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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
Long-term outcomes of early and continuous ocrelizumab treatment in relapsing MS
Key clinical point: Early and continuous ocrelizumab treatment can provide sustained benefit on clinical and magnetic resonance imaging measures for disease progression in patients with relapsing multiple sclerosis (MS).
Major finding: At 5 years, the cumulative proportion of patients with 24-week confirmed disability progression was lower among those who continued ocrelizumab vs those who switched from interferon (IFN) β-1a to ocrelizumab (16.1% vs 21.3%; P = .014). Similarly, brain atrophy was significantly lower among those who continued ocrelizumab than in those who switched to ocrelizumab (P less than .01).
Study details: The OPERA open label extension study evaluated long-term efficacy and safety (5 years follow-up) of ocrelizumab (600 mg) in adults with relapsing MS. Patients previously assigned to INF β-1a (n = 829) and ocrelizumab (n = 827) entered the open-label extension phase in this study, of which 623 switched to ocrelizumab and 702 continued ocrelizumab, respectively
Disclosures: This study was supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland. The lead author reporting receiving travel reimbursement and writing assistance from F. Hoffmann-La Roche Ltd for CD20-related meetings and presentations. Some of his coinvestigators reported owning stock in, being an employee of, receiving support from, and/or serving on scientific advisory board for F. Hoffmann-La Roche Ltd.
Citation: Hauser SL et al. Neurology. 2020 Jul 20. doi: 10.1212/WNL.0000000000010376.
Key clinical point: Early and continuous ocrelizumab treatment can provide sustained benefit on clinical and magnetic resonance imaging measures for disease progression in patients with relapsing multiple sclerosis (MS).
Major finding: At 5 years, the cumulative proportion of patients with 24-week confirmed disability progression was lower among those who continued ocrelizumab vs those who switched from interferon (IFN) β-1a to ocrelizumab (16.1% vs 21.3%; P = .014). Similarly, brain atrophy was significantly lower among those who continued ocrelizumab than in those who switched to ocrelizumab (P less than .01).
Study details: The OPERA open label extension study evaluated long-term efficacy and safety (5 years follow-up) of ocrelizumab (600 mg) in adults with relapsing MS. Patients previously assigned to INF β-1a (n = 829) and ocrelizumab (n = 827) entered the open-label extension phase in this study, of which 623 switched to ocrelizumab and 702 continued ocrelizumab, respectively
Disclosures: This study was supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland. The lead author reporting receiving travel reimbursement and writing assistance from F. Hoffmann-La Roche Ltd for CD20-related meetings and presentations. Some of his coinvestigators reported owning stock in, being an employee of, receiving support from, and/or serving on scientific advisory board for F. Hoffmann-La Roche Ltd.
Citation: Hauser SL et al. Neurology. 2020 Jul 20. doi: 10.1212/WNL.0000000000010376.
Key clinical point: Early and continuous ocrelizumab treatment can provide sustained benefit on clinical and magnetic resonance imaging measures for disease progression in patients with relapsing multiple sclerosis (MS).
Major finding: At 5 years, the cumulative proportion of patients with 24-week confirmed disability progression was lower among those who continued ocrelizumab vs those who switched from interferon (IFN) β-1a to ocrelizumab (16.1% vs 21.3%; P = .014). Similarly, brain atrophy was significantly lower among those who continued ocrelizumab than in those who switched to ocrelizumab (P less than .01).
Study details: The OPERA open label extension study evaluated long-term efficacy and safety (5 years follow-up) of ocrelizumab (600 mg) in adults with relapsing MS. Patients previously assigned to INF β-1a (n = 829) and ocrelizumab (n = 827) entered the open-label extension phase in this study, of which 623 switched to ocrelizumab and 702 continued ocrelizumab, respectively
Disclosures: This study was supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland. The lead author reporting receiving travel reimbursement and writing assistance from F. Hoffmann-La Roche Ltd for CD20-related meetings and presentations. Some of his coinvestigators reported owning stock in, being an employee of, receiving support from, and/or serving on scientific advisory board for F. Hoffmann-La Roche Ltd.
Citation: Hauser SL et al. Neurology. 2020 Jul 20. doi: 10.1212/WNL.0000000000010376.
Neurodegeneration in MS: Association of cholesterol biomarkers with serum neurofilaments
Key clinical point: Increased high-density lipoprotein cholesterol (HDL-C) is associated with decreased gray matter and cortical atrophy in patients with multiple sclerosis (MS) after adjusting for baseline serum neurofilaments (sNfL).
Major finding: Gray matter volume and cortical volume had significant associations with percent change in HDL-C (P = .0024 and P less than .001, respectively) after adjusting for sNfL as a predictor.
Study details: This prospective longitudinal study assessed patients with relapsing-remitting MS (n = 75) and progressive multiple sclerosis (n = 37) over a 5-year follow-up period.
Disclosures: The study was funded by the National Center for Advancing Translational Sciences of the National Institutes of Health. B Weinstock-Guttman, J Kuhle, R Zivadinov and M Ramanathan reported ties with multiple pharmaceutical companies. The remaining authors declared no conflicts of interest.
Citation: McComb M et al. Mult Scler Relat Disord. 2020 Jul 11. doi: 10.1016/j.msard.2020.102389.
Key clinical point: Increased high-density lipoprotein cholesterol (HDL-C) is associated with decreased gray matter and cortical atrophy in patients with multiple sclerosis (MS) after adjusting for baseline serum neurofilaments (sNfL).
Major finding: Gray matter volume and cortical volume had significant associations with percent change in HDL-C (P = .0024 and P less than .001, respectively) after adjusting for sNfL as a predictor.
Study details: This prospective longitudinal study assessed patients with relapsing-remitting MS (n = 75) and progressive multiple sclerosis (n = 37) over a 5-year follow-up period.
Disclosures: The study was funded by the National Center for Advancing Translational Sciences of the National Institutes of Health. B Weinstock-Guttman, J Kuhle, R Zivadinov and M Ramanathan reported ties with multiple pharmaceutical companies. The remaining authors declared no conflicts of interest.
Citation: McComb M et al. Mult Scler Relat Disord. 2020 Jul 11. doi: 10.1016/j.msard.2020.102389.
Key clinical point: Increased high-density lipoprotein cholesterol (HDL-C) is associated with decreased gray matter and cortical atrophy in patients with multiple sclerosis (MS) after adjusting for baseline serum neurofilaments (sNfL).
Major finding: Gray matter volume and cortical volume had significant associations with percent change in HDL-C (P = .0024 and P less than .001, respectively) after adjusting for sNfL as a predictor.
Study details: This prospective longitudinal study assessed patients with relapsing-remitting MS (n = 75) and progressive multiple sclerosis (n = 37) over a 5-year follow-up period.
Disclosures: The study was funded by the National Center for Advancing Translational Sciences of the National Institutes of Health. B Weinstock-Guttman, J Kuhle, R Zivadinov and M Ramanathan reported ties with multiple pharmaceutical companies. The remaining authors declared no conflicts of interest.
Citation: McComb M et al. Mult Scler Relat Disord. 2020 Jul 11. doi: 10.1016/j.msard.2020.102389.
Relapsing-remitting MS: Natalizumab effective on inflammatory phase
Key clinical point: Natalizumab is effective on the inflammatory phase of relapsing-remitting multiple sclerosis (RRMS). The frequency of poor outcomes is low and are predicted by disease activity criteria.
Major finding: At 10 years, the cumulative probabilities for secondary progressive multiple sclerosis (SPMS) conversion, Expanded Disability Status Scale (EDSS) worsening, reaching EDSS-4 and EDSS-6 were 23.7%, 30.4%, 25.1%, and 12.4%, respectively with natalizumab. The mean reduction in annualized relapsed rate at 10 years was 97.5% (P less than .0001). Factors predictive of disability at the long-term were not reaching ‘no evidence of disease activity’ (NEDA)-3, MRI worsening, increased EDSS score, and to a lesser extent the occurrence of relapse.
Study details: TYSTEN was a real-life observational study that assessed 770 patients with RRMS starting Natalizumab between 2007 and 2012. The mean follow-up duration was 97.2 months and mean treatment duration for natalizumab was 66 months.
Disclosures: The study received no funding. The presenting author had no disclosures. Some of his coinvestigators reported ties with Biogen Idec.
Citation: Bigaut K et al. Mult Scler. 2020 Jul 9. doi: 10.1177/1352458520936239.
Key clinical point: Natalizumab is effective on the inflammatory phase of relapsing-remitting multiple sclerosis (RRMS). The frequency of poor outcomes is low and are predicted by disease activity criteria.
Major finding: At 10 years, the cumulative probabilities for secondary progressive multiple sclerosis (SPMS) conversion, Expanded Disability Status Scale (EDSS) worsening, reaching EDSS-4 and EDSS-6 were 23.7%, 30.4%, 25.1%, and 12.4%, respectively with natalizumab. The mean reduction in annualized relapsed rate at 10 years was 97.5% (P less than .0001). Factors predictive of disability at the long-term were not reaching ‘no evidence of disease activity’ (NEDA)-3, MRI worsening, increased EDSS score, and to a lesser extent the occurrence of relapse.
Study details: TYSTEN was a real-life observational study that assessed 770 patients with RRMS starting Natalizumab between 2007 and 2012. The mean follow-up duration was 97.2 months and mean treatment duration for natalizumab was 66 months.
Disclosures: The study received no funding. The presenting author had no disclosures. Some of his coinvestigators reported ties with Biogen Idec.
Citation: Bigaut K et al. Mult Scler. 2020 Jul 9. doi: 10.1177/1352458520936239.
Key clinical point: Natalizumab is effective on the inflammatory phase of relapsing-remitting multiple sclerosis (RRMS). The frequency of poor outcomes is low and are predicted by disease activity criteria.
Major finding: At 10 years, the cumulative probabilities for secondary progressive multiple sclerosis (SPMS) conversion, Expanded Disability Status Scale (EDSS) worsening, reaching EDSS-4 and EDSS-6 were 23.7%, 30.4%, 25.1%, and 12.4%, respectively with natalizumab. The mean reduction in annualized relapsed rate at 10 years was 97.5% (P less than .0001). Factors predictive of disability at the long-term were not reaching ‘no evidence of disease activity’ (NEDA)-3, MRI worsening, increased EDSS score, and to a lesser extent the occurrence of relapse.
Study details: TYSTEN was a real-life observational study that assessed 770 patients with RRMS starting Natalizumab between 2007 and 2012. The mean follow-up duration was 97.2 months and mean treatment duration for natalizumab was 66 months.
Disclosures: The study received no funding. The presenting author had no disclosures. Some of his coinvestigators reported ties with Biogen Idec.
Citation: Bigaut K et al. Mult Scler. 2020 Jul 9. doi: 10.1177/1352458520936239.
Stressful life events may increase MS risk
Key clinical point: Stressful life events are associated with an increased risk of developing multiple sclerosis (MS).
Major finding: Stressful major life events that happened prior to disease onset significantly increased the risk by 17%-30%. Women were more vulnerable than men under certain stressful scenarios such as conflict at work or within families, marriage, sickness, or accident of family members.
Study details: A large Swedish case-control study of 2,930 patients with MS and 6,170 control participants.
Disclosures: Dr. Jiang was supported by a starting package from the Swedish Research Council.
Citation: Jiang X et al. Eur J Neurol. 2020 Aug 2. doi: 10.1111/ene.14458.
Key clinical point: Stressful life events are associated with an increased risk of developing multiple sclerosis (MS).
Major finding: Stressful major life events that happened prior to disease onset significantly increased the risk by 17%-30%. Women were more vulnerable than men under certain stressful scenarios such as conflict at work or within families, marriage, sickness, or accident of family members.
Study details: A large Swedish case-control study of 2,930 patients with MS and 6,170 control participants.
Disclosures: Dr. Jiang was supported by a starting package from the Swedish Research Council.
Citation: Jiang X et al. Eur J Neurol. 2020 Aug 2. doi: 10.1111/ene.14458.
Key clinical point: Stressful life events are associated with an increased risk of developing multiple sclerosis (MS).
Major finding: Stressful major life events that happened prior to disease onset significantly increased the risk by 17%-30%. Women were more vulnerable than men under certain stressful scenarios such as conflict at work or within families, marriage, sickness, or accident of family members.
Study details: A large Swedish case-control study of 2,930 patients with MS and 6,170 control participants.
Disclosures: Dr. Jiang was supported by a starting package from the Swedish Research Council.
Citation: Jiang X et al. Eur J Neurol. 2020 Aug 2. doi: 10.1111/ene.14458.
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
Multiple sclerosis prodrome holds promise of earlier diagnosis
“It is time that the prodromal phase of multiple sclerosis [MS] is formally recognized.” That was the conclusion of Helen Tremlett, PhD, delivering the opening plenary session 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.
There is a myriad of prodromal features but none that are specific to MS,” Dr. Tremlett said.
“These findings show that in future there could be an earlier window of opportunity to identify and manage MS,” she suggested.
In an interview, Dr. Tremlett, who is professor and Canada Research Chair in Neuroepidemiology and Multiple Sclerosis at the University of British Columbia, Vancouver, explained that for MS a prodrome is a relatively new concept. “Right up until the year 2000, MS leaders were specifically saying that a prodrome did not exist,” she said. “But things have changed. Studies started emerging in the last decade suggestive of a prodrome, and I think we can now say there is definitely proof that a prodrome does exist. If you ask MS patients, the vast majority of them will say they had an increase in health issues in the years before diagnosis.”
In her plenary talk, Dr. Tremlett summarized the available evidence showing that, in the years before the first demyelinating event, patients are more likely to be have multiple health issues and an increase in hospitalizations and physician visits.
In a 2018 study, her group analyzed data from four Canadian provinces, including 14,000 patients with MS and 75,000 matched controls, and found a 75% increase in the rate of hospitalization, a 88% higher rate of physician service use, and a 49% increase in prescription numbers in the 5 years before the first demyelinating event in the patients with MS, compared with controls.
This included a 50% increase in mental health visits to physicians and increased rates of fibromyalgia, pain, headache, migraine, sleep disturbances, urology, and dermatology referrals, as well as irritable bowel syndrome. In addition, there were fewer pregnancies and increased prescriptions for contraception in the female patients later diagnosed with MS.
“There is a huge range of nonspecific symptoms in the 5 years before MS diagnosis, and some of these are really intriguing and unanticipated,” Dr. Tremlett said. “We are not surprised by the findings that fatigue, mental health issues, and bladder and bowel symptoms are increased, but the finding that there are more visits to a dermatologist and an increase in prescriptions for skin conditions was completely unexpected.”
The researchers found that dermatology referrals increased in patients who went on to develop relapsing remitting but not primary progressive forms of MS, which correlates with the established knowledge that the relapsing form has an inflammatory component not seen in progressive MS.
In a large U.K. population study of 10,000 patients with MS and 39,000 matched controls sourced from primary care doctors’ records, there was an increase in gastrointestinal and urinary issues, pain, anxiety and depression, insomnia, and fatigue in the 10 years before the first diagnosis of MS or clinically isolated syndrome (CIS) in patients later diagnosed with those conditions, compared with controls, Dr. Tremlett reported.
Other data have suggested that sex and age may affect the prodrome. In a study published this year, anemia was increased in the year before the first demyelinating event and pain was increased for 5 years beforehand. But anemia was more common in male patients later diagnosed with MS/CIS (odds ratio compared with controls, 2.4) than in female patients (OR compared with controls, 1.2).
The increase in pain seemed to be greater with age, with ORs of 1.8 for those younger than 30 years, 2.1 for those age 30-49 years, and 2.4 for those older than 50 years compared with controls.
A Norwegian military study in men that included 900 patients with MS and 19,000 matched controls found that cognitive performance was reduced in the 2 years before MS symptoms developed and up to 20 years before symptoms in those who developed primary progressive MS. “This suggests that primary progressive MS could start decades before the first apparent symptoms become obvious,” Dr. Tremlett commented.
A study in pediatric MS found that the mothers of the patients had higher use of health care (rate ratio, 1.16) and mental health (rate ratio, 1.33) services in the 5 years before their children had their first demyelinating event.
A study in Bavaria, Germany, including 10,000 patients with MS and 73,000 controls, concluded that “many physician visits before MS diagnosis were, in hindsight, likely a demyelinating event,” with the implication that this is evidence of missed opportunity for earlier diagnosis, Dr. Tremlett noted.
In a 2019 study, psychiatric symptoms were more common before MS diagnosis across various different immune-mediated disease (MS, rheumatoid arthritis, inflammatory bowel disease), with an incidence rate ratio of 1.6. The rate was even increased 10 years before diagnosis (incidence rate ratio, 1.5).
“This is evidence for shared prodromal features across immune diseases, but there isn’t a single feature specific to MS,” Dr. Tremlett said. She also referred to evidence that the blood biomarker of neuronal damage, neurofilament light chain (NfL), is raised several years before MS diagnosis. In a U.S. military study that examined serum repository samples, NfL was increased for 6 years before disease onset in 30 patients with MS, compared with 30 matched controls.
What are the implications?
Dr. Tremlett said the immediate impact of these observations about the prodrome is focused on research, particularly investigation of risk factors for MS. “If we want to know what causes MS, we have to be very careful that we are not detecting prodromal symptoms and mistaking that for a causal MS risk factor. We need to make sure we look further back than just the last few years when looking for risk factors.”
She gave the example of the observation that women in the years before MS diagnosis are less likely to have a pregnancy and more likely to fill a prescription for contraception. “This has led to the idea that avoiding pregnancy and using contraceptives increases the risk of MS, but I interpret it as these women know that something odd is going on and make the lifestyle decision not to become pregnant.”
She believes the longer-term impact of the prodrome is going to require much thought. “There is no such diagnosis of prodromal MS at the moment, but there could be in future. But the idea that we can use this information to detect MS earlier is going to require collaboration from many international stakeholders and MS organizations. We can’t automatically suspect MS in people who have these symptoms because they are so nonspecific. I think to request an MRI in patients experiencing headaches/fatigue/bowel issues is jumping the gun at the present moment as these symptoms are very common.”
On the idea of measuring NfL in patients with some of these symptoms, she believes that may be a possibility in the future but much more data are required.“We do have some evidence suggesting that the NfL blood biomarker is raised before MS diagnosis, and this was from a very well-designed study, but it was small so I think it is too early to start looking at this in clinical practice,” she said. “But it does justify doing this as part of a research study. We definitely need more data on this. We must be cautious as NfL is not specific for MS – many other conditions are also associated with raised levels, but it is certainly an interesting marker if used carefully.”
Following in the footsteps of Parkinson disease
She suggested that the way forward will be to package up these symptoms with information on biomarkers, such as NfL and imaging information, to enhance the ability to identify prodromal MS. “We could create a risk score and when a certain level of confidence is reached that this could be prodromal MS, then these patients could be enrolled in an intervention research study.”
Dr. Tremlett pointed out that, in the Parkinson disease field, a set of validated criteria for a prodrome have already been identified. “This is not used in clinical practice yet, but it is being used to identify patients for enrollment into clinical trials. I’m hoping that MS will follow in their footsteps.”
Commenting on the presentation, ACTRIMS president, Jeffrey Cohen, MD, Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, said: “There is no doubt that the MS disease process begins prior to the first attack (in the case of relapsing MS) or the onset of overt disability progression (in the case of primary progressive MS).”
He explained that this is demonstrated by the presence of old lesions on MRI in most patients at the time of presentation, the existence of so-called radiologically isolated syndrome (patients without symptoms of MS who undergo MRI for another reason and are found to have lesions suggesting of MS, many of whom go on to develop MS at a later date), and the occurrence of a variety of symptoms 5-10 years before presentation to a neurologist.
“Those symptoms are ones that are common in MS, though not specific for MS,” Dr. Cohen noted. “The main implication is that the timeline for MS needs to be moved earlier – for diagnosis, categorization of disease course, prognostic studies, and treatment. The issue is that the symptoms of the prodrome are rather nonspecific and most people with those symptoms do not have MS.”
New incoming president of ECTRIMS, Maria Pia Amato, MD, professor of neurology at the University of Florence (Italy), added: “The million-dollar question is when does progression really begin? This plenary talk tells us the disease is there years and years before it manifests itself with first demyelinating event. This opens up an immense opportunity for research and to open the window to the possibility of earlier diagnosis and treatment.”
Dr. Tremlett reports an investment in Precision NanoSystems.
A version of this article originally appeared on Medscape.com.
“It is time that the prodromal phase of multiple sclerosis [MS] is formally recognized.” That was the conclusion of Helen Tremlett, PhD, delivering the opening plenary session 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.
There is a myriad of prodromal features but none that are specific to MS,” Dr. Tremlett said.
“These findings show that in future there could be an earlier window of opportunity to identify and manage MS,” she suggested.
In an interview, Dr. Tremlett, who is professor and Canada Research Chair in Neuroepidemiology and Multiple Sclerosis at the University of British Columbia, Vancouver, explained that for MS a prodrome is a relatively new concept. “Right up until the year 2000, MS leaders were specifically saying that a prodrome did not exist,” she said. “But things have changed. Studies started emerging in the last decade suggestive of a prodrome, and I think we can now say there is definitely proof that a prodrome does exist. If you ask MS patients, the vast majority of them will say they had an increase in health issues in the years before diagnosis.”
In her plenary talk, Dr. Tremlett summarized the available evidence showing that, in the years before the first demyelinating event, patients are more likely to be have multiple health issues and an increase in hospitalizations and physician visits.
In a 2018 study, her group analyzed data from four Canadian provinces, including 14,000 patients with MS and 75,000 matched controls, and found a 75% increase in the rate of hospitalization, a 88% higher rate of physician service use, and a 49% increase in prescription numbers in the 5 years before the first demyelinating event in the patients with MS, compared with controls.
This included a 50% increase in mental health visits to physicians and increased rates of fibromyalgia, pain, headache, migraine, sleep disturbances, urology, and dermatology referrals, as well as irritable bowel syndrome. In addition, there were fewer pregnancies and increased prescriptions for contraception in the female patients later diagnosed with MS.
“There is a huge range of nonspecific symptoms in the 5 years before MS diagnosis, and some of these are really intriguing and unanticipated,” Dr. Tremlett said. “We are not surprised by the findings that fatigue, mental health issues, and bladder and bowel symptoms are increased, but the finding that there are more visits to a dermatologist and an increase in prescriptions for skin conditions was completely unexpected.”
The researchers found that dermatology referrals increased in patients who went on to develop relapsing remitting but not primary progressive forms of MS, which correlates with the established knowledge that the relapsing form has an inflammatory component not seen in progressive MS.
In a large U.K. population study of 10,000 patients with MS and 39,000 matched controls sourced from primary care doctors’ records, there was an increase in gastrointestinal and urinary issues, pain, anxiety and depression, insomnia, and fatigue in the 10 years before the first diagnosis of MS or clinically isolated syndrome (CIS) in patients later diagnosed with those conditions, compared with controls, Dr. Tremlett reported.
Other data have suggested that sex and age may affect the prodrome. In a study published this year, anemia was increased in the year before the first demyelinating event and pain was increased for 5 years beforehand. But anemia was more common in male patients later diagnosed with MS/CIS (odds ratio compared with controls, 2.4) than in female patients (OR compared with controls, 1.2).
The increase in pain seemed to be greater with age, with ORs of 1.8 for those younger than 30 years, 2.1 for those age 30-49 years, and 2.4 for those older than 50 years compared with controls.
A Norwegian military study in men that included 900 patients with MS and 19,000 matched controls found that cognitive performance was reduced in the 2 years before MS symptoms developed and up to 20 years before symptoms in those who developed primary progressive MS. “This suggests that primary progressive MS could start decades before the first apparent symptoms become obvious,” Dr. Tremlett commented.
A study in pediatric MS found that the mothers of the patients had higher use of health care (rate ratio, 1.16) and mental health (rate ratio, 1.33) services in the 5 years before their children had their first demyelinating event.
A study in Bavaria, Germany, including 10,000 patients with MS and 73,000 controls, concluded that “many physician visits before MS diagnosis were, in hindsight, likely a demyelinating event,” with the implication that this is evidence of missed opportunity for earlier diagnosis, Dr. Tremlett noted.
In a 2019 study, psychiatric symptoms were more common before MS diagnosis across various different immune-mediated disease (MS, rheumatoid arthritis, inflammatory bowel disease), with an incidence rate ratio of 1.6. The rate was even increased 10 years before diagnosis (incidence rate ratio, 1.5).
“This is evidence for shared prodromal features across immune diseases, but there isn’t a single feature specific to MS,” Dr. Tremlett said. She also referred to evidence that the blood biomarker of neuronal damage, neurofilament light chain (NfL), is raised several years before MS diagnosis. In a U.S. military study that examined serum repository samples, NfL was increased for 6 years before disease onset in 30 patients with MS, compared with 30 matched controls.
What are the implications?
Dr. Tremlett said the immediate impact of these observations about the prodrome is focused on research, particularly investigation of risk factors for MS. “If we want to know what causes MS, we have to be very careful that we are not detecting prodromal symptoms and mistaking that for a causal MS risk factor. We need to make sure we look further back than just the last few years when looking for risk factors.”
She gave the example of the observation that women in the years before MS diagnosis are less likely to have a pregnancy and more likely to fill a prescription for contraception. “This has led to the idea that avoiding pregnancy and using contraceptives increases the risk of MS, but I interpret it as these women know that something odd is going on and make the lifestyle decision not to become pregnant.”
She believes the longer-term impact of the prodrome is going to require much thought. “There is no such diagnosis of prodromal MS at the moment, but there could be in future. But the idea that we can use this information to detect MS earlier is going to require collaboration from many international stakeholders and MS organizations. We can’t automatically suspect MS in people who have these symptoms because they are so nonspecific. I think to request an MRI in patients experiencing headaches/fatigue/bowel issues is jumping the gun at the present moment as these symptoms are very common.”
On the idea of measuring NfL in patients with some of these symptoms, she believes that may be a possibility in the future but much more data are required.“We do have some evidence suggesting that the NfL blood biomarker is raised before MS diagnosis, and this was from a very well-designed study, but it was small so I think it is too early to start looking at this in clinical practice,” she said. “But it does justify doing this as part of a research study. We definitely need more data on this. We must be cautious as NfL is not specific for MS – many other conditions are also associated with raised levels, but it is certainly an interesting marker if used carefully.”
Following in the footsteps of Parkinson disease
She suggested that the way forward will be to package up these symptoms with information on biomarkers, such as NfL and imaging information, to enhance the ability to identify prodromal MS. “We could create a risk score and when a certain level of confidence is reached that this could be prodromal MS, then these patients could be enrolled in an intervention research study.”
Dr. Tremlett pointed out that, in the Parkinson disease field, a set of validated criteria for a prodrome have already been identified. “This is not used in clinical practice yet, but it is being used to identify patients for enrollment into clinical trials. I’m hoping that MS will follow in their footsteps.”
Commenting on the presentation, ACTRIMS president, Jeffrey Cohen, MD, Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, said: “There is no doubt that the MS disease process begins prior to the first attack (in the case of relapsing MS) or the onset of overt disability progression (in the case of primary progressive MS).”
He explained that this is demonstrated by the presence of old lesions on MRI in most patients at the time of presentation, the existence of so-called radiologically isolated syndrome (patients without symptoms of MS who undergo MRI for another reason and are found to have lesions suggesting of MS, many of whom go on to develop MS at a later date), and the occurrence of a variety of symptoms 5-10 years before presentation to a neurologist.
“Those symptoms are ones that are common in MS, though not specific for MS,” Dr. Cohen noted. “The main implication is that the timeline for MS needs to be moved earlier – for diagnosis, categorization of disease course, prognostic studies, and treatment. The issue is that the symptoms of the prodrome are rather nonspecific and most people with those symptoms do not have MS.”
New incoming president of ECTRIMS, Maria Pia Amato, MD, professor of neurology at the University of Florence (Italy), added: “The million-dollar question is when does progression really begin? This plenary talk tells us the disease is there years and years before it manifests itself with first demyelinating event. This opens up an immense opportunity for research and to open the window to the possibility of earlier diagnosis and treatment.”
Dr. Tremlett reports an investment in Precision NanoSystems.
A version of this article originally appeared on Medscape.com.
“It is time that the prodromal phase of multiple sclerosis [MS] is formally recognized.” That was the conclusion of Helen Tremlett, PhD, delivering the opening plenary session 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.
There is a myriad of prodromal features but none that are specific to MS,” Dr. Tremlett said.
“These findings show that in future there could be an earlier window of opportunity to identify and manage MS,” she suggested.
In an interview, Dr. Tremlett, who is professor and Canada Research Chair in Neuroepidemiology and Multiple Sclerosis at the University of British Columbia, Vancouver, explained that for MS a prodrome is a relatively new concept. “Right up until the year 2000, MS leaders were specifically saying that a prodrome did not exist,” she said. “But things have changed. Studies started emerging in the last decade suggestive of a prodrome, and I think we can now say there is definitely proof that a prodrome does exist. If you ask MS patients, the vast majority of them will say they had an increase in health issues in the years before diagnosis.”
In her plenary talk, Dr. Tremlett summarized the available evidence showing that, in the years before the first demyelinating event, patients are more likely to be have multiple health issues and an increase in hospitalizations and physician visits.
In a 2018 study, her group analyzed data from four Canadian provinces, including 14,000 patients with MS and 75,000 matched controls, and found a 75% increase in the rate of hospitalization, a 88% higher rate of physician service use, and a 49% increase in prescription numbers in the 5 years before the first demyelinating event in the patients with MS, compared with controls.
This included a 50% increase in mental health visits to physicians and increased rates of fibromyalgia, pain, headache, migraine, sleep disturbances, urology, and dermatology referrals, as well as irritable bowel syndrome. In addition, there were fewer pregnancies and increased prescriptions for contraception in the female patients later diagnosed with MS.
“There is a huge range of nonspecific symptoms in the 5 years before MS diagnosis, and some of these are really intriguing and unanticipated,” Dr. Tremlett said. “We are not surprised by the findings that fatigue, mental health issues, and bladder and bowel symptoms are increased, but the finding that there are more visits to a dermatologist and an increase in prescriptions for skin conditions was completely unexpected.”
The researchers found that dermatology referrals increased in patients who went on to develop relapsing remitting but not primary progressive forms of MS, which correlates with the established knowledge that the relapsing form has an inflammatory component not seen in progressive MS.
In a large U.K. population study of 10,000 patients with MS and 39,000 matched controls sourced from primary care doctors’ records, there was an increase in gastrointestinal and urinary issues, pain, anxiety and depression, insomnia, and fatigue in the 10 years before the first diagnosis of MS or clinically isolated syndrome (CIS) in patients later diagnosed with those conditions, compared with controls, Dr. Tremlett reported.
Other data have suggested that sex and age may affect the prodrome. In a study published this year, anemia was increased in the year before the first demyelinating event and pain was increased for 5 years beforehand. But anemia was more common in male patients later diagnosed with MS/CIS (odds ratio compared with controls, 2.4) than in female patients (OR compared with controls, 1.2).
The increase in pain seemed to be greater with age, with ORs of 1.8 for those younger than 30 years, 2.1 for those age 30-49 years, and 2.4 for those older than 50 years compared with controls.
A Norwegian military study in men that included 900 patients with MS and 19,000 matched controls found that cognitive performance was reduced in the 2 years before MS symptoms developed and up to 20 years before symptoms in those who developed primary progressive MS. “This suggests that primary progressive MS could start decades before the first apparent symptoms become obvious,” Dr. Tremlett commented.
A study in pediatric MS found that the mothers of the patients had higher use of health care (rate ratio, 1.16) and mental health (rate ratio, 1.33) services in the 5 years before their children had their first demyelinating event.
A study in Bavaria, Germany, including 10,000 patients with MS and 73,000 controls, concluded that “many physician visits before MS diagnosis were, in hindsight, likely a demyelinating event,” with the implication that this is evidence of missed opportunity for earlier diagnosis, Dr. Tremlett noted.
In a 2019 study, psychiatric symptoms were more common before MS diagnosis across various different immune-mediated disease (MS, rheumatoid arthritis, inflammatory bowel disease), with an incidence rate ratio of 1.6. The rate was even increased 10 years before diagnosis (incidence rate ratio, 1.5).
“This is evidence for shared prodromal features across immune diseases, but there isn’t a single feature specific to MS,” Dr. Tremlett said. She also referred to evidence that the blood biomarker of neuronal damage, neurofilament light chain (NfL), is raised several years before MS diagnosis. In a U.S. military study that examined serum repository samples, NfL was increased for 6 years before disease onset in 30 patients with MS, compared with 30 matched controls.
What are the implications?
Dr. Tremlett said the immediate impact of these observations about the prodrome is focused on research, particularly investigation of risk factors for MS. “If we want to know what causes MS, we have to be very careful that we are not detecting prodromal symptoms and mistaking that for a causal MS risk factor. We need to make sure we look further back than just the last few years when looking for risk factors.”
She gave the example of the observation that women in the years before MS diagnosis are less likely to have a pregnancy and more likely to fill a prescription for contraception. “This has led to the idea that avoiding pregnancy and using contraceptives increases the risk of MS, but I interpret it as these women know that something odd is going on and make the lifestyle decision not to become pregnant.”
She believes the longer-term impact of the prodrome is going to require much thought. “There is no such diagnosis of prodromal MS at the moment, but there could be in future. But the idea that we can use this information to detect MS earlier is going to require collaboration from many international stakeholders and MS organizations. We can’t automatically suspect MS in people who have these symptoms because they are so nonspecific. I think to request an MRI in patients experiencing headaches/fatigue/bowel issues is jumping the gun at the present moment as these symptoms are very common.”
On the idea of measuring NfL in patients with some of these symptoms, she believes that may be a possibility in the future but much more data are required.“We do have some evidence suggesting that the NfL blood biomarker is raised before MS diagnosis, and this was from a very well-designed study, but it was small so I think it is too early to start looking at this in clinical practice,” she said. “But it does justify doing this as part of a research study. We definitely need more data on this. We must be cautious as NfL is not specific for MS – many other conditions are also associated with raised levels, but it is certainly an interesting marker if used carefully.”
Following in the footsteps of Parkinson disease
She suggested that the way forward will be to package up these symptoms with information on biomarkers, such as NfL and imaging information, to enhance the ability to identify prodromal MS. “We could create a risk score and when a certain level of confidence is reached that this could be prodromal MS, then these patients could be enrolled in an intervention research study.”
Dr. Tremlett pointed out that, in the Parkinson disease field, a set of validated criteria for a prodrome have already been identified. “This is not used in clinical practice yet, but it is being used to identify patients for enrollment into clinical trials. I’m hoping that MS will follow in their footsteps.”
Commenting on the presentation, ACTRIMS president, Jeffrey Cohen, MD, Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, said: “There is no doubt that the MS disease process begins prior to the first attack (in the case of relapsing MS) or the onset of overt disability progression (in the case of primary progressive MS).”
He explained that this is demonstrated by the presence of old lesions on MRI in most patients at the time of presentation, the existence of so-called radiologically isolated syndrome (patients without symptoms of MS who undergo MRI for another reason and are found to have lesions suggesting of MS, many of whom go on to develop MS at a later date), and the occurrence of a variety of symptoms 5-10 years before presentation to a neurologist.
“Those symptoms are ones that are common in MS, though not specific for MS,” Dr. Cohen noted. “The main implication is that the timeline for MS needs to be moved earlier – for diagnosis, categorization of disease course, prognostic studies, and treatment. The issue is that the symptoms of the prodrome are rather nonspecific and most people with those symptoms do not have MS.”
New incoming president of ECTRIMS, Maria Pia Amato, MD, professor of neurology at the University of Florence (Italy), added: “The million-dollar question is when does progression really begin? This plenary talk tells us the disease is there years and years before it manifests itself with first demyelinating event. This opens up an immense opportunity for research and to open the window to the possibility of earlier diagnosis and treatment.”
Dr. Tremlett reports an investment in Precision NanoSystems.
A version of this article originally appeared on Medscape.com.
FROM MSVIRTUAL2020
High plasma GFAP level predicts disability accumulation in secondary progressive MS
according to investigators. The biomarker appears to have a stronger correlation with disability in people with nonactive disease, compared with those with active disease. These data 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.
Astroglial injury and activation is one of the characteristic features of progressive MS. Following such injury, GFAP is released into the cerebrospinal fluid and blood.
“It may be that GFAP plays an especially important role in patients without focal inflammatory activity and is more associated with insidious progression,” said Jens Kuhle, MD, PhD, head of the MS center at University Hospital Basel (Switzerland). “This [finding] needs to be investigated further within the same cohort, but also [within] additional well-characterized other cohorts.”
Dr. Kuhle and colleagues examined GFAP as a prognostic biomarker of disability worsening by analyzing data for patients with active or nonactive secondary progressive MS who participated in the phase 3 EXPAND study, which compared siponimod with placebo. In this post hoc analysis, the investigators quantified baseline GFAP in plasma samples using single-molecule array technology. They categorized GFAP as high or low according to the gender-stratified 80th percentile.
Dr. Kuhle’s group assessed the effect of GFAP on time to an Expanded Disability Status Scale score of 7 (i.e., restriction to wheelchair) using a Cox regression model adjusted for age, gender, disease duration, treatment, relapses in the 24 months prior to study start, and baseline EDSS. In addition, they performed subgroup analyses in patients with active secondary progressive MS and those with nonactive secondary progressive MS. They defined active disease as having relapses at 24 or fewer months before study entry or gadolinium-enhancing T1 lesions at baseline. Participants without these characteristics were classified as having nonactive disease. The investigators also stratified the results by gender.
Correlation was strongest in nonactive disease
The current analysis included samples for 1,405 of the 1,651 patients who had been randomly assigned to treatment in the EXPAND study. The median GFAP level was 119.6 pg/mL among men and 141.4 pg/mL among women.
The risk of reaching an EDSS score of 7 was higher in patients with a high baseline GFAP level. Of 281 (12.1%) participants with a high baseline GFAP level, 34 reached this endpoint, compared with 54 of 1,117 (4.8%) participants with a low baseline GFAP level. For patients with a high GFAP level at baseline, the hazard ratio of this outcome was 1.96.
Subgroup analyses indicated that the increased risk of reaching an EDSS score of 7 was seen mainly in women. Of 169 women (13.6%) with high baseline GFAP level, 23 reached this endpoint, compared with 34 of 673 women (5.1%) without a high baseline GFAP level (HR, 2.22). Among men, the difference was not significant. Of 112 men (9.8%) with a high baseline GFAP level, 11 reached an EDSS score of 7, compared with 20 of 444 men (4.5%) without a high baseline GFAP level (HR, 1.45). The reason for this sex difference is unknown, said Dr. Kuhle. “A next important step is to ensure this [finding] is not influenced by other hidden factors.”
Dr. Kuhle and colleagues also found that the increase in risk of reaching an EDSS score of 7 was mainly observed in patients with nonactive secondary progressive MS. Among 133 such patients with a high baseline GFAP level, 14 (10.5%) reached this endpoint, compared with 22 of 570 patients (3.9%) without a high baseline GFAP level (HR, 3.40). The difference among patients with active secondary progressive MS was not significant (20 of 144 patients [13.9%] with high baseline GFAP level, compared with 30 of 521 patients [5.8%] without a high baseline GFAP level; HR, 1.58). Dr. Kuhle and colleagues found similar trends in the associations between baseline GFAP levels and time to 6-month confirmed disability progression, but these trends were less pronounced.
“The measurement of plasma or blood neurofilament light chain [NfL] is certainly closer to a potential clinical application than [the measurement of] GFAP,” Dr. Kuhle admitted. “However, highly sensitive platforms open the field to the fascinating possibility of finding meaningful biomarkers in the blood compartment in MS.” This development should be developed further. It is necessary to validate the significance of GFAP measures in individual patients and describe them with greater precision before they can be applied clinically. It also is necessary to create normative data and explore for the impact of other variables like age and comorbidities, he added.
“We are currently analyzing the EXPAND data further to see which characteristics at baseline and at end of study are driving plasma GFAP concentrations,” said Dr. Kuhle. “We also need to investigate whether progression events are captured accurately by GFAP in plasma. It will also be important to combine the GFAP data with NfL measures that are already available in this cohort.”
Study addresses a clinical need
“There is great need for a reliable, easy-to-measure, and relevant fluid biomarker for use in MS,” said Robert J. Fox, MD, staff neurologist at the Cleveland Clinic’s Mellen Center for MS. Neurofilaments have been a leading candidate among biomarkers, but researchers are exploring other candidates as well. An advantage of the present study is that Dr. Kuhle and colleagues examined a large number of patients with secondary progressive MS who underwent highly structured follow-up over several years, Dr. Fox said.
“What is most interesting is that the predictive capacity was greater in nonrelapsing secondary progressive MS, and so may have advantages over neurofilament in this group of patients,” he added. “Currently, GFAP is a research test and isn’t available for clinical practice.”
Researchers should investigate other ways in which GFAP is related to future disease activity (e.g., in the form of relapses or new MRI lesions) as well as to other measures of disability progression besides restriction to a wheelchair, said Dr. Fox. “Future research needs to examine whether this biomarker is helpful at the individual patient level. Can it guide a patient’s clinician toward treatment recommendations?”
This study was funded by Novartis. Neither Dr. Kuhle nor Dr. Fox had no relevant disclosures to report.
This article was updated 9/14/2020.
according to investigators. The biomarker appears to have a stronger correlation with disability in people with nonactive disease, compared with those with active disease. These data 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.
Astroglial injury and activation is one of the characteristic features of progressive MS. Following such injury, GFAP is released into the cerebrospinal fluid and blood.
“It may be that GFAP plays an especially important role in patients without focal inflammatory activity and is more associated with insidious progression,” said Jens Kuhle, MD, PhD, head of the MS center at University Hospital Basel (Switzerland). “This [finding] needs to be investigated further within the same cohort, but also [within] additional well-characterized other cohorts.”
Dr. Kuhle and colleagues examined GFAP as a prognostic biomarker of disability worsening by analyzing data for patients with active or nonactive secondary progressive MS who participated in the phase 3 EXPAND study, which compared siponimod with placebo. In this post hoc analysis, the investigators quantified baseline GFAP in plasma samples using single-molecule array technology. They categorized GFAP as high or low according to the gender-stratified 80th percentile.
Dr. Kuhle’s group assessed the effect of GFAP on time to an Expanded Disability Status Scale score of 7 (i.e., restriction to wheelchair) using a Cox regression model adjusted for age, gender, disease duration, treatment, relapses in the 24 months prior to study start, and baseline EDSS. In addition, they performed subgroup analyses in patients with active secondary progressive MS and those with nonactive secondary progressive MS. They defined active disease as having relapses at 24 or fewer months before study entry or gadolinium-enhancing T1 lesions at baseline. Participants without these characteristics were classified as having nonactive disease. The investigators also stratified the results by gender.
Correlation was strongest in nonactive disease
The current analysis included samples for 1,405 of the 1,651 patients who had been randomly assigned to treatment in the EXPAND study. The median GFAP level was 119.6 pg/mL among men and 141.4 pg/mL among women.
The risk of reaching an EDSS score of 7 was higher in patients with a high baseline GFAP level. Of 281 (12.1%) participants with a high baseline GFAP level, 34 reached this endpoint, compared with 54 of 1,117 (4.8%) participants with a low baseline GFAP level. For patients with a high GFAP level at baseline, the hazard ratio of this outcome was 1.96.
Subgroup analyses indicated that the increased risk of reaching an EDSS score of 7 was seen mainly in women. Of 169 women (13.6%) with high baseline GFAP level, 23 reached this endpoint, compared with 34 of 673 women (5.1%) without a high baseline GFAP level (HR, 2.22). Among men, the difference was not significant. Of 112 men (9.8%) with a high baseline GFAP level, 11 reached an EDSS score of 7, compared with 20 of 444 men (4.5%) without a high baseline GFAP level (HR, 1.45). The reason for this sex difference is unknown, said Dr. Kuhle. “A next important step is to ensure this [finding] is not influenced by other hidden factors.”
Dr. Kuhle and colleagues also found that the increase in risk of reaching an EDSS score of 7 was mainly observed in patients with nonactive secondary progressive MS. Among 133 such patients with a high baseline GFAP level, 14 (10.5%) reached this endpoint, compared with 22 of 570 patients (3.9%) without a high baseline GFAP level (HR, 3.40). The difference among patients with active secondary progressive MS was not significant (20 of 144 patients [13.9%] with high baseline GFAP level, compared with 30 of 521 patients [5.8%] without a high baseline GFAP level; HR, 1.58). Dr. Kuhle and colleagues found similar trends in the associations between baseline GFAP levels and time to 6-month confirmed disability progression, but these trends were less pronounced.
“The measurement of plasma or blood neurofilament light chain [NfL] is certainly closer to a potential clinical application than [the measurement of] GFAP,” Dr. Kuhle admitted. “However, highly sensitive platforms open the field to the fascinating possibility of finding meaningful biomarkers in the blood compartment in MS.” This development should be developed further. It is necessary to validate the significance of GFAP measures in individual patients and describe them with greater precision before they can be applied clinically. It also is necessary to create normative data and explore for the impact of other variables like age and comorbidities, he added.
“We are currently analyzing the EXPAND data further to see which characteristics at baseline and at end of study are driving plasma GFAP concentrations,” said Dr. Kuhle. “We also need to investigate whether progression events are captured accurately by GFAP in plasma. It will also be important to combine the GFAP data with NfL measures that are already available in this cohort.”
Study addresses a clinical need
“There is great need for a reliable, easy-to-measure, and relevant fluid biomarker for use in MS,” said Robert J. Fox, MD, staff neurologist at the Cleveland Clinic’s Mellen Center for MS. Neurofilaments have been a leading candidate among biomarkers, but researchers are exploring other candidates as well. An advantage of the present study is that Dr. Kuhle and colleagues examined a large number of patients with secondary progressive MS who underwent highly structured follow-up over several years, Dr. Fox said.
“What is most interesting is that the predictive capacity was greater in nonrelapsing secondary progressive MS, and so may have advantages over neurofilament in this group of patients,” he added. “Currently, GFAP is a research test and isn’t available for clinical practice.”
Researchers should investigate other ways in which GFAP is related to future disease activity (e.g., in the form of relapses or new MRI lesions) as well as to other measures of disability progression besides restriction to a wheelchair, said Dr. Fox. “Future research needs to examine whether this biomarker is helpful at the individual patient level. Can it guide a patient’s clinician toward treatment recommendations?”
This study was funded by Novartis. Neither Dr. Kuhle nor Dr. Fox had no relevant disclosures to report.
This article was updated 9/14/2020.
according to investigators. The biomarker appears to have a stronger correlation with disability in people with nonactive disease, compared with those with active disease. These data 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.
Astroglial injury and activation is one of the characteristic features of progressive MS. Following such injury, GFAP is released into the cerebrospinal fluid and blood.
“It may be that GFAP plays an especially important role in patients without focal inflammatory activity and is more associated with insidious progression,” said Jens Kuhle, MD, PhD, head of the MS center at University Hospital Basel (Switzerland). “This [finding] needs to be investigated further within the same cohort, but also [within] additional well-characterized other cohorts.”
Dr. Kuhle and colleagues examined GFAP as a prognostic biomarker of disability worsening by analyzing data for patients with active or nonactive secondary progressive MS who participated in the phase 3 EXPAND study, which compared siponimod with placebo. In this post hoc analysis, the investigators quantified baseline GFAP in plasma samples using single-molecule array technology. They categorized GFAP as high or low according to the gender-stratified 80th percentile.
Dr. Kuhle’s group assessed the effect of GFAP on time to an Expanded Disability Status Scale score of 7 (i.e., restriction to wheelchair) using a Cox regression model adjusted for age, gender, disease duration, treatment, relapses in the 24 months prior to study start, and baseline EDSS. In addition, they performed subgroup analyses in patients with active secondary progressive MS and those with nonactive secondary progressive MS. They defined active disease as having relapses at 24 or fewer months before study entry or gadolinium-enhancing T1 lesions at baseline. Participants without these characteristics were classified as having nonactive disease. The investigators also stratified the results by gender.
Correlation was strongest in nonactive disease
The current analysis included samples for 1,405 of the 1,651 patients who had been randomly assigned to treatment in the EXPAND study. The median GFAP level was 119.6 pg/mL among men and 141.4 pg/mL among women.
The risk of reaching an EDSS score of 7 was higher in patients with a high baseline GFAP level. Of 281 (12.1%) participants with a high baseline GFAP level, 34 reached this endpoint, compared with 54 of 1,117 (4.8%) participants with a low baseline GFAP level. For patients with a high GFAP level at baseline, the hazard ratio of this outcome was 1.96.
Subgroup analyses indicated that the increased risk of reaching an EDSS score of 7 was seen mainly in women. Of 169 women (13.6%) with high baseline GFAP level, 23 reached this endpoint, compared with 34 of 673 women (5.1%) without a high baseline GFAP level (HR, 2.22). Among men, the difference was not significant. Of 112 men (9.8%) with a high baseline GFAP level, 11 reached an EDSS score of 7, compared with 20 of 444 men (4.5%) without a high baseline GFAP level (HR, 1.45). The reason for this sex difference is unknown, said Dr. Kuhle. “A next important step is to ensure this [finding] is not influenced by other hidden factors.”
Dr. Kuhle and colleagues also found that the increase in risk of reaching an EDSS score of 7 was mainly observed in patients with nonactive secondary progressive MS. Among 133 such patients with a high baseline GFAP level, 14 (10.5%) reached this endpoint, compared with 22 of 570 patients (3.9%) without a high baseline GFAP level (HR, 3.40). The difference among patients with active secondary progressive MS was not significant (20 of 144 patients [13.9%] with high baseline GFAP level, compared with 30 of 521 patients [5.8%] without a high baseline GFAP level; HR, 1.58). Dr. Kuhle and colleagues found similar trends in the associations between baseline GFAP levels and time to 6-month confirmed disability progression, but these trends were less pronounced.
“The measurement of plasma or blood neurofilament light chain [NfL] is certainly closer to a potential clinical application than [the measurement of] GFAP,” Dr. Kuhle admitted. “However, highly sensitive platforms open the field to the fascinating possibility of finding meaningful biomarkers in the blood compartment in MS.” This development should be developed further. It is necessary to validate the significance of GFAP measures in individual patients and describe them with greater precision before they can be applied clinically. It also is necessary to create normative data and explore for the impact of other variables like age and comorbidities, he added.
“We are currently analyzing the EXPAND data further to see which characteristics at baseline and at end of study are driving plasma GFAP concentrations,” said Dr. Kuhle. “We also need to investigate whether progression events are captured accurately by GFAP in plasma. It will also be important to combine the GFAP data with NfL measures that are already available in this cohort.”
Study addresses a clinical need
“There is great need for a reliable, easy-to-measure, and relevant fluid biomarker for use in MS,” said Robert J. Fox, MD, staff neurologist at the Cleveland Clinic’s Mellen Center for MS. Neurofilaments have been a leading candidate among biomarkers, but researchers are exploring other candidates as well. An advantage of the present study is that Dr. Kuhle and colleagues examined a large number of patients with secondary progressive MS who underwent highly structured follow-up over several years, Dr. Fox said.
“What is most interesting is that the predictive capacity was greater in nonrelapsing secondary progressive MS, and so may have advantages over neurofilament in this group of patients,” he added. “Currently, GFAP is a research test and isn’t available for clinical practice.”
Researchers should investigate other ways in which GFAP is related to future disease activity (e.g., in the form of relapses or new MRI lesions) as well as to other measures of disability progression besides restriction to a wheelchair, said Dr. Fox. “Future research needs to examine whether this biomarker is helpful at the individual patient level. Can it guide a patient’s clinician toward treatment recommendations?”
This study was funded by Novartis. Neither Dr. Kuhle nor Dr. Fox had no relevant disclosures to report.
This article was updated 9/14/2020.
FROM MSVIRTUAL2020
App for MS aims to capture elusive signals of progression
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, researchers at the University Hospital and University of Basel in Switzerland, presented data on their dreaMS app. The investigators are validating the app in a nonblinded cohort of 30 people with MS in the early to middle stages of progression and 30 controls without MS.
The application comprises a series of active tests measuring movement, fine motor skills, cognition, and vision, as well as questionnaires to assess quality of life, walking ability, and fatigue in people with Expanded Disability Status Scale (EDSS) scores of 6.5 or lower. A wrist device, used concurrently with the app, passively monitors subjects’ step count, heart rate, and different measures of activity.
If validated, such smartphone-based “digital biomarkers” will provide clinicians and investigators with a steadier flow of information for assessing MS disease progression and informing clinical decision-making. In June, Ludwig Kappos, MD, the app study’s senior researcher, co-authored an analysis of randomized trial data that argued for discarding the standard categories of relapsing and progressive MS in favor of seeing the disease as a continuum, in which progression can and does occur in the absence of relapses.
The digital biomarker work builds on that more unified view of the disease, Dr. Kappos said in an interview.
Outside of disease exacerbations or relapses, “progression can be very difficult to capture, especially in the first stage of the disease because of compensation in the central nervous system,” he said. “Our ability to see these very slight changes during a neurological examination is limited even if we do it very thoroughly. But by having these more frequent assessments we may be able to.”
Smartphone-gleaned biomarkers may have implications for prognosis and for choice of therapy, Dr. Kappos added. “We expect that these digital biomarkers will be even more sensitive and to be able to recognize before severe deficits are evident who is a candidate for a more intensive treatment and who is not.”
At the MSVirtual2020 congress, Dr. Kappos’s colleagues at the university Johannes Lorscheider, MD, and Yvonne Naegelin, MD, presented their feasibility and acceptance study currently underway in 60 volunteers. One of the concerns the investigators have had was whether engaged users would remain with the app. “We have designed the tests as little challenges to help keep people interested—we want to make these tests as appealing as possible,” Dr. Kappos said.
In this study, the reliability of each test is determined by intra-class correlation and median coefficient of variation. Preliminary reliability testing with healthy controls showed intra-class correlation coefficients of greater than 60% for the digital biomarkers and greater than 80% for at least one in every domain.
Once the best tests are selected and the app is fine-tuned, the group intends to embark on larger studies of the digital biomarkers. The next, planned for 2021, will recruit approximately 400 patients from the Swiss MS cohort, whose 1,000-some MS participants are followed with standardized examination and imaging protocols across healthcare centers.
“This is a very well characterized group of patients who are followed continuously with state-of-the-art neurological examinations, high-end MRI, and blood biomarkers,” Dr. Kappos said. “We want to see if we can add value by using digital biomarkers.”
The dreaMS app project is an independent investigator-initiated venture in cooperation with a technological partner. The study was supported by the Swiss Innovation Agency. The University Hospital Basel has received research funding for clinical trials from a number of pharmaceutical manufacturers.
SOURCE: Lorscheider J, et al. MSVirtual2020. Abstract P0069.
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, researchers at the University Hospital and University of Basel in Switzerland, presented data on their dreaMS app. The investigators are validating the app in a nonblinded cohort of 30 people with MS in the early to middle stages of progression and 30 controls without MS.
The application comprises a series of active tests measuring movement, fine motor skills, cognition, and vision, as well as questionnaires to assess quality of life, walking ability, and fatigue in people with Expanded Disability Status Scale (EDSS) scores of 6.5 or lower. A wrist device, used concurrently with the app, passively monitors subjects’ step count, heart rate, and different measures of activity.
If validated, such smartphone-based “digital biomarkers” will provide clinicians and investigators with a steadier flow of information for assessing MS disease progression and informing clinical decision-making. In June, Ludwig Kappos, MD, the app study’s senior researcher, co-authored an analysis of randomized trial data that argued for discarding the standard categories of relapsing and progressive MS in favor of seeing the disease as a continuum, in which progression can and does occur in the absence of relapses.
The digital biomarker work builds on that more unified view of the disease, Dr. Kappos said in an interview.
Outside of disease exacerbations or relapses, “progression can be very difficult to capture, especially in the first stage of the disease because of compensation in the central nervous system,” he said. “Our ability to see these very slight changes during a neurological examination is limited even if we do it very thoroughly. But by having these more frequent assessments we may be able to.”
Smartphone-gleaned biomarkers may have implications for prognosis and for choice of therapy, Dr. Kappos added. “We expect that these digital biomarkers will be even more sensitive and to be able to recognize before severe deficits are evident who is a candidate for a more intensive treatment and who is not.”
At the MSVirtual2020 congress, Dr. Kappos’s colleagues at the university Johannes Lorscheider, MD, and Yvonne Naegelin, MD, presented their feasibility and acceptance study currently underway in 60 volunteers. One of the concerns the investigators have had was whether engaged users would remain with the app. “We have designed the tests as little challenges to help keep people interested—we want to make these tests as appealing as possible,” Dr. Kappos said.
In this study, the reliability of each test is determined by intra-class correlation and median coefficient of variation. Preliminary reliability testing with healthy controls showed intra-class correlation coefficients of greater than 60% for the digital biomarkers and greater than 80% for at least one in every domain.
Once the best tests are selected and the app is fine-tuned, the group intends to embark on larger studies of the digital biomarkers. The next, planned for 2021, will recruit approximately 400 patients from the Swiss MS cohort, whose 1,000-some MS participants are followed with standardized examination and imaging protocols across healthcare centers.
“This is a very well characterized group of patients who are followed continuously with state-of-the-art neurological examinations, high-end MRI, and blood biomarkers,” Dr. Kappos said. “We want to see if we can add value by using digital biomarkers.”
The dreaMS app project is an independent investigator-initiated venture in cooperation with a technological partner. The study was supported by the Swiss Innovation Agency. The University Hospital Basel has received research funding for clinical trials from a number of pharmaceutical manufacturers.
SOURCE: Lorscheider J, et al. MSVirtual2020. Abstract P0069.
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, researchers at the University Hospital and University of Basel in Switzerland, presented data on their dreaMS app. The investigators are validating the app in a nonblinded cohort of 30 people with MS in the early to middle stages of progression and 30 controls without MS.
The application comprises a series of active tests measuring movement, fine motor skills, cognition, and vision, as well as questionnaires to assess quality of life, walking ability, and fatigue in people with Expanded Disability Status Scale (EDSS) scores of 6.5 or lower. A wrist device, used concurrently with the app, passively monitors subjects’ step count, heart rate, and different measures of activity.
If validated, such smartphone-based “digital biomarkers” will provide clinicians and investigators with a steadier flow of information for assessing MS disease progression and informing clinical decision-making. In June, Ludwig Kappos, MD, the app study’s senior researcher, co-authored an analysis of randomized trial data that argued for discarding the standard categories of relapsing and progressive MS in favor of seeing the disease as a continuum, in which progression can and does occur in the absence of relapses.
The digital biomarker work builds on that more unified view of the disease, Dr. Kappos said in an interview.
Outside of disease exacerbations or relapses, “progression can be very difficult to capture, especially in the first stage of the disease because of compensation in the central nervous system,” he said. “Our ability to see these very slight changes during a neurological examination is limited even if we do it very thoroughly. But by having these more frequent assessments we may be able to.”
Smartphone-gleaned biomarkers may have implications for prognosis and for choice of therapy, Dr. Kappos added. “We expect that these digital biomarkers will be even more sensitive and to be able to recognize before severe deficits are evident who is a candidate for a more intensive treatment and who is not.”
At the MSVirtual2020 congress, Dr. Kappos’s colleagues at the university Johannes Lorscheider, MD, and Yvonne Naegelin, MD, presented their feasibility and acceptance study currently underway in 60 volunteers. One of the concerns the investigators have had was whether engaged users would remain with the app. “We have designed the tests as little challenges to help keep people interested—we want to make these tests as appealing as possible,” Dr. Kappos said.
In this study, the reliability of each test is determined by intra-class correlation and median coefficient of variation. Preliminary reliability testing with healthy controls showed intra-class correlation coefficients of greater than 60% for the digital biomarkers and greater than 80% for at least one in every domain.
Once the best tests are selected and the app is fine-tuned, the group intends to embark on larger studies of the digital biomarkers. The next, planned for 2021, will recruit approximately 400 patients from the Swiss MS cohort, whose 1,000-some MS participants are followed with standardized examination and imaging protocols across healthcare centers.
“This is a very well characterized group of patients who are followed continuously with state-of-the-art neurological examinations, high-end MRI, and blood biomarkers,” Dr. Kappos said. “We want to see if we can add value by using digital biomarkers.”
The dreaMS app project is an independent investigator-initiated venture in cooperation with a technological partner. The study was supported by the Swiss Innovation Agency. The University Hospital Basel has received research funding for clinical trials from a number of pharmaceutical manufacturers.
SOURCE: Lorscheider J, et al. MSVirtual2020. Abstract P0069.
FROM MSVirtual2020