease, chronic kidney disease, chronic lung disease, diabetes, hypertension, morbid obesity), and disease-modifying therapy use.
In multivariable logistic regression analyses, older age, having chronic renal disease, and being nonambulatory were consistently associated with increased odds of poorer outcomes. Chronic kidney disease had the strongest association with mortality (odds ratio, 28.6; P < .001). Other factors associated with mortality included cardiovascular disease (OR, 4.35; P = .009); age (OR per 10 years, 1.91; P = .012), and male sex (OR, 2.60; P = .041).
Patients who were nonambulatory had a higher risk of mortality/ICU admission/hospitalization (OR, 3.32; P = .003). This endpoint was also increased in patients on anti-CD20 drugs, compared with other disease-modifying treatment (OR, 2.31; P = .002), consistent with results from at least two other studies.
Disease-modifying therapy in general was not associated with an increased risk of worse outcomes. “There was some concern at the outset about the effect of disease-modifying therapies on COVID-19 outcomes, but most studies have not found an increased risk of worse outcomes in patients on such drug treatments, with the possible exception of anti-CD20 drugs,” Dr. Salter said.
“Some disease-modifying therapies may actually be protective (particularly interferon) and studies are investigating whether they may have a role in the treatment of COVID-19,” she added.
“The factors in MS patients that we and others have found to be associated with worse COVID-19 outcomes may not be specific to MS. Older age is known to be a primary risk factor for worse COVID-19 outcomes in the general population, and increasing disability presumably tracks with worse general heath,” Dr. Salter commented.
“I would say the overall data are fairly reassuring for MS patents,” she concluded.
Black patients have higher risk
One worrying finding in the North American data, however, was the effect of race. “We found an independent effect of race for worse COVID-19 outcomes in MS patients,” Dr. Slater said.
Of the 858 patients in the COViMS registry, 65.7% were White and 26.1% were Black. Black individuals were more likely to be younger, never smokers, have shorter MS duration, a relapsing MS course, and have comorbidities, compared with White patients. A higher proportion of Black patients had hypertension (40.2% vs 19.5%) and morbid obesity (17% vs. 9.5%).
Results showed that mortality rates were not statistically different between White and Black patients, but Black race was associated with increased risk of mortality and/or ICU admission, compared with White patients (16.9% vs. 12.8%), and multivariate logistic regression analysis showed Black race was independently associated with mortality/ICU admission after adjustments for covariates (OR, 3.7; P = .002).
Black race was also associated with increased risk of mortality/ICU admission/hospital admission (35.8% vs. 30.2%), and after adjustment for covariates this was found to be an independent predictor (OR, 1.7; P = .04).
“This higher COVID-19 risk in Black individuals is also seen in the general population, so these results are not that surprising and it doesn’t appear to be an effect specific to MS patients,” Dr. Salter commented.
U.K. data on risk of contracting COVID-19
A U.K. study also suggested race to be an independent predictor in the risk of contracting COVID-19 in patients with MS.
The study of more than 5,000 patients with MS showed that those from a Black, Asian, and Minority Ethnic group were twice as likely to report having COVID-19 than those who were White.
The study, which was conducted during the U.K. lockdown, also found that the trend of COVID-19 infection in patients with MS is comparable with that of the U.K. general population.
Presenting the data, Afagh Garjani, MD, concluded: “During a period with strict physical distancing measures, patients with MS are not at an increased risk of contracting COVID-19.”
Dr. Garjani, a neurology clinical research fellow at the University of Nottingham, (England), explained that the COVID-19 pandemic has introduced uncertainties into the MS community, and the focus so far has been the severity of infection among people with MS who have COVID-19.
“This approach has left questions about the risk of contracting disease in people with MS unanswered, which has implications as society gradually returns to normal,” she said.
Dr. Garjani presented data from the United Kingdom MS Register (UKMSR), which has been collecting demographic and MS-related data since 2011 from patients with MS throughout the United Kingdom.
On March 17 – just before the lockdown in United Kingdom – existing participants of the UKMSR were asked to join the COVID-19 study. The study was also advertised through social media. In this ongoing study, people with MS answered a COVID-19–related survey at participation and a different follow-up survey every 2 weeks depending on whether they contracted COVID-19.
The COVID-19 study included 5,309 patients with MS. The mean age of the study population was 52.4 years, 76.1% were female, and 95.7% were White. Of the 5,309 patients, 535 (10%) reported a self-diagnosis of COVID-19. Because of limited availability of tests in the United Kingdom at the time, only 75 patents had a positive polymerase chain reaction result.
“To our knowledge, this is the largest community-based study of COVID-19 in patients with MS worldwide,” Dr. Garjani said. She presented results from the period March 23 to June 24, when the United Kingdom was in a period of lockdown with vulnerable groups encouraged to self-isolate completely.
In this MS cohort, 47% reported self-isolating at some point. Those at older age and higher Expanded Disability Status Scale (EDSS) score were more likely to have self-isolated.
The researchers did not find that patients with progressive MS or those on disease-modifying therapies in general isolated more, but patients on monoclonal antibody drugs and fingolimod were more likely to self-isolate versus those on other therapies. “This may be because there are concerns about infection with these drugs and patients on these therapies may be more concerned about contracting COVID-19,” Dr. Garjani suggested.
In terms of contracting COVID, the researchers found a reduced risk of COVID-19 (self-diagnosed) in patients with older age and higher EDSS. “This is not really surprising that these patients were more likely to self-isolate,” Dr. Garjani commented.
No association was seen between type of MS, disease duration, disease-modifying therapy in general, and risk of COVID-19. No individual drug treatment increased risk versus no therapy or versus self-injectables. But there was an increased risk of contracting the virus in patients whose race was Black, Asian, or Minority Ethnic (OR, 2.2), which is in line with findings from the general population.
“This study is unique – the denominator is all people with MS. We are looking primarily at the risk of contracting COVID-19. Other studies are focusing more on people with MS who have COVID and assessing risk of a severe COVID outcome. Our results are not contradicting the findings from those studies,” Dr. Garjani said.
The results were similar only when patients with a confirmed COVID-19 test were considered.
In terms of outcomes in those who reported COVID-19 infection, preliminary results have not shown any MS factors – such as EDSS, age, type of MS, drug therapy in general – to be associated with outcome.
“Since the COVID-19 outbreak started there has been concern among MS patients, especially among those on disease-modifying therapies, about whether they are at increased risk of infection and severe disease,” Dr. Garjani said.
“We found similar trends of rates of infection in MS patients and the general population, and no signal of increased risks in those with higher EDSS or progressive MS. The caveat is that this study was conducted in a period of lockdown, but we adjusted for self-isolating behavior in the multivariable regression analysis,” she noted.
Dr. Salter is a statistical editor for the American Heart Association journal Circulation: Cardiovascular Imaging. Dr. Garjani has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
new U.S. data suggest. A separate study from the United Kingdom also found similar trends of rates of COVID-19 infection in patients with MS and the general population.
Both studies were presented Sept. 26 at a special session on multiple sclerosis and COVID-19 at a final “Encore” event as part of the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
The U.S. data appear consistent with studies from several other countries, in that worse COVID-19 outcomes increase with age and higher disability levels, both of which would be expected from findings in the general population.
The U.S. data also show a clear effect of race in MS, with higher rates of adverse COVID-19 outcomes in Black patients, again in line with what is seen in the general population.
“I would say the results from our study and in general do not suggest that MS itself is associated with higher risks of severe COVID-19 outcomes, compared with the general population,” said Amber Salter, PhD.
Dr. Salter, who is assistant professor of biostatistics at Washington University, St. Louis, presented data from the COViMS North American registry, set up for health care providers to report persons with MS who are infected with COVID-19.
The COViMS registry so far has information on 858 patients with MS who have COVID-19 (80% verified by a positive test), as reported from 150 different health care providers in the United States and Canada. The average age was 48 years, with average disease duration of 13.6 years. MS clinical course was reported as relapsing remitting in 78%, secondary progressive in 15%, and primary progressive in 5%. Most patients (72%) were fully ambulatory, 16% could walk with assistance, and 12% were nonambulatory.
Severe COVID-19 outcomes were classified as mortality (which occurred in 5.7% of the cohort), mortality/ICU admission (13.6%) and mortality/ICU admission/hospitalization (30.2%).
Results were adjusted for many different covariates, including sex, age, smoking, MS clinical course (relapsing, progressive), disease duration, ambulation, individual comorbidities (cardiovascular disease, cerebrovascular disease, chronic kidney disease, chronic lung disease, diabetes, hypertension, morbid obesity), and disease-modifying therapy use.
In multivariable logistic regression analyses, older age, having chronic renal disease, and being nonambulatory were consistently associated with increased odds of poorer outcomes. Chronic kidney disease had the strongest association with mortality (odds ratio, 28.6; P < .001). Other factors associated with mortality included cardiovascular disease (OR, 4.35; P = .009); age (OR per 10 years, 1.91; P = .012), and male sex (OR, 2.60; P = .041).
Patients who were nonambulatory had a higher risk of mortality/ICU admission/hospitalization (OR, 3.32; P = .003). This endpoint was also increased in patients on anti-CD20 drugs, compared with other disease-modifying treatment (OR, 2.31; P = .002), consistent with results from at least two other studies.
Disease-modifying therapy in general was not associated with an increased risk of worse outcomes. “There was some concern at the outset about the effect of disease-modifying therapies on COVID-19 outcomes, but most studies have not found an increased risk of worse outcomes in patients on such drug treatments, with the possible exception of anti-CD20 drugs,” Dr. Salter said.
“Some disease-modifying therapies may actually be protective (particularly interferon) and studies are investigating whether they may have a role in the treatment of COVID-19,” she added.
“The factors in MS patients that we and others have found to be associated with worse COVID-19 outcomes may not be specific to MS. Older age is known to be a primary risk factor for worse COVID-19 outcomes in the general population, and increasing disability presumably tracks with worse general heath,” Dr. Salter commented.
“I would say the overall data are fairly reassuring for MS patents,” she concluded.
Black patients have higher risk
One worrying finding in the North American data, however, was the effect of race. “We found an independent effect of race for worse COVID-19 outcomes in MS patients,” Dr. Slater said.
Of the 858 patients in the COViMS registry, 65.7% were White and 26.1% were Black. Black individuals were more likely to be younger, never smokers, have shorter MS duration, a relapsing MS course, and have comorbidities, compared with White patients. A higher proportion of Black patients had hypertension (40.2% vs 19.5%) and morbid obesity (17% vs. 9.5%).
Results showed that mortality rates were not statistically different between White and Black patients, but Black race was associated with increased risk of mortality and/or ICU admission, compared with White patients (16.9% vs. 12.8%), and multivariate logistic regression analysis showed Black race was independently associated with mortality/ICU admission after adjustments for covariates (OR, 3.7; P = .002).
Black race was also associated with increased risk of mortality/ICU admission/hospital admission (35.8% vs. 30.2%), and after adjustment for covariates this was found to be an independent predictor (OR, 1.7; P = .04).
“This higher COVID-19 risk in Black individuals is also seen in the general population, so these results are not that surprising and it doesn’t appear to be an effect specific to MS patients,” Dr. Salter commented.
U.K. data on risk of contracting COVID-19
A U.K. study also suggested race to be an independent predictor in the risk of contracting COVID-19 in patients with MS.
The study of more than 5,000 patients with MS showed that those from a Black, Asian, and Minority Ethnic group were twice as likely to report having COVID-19 than those who were White.
The study, which was conducted during the U.K. lockdown, also found that the trend of COVID-19 infection in patients with MS is comparable with that of the U.K. general population.
Presenting the data, Afagh Garjani, MD, concluded: “During a period with strict physical distancing measures, patients with MS are not at an increased risk of contracting COVID-19.”
Dr. Garjani, a neurology clinical research fellow at the University of Nottingham, (England), explained that the COVID-19 pandemic has introduced uncertainties into the MS community, and the focus so far has been the severity of infection among people with MS who have COVID-19.
“This approach has left questions about the risk of contracting disease in people with MS unanswered, which has implications as society gradually returns to normal,” she said.
Dr. Garjani presented data from the United Kingdom MS Register (UKMSR), which has been collecting demographic and MS-related data since 2011 from patients with MS throughout the United Kingdom.
On March 17 – just before the lockdown in United Kingdom – existing participants of the UKMSR were asked to join the COVID-19 study. The study was also advertised through social media. In this ongoing study, people with MS answered a COVID-19–related survey at participation and a different follow-up survey every 2 weeks depending on whether they contracted COVID-19.
The COVID-19 study included 5,309 patients with MS. The mean age of the study population was 52.4 years, 76.1% were female, and 95.7% were White. Of the 5,309 patients, 535 (10%) reported a self-diagnosis of COVID-19. Because of limited availability of tests in the United Kingdom at the time, only 75 patents had a positive polymerase chain reaction result.
“To our knowledge, this is the largest community-based study of COVID-19 in patients with MS worldwide,” Dr. Garjani said. She presented results from the period March 23 to June 24, when the United Kingdom was in a period of lockdown with vulnerable groups encouraged to self-isolate completely.
In this MS cohort, 47% reported self-isolating at some point. Those at older age and higher Expanded Disability Status Scale (EDSS) score were more likely to have self-isolated.
The researchers did not find that patients with progressive MS or those on disease-modifying therapies in general isolated more, but patients on monoclonal antibody drugs and fingolimod were more likely to self-isolate versus those on other therapies. “This may be because there are concerns about infection with these drugs and patients on these therapies may be more concerned about contracting COVID-19,” Dr. Garjani suggested.
In terms of contracting COVID, the researchers found a reduced risk of COVID-19 (self-diagnosed) in patients with older age and higher EDSS. “This is not really surprising that these patients were more likely to self-isolate,” Dr. Garjani commented.
No association was seen between type of MS, disease duration, disease-modifying therapy in general, and risk of COVID-19. No individual drug treatment increased risk versus no therapy or versus self-injectables. But there was an increased risk of contracting the virus in patients whose race was Black, Asian, or Minority Ethnic (OR, 2.2), which is in line with findings from the general population.
“This study is unique – the denominator is all people with MS. We are looking primarily at the risk of contracting COVID-19. Other studies are focusing more on people with MS who have COVID and assessing risk of a severe COVID outcome. Our results are not contradicting the findings from those studies,” Dr. Garjani said.
The results were similar only when patients with a confirmed COVID-19 test were considered.
In terms of outcomes in those who reported COVID-19 infection, preliminary results have not shown any MS factors – such as EDSS, age, type of MS, drug therapy in general – to be associated with outcome.
“Since the COVID-19 outbreak started there has been concern among MS patients, especially among those on disease-modifying therapies, about whether they are at increased risk of infection and severe disease,” Dr. Garjani said.
“We found similar trends of rates of infection in MS patients and the general population, and no signal of increased risks in those with higher EDSS or progressive MS. The caveat is that this study was conducted in a period of lockdown, but we adjusted for self-isolating behavior in the multivariable regression analysis,” she noted.
Dr. Salter is a statistical editor for the American Heart Association journal Circulation: Cardiovascular Imaging. Dr. Garjani has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
new U.S. data suggest. A separate study from the United Kingdom also found similar trends of rates of COVID-19 infection in patients with MS and the general population.
Both studies were presented Sept. 26 at a special session on multiple sclerosis and COVID-19 at a final “Encore” event as part of the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
The U.S. data appear consistent with studies from several other countries, in that worse COVID-19 outcomes increase with age and higher disability levels, both of which would be expected from findings in the general population.
The U.S. data also show a clear effect of race in MS, with higher rates of adverse COVID-19 outcomes in Black patients, again in line with what is seen in the general population.
“I would say the results from our study and in general do not suggest that MS itself is associated with higher risks of severe COVID-19 outcomes, compared with the general population,” said Amber Salter, PhD.
Dr. Salter, who is assistant professor of biostatistics at Washington University, St. Louis, presented data from the COViMS North American registry, set up for health care providers to report persons with MS who are infected with COVID-19.
The COViMS registry so far has information on 858 patients with MS who have COVID-19 (80% verified by a positive test), as reported from 150 different health care providers in the United States and Canada. The average age was 48 years, with average disease duration of 13.6 years. MS clinical course was reported as relapsing remitting in 78%, secondary progressive in 15%, and primary progressive in 5%. Most patients (72%) were fully ambulatory, 16% could walk with assistance, and 12% were nonambulatory.
Severe COVID-19 outcomes were classified as mortality (which occurred in 5.7% of the cohort), mortality/ICU admission (13.6%) and mortality/ICU admission/hospitalization (30.2%).
Results were adjusted for many different covariates, including sex, age, smoking, MS clinical course (relapsing, progressive), disease duration, ambulation, individual comorbidities (cardiovascular disease, cerebrovascular disease, chronic kidney disease, chronic lung disease, diabetes, hypertension, morbid obesity), and disease-modifying therapy use.
In multivariable logistic regression analyses, older age, having chronic renal disease, and being nonambulatory were consistently associated with increased odds of poorer outcomes. Chronic kidney disease had the strongest association with mortality (odds ratio, 28.6; P < .001). Other factors associated with mortality included cardiovascular disease (OR, 4.35; P = .009); age (OR per 10 years, 1.91; P = .012), and male sex (OR, 2.60; P = .041).
Patients who were nonambulatory had a higher risk of mortality/ICU admission/hospitalization (OR, 3.32; P = .003). This endpoint was also increased in patients on anti-CD20 drugs, compared with other disease-modifying treatment (OR, 2.31; P = .002), consistent with results from at least two other studies.
Disease-modifying therapy in general was not associated with an increased risk of worse outcomes. “There was some concern at the outset about the effect of disease-modifying therapies on COVID-19 outcomes, but most studies have not found an increased risk of worse outcomes in patients on such drug treatments, with the possible exception of anti-CD20 drugs,” Dr. Salter said.
“Some disease-modifying therapies may actually be protective (particularly interferon) and studies are investigating whether they may have a role in the treatment of COVID-19,” she added.
“The factors in MS patients that we and others have found to be associated with worse COVID-19 outcomes may not be specific to MS. Older age is known to be a primary risk factor for worse COVID-19 outcomes in the general population, and increasing disability presumably tracks with worse general heath,” Dr. Salter commented.
“I would say the overall data are fairly reassuring for MS patents,” she concluded.
Black patients have higher risk
One worrying finding in the North American data, however, was the effect of race. “We found an independent effect of race for worse COVID-19 outcomes in MS patients,” Dr. Slater said.
Of the 858 patients in the COViMS registry, 65.7% were White and 26.1% were Black. Black individuals were more likely to be younger, never smokers, have shorter MS duration, a relapsing MS course, and have comorbidities, compared with White patients. A higher proportion of Black patients had hypertension (40.2% vs 19.5%) and morbid obesity (17% vs. 9.5%).
Results showed that mortality rates were not statistically different between White and Black patients, but Black race was associated with increased risk of mortality and/or ICU admission, compared with White patients (16.9% vs. 12.8%), and multivariate logistic regression analysis showed Black race was independently associated with mortality/ICU admission after adjustments for covariates (OR, 3.7; P = .002).
Black race was also associated with increased risk of mortality/ICU admission/hospital admission (35.8% vs. 30.2%), and after adjustment for covariates this was found to be an independent predictor (OR, 1.7; P = .04).
“This higher COVID-19 risk in Black individuals is also seen in the general population, so these results are not that surprising and it doesn’t appear to be an effect specific to MS patients,” Dr. Salter commented.
U.K. data on risk of contracting COVID-19
A U.K. study also suggested race to be an independent predictor in the risk of contracting COVID-19 in patients with MS.
The study of more than 5,000 patients with MS showed that those from a Black, Asian, and Minority Ethnic group were twice as likely to report having COVID-19 than those who were White.
The study, which was conducted during the U.K. lockdown, also found that the trend of COVID-19 infection in patients with MS is comparable with that of the U.K. general population.
Presenting the data, Afagh Garjani, MD, concluded: “During a period with strict physical distancing measures, patients with MS are not at an increased risk of contracting COVID-19.”
Dr. Garjani, a neurology clinical research fellow at the University of Nottingham, (England), explained that the COVID-19 pandemic has introduced uncertainties into the MS community, and the focus so far has been the severity of infection among people with MS who have COVID-19.
“This approach has left questions about the risk of contracting disease in people with MS unanswered, which has implications as society gradually returns to normal,” she said.
Dr. Garjani presented data from the United Kingdom MS Register (UKMSR), which has been collecting demographic and MS-related data since 2011 from patients with MS throughout the United Kingdom.
On March 17 – just before the lockdown in United Kingdom – existing participants of the UKMSR were asked to join the COVID-19 study. The study was also advertised through social media. In this ongoing study, people with MS answered a COVID-19–related survey at participation and a different follow-up survey every 2 weeks depending on whether they contracted COVID-19.
The COVID-19 study included 5,309 patients with MS. The mean age of the study population was 52.4 years, 76.1% were female, and 95.7% were White. Of the 5,309 patients, 535 (10%) reported a self-diagnosis of COVID-19. Because of limited availability of tests in the United Kingdom at the time, only 75 patents had a positive polymerase chain reaction result.
“To our knowledge, this is the largest community-based study of COVID-19 in patients with MS worldwide,” Dr. Garjani said. She presented results from the period March 23 to June 24, when the United Kingdom was in a period of lockdown with vulnerable groups encouraged to self-isolate completely.
In this MS cohort, 47% reported self-isolating at some point. Those at older age and higher Expanded Disability Status Scale (EDSS) score were more likely to have self-isolated.
The researchers did not find that patients with progressive MS or those on disease-modifying therapies in general isolated more, but patients on monoclonal antibody drugs and fingolimod were more likely to self-isolate versus those on other therapies. “This may be because there are concerns about infection with these drugs and patients on these therapies may be more concerned about contracting COVID-19,” Dr. Garjani suggested.
In terms of contracting COVID, the researchers found a reduced risk of COVID-19 (self-diagnosed) in patients with older age and higher EDSS. “This is not really surprising that these patients were more likely to self-isolate,” Dr. Garjani commented.
No association was seen between type of MS, disease duration, disease-modifying therapy in general, and risk of COVID-19. No individual drug treatment increased risk versus no therapy or versus self-injectables. But there was an increased risk of contracting the virus in patients whose race was Black, Asian, or Minority Ethnic (OR, 2.2), which is in line with findings from the general population.
“This study is unique – the denominator is all people with MS. We are looking primarily at the risk of contracting COVID-19. Other studies are focusing more on people with MS who have COVID and assessing risk of a severe COVID outcome. Our results are not contradicting the findings from those studies,” Dr. Garjani said.
The results were similar only when patients with a confirmed COVID-19 test were considered.
In terms of outcomes in those who reported COVID-19 infection, preliminary results have not shown any MS factors – such as EDSS, age, type of MS, drug therapy in general – to be associated with outcome.
“Since the COVID-19 outbreak started there has been concern among MS patients, especially among those on disease-modifying therapies, about whether they are at increased risk of infection and severe disease,” Dr. Garjani said.
“We found similar trends of rates of infection in MS patients and the general population, and no signal of increased risks in those with higher EDSS or progressive MS. The caveat is that this study was conducted in a period of lockdown, but we adjusted for self-isolating behavior in the multivariable regression analysis,” she noted.
Dr. Salter is a statistical editor for the American Heart Association journal Circulation: Cardiovascular Imaging. Dr. Garjani has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM MSVIRTUAL2020
Women with MS may have increased subclinical disease activity during pregnancy
The increase in sNfL is independent of relapses, which suggests that patients have increased subclinical disease activity during this period, according to the researchers.
When the investigators controlled their data for exposure to disease-modifying therapy (DMT), the effect of pregnancy on sNfL was no longer evident. These data were presented said at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
The results suggest that “sNfL may qualify as a sensitive and minimally invasive measure of disease activity in pregnancy,” said Özgür Yaldizli, MD, consultant neurologist at University Hospital Basel (Switzerland). “Strategies allowing the continuation of DMT during pregnancy may be warranted.”
MS preferentially affects women in their reproductive years, said Dr. Yaldizli. Almost one-third of women with MS become pregnant after they receive their diagnosis. A decrease in disease activity is typical in the third trimester, as is an increase in relapse frequency post partum.
DMTs reduce the risk of relapse, but have potential side effects for the woman and the fetus. Some DMTs are immunosuppressants, and they increase the risk of infection during pregnancy. Other DMTs may harm the development of the fetus, particularly if administered early during pregnancy.
“There is an urgent need to identify patients with high disease activity during pregnancy,” said Dr. Yaldizli. Increased levels of NfL, a specific biomarker of neuroaxonal injury, are associated with relapses, MRI activity, and disability worsening among patients with MS. Response to DMT is associated with decreased NfL levels. But few data about sNfL during pregnancy or post partum are available.
Relapses were associated with increased sNfL
Dr. Yaldizli and colleagues examined data from the Swiss MS Cohort Study to describe DMT use before, during, and after pregnancy. They also sought to assess sNfL as a marker of disease activity during and after pregnancy and to evaluate whether interrupting DMT because of pregnancy leads to increased sNfL levels.
Eligible participants had prospectively documented pregnancies, and Dr. Yaldizli’s group excluded pregnancies with early termination from their analysis. Serum samples were collected every 6 or 12 months and analyzed using the Simoa NF-light assay. The investigators used univariable and multivariable mixed-effects models to investigate associations between clinical characteristics and longitudinal sNfL levels in women before pregnancy, during pregnancy, and post partum.
Dr. Yaldizli and colleagues included 72 pregnancies in 63 patients with relapsing MS in their analysis. Nine patients had two pregnancies during follow-up. The population’s median age was 31.4 years, and median disease duration was 7.1 years. Median Expanded Disability Status Scale (EDSS) score at last visit before birth was 1.5. Median follow-up time was 6 years.
Most patients were treated with DMT before or during pregnancy. For most patients (39), fingolimod or natalizumab was the last DMT given before birth. Four patients did not use DMT before, during, or after pregnancy. In 14 pregnancies, the patient continued DMT for more than 6 months.
The univariable analysis showed that sNfL levels were 22% higher during pregnancy, compared with outside the pregnancy and postpartum period. The investigators recorded 29 relapses during the pregnancy and postpartum period. Relapses were more likely to occur during the first trimester and the first 3 months post partum. In the multivariable analysis, relapses that occurred within 120 days before serum sampling were associated with 98% higher levels of sNfL. In addition, sNfL was 7% higher for each step increase in EDSS and 13% higher during the pregnancy and postpartum period, compared with outside of that period.
When the investigators included DMT exposure at sampling time in the model, however, the pregnancy and postpartum period no longer had an effect on sNfL. The sNfL levels were 12% lower among patients exposed to DMT, compared with patients without DMT exposure.
Some DMTs, such as interferon-beta, are relatively safe during pregnancy, but the greater the medication’s efficacy, the more problematic it can be, said Dr. Yaldizi. “There are medications that are given, for example, every 6 months, like ocrelizumab. There are other medications that have to be taken daily. Probably the safest medications are those that are not given so often during pregnancy.”
Future research should examine the escalation therapies (i.e., the newer and more effective DMTs) during pregnancy in patients with MS, he added. “Not only in pregnancy, but also in general, we have to look for ways to measure disease activity in patients who switch therapy, who deescalate therapy.”
Pregnancy may not forestall disease activity
“The results of this study demonstrate that DMT withdrawal in the context of pregnancy can lead to subclinical disease re-emergence, as evidenced by increased sNfL levels in the DMT-free period,” said Vilija G. Jokubaitis, PhD, senior research fellow in the department of neuroscience at Monash University, Melbourne. Dr. Jokubaitis was not involved in the study.
“Interestingly, the median EDSS score in this cohort was quite low, demonstrating that, even in women with mild disease, pregnancy may not be sufficient to protect against ongoing MS activity.” Nevertheless, 28 of the 63 women were exposed to monoclonal antibody therapy, so it is unclear whether these women have mild disease or well-managed disease on DMT, she added.
“This study provides further evidence that pregnancy planning requires advanced planning, and that therapy continuation into pregnancy should be considered, particularly in women with moderate disease activity, to protect against disease reactivation,” said Dr. Jokubaitis.
The strengths of the study include its prospective design, the investigators’ ability to describe the various DMT exposures before and during pregnancy, and the multivariable mixed-effects modeling, she added. On the other hand, the results are at the group level, individual trajectories in sNfL level are not described, and the small sample size prevented the investigators from differentiating between the effects of various DMTs on sNfL outcomes. In addition, Dr. Yaldizli and colleagues did not take time off DMT into account in the models; they considered DMT exposure as a dichotomous variable.
“More work is needed to determine the therapeutic strategies that will give women with MS the greatest protection against disease reactivation in pregnancy and post partum, whilst also protecting fetal and neonatal outcomes,” said Dr. Jokubaitis. Group studies will enable researchers to identify trends, but neurologists ultimately need to provide individualized advice to their patients. “There is a need to look at [the effect of] DMT identity, timing, and duration of DMT withdrawal on fluctuation of sNfL levels, and how these relate to baseline disease severity,” Dr. Jokubaitis added. Furthermore, researchers must compare sNfL changes in pregnancy between patients with MS and healthy women in large cohorts.
The analysis by Dr. Yaldizli and colleagues was conducted without outside funding. The Swiss MS Cohort receives funding from the Swiss MS society, Biogen, Celgene, Sanofi, Merck, Novartis, Roche, and research associations such as the International Progressive MS Alliance and the Swiss National Science Foundation. Dr. Yaldizli received grants from ECTRIMS/MAGNIMS, the University of Basel, Pro Patient Stiftung, University Hospital Basel, Free Academy Basel, and the Swiss MS Society. He has received advisory board fees from Sanofi Genzyme, Biogen, Almirall, and Novartis. Dr. Jokubaitis has received conference travel support from Merck and Roche and speakers honoraria from Biogen and Roche. These relationships are not related to the current study. Dr. Jokubaitis receives research support from the Australian National Health and Medical Research Grant and MS Research Australia.
The increase in sNfL is independent of relapses, which suggests that patients have increased subclinical disease activity during this period, according to the researchers.
When the investigators controlled their data for exposure to disease-modifying therapy (DMT), the effect of pregnancy on sNfL was no longer evident. These data were presented said at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
The results suggest that “sNfL may qualify as a sensitive and minimally invasive measure of disease activity in pregnancy,” said Özgür Yaldizli, MD, consultant neurologist at University Hospital Basel (Switzerland). “Strategies allowing the continuation of DMT during pregnancy may be warranted.”
MS preferentially affects women in their reproductive years, said Dr. Yaldizli. Almost one-third of women with MS become pregnant after they receive their diagnosis. A decrease in disease activity is typical in the third trimester, as is an increase in relapse frequency post partum.
DMTs reduce the risk of relapse, but have potential side effects for the woman and the fetus. Some DMTs are immunosuppressants, and they increase the risk of infection during pregnancy. Other DMTs may harm the development of the fetus, particularly if administered early during pregnancy.
“There is an urgent need to identify patients with high disease activity during pregnancy,” said Dr. Yaldizli. Increased levels of NfL, a specific biomarker of neuroaxonal injury, are associated with relapses, MRI activity, and disability worsening among patients with MS. Response to DMT is associated with decreased NfL levels. But few data about sNfL during pregnancy or post partum are available.
Relapses were associated with increased sNfL
Dr. Yaldizli and colleagues examined data from the Swiss MS Cohort Study to describe DMT use before, during, and after pregnancy. They also sought to assess sNfL as a marker of disease activity during and after pregnancy and to evaluate whether interrupting DMT because of pregnancy leads to increased sNfL levels.
Eligible participants had prospectively documented pregnancies, and Dr. Yaldizli’s group excluded pregnancies with early termination from their analysis. Serum samples were collected every 6 or 12 months and analyzed using the Simoa NF-light assay. The investigators used univariable and multivariable mixed-effects models to investigate associations between clinical characteristics and longitudinal sNfL levels in women before pregnancy, during pregnancy, and post partum.
Dr. Yaldizli and colleagues included 72 pregnancies in 63 patients with relapsing MS in their analysis. Nine patients had two pregnancies during follow-up. The population’s median age was 31.4 years, and median disease duration was 7.1 years. Median Expanded Disability Status Scale (EDSS) score at last visit before birth was 1.5. Median follow-up time was 6 years.
Most patients were treated with DMT before or during pregnancy. For most patients (39), fingolimod or natalizumab was the last DMT given before birth. Four patients did not use DMT before, during, or after pregnancy. In 14 pregnancies, the patient continued DMT for more than 6 months.
The univariable analysis showed that sNfL levels were 22% higher during pregnancy, compared with outside the pregnancy and postpartum period. The investigators recorded 29 relapses during the pregnancy and postpartum period. Relapses were more likely to occur during the first trimester and the first 3 months post partum. In the multivariable analysis, relapses that occurred within 120 days before serum sampling were associated with 98% higher levels of sNfL. In addition, sNfL was 7% higher for each step increase in EDSS and 13% higher during the pregnancy and postpartum period, compared with outside of that period.
When the investigators included DMT exposure at sampling time in the model, however, the pregnancy and postpartum period no longer had an effect on sNfL. The sNfL levels were 12% lower among patients exposed to DMT, compared with patients without DMT exposure.
Some DMTs, such as interferon-beta, are relatively safe during pregnancy, but the greater the medication’s efficacy, the more problematic it can be, said Dr. Yaldizi. “There are medications that are given, for example, every 6 months, like ocrelizumab. There are other medications that have to be taken daily. Probably the safest medications are those that are not given so often during pregnancy.”
Future research should examine the escalation therapies (i.e., the newer and more effective DMTs) during pregnancy in patients with MS, he added. “Not only in pregnancy, but also in general, we have to look for ways to measure disease activity in patients who switch therapy, who deescalate therapy.”
Pregnancy may not forestall disease activity
“The results of this study demonstrate that DMT withdrawal in the context of pregnancy can lead to subclinical disease re-emergence, as evidenced by increased sNfL levels in the DMT-free period,” said Vilija G. Jokubaitis, PhD, senior research fellow in the department of neuroscience at Monash University, Melbourne. Dr. Jokubaitis was not involved in the study.
“Interestingly, the median EDSS score in this cohort was quite low, demonstrating that, even in women with mild disease, pregnancy may not be sufficient to protect against ongoing MS activity.” Nevertheless, 28 of the 63 women were exposed to monoclonal antibody therapy, so it is unclear whether these women have mild disease or well-managed disease on DMT, she added.
“This study provides further evidence that pregnancy planning requires advanced planning, and that therapy continuation into pregnancy should be considered, particularly in women with moderate disease activity, to protect against disease reactivation,” said Dr. Jokubaitis.
The strengths of the study include its prospective design, the investigators’ ability to describe the various DMT exposures before and during pregnancy, and the multivariable mixed-effects modeling, she added. On the other hand, the results are at the group level, individual trajectories in sNfL level are not described, and the small sample size prevented the investigators from differentiating between the effects of various DMTs on sNfL outcomes. In addition, Dr. Yaldizli and colleagues did not take time off DMT into account in the models; they considered DMT exposure as a dichotomous variable.
“More work is needed to determine the therapeutic strategies that will give women with MS the greatest protection against disease reactivation in pregnancy and post partum, whilst also protecting fetal and neonatal outcomes,” said Dr. Jokubaitis. Group studies will enable researchers to identify trends, but neurologists ultimately need to provide individualized advice to their patients. “There is a need to look at [the effect of] DMT identity, timing, and duration of DMT withdrawal on fluctuation of sNfL levels, and how these relate to baseline disease severity,” Dr. Jokubaitis added. Furthermore, researchers must compare sNfL changes in pregnancy between patients with MS and healthy women in large cohorts.
The analysis by Dr. Yaldizli and colleagues was conducted without outside funding. The Swiss MS Cohort receives funding from the Swiss MS society, Biogen, Celgene, Sanofi, Merck, Novartis, Roche, and research associations such as the International Progressive MS Alliance and the Swiss National Science Foundation. Dr. Yaldizli received grants from ECTRIMS/MAGNIMS, the University of Basel, Pro Patient Stiftung, University Hospital Basel, Free Academy Basel, and the Swiss MS Society. He has received advisory board fees from Sanofi Genzyme, Biogen, Almirall, and Novartis. Dr. Jokubaitis has received conference travel support from Merck and Roche and speakers honoraria from Biogen and Roche. These relationships are not related to the current study. Dr. Jokubaitis receives research support from the Australian National Health and Medical Research Grant and MS Research Australia.
The increase in sNfL is independent of relapses, which suggests that patients have increased subclinical disease activity during this period, according to the researchers.
When the investigators controlled their data for exposure to disease-modifying therapy (DMT), the effect of pregnancy on sNfL was no longer evident. These data were presented said at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
The results suggest that “sNfL may qualify as a sensitive and minimally invasive measure of disease activity in pregnancy,” said Özgür Yaldizli, MD, consultant neurologist at University Hospital Basel (Switzerland). “Strategies allowing the continuation of DMT during pregnancy may be warranted.”
MS preferentially affects women in their reproductive years, said Dr. Yaldizli. Almost one-third of women with MS become pregnant after they receive their diagnosis. A decrease in disease activity is typical in the third trimester, as is an increase in relapse frequency post partum.
DMTs reduce the risk of relapse, but have potential side effects for the woman and the fetus. Some DMTs are immunosuppressants, and they increase the risk of infection during pregnancy. Other DMTs may harm the development of the fetus, particularly if administered early during pregnancy.
“There is an urgent need to identify patients with high disease activity during pregnancy,” said Dr. Yaldizli. Increased levels of NfL, a specific biomarker of neuroaxonal injury, are associated with relapses, MRI activity, and disability worsening among patients with MS. Response to DMT is associated with decreased NfL levels. But few data about sNfL during pregnancy or post partum are available.
Relapses were associated with increased sNfL
Dr. Yaldizli and colleagues examined data from the Swiss MS Cohort Study to describe DMT use before, during, and after pregnancy. They also sought to assess sNfL as a marker of disease activity during and after pregnancy and to evaluate whether interrupting DMT because of pregnancy leads to increased sNfL levels.
Eligible participants had prospectively documented pregnancies, and Dr. Yaldizli’s group excluded pregnancies with early termination from their analysis. Serum samples were collected every 6 or 12 months and analyzed using the Simoa NF-light assay. The investigators used univariable and multivariable mixed-effects models to investigate associations between clinical characteristics and longitudinal sNfL levels in women before pregnancy, during pregnancy, and post partum.
Dr. Yaldizli and colleagues included 72 pregnancies in 63 patients with relapsing MS in their analysis. Nine patients had two pregnancies during follow-up. The population’s median age was 31.4 years, and median disease duration was 7.1 years. Median Expanded Disability Status Scale (EDSS) score at last visit before birth was 1.5. Median follow-up time was 6 years.
Most patients were treated with DMT before or during pregnancy. For most patients (39), fingolimod or natalizumab was the last DMT given before birth. Four patients did not use DMT before, during, or after pregnancy. In 14 pregnancies, the patient continued DMT for more than 6 months.
The univariable analysis showed that sNfL levels were 22% higher during pregnancy, compared with outside the pregnancy and postpartum period. The investigators recorded 29 relapses during the pregnancy and postpartum period. Relapses were more likely to occur during the first trimester and the first 3 months post partum. In the multivariable analysis, relapses that occurred within 120 days before serum sampling were associated with 98% higher levels of sNfL. In addition, sNfL was 7% higher for each step increase in EDSS and 13% higher during the pregnancy and postpartum period, compared with outside of that period.
When the investigators included DMT exposure at sampling time in the model, however, the pregnancy and postpartum period no longer had an effect on sNfL. The sNfL levels were 12% lower among patients exposed to DMT, compared with patients without DMT exposure.
Some DMTs, such as interferon-beta, are relatively safe during pregnancy, but the greater the medication’s efficacy, the more problematic it can be, said Dr. Yaldizi. “There are medications that are given, for example, every 6 months, like ocrelizumab. There are other medications that have to be taken daily. Probably the safest medications are those that are not given so often during pregnancy.”
Future research should examine the escalation therapies (i.e., the newer and more effective DMTs) during pregnancy in patients with MS, he added. “Not only in pregnancy, but also in general, we have to look for ways to measure disease activity in patients who switch therapy, who deescalate therapy.”
Pregnancy may not forestall disease activity
“The results of this study demonstrate that DMT withdrawal in the context of pregnancy can lead to subclinical disease re-emergence, as evidenced by increased sNfL levels in the DMT-free period,” said Vilija G. Jokubaitis, PhD, senior research fellow in the department of neuroscience at Monash University, Melbourne. Dr. Jokubaitis was not involved in the study.
“Interestingly, the median EDSS score in this cohort was quite low, demonstrating that, even in women with mild disease, pregnancy may not be sufficient to protect against ongoing MS activity.” Nevertheless, 28 of the 63 women were exposed to monoclonal antibody therapy, so it is unclear whether these women have mild disease or well-managed disease on DMT, she added.
“This study provides further evidence that pregnancy planning requires advanced planning, and that therapy continuation into pregnancy should be considered, particularly in women with moderate disease activity, to protect against disease reactivation,” said Dr. Jokubaitis.
The strengths of the study include its prospective design, the investigators’ ability to describe the various DMT exposures before and during pregnancy, and the multivariable mixed-effects modeling, she added. On the other hand, the results are at the group level, individual trajectories in sNfL level are not described, and the small sample size prevented the investigators from differentiating between the effects of various DMTs on sNfL outcomes. In addition, Dr. Yaldizli and colleagues did not take time off DMT into account in the models; they considered DMT exposure as a dichotomous variable.
“More work is needed to determine the therapeutic strategies that will give women with MS the greatest protection against disease reactivation in pregnancy and post partum, whilst also protecting fetal and neonatal outcomes,” said Dr. Jokubaitis. Group studies will enable researchers to identify trends, but neurologists ultimately need to provide individualized advice to their patients. “There is a need to look at [the effect of] DMT identity, timing, and duration of DMT withdrawal on fluctuation of sNfL levels, and how these relate to baseline disease severity,” Dr. Jokubaitis added. Furthermore, researchers must compare sNfL changes in pregnancy between patients with MS and healthy women in large cohorts.
The analysis by Dr. Yaldizli and colleagues was conducted without outside funding. The Swiss MS Cohort receives funding from the Swiss MS society, Biogen, Celgene, Sanofi, Merck, Novartis, Roche, and research associations such as the International Progressive MS Alliance and the Swiss National Science Foundation. Dr. Yaldizli received grants from ECTRIMS/MAGNIMS, the University of Basel, Pro Patient Stiftung, University Hospital Basel, Free Academy Basel, and the Swiss MS Society. He has received advisory board fees from Sanofi Genzyme, Biogen, Almirall, and Novartis. Dr. Jokubaitis has received conference travel support from Merck and Roche and speakers honoraria from Biogen and Roche. These relationships are not related to the current study. Dr. Jokubaitis receives research support from the Australian National Health and Medical Research Grant and MS Research Australia.
FROM MSVIRTUAL2020
Lower rituximab doses may be as effective, safer in MS
Further data suggesting that (MS), according to a new observational study. “We showed similar numbers of relapses, MRI new/active lesions, and effects on disability with a higher and lower dose of rituximab over a median follow of 16 months,” said lead author, Luciana Midaglia, MD, Multiple Sclerosis Centre of Catalonia (Cemcat) at Vall d’Hebron University Hospital, Barcelona. “But adverse effects – particularly frequency of infection – were increased in the high-dose group.”
Dr. Midaglia presented the findings at the recent Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
“There haven’t been large studies of rituximab in MS as the company [Genentech/Roche] prioritized development of ocrelizumab over rituximab,” she explained. Rituximab has, therefore, never been approved for this indication. But it is available for several other conditions, and it is often used off label for MS.
“Although we now have a lot of experience with rituximab in MS, a dosage regimen has not been standardized,” Dr. Midaglia noted.
The current study was conducted to compare the efficacy and safety of two different dosage regimens of rituximab used at two different Catalan MS centers.
In the Barcelona center, 249 patients received a regimen of 2 g IV for the first three 6-month cycles followed by 1 g every 6 months thereafter (higher-dose group). In the Girona center, 54 patients received just one loading dose of 2 g followed by 500 mg every 6 months thereafter (lower-dose group).
Patients were followed up clinically every 6 months, and MRI brain scans were performed at baseline and yearly thereafter. Blood samples for safety and B cell/immunoglobulin monitoring were drawn at 3 months after rituximab infusions.
Results showed that the annualized relapse rate reduced by 87% (from 0.4 to 0.05; P < .001) in the higher-dose cohort, and by 90% (from 0.31 to 0.03; P = .018) in the lower-dose cohort.
The Expanded Disability Status Scale score remained stable or improved in 83% of the higher-dose group versus 72% of the lower-dose group (P = .09).
Contrast-enhancing lesions were reduced by 92% by 12 months and by 100% by 36 months in the higher-dose group and by 81% and 100%, respectively, in the lower-dose group.
New T2 lesions were present in 19% of patients at 12 months and in 12% at 36 months in the higher-dose group and in 16% and 0%, respectively, in the lower-dose group.
Reductions in B cell levels were similar with both doses. However, a reduced rate of adverse effects, mainly infections, was seen in the lower-dose group.
Infections were reported in 7.2% of the higher-dose group and 3.7% of the lower-dose group at 1 year, in 9.7% versus 0% in the second year, and in 9.7% versus 0% in the third year. Urinary tract infections, followed by respiratory infections, were the most prevalent.
A randomized phase 3 study is now underway testing an even lower dose of rituximab. The trial, known as RIDOSE-MS, is comparing maintenance doses of 500 mg every 6 months and 500 mg every 12 months.
Dr. Midaglia said that most centers are using higher doses of rituximab – similar to the Barcelona cohort in this study.
“After this study, we will we now start a new protocol and use the lower dose for all MS patients,” she said.
She reported that her hospital has been using rituximab extensively in MS.
“There were delays to ocrelizumab being introduced in Spain, and while we were waiting, we started using rituximab,” she said. “We believe it is similarly effective to ocrelizumab. It has exactly the same mechanism of action. The only difference is that rituximab is a chimeric antibody while ocrelizumab is fully humanized.”
While rituximab has not had the validation of a full phase 3 trial, she added, “there are data available from several smaller studies and we feel we have learned how to use it in the real world, but we don’t have an approved dosage schedule. We started off using the dose approved for use in rheumatological and hematological conditions.”
Now that ocrelizumab is approved, Dr. Midaglia said they are using that drug for the patients who meet the approved criteria, but there are many patients who don’t qualify.
“For example, in progressive MS, ocrelizumab has quite a narrow indication – it is not reimbursed for patients without any inflammatory activity. So for these patients, we tend to use rituximab,” she noted.
“While there is no good data on its efficacy in these patients, we believe it has some effect and there is no other option at present. Rituximab is an inexpensive drug and has a long safety record in other conditions, so we feel it’s worth a try,” Dr. Midaglia concluded. “And now we have better data on the optimal dosage.”
Commenting on the study, Daniel Ontaneda, MD, comoderator of the session at which the study was presented, said: “Rituximab is not an [Food and Drug Administration]–approved medication for MS, but it has been used in clinical practice quite extensively in the U.S. and also in Europe. The study is of interest as it showed that the lower dose of rituximab achieved good control of disease activity.”
Dr. Ontaneda, a neurologist at the Mellen Center for MS at the Cleveland Clinic, Ohio, added: “Many centers have been using lower doses or less frequent infusions and this study supports this practice. Some degree of residual confounding in the study in the differences in side effects may be related to the two different sites, but overall I think these results add to the real-world observational data now available for anti-CD20 therapies.”
Dr. Midaglia reported receiving travel funding from Genzyme, Roche, Biogen Idec, and Novartis, and personal fees for lectures from Roche.
A version of this article originally appeared on Medscape.com.
Further data suggesting that (MS), according to a new observational study. “We showed similar numbers of relapses, MRI new/active lesions, and effects on disability with a higher and lower dose of rituximab over a median follow of 16 months,” said lead author, Luciana Midaglia, MD, Multiple Sclerosis Centre of Catalonia (Cemcat) at Vall d’Hebron University Hospital, Barcelona. “But adverse effects – particularly frequency of infection – were increased in the high-dose group.”
Dr. Midaglia presented the findings at the recent Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
“There haven’t been large studies of rituximab in MS as the company [Genentech/Roche] prioritized development of ocrelizumab over rituximab,” she explained. Rituximab has, therefore, never been approved for this indication. But it is available for several other conditions, and it is often used off label for MS.
“Although we now have a lot of experience with rituximab in MS, a dosage regimen has not been standardized,” Dr. Midaglia noted.
The current study was conducted to compare the efficacy and safety of two different dosage regimens of rituximab used at two different Catalan MS centers.
In the Barcelona center, 249 patients received a regimen of 2 g IV for the first three 6-month cycles followed by 1 g every 6 months thereafter (higher-dose group). In the Girona center, 54 patients received just one loading dose of 2 g followed by 500 mg every 6 months thereafter (lower-dose group).
Patients were followed up clinically every 6 months, and MRI brain scans were performed at baseline and yearly thereafter. Blood samples for safety and B cell/immunoglobulin monitoring were drawn at 3 months after rituximab infusions.
Results showed that the annualized relapse rate reduced by 87% (from 0.4 to 0.05; P < .001) in the higher-dose cohort, and by 90% (from 0.31 to 0.03; P = .018) in the lower-dose cohort.
The Expanded Disability Status Scale score remained stable or improved in 83% of the higher-dose group versus 72% of the lower-dose group (P = .09).
Contrast-enhancing lesions were reduced by 92% by 12 months and by 100% by 36 months in the higher-dose group and by 81% and 100%, respectively, in the lower-dose group.
New T2 lesions were present in 19% of patients at 12 months and in 12% at 36 months in the higher-dose group and in 16% and 0%, respectively, in the lower-dose group.
Reductions in B cell levels were similar with both doses. However, a reduced rate of adverse effects, mainly infections, was seen in the lower-dose group.
Infections were reported in 7.2% of the higher-dose group and 3.7% of the lower-dose group at 1 year, in 9.7% versus 0% in the second year, and in 9.7% versus 0% in the third year. Urinary tract infections, followed by respiratory infections, were the most prevalent.
A randomized phase 3 study is now underway testing an even lower dose of rituximab. The trial, known as RIDOSE-MS, is comparing maintenance doses of 500 mg every 6 months and 500 mg every 12 months.
Dr. Midaglia said that most centers are using higher doses of rituximab – similar to the Barcelona cohort in this study.
“After this study, we will we now start a new protocol and use the lower dose for all MS patients,” she said.
She reported that her hospital has been using rituximab extensively in MS.
“There were delays to ocrelizumab being introduced in Spain, and while we were waiting, we started using rituximab,” she said. “We believe it is similarly effective to ocrelizumab. It has exactly the same mechanism of action. The only difference is that rituximab is a chimeric antibody while ocrelizumab is fully humanized.”
While rituximab has not had the validation of a full phase 3 trial, she added, “there are data available from several smaller studies and we feel we have learned how to use it in the real world, but we don’t have an approved dosage schedule. We started off using the dose approved for use in rheumatological and hematological conditions.”
Now that ocrelizumab is approved, Dr. Midaglia said they are using that drug for the patients who meet the approved criteria, but there are many patients who don’t qualify.
“For example, in progressive MS, ocrelizumab has quite a narrow indication – it is not reimbursed for patients without any inflammatory activity. So for these patients, we tend to use rituximab,” she noted.
“While there is no good data on its efficacy in these patients, we believe it has some effect and there is no other option at present. Rituximab is an inexpensive drug and has a long safety record in other conditions, so we feel it’s worth a try,” Dr. Midaglia concluded. “And now we have better data on the optimal dosage.”
Commenting on the study, Daniel Ontaneda, MD, comoderator of the session at which the study was presented, said: “Rituximab is not an [Food and Drug Administration]–approved medication for MS, but it has been used in clinical practice quite extensively in the U.S. and also in Europe. The study is of interest as it showed that the lower dose of rituximab achieved good control of disease activity.”
Dr. Ontaneda, a neurologist at the Mellen Center for MS at the Cleveland Clinic, Ohio, added: “Many centers have been using lower doses or less frequent infusions and this study supports this practice. Some degree of residual confounding in the study in the differences in side effects may be related to the two different sites, but overall I think these results add to the real-world observational data now available for anti-CD20 therapies.”
Dr. Midaglia reported receiving travel funding from Genzyme, Roche, Biogen Idec, and Novartis, and personal fees for lectures from Roche.
A version of this article originally appeared on Medscape.com.
Further data suggesting that (MS), according to a new observational study. “We showed similar numbers of relapses, MRI new/active lesions, and effects on disability with a higher and lower dose of rituximab over a median follow of 16 months,” said lead author, Luciana Midaglia, MD, Multiple Sclerosis Centre of Catalonia (Cemcat) at Vall d’Hebron University Hospital, Barcelona. “But adverse effects – particularly frequency of infection – were increased in the high-dose group.”
Dr. Midaglia presented the findings at the recent Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
“There haven’t been large studies of rituximab in MS as the company [Genentech/Roche] prioritized development of ocrelizumab over rituximab,” she explained. Rituximab has, therefore, never been approved for this indication. But it is available for several other conditions, and it is often used off label for MS.
“Although we now have a lot of experience with rituximab in MS, a dosage regimen has not been standardized,” Dr. Midaglia noted.
The current study was conducted to compare the efficacy and safety of two different dosage regimens of rituximab used at two different Catalan MS centers.
In the Barcelona center, 249 patients received a regimen of 2 g IV for the first three 6-month cycles followed by 1 g every 6 months thereafter (higher-dose group). In the Girona center, 54 patients received just one loading dose of 2 g followed by 500 mg every 6 months thereafter (lower-dose group).
Patients were followed up clinically every 6 months, and MRI brain scans were performed at baseline and yearly thereafter. Blood samples for safety and B cell/immunoglobulin monitoring were drawn at 3 months after rituximab infusions.
Results showed that the annualized relapse rate reduced by 87% (from 0.4 to 0.05; P < .001) in the higher-dose cohort, and by 90% (from 0.31 to 0.03; P = .018) in the lower-dose cohort.
The Expanded Disability Status Scale score remained stable or improved in 83% of the higher-dose group versus 72% of the lower-dose group (P = .09).
Contrast-enhancing lesions were reduced by 92% by 12 months and by 100% by 36 months in the higher-dose group and by 81% and 100%, respectively, in the lower-dose group.
New T2 lesions were present in 19% of patients at 12 months and in 12% at 36 months in the higher-dose group and in 16% and 0%, respectively, in the lower-dose group.
Reductions in B cell levels were similar with both doses. However, a reduced rate of adverse effects, mainly infections, was seen in the lower-dose group.
Infections were reported in 7.2% of the higher-dose group and 3.7% of the lower-dose group at 1 year, in 9.7% versus 0% in the second year, and in 9.7% versus 0% in the third year. Urinary tract infections, followed by respiratory infections, were the most prevalent.
A randomized phase 3 study is now underway testing an even lower dose of rituximab. The trial, known as RIDOSE-MS, is comparing maintenance doses of 500 mg every 6 months and 500 mg every 12 months.
Dr. Midaglia said that most centers are using higher doses of rituximab – similar to the Barcelona cohort in this study.
“After this study, we will we now start a new protocol and use the lower dose for all MS patients,” she said.
She reported that her hospital has been using rituximab extensively in MS.
“There were delays to ocrelizumab being introduced in Spain, and while we were waiting, we started using rituximab,” she said. “We believe it is similarly effective to ocrelizumab. It has exactly the same mechanism of action. The only difference is that rituximab is a chimeric antibody while ocrelizumab is fully humanized.”
While rituximab has not had the validation of a full phase 3 trial, she added, “there are data available from several smaller studies and we feel we have learned how to use it in the real world, but we don’t have an approved dosage schedule. We started off using the dose approved for use in rheumatological and hematological conditions.”
Now that ocrelizumab is approved, Dr. Midaglia said they are using that drug for the patients who meet the approved criteria, but there are many patients who don’t qualify.
“For example, in progressive MS, ocrelizumab has quite a narrow indication – it is not reimbursed for patients without any inflammatory activity. So for these patients, we tend to use rituximab,” she noted.
“While there is no good data on its efficacy in these patients, we believe it has some effect and there is no other option at present. Rituximab is an inexpensive drug and has a long safety record in other conditions, so we feel it’s worth a try,” Dr. Midaglia concluded. “And now we have better data on the optimal dosage.”
Commenting on the study, Daniel Ontaneda, MD, comoderator of the session at which the study was presented, said: “Rituximab is not an [Food and Drug Administration]–approved medication for MS, but it has been used in clinical practice quite extensively in the U.S. and also in Europe. The study is of interest as it showed that the lower dose of rituximab achieved good control of disease activity.”
Dr. Ontaneda, a neurologist at the Mellen Center for MS at the Cleveland Clinic, Ohio, added: “Many centers have been using lower doses or less frequent infusions and this study supports this practice. Some degree of residual confounding in the study in the differences in side effects may be related to the two different sites, but overall I think these results add to the real-world observational data now available for anti-CD20 therapies.”
Dr. Midaglia reported receiving travel funding from Genzyme, Roche, Biogen Idec, and Novartis, and personal fees for lectures from Roche.
A version of this article originally appeared on Medscape.com.
FROM MSVIRTUAL2020
Prior autoimmunity does not predict adverse events of alemtuzumab
a new study has shown.
These latest data were reported by Alasdair J. Coles, MD, University of Cambridge (England), at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
Dr. Coles, who led the initial research to develop alemtuzumab in partnership with Genzyme, explained that autoimmune disease is a well-described and common adverse event with the drug, manifesting mainly as autoimmune thyroid events that can occur in up to 40% of patients.
But as postmarketing experience has grown, it has become clear that there is a low frequency of more serious autoimmune disease, he noted. In an effort to understand this better, regulators have suggested that the presence of non–multiple sclerosis (MS) autoimmune disease before alemtuzumab treatment and the emergence of autoimmune disease after alemtuzumab treatment may define a group that is at higher risk of one of the rare but serious autoimmune events for those on the drug.
To investigate if this was the case, Dr. Coles and colleagues analyzed data on 1,216 patients who received alemtuzumab in the clinical development program. Of these, 96 had preexisting non-MS autoimmunity.
Results showed that up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) versus without (35.3%) preexisting autoimmunity.
Similar percentages of patients with versus without preexisting autoimmunity had two or more new autoimmune events (5.2% vs. 8.2%, respectively). And most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab.
In addition, treatment-emergent thyroid autoimmunity after the first alemtuzumab course was not associated with subsequent nonthyroid autoimmunity after the second course. Similarly, thyroid autoimmunity after the second course did not predict non-thyroid autoimmunity after the third course.
In another analysis of the incidence of serious autoimmune events from postmarketing data on 25,292 patients treated with alemtuzumab, immune thrombocytopenic purpura was reported in 43 patients, newly identified autoimmune hepatitis in 11 patients, and hemophagocytic lymphohistiocytosis in 9 patients.
There was “no hint at all” that baseline thyroid disorders or postalemtuzumab thyroid disorders are associated with increased risk of these serious autoimmune adverse events, Dr. Coles said.
He calculated that the incidence of serious autoimmune diseases that could be life-threatening after alemtuzumab treatment was 10.7 per 10,000 patients treated for autoimmune hepatitis and 2.7 per 10,000 patients treated for hemophagocytic lymphohistiocytosis.
“From two separate data sources – phase 2/3 trials populations combined and postmarketing data – there is no evidence to support the hypothesis that preexisting non-MS autoimmunity predisposes to the serious but rare autoimmune events that have newly been described, nor does thyroid autoimmunity following the use of alemtuzumab,” Dr. Coles stated.
“In my opinion it is not appropriate to preclude the use of alemtuzumab to patients who have had previous autoimmune disease before treatment or who develop thyroid autoimmunity after alemtuzumab,” he said.
“It remains in my view a reasonable treatment option for patients with active MS to receive this highly effective therapy in the face of well-managed, well-understood thyroid autoimmunity and the very unlikely, rare, but serious autoimmune disease,” he concluded.
Risk stratification
Commenting on the presentation, Robert J. Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis, Cleveland Clinic, Ohio, explained that, whenever there is a serious risk of a complication, clinicians like to try to stratify that risk.
“We like to identify those at higher risk [and perhaps not use the therapy] and those at lower risk [and perhaps consider more likely the use of that therapy],” he said.
With regard to alemtuzumab, Dr. Fox noted: “We’d like to stratify the risk of autoimmune complications, which could help guide us regarding the patients in whom therapy may be safer. Unfortunately, these findings did not point to a risk stratification to help guide its use towards lower-risk patients.
“I view this as an unfortunate result, because it leaves me without a way to stratify the risks of alemtuzumab, which are quite significant and currently limit my use of that MS therapy only to those with no other treatment options,” he added.
On Dr. Coles’ view of alemtuzumab as a “reasonable” treatment option, Dr. Fox commented: “I guess it depends upon how that’s interpreted. Given the risks of serious, life-threatening immune and infectious complications, I only consider alemtuzumab when all other immune-modulating therapies have been tried or are not a reasonable treatment option. So, yes, I see it as ‘reasonable,’ but only when there are no other available treatment options.”
The current work was supported by Sanofi and Bayer HealthCare. Dr. Coles reported sitting on advisory boards for Genzyme (Sanofi). He is credited as an inventor on several patents related to the technology on which alemtuzumab is based. Dr. Fox has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
a new study has shown.
These latest data were reported by Alasdair J. Coles, MD, University of Cambridge (England), at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
Dr. Coles, who led the initial research to develop alemtuzumab in partnership with Genzyme, explained that autoimmune disease is a well-described and common adverse event with the drug, manifesting mainly as autoimmune thyroid events that can occur in up to 40% of patients.
But as postmarketing experience has grown, it has become clear that there is a low frequency of more serious autoimmune disease, he noted. In an effort to understand this better, regulators have suggested that the presence of non–multiple sclerosis (MS) autoimmune disease before alemtuzumab treatment and the emergence of autoimmune disease after alemtuzumab treatment may define a group that is at higher risk of one of the rare but serious autoimmune events for those on the drug.
To investigate if this was the case, Dr. Coles and colleagues analyzed data on 1,216 patients who received alemtuzumab in the clinical development program. Of these, 96 had preexisting non-MS autoimmunity.
Results showed that up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) versus without (35.3%) preexisting autoimmunity.
Similar percentages of patients with versus without preexisting autoimmunity had two or more new autoimmune events (5.2% vs. 8.2%, respectively). And most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab.
In addition, treatment-emergent thyroid autoimmunity after the first alemtuzumab course was not associated with subsequent nonthyroid autoimmunity after the second course. Similarly, thyroid autoimmunity after the second course did not predict non-thyroid autoimmunity after the third course.
In another analysis of the incidence of serious autoimmune events from postmarketing data on 25,292 patients treated with alemtuzumab, immune thrombocytopenic purpura was reported in 43 patients, newly identified autoimmune hepatitis in 11 patients, and hemophagocytic lymphohistiocytosis in 9 patients.
There was “no hint at all” that baseline thyroid disorders or postalemtuzumab thyroid disorders are associated with increased risk of these serious autoimmune adverse events, Dr. Coles said.
He calculated that the incidence of serious autoimmune diseases that could be life-threatening after alemtuzumab treatment was 10.7 per 10,000 patients treated for autoimmune hepatitis and 2.7 per 10,000 patients treated for hemophagocytic lymphohistiocytosis.
“From two separate data sources – phase 2/3 trials populations combined and postmarketing data – there is no evidence to support the hypothesis that preexisting non-MS autoimmunity predisposes to the serious but rare autoimmune events that have newly been described, nor does thyroid autoimmunity following the use of alemtuzumab,” Dr. Coles stated.
“In my opinion it is not appropriate to preclude the use of alemtuzumab to patients who have had previous autoimmune disease before treatment or who develop thyroid autoimmunity after alemtuzumab,” he said.
“It remains in my view a reasonable treatment option for patients with active MS to receive this highly effective therapy in the face of well-managed, well-understood thyroid autoimmunity and the very unlikely, rare, but serious autoimmune disease,” he concluded.
Risk stratification
Commenting on the presentation, Robert J. Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis, Cleveland Clinic, Ohio, explained that, whenever there is a serious risk of a complication, clinicians like to try to stratify that risk.
“We like to identify those at higher risk [and perhaps not use the therapy] and those at lower risk [and perhaps consider more likely the use of that therapy],” he said.
With regard to alemtuzumab, Dr. Fox noted: “We’d like to stratify the risk of autoimmune complications, which could help guide us regarding the patients in whom therapy may be safer. Unfortunately, these findings did not point to a risk stratification to help guide its use towards lower-risk patients.
“I view this as an unfortunate result, because it leaves me without a way to stratify the risks of alemtuzumab, which are quite significant and currently limit my use of that MS therapy only to those with no other treatment options,” he added.
On Dr. Coles’ view of alemtuzumab as a “reasonable” treatment option, Dr. Fox commented: “I guess it depends upon how that’s interpreted. Given the risks of serious, life-threatening immune and infectious complications, I only consider alemtuzumab when all other immune-modulating therapies have been tried or are not a reasonable treatment option. So, yes, I see it as ‘reasonable,’ but only when there are no other available treatment options.”
The current work was supported by Sanofi and Bayer HealthCare. Dr. Coles reported sitting on advisory boards for Genzyme (Sanofi). He is credited as an inventor on several patents related to the technology on which alemtuzumab is based. Dr. Fox has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
a new study has shown.
These latest data were reported by Alasdair J. Coles, MD, University of Cambridge (England), at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
Dr. Coles, who led the initial research to develop alemtuzumab in partnership with Genzyme, explained that autoimmune disease is a well-described and common adverse event with the drug, manifesting mainly as autoimmune thyroid events that can occur in up to 40% of patients.
But as postmarketing experience has grown, it has become clear that there is a low frequency of more serious autoimmune disease, he noted. In an effort to understand this better, regulators have suggested that the presence of non–multiple sclerosis (MS) autoimmune disease before alemtuzumab treatment and the emergence of autoimmune disease after alemtuzumab treatment may define a group that is at higher risk of one of the rare but serious autoimmune events for those on the drug.
To investigate if this was the case, Dr. Coles and colleagues analyzed data on 1,216 patients who received alemtuzumab in the clinical development program. Of these, 96 had preexisting non-MS autoimmunity.
Results showed that up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) versus without (35.3%) preexisting autoimmunity.
Similar percentages of patients with versus without preexisting autoimmunity had two or more new autoimmune events (5.2% vs. 8.2%, respectively). And most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab.
In addition, treatment-emergent thyroid autoimmunity after the first alemtuzumab course was not associated with subsequent nonthyroid autoimmunity after the second course. Similarly, thyroid autoimmunity after the second course did not predict non-thyroid autoimmunity after the third course.
In another analysis of the incidence of serious autoimmune events from postmarketing data on 25,292 patients treated with alemtuzumab, immune thrombocytopenic purpura was reported in 43 patients, newly identified autoimmune hepatitis in 11 patients, and hemophagocytic lymphohistiocytosis in 9 patients.
There was “no hint at all” that baseline thyroid disorders or postalemtuzumab thyroid disorders are associated with increased risk of these serious autoimmune adverse events, Dr. Coles said.
He calculated that the incidence of serious autoimmune diseases that could be life-threatening after alemtuzumab treatment was 10.7 per 10,000 patients treated for autoimmune hepatitis and 2.7 per 10,000 patients treated for hemophagocytic lymphohistiocytosis.
“From two separate data sources – phase 2/3 trials populations combined and postmarketing data – there is no evidence to support the hypothesis that preexisting non-MS autoimmunity predisposes to the serious but rare autoimmune events that have newly been described, nor does thyroid autoimmunity following the use of alemtuzumab,” Dr. Coles stated.
“In my opinion it is not appropriate to preclude the use of alemtuzumab to patients who have had previous autoimmune disease before treatment or who develop thyroid autoimmunity after alemtuzumab,” he said.
“It remains in my view a reasonable treatment option for patients with active MS to receive this highly effective therapy in the face of well-managed, well-understood thyroid autoimmunity and the very unlikely, rare, but serious autoimmune disease,” he concluded.
Risk stratification
Commenting on the presentation, Robert J. Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis, Cleveland Clinic, Ohio, explained that, whenever there is a serious risk of a complication, clinicians like to try to stratify that risk.
“We like to identify those at higher risk [and perhaps not use the therapy] and those at lower risk [and perhaps consider more likely the use of that therapy],” he said.
With regard to alemtuzumab, Dr. Fox noted: “We’d like to stratify the risk of autoimmune complications, which could help guide us regarding the patients in whom therapy may be safer. Unfortunately, these findings did not point to a risk stratification to help guide its use towards lower-risk patients.
“I view this as an unfortunate result, because it leaves me without a way to stratify the risks of alemtuzumab, which are quite significant and currently limit my use of that MS therapy only to those with no other treatment options,” he added.
On Dr. Coles’ view of alemtuzumab as a “reasonable” treatment option, Dr. Fox commented: “I guess it depends upon how that’s interpreted. Given the risks of serious, life-threatening immune and infectious complications, I only consider alemtuzumab when all other immune-modulating therapies have been tried or are not a reasonable treatment option. So, yes, I see it as ‘reasonable,’ but only when there are no other available treatment options.”
The current work was supported by Sanofi and Bayer HealthCare. Dr. Coles reported sitting on advisory boards for Genzyme (Sanofi). He is credited as an inventor on several patents related to the technology on which alemtuzumab is based. Dr. Fox has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM MSVIRTUAL2020
B-cell test predicts alemtuzumab autoimmunity in MS
a new study suggests.
“Alemtuzumab has proven to be an effective treatment for patients with highly active remitting relapsing MS, but adverse events may limit the use of this drug, particularly autoimmune adverse events, which are the most prevalent, occurring in about 30% of patients. Reliable biomarkers to assess patient risk for developing this complication would be of great importance,” said lead author Paulette Walo, MD.
“Our results suggest that a higher percentage of total B cells, and in particular plasmablasts, could be a very predictive biomarker for autoimmunity after alemtuzumab treatment. This could help us in choosing the patients for this drug,” said Dr. Walo, an immunologist at Ramon y Cajal University Hospital, Madrid. She presented the findings at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
The objective of this study was to explore if patient blood lymphocyte profile before alemtuzumab treatment initiation can identify patients with an increased risk of developing later autoimmunity, Dr. Walo explained.
The study included 54 patients from five hospitals throughout Spain who had received treatment with alemtuzumab. Of these, the vast majority had received the normal two-dose cycle and two patients had received a third dose because of worsening MS activity.
Blood samples were collected before initiating treatment with alemtuzumab. Peripheral blood mononuclear cells were obtained and cryopreserved. Leukocyte populations were assessed by flow cytometry.
Autoimmune adverse events were defined as the development, at any point within 2 years of follow-up, of any autoimmune thyroid-associated event, immune thrombocytopenia, and/or autoimmune nephropathy.
Over the 2 years of follow-up, 14 patients (25.9%) experienced autoimmune adverse events, all of which were dysthyroidism. No immune thrombocytopenia or nephropathies were observed.
No statistical differences were found in clinical and demographic characteristics between patients who developed autoimmune adverse events and those who did not. Previous treatments did not influence B-cell percentages.
Analysis of blood lymphocyte profiles showed no difference in T-cell subsets between those who had an autoimmune event and those who did not.
Still, there were important differences in the B-cell profile, Dr. Walo said. “Total B cells were higher in patients who had an autoimmune event mainly due to naive B cells and plasmablasts.”
Patients who experienced autoimmune adverse events before treatment onset had a higher percentage of blood CD19+ B cells (P = .001), with a higher relative percentage of naive B cells and plasmablasts.
When individual types of cell numbers were explored, only plasmablast levels remained significant (P = .02).
The researchers calculated a CD19+ B-cell predictive value for autoimmunity of 7.6%. If patients had more than 7.6% B cells, they were at higher risk of an autoimmune adverse event after alemtuzumab treatment versus those with lower levels (odds ratio, 14.67; P ≤ .0001).
Similarly, the predictive value for plasmablasts was 0.13%. If patients had levels higher than 0.13% they had a higher risk of an autoimmune event after alemtuzumab treatment (P = .002). Plasmablasts are a category of B cells which are very differentiated and have the capacity to produce antibodies; they are a very active and aggressive subtype of B cells, Dr. Walo noted.
She explained that, as was the case in this study, autoimmune events after alemtuzumab treatment normally manifests as the development of antibodies against the thyroid gland, with the development of either hyperthyroidism or hypothyroidism, necessitating long-term treatment to manage these conditions.
“Autoimmunity develops at variable timescales. It can appear in the first year after alemtuzumab treatment but it can also appear later on,” she said.
Dr. Walo’s group is hoping to validate their results in a larger study. “This is only a small study so we need to replicate these findings in a larger cohort. We are in the process of doing this, collaborating with other hospitals,” she commented.
She said that, if the results are validated, then patients could undergo blood tests before alemtuzumab treatment to analyze their B-cell counts.
“For those with high levels of B cells – and particularly plasmablasts – alemtuzumab may not be the best treatment to choose,” Dr. Walo said.
Personalized strategy
During the postpresentation discussion, the suggestion was raised of giving an anti–B-cell drug before alemtuzumab to try and prevent autoimmunity. Dr. Walo responded that this is a possibility. “This is something that we are going to look into. If our larger study validates our initial results, then we would plan a study to give an anti–B-cell treatment such as rituximab before alemtuzumab and see whether this reduces the risk of autoimmunity.”
Commenting on the study, session comoderator Darin Okuda, MD, professor in the department of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center, Dallas, said: “This is an intriguing approach and suggests a more personalized strategy for sure if we can identify patients who are at higher risk of developing autoimmunity.”
Also commenting, ACTRIMS president Jeffrey Cohen, MD, said: “One of the main drawbacks of alemtuzumab is the risk of antibody-mediated autoimmune conditions, so the ability to predict who is at risk for autoimmune adverse events prior to initiating alemtuzumab would be useful. Not surprisingly, factors related to B-cell number and profile were predictive.”
Dr. Cohen, who is a director of experimental neurotherapeutics at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, added however that the suggestion of pretreating patients with an anti-CD20 monoclonal antibody “does not seem tenable to me,” because of the potential cost of such a strategy, and “no efficacy advantage for most patients over an anti-CD20 antibody alone.”
Commenting on this presentation, Alasdair J. Coles, MD, University of Cambridge (England), who was one of the co-inventors of alemtuzumab, said observations of an increased B-cell count before treatment as a risk predictor of thyroid autoimmunity after alemtuzumab had not been replicated in the clinical trial datasets of the drug. “So I fear we still do not have a reliable biomarker,” he added.
The study had no specific funding listed. Dr. Walo has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
a new study suggests.
“Alemtuzumab has proven to be an effective treatment for patients with highly active remitting relapsing MS, but adverse events may limit the use of this drug, particularly autoimmune adverse events, which are the most prevalent, occurring in about 30% of patients. Reliable biomarkers to assess patient risk for developing this complication would be of great importance,” said lead author Paulette Walo, MD.
“Our results suggest that a higher percentage of total B cells, and in particular plasmablasts, could be a very predictive biomarker for autoimmunity after alemtuzumab treatment. This could help us in choosing the patients for this drug,” said Dr. Walo, an immunologist at Ramon y Cajal University Hospital, Madrid. She presented the findings at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
The objective of this study was to explore if patient blood lymphocyte profile before alemtuzumab treatment initiation can identify patients with an increased risk of developing later autoimmunity, Dr. Walo explained.
The study included 54 patients from five hospitals throughout Spain who had received treatment with alemtuzumab. Of these, the vast majority had received the normal two-dose cycle and two patients had received a third dose because of worsening MS activity.
Blood samples were collected before initiating treatment with alemtuzumab. Peripheral blood mononuclear cells were obtained and cryopreserved. Leukocyte populations were assessed by flow cytometry.
Autoimmune adverse events were defined as the development, at any point within 2 years of follow-up, of any autoimmune thyroid-associated event, immune thrombocytopenia, and/or autoimmune nephropathy.
Over the 2 years of follow-up, 14 patients (25.9%) experienced autoimmune adverse events, all of which were dysthyroidism. No immune thrombocytopenia or nephropathies were observed.
No statistical differences were found in clinical and demographic characteristics between patients who developed autoimmune adverse events and those who did not. Previous treatments did not influence B-cell percentages.
Analysis of blood lymphocyte profiles showed no difference in T-cell subsets between those who had an autoimmune event and those who did not.
Still, there were important differences in the B-cell profile, Dr. Walo said. “Total B cells were higher in patients who had an autoimmune event mainly due to naive B cells and plasmablasts.”
Patients who experienced autoimmune adverse events before treatment onset had a higher percentage of blood CD19+ B cells (P = .001), with a higher relative percentage of naive B cells and plasmablasts.
When individual types of cell numbers were explored, only plasmablast levels remained significant (P = .02).
The researchers calculated a CD19+ B-cell predictive value for autoimmunity of 7.6%. If patients had more than 7.6% B cells, they were at higher risk of an autoimmune adverse event after alemtuzumab treatment versus those with lower levels (odds ratio, 14.67; P ≤ .0001).
Similarly, the predictive value for plasmablasts was 0.13%. If patients had levels higher than 0.13% they had a higher risk of an autoimmune event after alemtuzumab treatment (P = .002). Plasmablasts are a category of B cells which are very differentiated and have the capacity to produce antibodies; they are a very active and aggressive subtype of B cells, Dr. Walo noted.
She explained that, as was the case in this study, autoimmune events after alemtuzumab treatment normally manifests as the development of antibodies against the thyroid gland, with the development of either hyperthyroidism or hypothyroidism, necessitating long-term treatment to manage these conditions.
“Autoimmunity develops at variable timescales. It can appear in the first year after alemtuzumab treatment but it can also appear later on,” she said.
Dr. Walo’s group is hoping to validate their results in a larger study. “This is only a small study so we need to replicate these findings in a larger cohort. We are in the process of doing this, collaborating with other hospitals,” she commented.
She said that, if the results are validated, then patients could undergo blood tests before alemtuzumab treatment to analyze their B-cell counts.
“For those with high levels of B cells – and particularly plasmablasts – alemtuzumab may not be the best treatment to choose,” Dr. Walo said.
Personalized strategy
During the postpresentation discussion, the suggestion was raised of giving an anti–B-cell drug before alemtuzumab to try and prevent autoimmunity. Dr. Walo responded that this is a possibility. “This is something that we are going to look into. If our larger study validates our initial results, then we would plan a study to give an anti–B-cell treatment such as rituximab before alemtuzumab and see whether this reduces the risk of autoimmunity.”
Commenting on the study, session comoderator Darin Okuda, MD, professor in the department of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center, Dallas, said: “This is an intriguing approach and suggests a more personalized strategy for sure if we can identify patients who are at higher risk of developing autoimmunity.”
Also commenting, ACTRIMS president Jeffrey Cohen, MD, said: “One of the main drawbacks of alemtuzumab is the risk of antibody-mediated autoimmune conditions, so the ability to predict who is at risk for autoimmune adverse events prior to initiating alemtuzumab would be useful. Not surprisingly, factors related to B-cell number and profile were predictive.”
Dr. Cohen, who is a director of experimental neurotherapeutics at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, added however that the suggestion of pretreating patients with an anti-CD20 monoclonal antibody “does not seem tenable to me,” because of the potential cost of such a strategy, and “no efficacy advantage for most patients over an anti-CD20 antibody alone.”
Commenting on this presentation, Alasdair J. Coles, MD, University of Cambridge (England), who was one of the co-inventors of alemtuzumab, said observations of an increased B-cell count before treatment as a risk predictor of thyroid autoimmunity after alemtuzumab had not been replicated in the clinical trial datasets of the drug. “So I fear we still do not have a reliable biomarker,” he added.
The study had no specific funding listed. Dr. Walo has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
a new study suggests.
“Alemtuzumab has proven to be an effective treatment for patients with highly active remitting relapsing MS, but adverse events may limit the use of this drug, particularly autoimmune adverse events, which are the most prevalent, occurring in about 30% of patients. Reliable biomarkers to assess patient risk for developing this complication would be of great importance,” said lead author Paulette Walo, MD.
“Our results suggest that a higher percentage of total B cells, and in particular plasmablasts, could be a very predictive biomarker for autoimmunity after alemtuzumab treatment. This could help us in choosing the patients for this drug,” said Dr. Walo, an immunologist at Ramon y Cajal University Hospital, Madrid. She presented the findings at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
The objective of this study was to explore if patient blood lymphocyte profile before alemtuzumab treatment initiation can identify patients with an increased risk of developing later autoimmunity, Dr. Walo explained.
The study included 54 patients from five hospitals throughout Spain who had received treatment with alemtuzumab. Of these, the vast majority had received the normal two-dose cycle and two patients had received a third dose because of worsening MS activity.
Blood samples were collected before initiating treatment with alemtuzumab. Peripheral blood mononuclear cells were obtained and cryopreserved. Leukocyte populations were assessed by flow cytometry.
Autoimmune adverse events were defined as the development, at any point within 2 years of follow-up, of any autoimmune thyroid-associated event, immune thrombocytopenia, and/or autoimmune nephropathy.
Over the 2 years of follow-up, 14 patients (25.9%) experienced autoimmune adverse events, all of which were dysthyroidism. No immune thrombocytopenia or nephropathies were observed.
No statistical differences were found in clinical and demographic characteristics between patients who developed autoimmune adverse events and those who did not. Previous treatments did not influence B-cell percentages.
Analysis of blood lymphocyte profiles showed no difference in T-cell subsets between those who had an autoimmune event and those who did not.
Still, there were important differences in the B-cell profile, Dr. Walo said. “Total B cells were higher in patients who had an autoimmune event mainly due to naive B cells and plasmablasts.”
Patients who experienced autoimmune adverse events before treatment onset had a higher percentage of blood CD19+ B cells (P = .001), with a higher relative percentage of naive B cells and plasmablasts.
When individual types of cell numbers were explored, only plasmablast levels remained significant (P = .02).
The researchers calculated a CD19+ B-cell predictive value for autoimmunity of 7.6%. If patients had more than 7.6% B cells, they were at higher risk of an autoimmune adverse event after alemtuzumab treatment versus those with lower levels (odds ratio, 14.67; P ≤ .0001).
Similarly, the predictive value for plasmablasts was 0.13%. If patients had levels higher than 0.13% they had a higher risk of an autoimmune event after alemtuzumab treatment (P = .002). Plasmablasts are a category of B cells which are very differentiated and have the capacity to produce antibodies; they are a very active and aggressive subtype of B cells, Dr. Walo noted.
She explained that, as was the case in this study, autoimmune events after alemtuzumab treatment normally manifests as the development of antibodies against the thyroid gland, with the development of either hyperthyroidism or hypothyroidism, necessitating long-term treatment to manage these conditions.
“Autoimmunity develops at variable timescales. It can appear in the first year after alemtuzumab treatment but it can also appear later on,” she said.
Dr. Walo’s group is hoping to validate their results in a larger study. “This is only a small study so we need to replicate these findings in a larger cohort. We are in the process of doing this, collaborating with other hospitals,” she commented.
She said that, if the results are validated, then patients could undergo blood tests before alemtuzumab treatment to analyze their B-cell counts.
“For those with high levels of B cells – and particularly plasmablasts – alemtuzumab may not be the best treatment to choose,” Dr. Walo said.
Personalized strategy
During the postpresentation discussion, the suggestion was raised of giving an anti–B-cell drug before alemtuzumab to try and prevent autoimmunity. Dr. Walo responded that this is a possibility. “This is something that we are going to look into. If our larger study validates our initial results, then we would plan a study to give an anti–B-cell treatment such as rituximab before alemtuzumab and see whether this reduces the risk of autoimmunity.”
Commenting on the study, session comoderator Darin Okuda, MD, professor in the department of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center, Dallas, said: “This is an intriguing approach and suggests a more personalized strategy for sure if we can identify patients who are at higher risk of developing autoimmunity.”
Also commenting, ACTRIMS president Jeffrey Cohen, MD, said: “One of the main drawbacks of alemtuzumab is the risk of antibody-mediated autoimmune conditions, so the ability to predict who is at risk for autoimmune adverse events prior to initiating alemtuzumab would be useful. Not surprisingly, factors related to B-cell number and profile were predictive.”
Dr. Cohen, who is a director of experimental neurotherapeutics at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, added however that the suggestion of pretreating patients with an anti-CD20 monoclonal antibody “does not seem tenable to me,” because of the potential cost of such a strategy, and “no efficacy advantage for most patients over an anti-CD20 antibody alone.”
Commenting on this presentation, Alasdair J. Coles, MD, University of Cambridge (England), who was one of the co-inventors of alemtuzumab, said observations of an increased B-cell count before treatment as a risk predictor of thyroid autoimmunity after alemtuzumab had not been replicated in the clinical trial datasets of the drug. “So I fear we still do not have a reliable biomarker,” he added.
The study had no specific funding listed. Dr. Walo has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM MSVIRTUAL2020
Researchers identify five cognitive phenotypes in MS
The lead researcher described the clinical characteristics and MRI findings unique to each phenotype during a lecture at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
Between 40% and 70% of patients with MS have cognitive impairment, and the current results emphasize the importance of cognitive evaluation in clinical assessment, according to the investigators. “The identification of cognitive profiles can drive tailored rehabilitative strategies and introduce a new level in the evidence of disease activity assessment,” said Ermelinda De Meo, MD, a neurologist and PhD student at San Raffaele Hospital in Milan. Physical disability has been a major influence on treatment choices to date, but neurologists should consider that patients with minimal physical disability may have cognitive impairment, she added.
Information processing speed and episodic memory are the most commonly impaired cognitive functions in patients with MS, but executive function, verbal fluency, and visuospatial abilities also can be affected. Defining the neuroanatomical basis of cognitive dysfunction and developing effective strategies for rehabilitation requires a clearer understanding of cognitive deficits on an individual level, said Dr. De Meo.
A battery of clinical and imaging tests
She and her colleagues analyzed 1,212 patients with all forms of MS who presented to eight Italian centers. They also included 196 age-, sex-, and education-matched controls in their study. Patients underwent evaluation with the Expanded Disability Status Scale (EDSS) and a neuropsychological assessment that included Rao’s Brief Repeatable Battery and Stroop Test. The investigators also administered the Fatigue Severity Scale (FSS) and Montgomery Åsberg Depression Rating Scale (MADRS).
A subset of 172 patients with MS and 50 healthy controls underwent 3-T MRI. Dr. De Meo and colleagues examined T2 hyperintense and T1 hypointense lesion volumes. In addition, they quantified normalized brain volume, white matter volume, and gray matter volume and performed deep gray matter segmentation.
The subset of patients with MS who underwent MRI was not significantly different from the full cohort of patients with MS in the study, said Dr. De Meo. Because of the relatively small number of subjects who underwent MRI, she and her colleagues used simple MRI measures that are well validated, highly reproducible, and less susceptible to measurement error. “We know that advanced MRI technique could provide additional insights about the neural bases of these phenotypes. However, we can consider our MRI results as a starting point to better address future MRI studies,” she said.
Phenotypes had specific neural bases
The mean age did not differ significantly between patients (41.1 years) and controls (40.4 years). The sex ratio also was similar in both groups. Patients’ median EDSS score was 2.0, mean disease duration was 10.5 years, mean FSS score was 14.9, and mean MADRS score was 10.1.
The five cognitive phenotypes among patients with MS were characterized by preserved cognition (19%), mild verbal memory or semantic fluency impairment (30%), mild multidomain impairment (19%), severe attention or executive impairment with mild impairment of other domains (14%), and severe multidomain impairment (18%). Compared with patients with other phenotypes, those with preserved cognition and those with mild verbal memory or semantic fluency impairment were younger and had lower clinical disability and shorter disease duration. Patients with severe multidomain impairment had greater depressive symptoms. Patients with severe attention or executive phenotypes had higher FSS scores.
On MRI, patients with preserved cognition had lower thalamic volume than healthy controls. The researchers compared all other phenotypes to these two groups. Patients with mild verbal memory or semantic fluency impairment had reduced hippocampal volume. Patients with mild multidomain impairment had reduced cortical gray matter volume. Patients with severe attention or executive impairment had higher T2 lesion load. Patients with severe multidomain phenotypes had a broader pattern of atrophy, including decreased volume in the gray matter, white matter, thalamus, hippocampus, putamen, and nucleus accumbens.
“The present findings suggest that specific neural bases can be detected for each phenotype,” said Dr. De Meo. “Advanced and multimodal MRI techniques of analysis could help individuate the neural circuits and the neurotransmitter involved, also suggesting potential targets for the pharmacological treatment of cognitive decline.”
A need for longitudinal cohort studies
The study by Dr. De Meo and colleagues continues previous investigations of cognitive phenotypes in MS, which originally considered cognition to be either intact or impaired. Further research could “inform the development of targeted treatments for cognitive dysfunction in MS, which will ultimately bring us closer to a precision medicine model,” said Victoria M. Leavitt, PhD, of Columbia University Medical Center in New York.
“Clearly, we have to acknowledge that cognitive impairment is not a one-size-fits-all problem,” she added. “If a memory problem develops as a downstream consequence of language issues, targeting the hippocampus may not be effective. Separating patients into cognitive phenotype groups may be a key to understanding and identifying neural-level differences that underlie diverse cognitive issues.”
The evolution of cognitive changes over time must be understood clearly, because patients may develop memory impairment by separate pathways (e.g., focal lesions that precipitate hippocampal atrophy versus cortical thinning in parietal regions that result in white-matter disconnections among language regions), said Dr. Leavitt. “Longitudinal cohort studies and ... testable mechanistic models that incorporate multimodal neuroimaging metrics are an essential starting point. Machine-learning methods may also be a useful tool for beginning to look at how these different neuroimaging modalities work together dynamically to yield divergent cognitive phenotypes.”
The study was not supported by external funding. Dr. De Meo reported no relevant disclosures. Dr. Leavitt also reported no relevant disclosures.
SOURCE: De Meo E et al. MSVirtual2020, Abstract YI02.03.
The lead researcher described the clinical characteristics and MRI findings unique to each phenotype during a lecture at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
Between 40% and 70% of patients with MS have cognitive impairment, and the current results emphasize the importance of cognitive evaluation in clinical assessment, according to the investigators. “The identification of cognitive profiles can drive tailored rehabilitative strategies and introduce a new level in the evidence of disease activity assessment,” said Ermelinda De Meo, MD, a neurologist and PhD student at San Raffaele Hospital in Milan. Physical disability has been a major influence on treatment choices to date, but neurologists should consider that patients with minimal physical disability may have cognitive impairment, she added.
Information processing speed and episodic memory are the most commonly impaired cognitive functions in patients with MS, but executive function, verbal fluency, and visuospatial abilities also can be affected. Defining the neuroanatomical basis of cognitive dysfunction and developing effective strategies for rehabilitation requires a clearer understanding of cognitive deficits on an individual level, said Dr. De Meo.
A battery of clinical and imaging tests
She and her colleagues analyzed 1,212 patients with all forms of MS who presented to eight Italian centers. They also included 196 age-, sex-, and education-matched controls in their study. Patients underwent evaluation with the Expanded Disability Status Scale (EDSS) and a neuropsychological assessment that included Rao’s Brief Repeatable Battery and Stroop Test. The investigators also administered the Fatigue Severity Scale (FSS) and Montgomery Åsberg Depression Rating Scale (MADRS).
A subset of 172 patients with MS and 50 healthy controls underwent 3-T MRI. Dr. De Meo and colleagues examined T2 hyperintense and T1 hypointense lesion volumes. In addition, they quantified normalized brain volume, white matter volume, and gray matter volume and performed deep gray matter segmentation.
The subset of patients with MS who underwent MRI was not significantly different from the full cohort of patients with MS in the study, said Dr. De Meo. Because of the relatively small number of subjects who underwent MRI, she and her colleagues used simple MRI measures that are well validated, highly reproducible, and less susceptible to measurement error. “We know that advanced MRI technique could provide additional insights about the neural bases of these phenotypes. However, we can consider our MRI results as a starting point to better address future MRI studies,” she said.
Phenotypes had specific neural bases
The mean age did not differ significantly between patients (41.1 years) and controls (40.4 years). The sex ratio also was similar in both groups. Patients’ median EDSS score was 2.0, mean disease duration was 10.5 years, mean FSS score was 14.9, and mean MADRS score was 10.1.
The five cognitive phenotypes among patients with MS were characterized by preserved cognition (19%), mild verbal memory or semantic fluency impairment (30%), mild multidomain impairment (19%), severe attention or executive impairment with mild impairment of other domains (14%), and severe multidomain impairment (18%). Compared with patients with other phenotypes, those with preserved cognition and those with mild verbal memory or semantic fluency impairment were younger and had lower clinical disability and shorter disease duration. Patients with severe multidomain impairment had greater depressive symptoms. Patients with severe attention or executive phenotypes had higher FSS scores.
On MRI, patients with preserved cognition had lower thalamic volume than healthy controls. The researchers compared all other phenotypes to these two groups. Patients with mild verbal memory or semantic fluency impairment had reduced hippocampal volume. Patients with mild multidomain impairment had reduced cortical gray matter volume. Patients with severe attention or executive impairment had higher T2 lesion load. Patients with severe multidomain phenotypes had a broader pattern of atrophy, including decreased volume in the gray matter, white matter, thalamus, hippocampus, putamen, and nucleus accumbens.
“The present findings suggest that specific neural bases can be detected for each phenotype,” said Dr. De Meo. “Advanced and multimodal MRI techniques of analysis could help individuate the neural circuits and the neurotransmitter involved, also suggesting potential targets for the pharmacological treatment of cognitive decline.”
A need for longitudinal cohort studies
The study by Dr. De Meo and colleagues continues previous investigations of cognitive phenotypes in MS, which originally considered cognition to be either intact or impaired. Further research could “inform the development of targeted treatments for cognitive dysfunction in MS, which will ultimately bring us closer to a precision medicine model,” said Victoria M. Leavitt, PhD, of Columbia University Medical Center in New York.
“Clearly, we have to acknowledge that cognitive impairment is not a one-size-fits-all problem,” she added. “If a memory problem develops as a downstream consequence of language issues, targeting the hippocampus may not be effective. Separating patients into cognitive phenotype groups may be a key to understanding and identifying neural-level differences that underlie diverse cognitive issues.”
The evolution of cognitive changes over time must be understood clearly, because patients may develop memory impairment by separate pathways (e.g., focal lesions that precipitate hippocampal atrophy versus cortical thinning in parietal regions that result in white-matter disconnections among language regions), said Dr. Leavitt. “Longitudinal cohort studies and ... testable mechanistic models that incorporate multimodal neuroimaging metrics are an essential starting point. Machine-learning methods may also be a useful tool for beginning to look at how these different neuroimaging modalities work together dynamically to yield divergent cognitive phenotypes.”
The study was not supported by external funding. Dr. De Meo reported no relevant disclosures. Dr. Leavitt also reported no relevant disclosures.
SOURCE: De Meo E et al. MSVirtual2020, Abstract YI02.03.
The lead researcher described the clinical characteristics and MRI findings unique to each phenotype during a lecture at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
Between 40% and 70% of patients with MS have cognitive impairment, and the current results emphasize the importance of cognitive evaluation in clinical assessment, according to the investigators. “The identification of cognitive profiles can drive tailored rehabilitative strategies and introduce a new level in the evidence of disease activity assessment,” said Ermelinda De Meo, MD, a neurologist and PhD student at San Raffaele Hospital in Milan. Physical disability has been a major influence on treatment choices to date, but neurologists should consider that patients with minimal physical disability may have cognitive impairment, she added.
Information processing speed and episodic memory are the most commonly impaired cognitive functions in patients with MS, but executive function, verbal fluency, and visuospatial abilities also can be affected. Defining the neuroanatomical basis of cognitive dysfunction and developing effective strategies for rehabilitation requires a clearer understanding of cognitive deficits on an individual level, said Dr. De Meo.
A battery of clinical and imaging tests
She and her colleagues analyzed 1,212 patients with all forms of MS who presented to eight Italian centers. They also included 196 age-, sex-, and education-matched controls in their study. Patients underwent evaluation with the Expanded Disability Status Scale (EDSS) and a neuropsychological assessment that included Rao’s Brief Repeatable Battery and Stroop Test. The investigators also administered the Fatigue Severity Scale (FSS) and Montgomery Åsberg Depression Rating Scale (MADRS).
A subset of 172 patients with MS and 50 healthy controls underwent 3-T MRI. Dr. De Meo and colleagues examined T2 hyperintense and T1 hypointense lesion volumes. In addition, they quantified normalized brain volume, white matter volume, and gray matter volume and performed deep gray matter segmentation.
The subset of patients with MS who underwent MRI was not significantly different from the full cohort of patients with MS in the study, said Dr. De Meo. Because of the relatively small number of subjects who underwent MRI, she and her colleagues used simple MRI measures that are well validated, highly reproducible, and less susceptible to measurement error. “We know that advanced MRI technique could provide additional insights about the neural bases of these phenotypes. However, we can consider our MRI results as a starting point to better address future MRI studies,” she said.
Phenotypes had specific neural bases
The mean age did not differ significantly between patients (41.1 years) and controls (40.4 years). The sex ratio also was similar in both groups. Patients’ median EDSS score was 2.0, mean disease duration was 10.5 years, mean FSS score was 14.9, and mean MADRS score was 10.1.
The five cognitive phenotypes among patients with MS were characterized by preserved cognition (19%), mild verbal memory or semantic fluency impairment (30%), mild multidomain impairment (19%), severe attention or executive impairment with mild impairment of other domains (14%), and severe multidomain impairment (18%). Compared with patients with other phenotypes, those with preserved cognition and those with mild verbal memory or semantic fluency impairment were younger and had lower clinical disability and shorter disease duration. Patients with severe multidomain impairment had greater depressive symptoms. Patients with severe attention or executive phenotypes had higher FSS scores.
On MRI, patients with preserved cognition had lower thalamic volume than healthy controls. The researchers compared all other phenotypes to these two groups. Patients with mild verbal memory or semantic fluency impairment had reduced hippocampal volume. Patients with mild multidomain impairment had reduced cortical gray matter volume. Patients with severe attention or executive impairment had higher T2 lesion load. Patients with severe multidomain phenotypes had a broader pattern of atrophy, including decreased volume in the gray matter, white matter, thalamus, hippocampus, putamen, and nucleus accumbens.
“The present findings suggest that specific neural bases can be detected for each phenotype,” said Dr. De Meo. “Advanced and multimodal MRI techniques of analysis could help individuate the neural circuits and the neurotransmitter involved, also suggesting potential targets for the pharmacological treatment of cognitive decline.”
A need for longitudinal cohort studies
The study by Dr. De Meo and colleagues continues previous investigations of cognitive phenotypes in MS, which originally considered cognition to be either intact or impaired. Further research could “inform the development of targeted treatments for cognitive dysfunction in MS, which will ultimately bring us closer to a precision medicine model,” said Victoria M. Leavitt, PhD, of Columbia University Medical Center in New York.
“Clearly, we have to acknowledge that cognitive impairment is not a one-size-fits-all problem,” she added. “If a memory problem develops as a downstream consequence of language issues, targeting the hippocampus may not be effective. Separating patients into cognitive phenotype groups may be a key to understanding and identifying neural-level differences that underlie diverse cognitive issues.”
The evolution of cognitive changes over time must be understood clearly, because patients may develop memory impairment by separate pathways (e.g., focal lesions that precipitate hippocampal atrophy versus cortical thinning in parietal regions that result in white-matter disconnections among language regions), said Dr. Leavitt. “Longitudinal cohort studies and ... testable mechanistic models that incorporate multimodal neuroimaging metrics are an essential starting point. Machine-learning methods may also be a useful tool for beginning to look at how these different neuroimaging modalities work together dynamically to yield divergent cognitive phenotypes.”
The study was not supported by external funding. Dr. De Meo reported no relevant disclosures. Dr. Leavitt also reported no relevant disclosures.
SOURCE: De Meo E et al. MSVirtual2020, Abstract YI02.03.
FROM MSVIRTUAL2020
Masitinib impresses in nonactive progressive MS
“This is the first time that we have seen significant activity in slowing disability in a population of nonactive primary progressive and secondary progressive MS,” lead investigator, Patrick Vermersch, MD, commented. “There are no drugs available for these patients, which make up the vast majority of progressive MS patients, so these results are impressive. They are definitely a big deal.”
Dr. Vermersch, who is professor of neurology at the University of Lille, France, presented the study at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
“Masitinib – a first-in-class tyrosine kinase inhibitor targeting the innate immune system via inhibition of mast cell and microglia/macrophage activity – may provide a new treatment option for primary progressive and nonactive secondary progressive MS,” he concluded.
This study, known as AB07002, demonstrated a sustained and significant benefit for masitinib at a dose of 4.5 mg/kg per day in Expanded Disability Status Scale (EDSS) score change over 2 years versus placebo, with a 37% reduction in 3-month confirmed disability progression. This change “is relevant from a medical standpoint,” Dr. Vermersch reported.
However, a second dosing schedule, in which the drug was titrated up to 6 mg/kg per day, did not show significant benefit. Dr. Vermersch said this was because of an unexpected improvement in EDSS score in the placebo group.
In the 4.5-mg/kg group, the benefit was demonstrated across a broad population, with no difference with regard to age, duration of disease, or baseline disability. The benefits were similar in both primary and secondary MS phenotypes and were present irrespective of baseline active inflammation status.
Masitinib showed a safety profile “suitable for long-term administration in this population,” Dr. Vermersch said. “Masitinib addresses the huge unmet need in progressive MS,” he said. “The drugs currently used in MS target B cells and T cells. They are immunomodulating drugs and are used for relapsing/remitting MS. But in progressive forms of the disease, there is a strong involvement of innate immunity, so to be effective we need drugs that target this part of the immune system.”
Innate immunity is a major part of the immune system in primates; it is related to the immune cells inside tissues and the CNS and is separate from adaptive peripheral immunity, he explained.
Masitinib is a novel drug for MS in that it inhibits tyrosine kinase and blocks the activity of immune cells involved in the innate immune system – mainly microglia and mast cells. “Both of these types of cells are very involved in progressive MS. Masitinib has no action against T or B cells. It is a small molecule and penetrates the CNS,” Dr. Vermersch noted.
“This has opened up a whole new area of opportunity to develop treatments for progressive MS,” he added.
“We showed a positive significant result in slowing disability in patients with nonactive progressive MS,” he said. “The term ‘nonactive’ is important. Some other drugs [ocrelizumab and siponimod] have shown some modest activity in slowing progressive forms of MS, but this is driven by patients with some degree of inflammatory activity at baseline. Our study excluded such patients.”
The trial tested two different dosing schedules independently, each with its own placebo group. There were two subsets, each with 300 patients. The first subset was randomly assigned in a 2:1 ratio to daily masitinib at 4.5 mg/kg orally or placebo. The second subset was randomly assigned in a 2:1 ratio to daily masitinib titrated to 6 mg/kg or placebo.
The inclusion criteria were patients with primary progressive or secondary progressive MS without relapse (as measured by EDSS progression) within the previous 2 years. “No patients were enrolled who had superimposed relapses during the previous 2 years,” Dr. Vermersch stressed.
Baseline EDSS score was 5.0, and patients had an average disease duration of 15 years. Mean age was 50 years.
The primary endpoint was change from baseline in absolute EDSS value, which was measured every 12 weeks throughout the study, averaged over the 2-year study period (mean change in EDSS score).
Results in the 4.5-mg/kg group showed a mean increase in EDSS score in the masitinib recipients of 0.001 versus 0.098 in the placebo group, giving a mean difference of –0.097 for masitinib (P = 0.025). The results were similar in patients with primary or secondary progressive MS. Sensitivity analysis based on ordinal EDSS change showed a significant 39% increased probability of having more improvements in EDSS or fewer worsening EDSS scores with masitinib (odds ratio, 0.61; P = 0.044). Other results showed that masitinib reduced the risk for first disability progression by 42% (hazard ratio, 0.58; P = 0.034) and the risk for confirmed (3-month) disability progression by 37% (hazard ratio, 0.63; P = 0.15).
Masitinib also showed a 98% reduction in the risk of reaching an EDSS score of 7, corresponding to disability severe enough that the patient is restricted to a wheelchair (hazard ratio, 0.02; P = 0.009). No patients in the masitinib group reached the endpoint of confirmed (3-month) EDSS score of 7, compared with four patients in the placebo group.
In terms of safety in the 4.5-mg/kg group, the most common adverse events were rash (1,5%) gastrointestinal (GI) disturbances (1%), neutropenia (1%), and edema (1%). “We had a couple of patients with skin reactions and neutropenia, but all adverse events were mild to moderate and very manageable,” Dr. Vermersch commented.
He showed just one slide on the subset who were titrated up 6 mg/kg. “Numerically the change in EDSS was comparable in the 6-mg/kg–titrated group as it was in the 4.5-mg/kg group; however, the placebo arm of the 6-mg/kg subset unusually showed an improvement relative to baseline after 96 weeks. The placebo group of the 4.5-mg/kg cohort was consistent with the literature and expected worsening in EDSS score over 96 weeks,” Dr. Vermersch reported.
No new safety signal was observed in the 6-mg/kg cohort. Only the 4.5-mg/kg cohort will be pursued in further trials in MS.
Dr. Vermersch noted that masitinib is also being investigated in other indications and “there are thousands of patient-years of experience which show reassuring safety data.”
“There is some GI disturbances and skin reactions, but a very small percentage of patients discontinue treatment. If the drug is titrated slowly there are fewer adverse effects,” he said. “We will do that in the next study.”
A second confirmatory study is now being planned. The trial will enroll around 700 patients and is expected to recruit quickly because there is such a big unmet need, Dr. Vermersch added.
Commenting on the findings, ACTRIMS president Jeffrey Cohen, MD, of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, Ohio, said this is “an interesting study from several perspectives.”
“Masitinib is a new drug for MS with a completely novel mechanism of action targeting the innate immune system”, he said. “The study had several innovative features in that it combined primary and secondary progressive MS patients and measured disability in a different way to what we are used to.”
“It did show a slowing of disability, which is great news as we do not have any drugs for these patients at the moment, so this is a very hopeful result,” Dr. Cohen said.
The study was supported by AB Science. Dr. Vermersch reports sitting on advisory boards for Biogen, Sanofi-Genzyme, Teva, Roche, Novartis, Celgene, and Merck KGaA.
A version of this article originally appeared on Medscape.com.
“This is the first time that we have seen significant activity in slowing disability in a population of nonactive primary progressive and secondary progressive MS,” lead investigator, Patrick Vermersch, MD, commented. “There are no drugs available for these patients, which make up the vast majority of progressive MS patients, so these results are impressive. They are definitely a big deal.”
Dr. Vermersch, who is professor of neurology at the University of Lille, France, presented the study at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
“Masitinib – a first-in-class tyrosine kinase inhibitor targeting the innate immune system via inhibition of mast cell and microglia/macrophage activity – may provide a new treatment option for primary progressive and nonactive secondary progressive MS,” he concluded.
This study, known as AB07002, demonstrated a sustained and significant benefit for masitinib at a dose of 4.5 mg/kg per day in Expanded Disability Status Scale (EDSS) score change over 2 years versus placebo, with a 37% reduction in 3-month confirmed disability progression. This change “is relevant from a medical standpoint,” Dr. Vermersch reported.
However, a second dosing schedule, in which the drug was titrated up to 6 mg/kg per day, did not show significant benefit. Dr. Vermersch said this was because of an unexpected improvement in EDSS score in the placebo group.
In the 4.5-mg/kg group, the benefit was demonstrated across a broad population, with no difference with regard to age, duration of disease, or baseline disability. The benefits were similar in both primary and secondary MS phenotypes and were present irrespective of baseline active inflammation status.
Masitinib showed a safety profile “suitable for long-term administration in this population,” Dr. Vermersch said. “Masitinib addresses the huge unmet need in progressive MS,” he said. “The drugs currently used in MS target B cells and T cells. They are immunomodulating drugs and are used for relapsing/remitting MS. But in progressive forms of the disease, there is a strong involvement of innate immunity, so to be effective we need drugs that target this part of the immune system.”
Innate immunity is a major part of the immune system in primates; it is related to the immune cells inside tissues and the CNS and is separate from adaptive peripheral immunity, he explained.
Masitinib is a novel drug for MS in that it inhibits tyrosine kinase and blocks the activity of immune cells involved in the innate immune system – mainly microglia and mast cells. “Both of these types of cells are very involved in progressive MS. Masitinib has no action against T or B cells. It is a small molecule and penetrates the CNS,” Dr. Vermersch noted.
“This has opened up a whole new area of opportunity to develop treatments for progressive MS,” he added.
“We showed a positive significant result in slowing disability in patients with nonactive progressive MS,” he said. “The term ‘nonactive’ is important. Some other drugs [ocrelizumab and siponimod] have shown some modest activity in slowing progressive forms of MS, but this is driven by patients with some degree of inflammatory activity at baseline. Our study excluded such patients.”
The trial tested two different dosing schedules independently, each with its own placebo group. There were two subsets, each with 300 patients. The first subset was randomly assigned in a 2:1 ratio to daily masitinib at 4.5 mg/kg orally or placebo. The second subset was randomly assigned in a 2:1 ratio to daily masitinib titrated to 6 mg/kg or placebo.
The inclusion criteria were patients with primary progressive or secondary progressive MS without relapse (as measured by EDSS progression) within the previous 2 years. “No patients were enrolled who had superimposed relapses during the previous 2 years,” Dr. Vermersch stressed.
Baseline EDSS score was 5.0, and patients had an average disease duration of 15 years. Mean age was 50 years.
The primary endpoint was change from baseline in absolute EDSS value, which was measured every 12 weeks throughout the study, averaged over the 2-year study period (mean change in EDSS score).
Results in the 4.5-mg/kg group showed a mean increase in EDSS score in the masitinib recipients of 0.001 versus 0.098 in the placebo group, giving a mean difference of –0.097 for masitinib (P = 0.025). The results were similar in patients with primary or secondary progressive MS. Sensitivity analysis based on ordinal EDSS change showed a significant 39% increased probability of having more improvements in EDSS or fewer worsening EDSS scores with masitinib (odds ratio, 0.61; P = 0.044). Other results showed that masitinib reduced the risk for first disability progression by 42% (hazard ratio, 0.58; P = 0.034) and the risk for confirmed (3-month) disability progression by 37% (hazard ratio, 0.63; P = 0.15).
Masitinib also showed a 98% reduction in the risk of reaching an EDSS score of 7, corresponding to disability severe enough that the patient is restricted to a wheelchair (hazard ratio, 0.02; P = 0.009). No patients in the masitinib group reached the endpoint of confirmed (3-month) EDSS score of 7, compared with four patients in the placebo group.
In terms of safety in the 4.5-mg/kg group, the most common adverse events were rash (1,5%) gastrointestinal (GI) disturbances (1%), neutropenia (1%), and edema (1%). “We had a couple of patients with skin reactions and neutropenia, but all adverse events were mild to moderate and very manageable,” Dr. Vermersch commented.
He showed just one slide on the subset who were titrated up 6 mg/kg. “Numerically the change in EDSS was comparable in the 6-mg/kg–titrated group as it was in the 4.5-mg/kg group; however, the placebo arm of the 6-mg/kg subset unusually showed an improvement relative to baseline after 96 weeks. The placebo group of the 4.5-mg/kg cohort was consistent with the literature and expected worsening in EDSS score over 96 weeks,” Dr. Vermersch reported.
No new safety signal was observed in the 6-mg/kg cohort. Only the 4.5-mg/kg cohort will be pursued in further trials in MS.
Dr. Vermersch noted that masitinib is also being investigated in other indications and “there are thousands of patient-years of experience which show reassuring safety data.”
“There is some GI disturbances and skin reactions, but a very small percentage of patients discontinue treatment. If the drug is titrated slowly there are fewer adverse effects,” he said. “We will do that in the next study.”
A second confirmatory study is now being planned. The trial will enroll around 700 patients and is expected to recruit quickly because there is such a big unmet need, Dr. Vermersch added.
Commenting on the findings, ACTRIMS president Jeffrey Cohen, MD, of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, Ohio, said this is “an interesting study from several perspectives.”
“Masitinib is a new drug for MS with a completely novel mechanism of action targeting the innate immune system”, he said. “The study had several innovative features in that it combined primary and secondary progressive MS patients and measured disability in a different way to what we are used to.”
“It did show a slowing of disability, which is great news as we do not have any drugs for these patients at the moment, so this is a very hopeful result,” Dr. Cohen said.
The study was supported by AB Science. Dr. Vermersch reports sitting on advisory boards for Biogen, Sanofi-Genzyme, Teva, Roche, Novartis, Celgene, and Merck KGaA.
A version of this article originally appeared on Medscape.com.
“This is the first time that we have seen significant activity in slowing disability in a population of nonactive primary progressive and secondary progressive MS,” lead investigator, Patrick Vermersch, MD, commented. “There are no drugs available for these patients, which make up the vast majority of progressive MS patients, so these results are impressive. They are definitely a big deal.”
Dr. Vermersch, who is professor of neurology at the University of Lille, France, presented the study at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
“Masitinib – a first-in-class tyrosine kinase inhibitor targeting the innate immune system via inhibition of mast cell and microglia/macrophage activity – may provide a new treatment option for primary progressive and nonactive secondary progressive MS,” he concluded.
This study, known as AB07002, demonstrated a sustained and significant benefit for masitinib at a dose of 4.5 mg/kg per day in Expanded Disability Status Scale (EDSS) score change over 2 years versus placebo, with a 37% reduction in 3-month confirmed disability progression. This change “is relevant from a medical standpoint,” Dr. Vermersch reported.
However, a second dosing schedule, in which the drug was titrated up to 6 mg/kg per day, did not show significant benefit. Dr. Vermersch said this was because of an unexpected improvement in EDSS score in the placebo group.
In the 4.5-mg/kg group, the benefit was demonstrated across a broad population, with no difference with regard to age, duration of disease, or baseline disability. The benefits were similar in both primary and secondary MS phenotypes and were present irrespective of baseline active inflammation status.
Masitinib showed a safety profile “suitable for long-term administration in this population,” Dr. Vermersch said. “Masitinib addresses the huge unmet need in progressive MS,” he said. “The drugs currently used in MS target B cells and T cells. They are immunomodulating drugs and are used for relapsing/remitting MS. But in progressive forms of the disease, there is a strong involvement of innate immunity, so to be effective we need drugs that target this part of the immune system.”
Innate immunity is a major part of the immune system in primates; it is related to the immune cells inside tissues and the CNS and is separate from adaptive peripheral immunity, he explained.
Masitinib is a novel drug for MS in that it inhibits tyrosine kinase and blocks the activity of immune cells involved in the innate immune system – mainly microglia and mast cells. “Both of these types of cells are very involved in progressive MS. Masitinib has no action against T or B cells. It is a small molecule and penetrates the CNS,” Dr. Vermersch noted.
“This has opened up a whole new area of opportunity to develop treatments for progressive MS,” he added.
“We showed a positive significant result in slowing disability in patients with nonactive progressive MS,” he said. “The term ‘nonactive’ is important. Some other drugs [ocrelizumab and siponimod] have shown some modest activity in slowing progressive forms of MS, but this is driven by patients with some degree of inflammatory activity at baseline. Our study excluded such patients.”
The trial tested two different dosing schedules independently, each with its own placebo group. There were two subsets, each with 300 patients. The first subset was randomly assigned in a 2:1 ratio to daily masitinib at 4.5 mg/kg orally or placebo. The second subset was randomly assigned in a 2:1 ratio to daily masitinib titrated to 6 mg/kg or placebo.
The inclusion criteria were patients with primary progressive or secondary progressive MS without relapse (as measured by EDSS progression) within the previous 2 years. “No patients were enrolled who had superimposed relapses during the previous 2 years,” Dr. Vermersch stressed.
Baseline EDSS score was 5.0, and patients had an average disease duration of 15 years. Mean age was 50 years.
The primary endpoint was change from baseline in absolute EDSS value, which was measured every 12 weeks throughout the study, averaged over the 2-year study period (mean change in EDSS score).
Results in the 4.5-mg/kg group showed a mean increase in EDSS score in the masitinib recipients of 0.001 versus 0.098 in the placebo group, giving a mean difference of –0.097 for masitinib (P = 0.025). The results were similar in patients with primary or secondary progressive MS. Sensitivity analysis based on ordinal EDSS change showed a significant 39% increased probability of having more improvements in EDSS or fewer worsening EDSS scores with masitinib (odds ratio, 0.61; P = 0.044). Other results showed that masitinib reduced the risk for first disability progression by 42% (hazard ratio, 0.58; P = 0.034) and the risk for confirmed (3-month) disability progression by 37% (hazard ratio, 0.63; P = 0.15).
Masitinib also showed a 98% reduction in the risk of reaching an EDSS score of 7, corresponding to disability severe enough that the patient is restricted to a wheelchair (hazard ratio, 0.02; P = 0.009). No patients in the masitinib group reached the endpoint of confirmed (3-month) EDSS score of 7, compared with four patients in the placebo group.
In terms of safety in the 4.5-mg/kg group, the most common adverse events were rash (1,5%) gastrointestinal (GI) disturbances (1%), neutropenia (1%), and edema (1%). “We had a couple of patients with skin reactions and neutropenia, but all adverse events were mild to moderate and very manageable,” Dr. Vermersch commented.
He showed just one slide on the subset who were titrated up 6 mg/kg. “Numerically the change in EDSS was comparable in the 6-mg/kg–titrated group as it was in the 4.5-mg/kg group; however, the placebo arm of the 6-mg/kg subset unusually showed an improvement relative to baseline after 96 weeks. The placebo group of the 4.5-mg/kg cohort was consistent with the literature and expected worsening in EDSS score over 96 weeks,” Dr. Vermersch reported.
No new safety signal was observed in the 6-mg/kg cohort. Only the 4.5-mg/kg cohort will be pursued in further trials in MS.
Dr. Vermersch noted that masitinib is also being investigated in other indications and “there are thousands of patient-years of experience which show reassuring safety data.”
“There is some GI disturbances and skin reactions, but a very small percentage of patients discontinue treatment. If the drug is titrated slowly there are fewer adverse effects,” he said. “We will do that in the next study.”
A second confirmatory study is now being planned. The trial will enroll around 700 patients and is expected to recruit quickly because there is such a big unmet need, Dr. Vermersch added.
Commenting on the findings, ACTRIMS president Jeffrey Cohen, MD, of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, Ohio, said this is “an interesting study from several perspectives.”
“Masitinib is a new drug for MS with a completely novel mechanism of action targeting the innate immune system”, he said. “The study had several innovative features in that it combined primary and secondary progressive MS patients and measured disability in a different way to what we are used to.”
“It did show a slowing of disability, which is great news as we do not have any drugs for these patients at the moment, so this is a very hopeful result,” Dr. Cohen said.
The study was supported by AB Science. Dr. Vermersch reports sitting on advisory boards for Biogen, Sanofi-Genzyme, Teva, Roche, Novartis, Celgene, and Merck KGaA.
A version of this article originally appeared on Medscape.com.
From MSVirtual2020