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High coffee consumption linked to decreased risk for MS
High coffee consumption decreased the odds of developing multiple sclerosis (MS) in two separate case-control studies conducted by Dr. Anna K. Hedström of the Karolinska Institute, Stockholm, and her associates.
The investigators analyzed coffee consumption across certain ages among 1,620 cases and 2,788 controls in the Swedish Epidemiological Investigation of Multiple Sclerosis (EIMS) and 1,159 cases and 1,172 controls in the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC).
In EIMS, the adjusted odds ratio (OR) was 0.70 (95% confidence interval, 0.49-0.99; P = .04) among participants who drank six or more cups of coffee (greater than 900 mL) daily at the index year, which was defined as the year of the initial appearance of symptoms indicative of MS. The corresponding OR for those who reported high coffee consumption at 5 and 10 years before the study was 0.72 and 0.71, respectively, but neither comparison reached statistical significance.
In KPNC, those who consumed four or more cups of coffee (more than 948 mL in this study) daily were significantly less likely to develop MS than were those who never drank coffee (OR, 0.69; 95% CI, 0.50-0.96; P = .05). And the cohorts who drank four or more cups of coffee daily at least 5 years prior to the study were associated with significantly reduced odds of MS (OR, 0.64).
The combined results of the two studies in a meta-analysis found a significant, 29% reduction in the likelihood of developing MS among the highest drinkers of coffee (greater than 900 mL daily in EIMS and greater than 948 mL in KPNC). The investigators adjusted all the analyses for many demographic and environmental risk factors for MS, including age, gender, residential area, ancestry, smoking habits, exposure to passive smoking, sun exposure habits, and body mass index at age 20 years.
No evidence was found for associations between increased amounts of tea or soda intake and MS.
“Further studies are required to establish if it is in fact caffeine, or if there is another molecule in coffee underlying the findings, to longitudinally assess the association between consumption of coffee and disease activity in MS, and to evaluate the mechanisms by which coffee may be acting, which could thus lead to new therapeutic targets,” the researchers concluded.
Find the full study in the Journal of Neurology, Neurosurgery & Psychiatry (doi: 10.1136/jnnp-2015-312176).
High coffee consumption decreased the odds of developing multiple sclerosis (MS) in two separate case-control studies conducted by Dr. Anna K. Hedström of the Karolinska Institute, Stockholm, and her associates.
The investigators analyzed coffee consumption across certain ages among 1,620 cases and 2,788 controls in the Swedish Epidemiological Investigation of Multiple Sclerosis (EIMS) and 1,159 cases and 1,172 controls in the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC).
In EIMS, the adjusted odds ratio (OR) was 0.70 (95% confidence interval, 0.49-0.99; P = .04) among participants who drank six or more cups of coffee (greater than 900 mL) daily at the index year, which was defined as the year of the initial appearance of symptoms indicative of MS. The corresponding OR for those who reported high coffee consumption at 5 and 10 years before the study was 0.72 and 0.71, respectively, but neither comparison reached statistical significance.
In KPNC, those who consumed four or more cups of coffee (more than 948 mL in this study) daily were significantly less likely to develop MS than were those who never drank coffee (OR, 0.69; 95% CI, 0.50-0.96; P = .05). And the cohorts who drank four or more cups of coffee daily at least 5 years prior to the study were associated with significantly reduced odds of MS (OR, 0.64).
The combined results of the two studies in a meta-analysis found a significant, 29% reduction in the likelihood of developing MS among the highest drinkers of coffee (greater than 900 mL daily in EIMS and greater than 948 mL in KPNC). The investigators adjusted all the analyses for many demographic and environmental risk factors for MS, including age, gender, residential area, ancestry, smoking habits, exposure to passive smoking, sun exposure habits, and body mass index at age 20 years.
No evidence was found for associations between increased amounts of tea or soda intake and MS.
“Further studies are required to establish if it is in fact caffeine, or if there is another molecule in coffee underlying the findings, to longitudinally assess the association between consumption of coffee and disease activity in MS, and to evaluate the mechanisms by which coffee may be acting, which could thus lead to new therapeutic targets,” the researchers concluded.
Find the full study in the Journal of Neurology, Neurosurgery & Psychiatry (doi: 10.1136/jnnp-2015-312176).
High coffee consumption decreased the odds of developing multiple sclerosis (MS) in two separate case-control studies conducted by Dr. Anna K. Hedström of the Karolinska Institute, Stockholm, and her associates.
The investigators analyzed coffee consumption across certain ages among 1,620 cases and 2,788 controls in the Swedish Epidemiological Investigation of Multiple Sclerosis (EIMS) and 1,159 cases and 1,172 controls in the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC).
In EIMS, the adjusted odds ratio (OR) was 0.70 (95% confidence interval, 0.49-0.99; P = .04) among participants who drank six or more cups of coffee (greater than 900 mL) daily at the index year, which was defined as the year of the initial appearance of symptoms indicative of MS. The corresponding OR for those who reported high coffee consumption at 5 and 10 years before the study was 0.72 and 0.71, respectively, but neither comparison reached statistical significance.
In KPNC, those who consumed four or more cups of coffee (more than 948 mL in this study) daily were significantly less likely to develop MS than were those who never drank coffee (OR, 0.69; 95% CI, 0.50-0.96; P = .05). And the cohorts who drank four or more cups of coffee daily at least 5 years prior to the study were associated with significantly reduced odds of MS (OR, 0.64).
The combined results of the two studies in a meta-analysis found a significant, 29% reduction in the likelihood of developing MS among the highest drinkers of coffee (greater than 900 mL daily in EIMS and greater than 948 mL in KPNC). The investigators adjusted all the analyses for many demographic and environmental risk factors for MS, including age, gender, residential area, ancestry, smoking habits, exposure to passive smoking, sun exposure habits, and body mass index at age 20 years.
No evidence was found for associations between increased amounts of tea or soda intake and MS.
“Further studies are required to establish if it is in fact caffeine, or if there is another molecule in coffee underlying the findings, to longitudinally assess the association between consumption of coffee and disease activity in MS, and to evaluate the mechanisms by which coffee may be acting, which could thus lead to new therapeutic targets,” the researchers concluded.
Find the full study in the Journal of Neurology, Neurosurgery & Psychiatry (doi: 10.1136/jnnp-2015-312176).
FROM JOURNAL OF NEUROLOGY, NEUROSURGERY & PSYCHIATRY
BENEFIT 11: No new safety signals with interferon beta-1b
NEW ORLEANS – The long-term safety of interferon beta-1b for the treatment of multiple sclerosis is well established, and 11-year outcomes from the randomized, placebo-controlled BENEFIT trial (BENEFIT 11) provide further support for the existing data.
Eleven years after patients with clinically isolated syndrome were randomized to receive 250 mcg every other day or placebo (with an option at 2 years to switch to active treatment), no new safety signals were found, and the safety profile remained favorable, Dr. Mark S. Freedman of the University of Ottawa and his colleagues reported in a poster at the meeting sponsored by the Americas Committee for Treatment and Research in Multiple Sclerosis.
In the 278 of the 468 patients originally enrolled in BENEFIT who were evaluated at 11 years, 107 (38.5%) reported one or more safety events (total, 278). Interferon beta-1b was used continuously during the 2 years prior to the 11-year evaluation in 82 patients (29.5%), and 28 (34.1%) of those reported an adverse event or medical history event (total, 72 events). Of 196 patients not treated continuously with interferon beta-1b in the 2 years prior to BENEFIT 11, 79 (40.3%) reported an adverse event or medical history event (total, 206 events), the investigators said.
The events reported in BENEFIT 11 were consistent with those seen previously in interferon beta-1b–treated patients; back pain was the most commonly reported musculoskeletal/connective tissue adverse event (reported by 2.4% of patients in the continuous treatment group and 2.6% in the remaining patients, and headache was the most common neurologic adverse event (reported by 1.2% and 2.0% of patients in the groups, respectively).
Neoplasms occurred in 3.7% and 3.6%; most were benign.
“Overall, the safety results from BENEFIT 11 supported the already well-established long-term safety profile of interferon beta-1b,” the investigators wrote.
The higher rates of some events in patients without continuous interferon beta-1b treatment may be due to escalation to second-line therapy in some patients who required agents that may be associated with greater frequency of safety events, they explained.
This study was supported by Bayer. Dr. Freedman has received compensation from Actelion, Bayer, Biogen Idec, Chugai, EMD Canada, Genzyme, Merck Serono, Novartis, Roche Canada, Sanofi-Aventis, and Teva Canada Innovation for consulting services. He also participates in a Genzyme-sponsored speakers bureau.
NEW ORLEANS – The long-term safety of interferon beta-1b for the treatment of multiple sclerosis is well established, and 11-year outcomes from the randomized, placebo-controlled BENEFIT trial (BENEFIT 11) provide further support for the existing data.
Eleven years after patients with clinically isolated syndrome were randomized to receive 250 mcg every other day or placebo (with an option at 2 years to switch to active treatment), no new safety signals were found, and the safety profile remained favorable, Dr. Mark S. Freedman of the University of Ottawa and his colleagues reported in a poster at the meeting sponsored by the Americas Committee for Treatment and Research in Multiple Sclerosis.
In the 278 of the 468 patients originally enrolled in BENEFIT who were evaluated at 11 years, 107 (38.5%) reported one or more safety events (total, 278). Interferon beta-1b was used continuously during the 2 years prior to the 11-year evaluation in 82 patients (29.5%), and 28 (34.1%) of those reported an adverse event or medical history event (total, 72 events). Of 196 patients not treated continuously with interferon beta-1b in the 2 years prior to BENEFIT 11, 79 (40.3%) reported an adverse event or medical history event (total, 206 events), the investigators said.
The events reported in BENEFIT 11 were consistent with those seen previously in interferon beta-1b–treated patients; back pain was the most commonly reported musculoskeletal/connective tissue adverse event (reported by 2.4% of patients in the continuous treatment group and 2.6% in the remaining patients, and headache was the most common neurologic adverse event (reported by 1.2% and 2.0% of patients in the groups, respectively).
Neoplasms occurred in 3.7% and 3.6%; most were benign.
“Overall, the safety results from BENEFIT 11 supported the already well-established long-term safety profile of interferon beta-1b,” the investigators wrote.
The higher rates of some events in patients without continuous interferon beta-1b treatment may be due to escalation to second-line therapy in some patients who required agents that may be associated with greater frequency of safety events, they explained.
This study was supported by Bayer. Dr. Freedman has received compensation from Actelion, Bayer, Biogen Idec, Chugai, EMD Canada, Genzyme, Merck Serono, Novartis, Roche Canada, Sanofi-Aventis, and Teva Canada Innovation for consulting services. He also participates in a Genzyme-sponsored speakers bureau.
NEW ORLEANS – The long-term safety of interferon beta-1b for the treatment of multiple sclerosis is well established, and 11-year outcomes from the randomized, placebo-controlled BENEFIT trial (BENEFIT 11) provide further support for the existing data.
Eleven years after patients with clinically isolated syndrome were randomized to receive 250 mcg every other day or placebo (with an option at 2 years to switch to active treatment), no new safety signals were found, and the safety profile remained favorable, Dr. Mark S. Freedman of the University of Ottawa and his colleagues reported in a poster at the meeting sponsored by the Americas Committee for Treatment and Research in Multiple Sclerosis.
In the 278 of the 468 patients originally enrolled in BENEFIT who were evaluated at 11 years, 107 (38.5%) reported one or more safety events (total, 278). Interferon beta-1b was used continuously during the 2 years prior to the 11-year evaluation in 82 patients (29.5%), and 28 (34.1%) of those reported an adverse event or medical history event (total, 72 events). Of 196 patients not treated continuously with interferon beta-1b in the 2 years prior to BENEFIT 11, 79 (40.3%) reported an adverse event or medical history event (total, 206 events), the investigators said.
The events reported in BENEFIT 11 were consistent with those seen previously in interferon beta-1b–treated patients; back pain was the most commonly reported musculoskeletal/connective tissue adverse event (reported by 2.4% of patients in the continuous treatment group and 2.6% in the remaining patients, and headache was the most common neurologic adverse event (reported by 1.2% and 2.0% of patients in the groups, respectively).
Neoplasms occurred in 3.7% and 3.6%; most were benign.
“Overall, the safety results from BENEFIT 11 supported the already well-established long-term safety profile of interferon beta-1b,” the investigators wrote.
The higher rates of some events in patients without continuous interferon beta-1b treatment may be due to escalation to second-line therapy in some patients who required agents that may be associated with greater frequency of safety events, they explained.
This study was supported by Bayer. Dr. Freedman has received compensation from Actelion, Bayer, Biogen Idec, Chugai, EMD Canada, Genzyme, Merck Serono, Novartis, Roche Canada, Sanofi-Aventis, and Teva Canada Innovation for consulting services. He also participates in a Genzyme-sponsored speakers bureau.
AT ACTRIMS FORUM 2016
Key clinical point: The long-term safety of interferon beta-1b for the treatment of multiple sclerosis is well established, and 11-year outcomes from the randomized, placebo-controlled BENEFIT trial (BENEFIT 11) provide further support for the existing data.
Major finding: 107 of 278 patients reported at least one safety event; no new safety signals were found.
Data source: The 11-year follow-up of 278 patients from the randomized controlled BENEFIT Trial.
Disclosures: This study was supported by Bayer. Dr. Freedman has received compensation from Actelion, Bayer, Biogen Idec, Chugai, EMD Canada, Genzyme, Merck Serono, Novartis, Roche Canada, Sanofi-Aventis, and Teva Canada Innovation for consulting services. He also participates in a Genzyme-sponsored speakers bureau.
Study examines efficacy of small group programs for fatigue in MS
NEW ORLEANS – Fatigue: Take Control (FTC), a 6-week group education and behavioral program widely used to address fatigue in patients with multiple sclerosis, was comparable to a general MS education program for decreasing fatigue and improving self-efficacy in a randomized, controlled study.
In 218 subjects randomized to participate in either FTC or a general MS education program (MS: Take Control, or MSTC), Modified Fatigue Impact Scale scores improved significantly, compared with baseline and regardless of group assignment; there was no difference between the groups at visit 6 (mean change, –4.5 and –3.6 in the FTC and MSTC groups, respectively), Cinda L. Hugos of the VA Portland (Ore.) Health Care System and her colleagues reported at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Multiple Sclerosis Self-Efficacy scale scores did, however, improve significantly in the FTC group vs. the MSTC group (mean increase of 45.5 vs. a decrease of 15.8), but the improvement was not maintained at 6 months, the investigators reported in a poster at the meeting.
The two groups had comparable baseline characteristics, with a mean age of nearly 54 years, as well as similar mean time since diagnosis (12.5 years), self-administered Expanded Disability Status Scale scores (5.2), and demographics.
Fatigue is common in MS patients, occurring in up to 95% of patients, and many report that it is the most disabling symptom. FTC, which addresses medical management of fatigue, exercise, environment, and changes and choices with respect to energy and fatigue control, is often used by chapters of the National MS Society, but its effectiveness for decreasing fatigue or improving self-efficacy has not been proven, the investigators noted.
To determine if FTC decreases fatigue and increases self-efficacy, compared with a general MS education program that addresses issues such as nutrition, emotional health, cognitive problems, and fitness, the investigators randomized subjects at four sites in groups of between 3 and 10 participants to either an FTC or MSTC group. All subjects had moderate to severe fatigue. Those with pregnancy, severe depression, uncontrolled problems that would limit participation, relapse in the prior month, or initiation of a new disease-modifying treatment within the prior 3 months were excluded.
“Both FTC and MSTC structured small group programs were associated with improved self-reported fatigue at program completion and at 3- and 6-month follow-up, but there were no significant differences in fatigue scores between FTC and MSTC participants at any time point,” the investigators wrote.
Self-efficacy was significantly better among FTC participants at program completion, but was not sustained, they noted, concluding that the findings suggest that “participating in structured small group programs is associated with prolonged reductions in fatigue in people with MS and that supporting goal setting provides short-term improvements in self-efficacy.”
Further research is needed to determine whether booster sessions would be beneficial for sustaining improvements in self-efficacy, they added.
This study was supported by the Rehabilitation, Research, & Development Service of the Veterans Affairs Office of Research & Development. The authors reported having no disclosures.
NEW ORLEANS – Fatigue: Take Control (FTC), a 6-week group education and behavioral program widely used to address fatigue in patients with multiple sclerosis, was comparable to a general MS education program for decreasing fatigue and improving self-efficacy in a randomized, controlled study.
In 218 subjects randomized to participate in either FTC or a general MS education program (MS: Take Control, or MSTC), Modified Fatigue Impact Scale scores improved significantly, compared with baseline and regardless of group assignment; there was no difference between the groups at visit 6 (mean change, –4.5 and –3.6 in the FTC and MSTC groups, respectively), Cinda L. Hugos of the VA Portland (Ore.) Health Care System and her colleagues reported at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Multiple Sclerosis Self-Efficacy scale scores did, however, improve significantly in the FTC group vs. the MSTC group (mean increase of 45.5 vs. a decrease of 15.8), but the improvement was not maintained at 6 months, the investigators reported in a poster at the meeting.
The two groups had comparable baseline characteristics, with a mean age of nearly 54 years, as well as similar mean time since diagnosis (12.5 years), self-administered Expanded Disability Status Scale scores (5.2), and demographics.
Fatigue is common in MS patients, occurring in up to 95% of patients, and many report that it is the most disabling symptom. FTC, which addresses medical management of fatigue, exercise, environment, and changes and choices with respect to energy and fatigue control, is often used by chapters of the National MS Society, but its effectiveness for decreasing fatigue or improving self-efficacy has not been proven, the investigators noted.
To determine if FTC decreases fatigue and increases self-efficacy, compared with a general MS education program that addresses issues such as nutrition, emotional health, cognitive problems, and fitness, the investigators randomized subjects at four sites in groups of between 3 and 10 participants to either an FTC or MSTC group. All subjects had moderate to severe fatigue. Those with pregnancy, severe depression, uncontrolled problems that would limit participation, relapse in the prior month, or initiation of a new disease-modifying treatment within the prior 3 months were excluded.
“Both FTC and MSTC structured small group programs were associated with improved self-reported fatigue at program completion and at 3- and 6-month follow-up, but there were no significant differences in fatigue scores between FTC and MSTC participants at any time point,” the investigators wrote.
Self-efficacy was significantly better among FTC participants at program completion, but was not sustained, they noted, concluding that the findings suggest that “participating in structured small group programs is associated with prolonged reductions in fatigue in people with MS and that supporting goal setting provides short-term improvements in self-efficacy.”
Further research is needed to determine whether booster sessions would be beneficial for sustaining improvements in self-efficacy, they added.
This study was supported by the Rehabilitation, Research, & Development Service of the Veterans Affairs Office of Research & Development. The authors reported having no disclosures.
NEW ORLEANS – Fatigue: Take Control (FTC), a 6-week group education and behavioral program widely used to address fatigue in patients with multiple sclerosis, was comparable to a general MS education program for decreasing fatigue and improving self-efficacy in a randomized, controlled study.
In 218 subjects randomized to participate in either FTC or a general MS education program (MS: Take Control, or MSTC), Modified Fatigue Impact Scale scores improved significantly, compared with baseline and regardless of group assignment; there was no difference between the groups at visit 6 (mean change, –4.5 and –3.6 in the FTC and MSTC groups, respectively), Cinda L. Hugos of the VA Portland (Ore.) Health Care System and her colleagues reported at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Multiple Sclerosis Self-Efficacy scale scores did, however, improve significantly in the FTC group vs. the MSTC group (mean increase of 45.5 vs. a decrease of 15.8), but the improvement was not maintained at 6 months, the investigators reported in a poster at the meeting.
The two groups had comparable baseline characteristics, with a mean age of nearly 54 years, as well as similar mean time since diagnosis (12.5 years), self-administered Expanded Disability Status Scale scores (5.2), and demographics.
Fatigue is common in MS patients, occurring in up to 95% of patients, and many report that it is the most disabling symptom. FTC, which addresses medical management of fatigue, exercise, environment, and changes and choices with respect to energy and fatigue control, is often used by chapters of the National MS Society, but its effectiveness for decreasing fatigue or improving self-efficacy has not been proven, the investigators noted.
To determine if FTC decreases fatigue and increases self-efficacy, compared with a general MS education program that addresses issues such as nutrition, emotional health, cognitive problems, and fitness, the investigators randomized subjects at four sites in groups of between 3 and 10 participants to either an FTC or MSTC group. All subjects had moderate to severe fatigue. Those with pregnancy, severe depression, uncontrolled problems that would limit participation, relapse in the prior month, or initiation of a new disease-modifying treatment within the prior 3 months were excluded.
“Both FTC and MSTC structured small group programs were associated with improved self-reported fatigue at program completion and at 3- and 6-month follow-up, but there were no significant differences in fatigue scores between FTC and MSTC participants at any time point,” the investigators wrote.
Self-efficacy was significantly better among FTC participants at program completion, but was not sustained, they noted, concluding that the findings suggest that “participating in structured small group programs is associated with prolonged reductions in fatigue in people with MS and that supporting goal setting provides short-term improvements in self-efficacy.”
Further research is needed to determine whether booster sessions would be beneficial for sustaining improvements in self-efficacy, they added.
This study was supported by the Rehabilitation, Research, & Development Service of the Veterans Affairs Office of Research & Development. The authors reported having no disclosures.
AT ACTRIMS FORUM 2016
Key clinical point: Fatigue: Take Control (FTC), a 6-week program widely used to address fatigue in patients with multiple sclerosis, was comparable to a general MS education program for decreasing fatigue and improving self-efficacy in a randomized, controlled study.
Major finding: FTC and a general MS education program improved Modified Fatigue Impact Scale scores significantly, with no difference between the groups at visit 6 (mean change, –4.5 and –3.6 in the groups, respectively).
Data source: A randomized, controlled trial of 218 MS patients.
Disclosures: This study was supported by the Rehabilitation, Research & Development Service of the VA Office of Research and Development. The authors reported having no disclosures.
L-Selectin May Not Predict PML Risk Accurately
The expression of L-selectin (CD62L) on specific T cells in peripheral blood in patients with relapsing forms of multiple sclerosis (MS) does not predict the risk of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment reliably, according to findings published January 26 in Neurology.
These findings contradict those of a previous preliminary study that used a different analytical technique. Investigators in the earlier study found a decrease in the percentage of CD4- and CD3-positive T cells expressing CD62L at least four months and often two years before PML diagnosis. They concluded that measuring the percentage of CD4- and CD3-positive T cells expressing CD62L “may improve stratification of patients taking natalizumab who are at risk for developing PML.”
Linda A. Lieberman, PhD, a research scientist at Biogen in Cambridge, Massachusetts, and colleagues sought to confirm the findings, enhance the reproducibility of the CD62L assay, “and potentially enable the deployment of CD62L as a biomarker for PML in a global setting.” The investigators, however, did not find a significant difference in the percentage of CD62L in cryopreserved peripheral blood mononuclear cells between 104 patients with relapsing forms of MS who received natalizumab and did not develop PML, and 21 patients who developed PML.
In the current study, the investigators detected a large range of CD62L (ie, 0.31% to 68.4%) in a subset of natalizumab-treated MS patients without PML at two time points at least six months apart. Because CD62L and the chemokine receptor CCR7 are coexpressed on CD4- and CD3-positive T cells, the researchers also examined the level of variation in simultaneous measurements of CD62L and CCR7 on the same cells at two separate time points in the same patients. They found that CD62L expression varied substantially, whereas CCR7 varied little, and the difference between the two was significant, “signifying that CD62L is not a stable outcome measure,” they wrote.
Dr. Lieberman and her colleagues also confirmed a positive correlation between lymphocyte viability and CD62L expression, which highlights the “technique-driven variability of the assay” used in the preliminary study.
In patient samples collected at least six months before PML diagnosis, the percentage of CD62L did not discriminate significantly between non-PML and active PML (defined as 0 to 6 months prior to diagnosis). The median percentage of CD62L varied according to the viability of cryopreserved CD4- and CD3-positive T cells. Median percentage of CD62L was no different between non-PML and pre-PML samples with lymphocyte viability greater than 75% (25.9% vs 26.3%, respectively), but was significantly lower than with non-PML and pre-PML samples with lymphocyte viability less than 75% (10.55% and 5.41%). There was no difference in lymphocyte viability between non-PML and pre-PML samples.
In a case–control comparison of patients receiving natalizumab who had multiple pre-PML samples, nine patients who developed PML had CD62L levels that in most samples were similar to those of nine matched control patients without PML.
Examination of samples from healthy controls demonstrated that CD62L also varied significantly in various disease states, such as after influenza vaccination and during hospitalization for total knee replacement surgery or methicillin-resistant Staphylococcus aureus infection, the researchers found.
—Jeff Evans
Suggested Reading
Lieberman LA, Zeng W, Singh C, et al. CD62L is not a reliable biomarker for predicting PML risk in natalizumab-treated R-MS patients. Neurology. 2016;86(4):375-381.
The expression of L-selectin (CD62L) on specific T cells in peripheral blood in patients with relapsing forms of multiple sclerosis (MS) does not predict the risk of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment reliably, according to findings published January 26 in Neurology.
These findings contradict those of a previous preliminary study that used a different analytical technique. Investigators in the earlier study found a decrease in the percentage of CD4- and CD3-positive T cells expressing CD62L at least four months and often two years before PML diagnosis. They concluded that measuring the percentage of CD4- and CD3-positive T cells expressing CD62L “may improve stratification of patients taking natalizumab who are at risk for developing PML.”
Linda A. Lieberman, PhD, a research scientist at Biogen in Cambridge, Massachusetts, and colleagues sought to confirm the findings, enhance the reproducibility of the CD62L assay, “and potentially enable the deployment of CD62L as a biomarker for PML in a global setting.” The investigators, however, did not find a significant difference in the percentage of CD62L in cryopreserved peripheral blood mononuclear cells between 104 patients with relapsing forms of MS who received natalizumab and did not develop PML, and 21 patients who developed PML.
In the current study, the investigators detected a large range of CD62L (ie, 0.31% to 68.4%) in a subset of natalizumab-treated MS patients without PML at two time points at least six months apart. Because CD62L and the chemokine receptor CCR7 are coexpressed on CD4- and CD3-positive T cells, the researchers also examined the level of variation in simultaneous measurements of CD62L and CCR7 on the same cells at two separate time points in the same patients. They found that CD62L expression varied substantially, whereas CCR7 varied little, and the difference between the two was significant, “signifying that CD62L is not a stable outcome measure,” they wrote.
Dr. Lieberman and her colleagues also confirmed a positive correlation between lymphocyte viability and CD62L expression, which highlights the “technique-driven variability of the assay” used in the preliminary study.
In patient samples collected at least six months before PML diagnosis, the percentage of CD62L did not discriminate significantly between non-PML and active PML (defined as 0 to 6 months prior to diagnosis). The median percentage of CD62L varied according to the viability of cryopreserved CD4- and CD3-positive T cells. Median percentage of CD62L was no different between non-PML and pre-PML samples with lymphocyte viability greater than 75% (25.9% vs 26.3%, respectively), but was significantly lower than with non-PML and pre-PML samples with lymphocyte viability less than 75% (10.55% and 5.41%). There was no difference in lymphocyte viability between non-PML and pre-PML samples.
In a case–control comparison of patients receiving natalizumab who had multiple pre-PML samples, nine patients who developed PML had CD62L levels that in most samples were similar to those of nine matched control patients without PML.
Examination of samples from healthy controls demonstrated that CD62L also varied significantly in various disease states, such as after influenza vaccination and during hospitalization for total knee replacement surgery or methicillin-resistant Staphylococcus aureus infection, the researchers found.
—Jeff Evans
The expression of L-selectin (CD62L) on specific T cells in peripheral blood in patients with relapsing forms of multiple sclerosis (MS) does not predict the risk of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment reliably, according to findings published January 26 in Neurology.
These findings contradict those of a previous preliminary study that used a different analytical technique. Investigators in the earlier study found a decrease in the percentage of CD4- and CD3-positive T cells expressing CD62L at least four months and often two years before PML diagnosis. They concluded that measuring the percentage of CD4- and CD3-positive T cells expressing CD62L “may improve stratification of patients taking natalizumab who are at risk for developing PML.”
Linda A. Lieberman, PhD, a research scientist at Biogen in Cambridge, Massachusetts, and colleagues sought to confirm the findings, enhance the reproducibility of the CD62L assay, “and potentially enable the deployment of CD62L as a biomarker for PML in a global setting.” The investigators, however, did not find a significant difference in the percentage of CD62L in cryopreserved peripheral blood mononuclear cells between 104 patients with relapsing forms of MS who received natalizumab and did not develop PML, and 21 patients who developed PML.
In the current study, the investigators detected a large range of CD62L (ie, 0.31% to 68.4%) in a subset of natalizumab-treated MS patients without PML at two time points at least six months apart. Because CD62L and the chemokine receptor CCR7 are coexpressed on CD4- and CD3-positive T cells, the researchers also examined the level of variation in simultaneous measurements of CD62L and CCR7 on the same cells at two separate time points in the same patients. They found that CD62L expression varied substantially, whereas CCR7 varied little, and the difference between the two was significant, “signifying that CD62L is not a stable outcome measure,” they wrote.
Dr. Lieberman and her colleagues also confirmed a positive correlation between lymphocyte viability and CD62L expression, which highlights the “technique-driven variability of the assay” used in the preliminary study.
In patient samples collected at least six months before PML diagnosis, the percentage of CD62L did not discriminate significantly between non-PML and active PML (defined as 0 to 6 months prior to diagnosis). The median percentage of CD62L varied according to the viability of cryopreserved CD4- and CD3-positive T cells. Median percentage of CD62L was no different between non-PML and pre-PML samples with lymphocyte viability greater than 75% (25.9% vs 26.3%, respectively), but was significantly lower than with non-PML and pre-PML samples with lymphocyte viability less than 75% (10.55% and 5.41%). There was no difference in lymphocyte viability between non-PML and pre-PML samples.
In a case–control comparison of patients receiving natalizumab who had multiple pre-PML samples, nine patients who developed PML had CD62L levels that in most samples were similar to those of nine matched control patients without PML.
Examination of samples from healthy controls demonstrated that CD62L also varied significantly in various disease states, such as after influenza vaccination and during hospitalization for total knee replacement surgery or methicillin-resistant Staphylococcus aureus infection, the researchers found.
—Jeff Evans
Suggested Reading
Lieberman LA, Zeng W, Singh C, et al. CD62L is not a reliable biomarker for predicting PML risk in natalizumab-treated R-MS patients. Neurology. 2016;86(4):375-381.
Suggested Reading
Lieberman LA, Zeng W, Singh C, et al. CD62L is not a reliable biomarker for predicting PML risk in natalizumab-treated R-MS patients. Neurology. 2016;86(4):375-381.
Proposal Requires Three Lesions for Diagnosis of MS
A European expert group has proposed several revisions to the 2010 McDonald criteria for the use of MRI in diagnosing multiple sclerosis (MS). In the January 25 online issue of Lancet Neurology, the MAGNIMS collaborative research network asserted that new data on the application of MRI, as well as improvements in MRI technology, demanded changes to the MS diagnostic criteria.
The first proposed recommendation is that three or more focal lesions, rather than a single lesion, should be present for a physician to diagnose the involvement of the periventricular region and to show disease dissemination in space. “A single lesion was deemed not sufficiently specific to determine whether involvement of the periventricular region is due to a demyelinating inflammatory event, and the use of one periventricular lesion for assessing dissemination in space has never been formally validated,” said Massimo Filippi, MD, Professor of Neurology at Vita-Salute San Raffaele University in Milan, and his coauthors. The authors also pointed out that incidental periventricular lesions are observed in as much as 30% of patients with migraine, and in individuals with other neurologic disorders.
In addition, the group recommended that optic nerve lesions be added to the criteria for dissemination in space. “Clinical documentation of optic nerve atrophy or pallor, neurophysiological confirmation of optic nerve dysfunction (slowed conduction), or imaging features of clinically silent optic nerve inflammation (MRI lesions or retinal nerve fiber layer thinning) support dissemination in space and, in patients without concurrent visual symptoms, dissemination in time.”
According to the new recommendations, disease dissemination in space can be shown by the involvement of at least two areas from a list of the following five possibilities: three or more periventricular lesions, one or more infratentorial lesions, one or more spinal cord lesions, one or more optic nerve lesions, or one or more cortical or juxtacortical lesions.
The group did not propose any significant changes to the criteria for dissemination in time. They did note, however, that the presence of nonenhancing black holes should not be considered as a potential alternative criterion to show dissemination in time in adult patients.
The committee also supported the existing recommendations that children age 11 or older with nonacute disseminated encephalomyelitis-like presentation should be diagnosed with the same criteria for dissemination in time and space as are applied to adults. “Several studies have confirmed that the 2010 McDonald criteria perform better than or similarly to previously proposed pediatric MS criteria for diagnosis of children with nonacute disseminated encephalomyelitis presentations and pediatric patients older than 11 years, and the consensus group therefore recommend caution when using these criteria in children younger than 11 years,” they said.
Other recommendations include that there be no distinction required between symptomatic and asymptomatic MRI lesions for diagnosing dissemination in time or space; that the whole spinal cord be imaged to define dissemination in space, particularly in patients who do not fulfill the brain MRI criteria; and that the same criteria for dissemination in space be used for primary progressive MS and relapse-onset MS, with CSF results considered for clinically uncertain cases of primary progressive MS.
—Bianca Nogrady
Suggested Reading
Filippi M, Rocca MA, Ciccarelli O, et al. MRI criteria for the diagnosis of multiple sclerosis: MAGNIMS consensus guidelines. Lancet Neurol. 2016 Jan 25 [Epub ahead of print].
A European expert group has proposed several revisions to the 2010 McDonald criteria for the use of MRI in diagnosing multiple sclerosis (MS). In the January 25 online issue of Lancet Neurology, the MAGNIMS collaborative research network asserted that new data on the application of MRI, as well as improvements in MRI technology, demanded changes to the MS diagnostic criteria.
The first proposed recommendation is that three or more focal lesions, rather than a single lesion, should be present for a physician to diagnose the involvement of the periventricular region and to show disease dissemination in space. “A single lesion was deemed not sufficiently specific to determine whether involvement of the periventricular region is due to a demyelinating inflammatory event, and the use of one periventricular lesion for assessing dissemination in space has never been formally validated,” said Massimo Filippi, MD, Professor of Neurology at Vita-Salute San Raffaele University in Milan, and his coauthors. The authors also pointed out that incidental periventricular lesions are observed in as much as 30% of patients with migraine, and in individuals with other neurologic disorders.
In addition, the group recommended that optic nerve lesions be added to the criteria for dissemination in space. “Clinical documentation of optic nerve atrophy or pallor, neurophysiological confirmation of optic nerve dysfunction (slowed conduction), or imaging features of clinically silent optic nerve inflammation (MRI lesions or retinal nerve fiber layer thinning) support dissemination in space and, in patients without concurrent visual symptoms, dissemination in time.”
According to the new recommendations, disease dissemination in space can be shown by the involvement of at least two areas from a list of the following five possibilities: three or more periventricular lesions, one or more infratentorial lesions, one or more spinal cord lesions, one or more optic nerve lesions, or one or more cortical or juxtacortical lesions.
The group did not propose any significant changes to the criteria for dissemination in time. They did note, however, that the presence of nonenhancing black holes should not be considered as a potential alternative criterion to show dissemination in time in adult patients.
The committee also supported the existing recommendations that children age 11 or older with nonacute disseminated encephalomyelitis-like presentation should be diagnosed with the same criteria for dissemination in time and space as are applied to adults. “Several studies have confirmed that the 2010 McDonald criteria perform better than or similarly to previously proposed pediatric MS criteria for diagnosis of children with nonacute disseminated encephalomyelitis presentations and pediatric patients older than 11 years, and the consensus group therefore recommend caution when using these criteria in children younger than 11 years,” they said.
Other recommendations include that there be no distinction required between symptomatic and asymptomatic MRI lesions for diagnosing dissemination in time or space; that the whole spinal cord be imaged to define dissemination in space, particularly in patients who do not fulfill the brain MRI criteria; and that the same criteria for dissemination in space be used for primary progressive MS and relapse-onset MS, with CSF results considered for clinically uncertain cases of primary progressive MS.
—Bianca Nogrady
A European expert group has proposed several revisions to the 2010 McDonald criteria for the use of MRI in diagnosing multiple sclerosis (MS). In the January 25 online issue of Lancet Neurology, the MAGNIMS collaborative research network asserted that new data on the application of MRI, as well as improvements in MRI technology, demanded changes to the MS diagnostic criteria.
The first proposed recommendation is that three or more focal lesions, rather than a single lesion, should be present for a physician to diagnose the involvement of the periventricular region and to show disease dissemination in space. “A single lesion was deemed not sufficiently specific to determine whether involvement of the periventricular region is due to a demyelinating inflammatory event, and the use of one periventricular lesion for assessing dissemination in space has never been formally validated,” said Massimo Filippi, MD, Professor of Neurology at Vita-Salute San Raffaele University in Milan, and his coauthors. The authors also pointed out that incidental periventricular lesions are observed in as much as 30% of patients with migraine, and in individuals with other neurologic disorders.
In addition, the group recommended that optic nerve lesions be added to the criteria for dissemination in space. “Clinical documentation of optic nerve atrophy or pallor, neurophysiological confirmation of optic nerve dysfunction (slowed conduction), or imaging features of clinically silent optic nerve inflammation (MRI lesions or retinal nerve fiber layer thinning) support dissemination in space and, in patients without concurrent visual symptoms, dissemination in time.”
According to the new recommendations, disease dissemination in space can be shown by the involvement of at least two areas from a list of the following five possibilities: three or more periventricular lesions, one or more infratentorial lesions, one or more spinal cord lesions, one or more optic nerve lesions, or one or more cortical or juxtacortical lesions.
The group did not propose any significant changes to the criteria for dissemination in time. They did note, however, that the presence of nonenhancing black holes should not be considered as a potential alternative criterion to show dissemination in time in adult patients.
The committee also supported the existing recommendations that children age 11 or older with nonacute disseminated encephalomyelitis-like presentation should be diagnosed with the same criteria for dissemination in time and space as are applied to adults. “Several studies have confirmed that the 2010 McDonald criteria perform better than or similarly to previously proposed pediatric MS criteria for diagnosis of children with nonacute disseminated encephalomyelitis presentations and pediatric patients older than 11 years, and the consensus group therefore recommend caution when using these criteria in children younger than 11 years,” they said.
Other recommendations include that there be no distinction required between symptomatic and asymptomatic MRI lesions for diagnosing dissemination in time or space; that the whole spinal cord be imaged to define dissemination in space, particularly in patients who do not fulfill the brain MRI criteria; and that the same criteria for dissemination in space be used for primary progressive MS and relapse-onset MS, with CSF results considered for clinically uncertain cases of primary progressive MS.
—Bianca Nogrady
Suggested Reading
Filippi M, Rocca MA, Ciccarelli O, et al. MRI criteria for the diagnosis of multiple sclerosis: MAGNIMS consensus guidelines. Lancet Neurol. 2016 Jan 25 [Epub ahead of print].
Suggested Reading
Filippi M, Rocca MA, Ciccarelli O, et al. MRI criteria for the diagnosis of multiple sclerosis: MAGNIMS consensus guidelines. Lancet Neurol. 2016 Jan 25 [Epub ahead of print].
Phenytoin May Offer Neuroprotection to Patients With Optic Neuritis
Patients with acute demyelinating optic neuritis who received phenytoin lost 30% less of their retinal nerve fiber layer (RNFL) than did placebo-treated patients in a randomized phase II study published online ahead of print January 25 in Lancet Neurology. “The results of this clinical trial support the concept of neuroprotection using phenytoin to inhibit voltage-gated sodium channels in patients with acute optic neuritis,” said Rhian Raftopoulos, MD, of the National Hospital for Neurology and Neurosurgery in London, and coauthors.
In the study of 86 people with acute optic neuritis, investigators randomized 29 participants to receive 4 mg/kg/day of oral phenytoin, 13 participants to receive 6 mg/kg/day of oral phenytoin, and 44 participants to receive placebo for three months. All participants were randomized within 14 days of vision loss. One-third of the patients had previously been diagnosed with multiple sclerosis or was diagnosed at presentation, and 74% had at least one brain lesion on MRI.
Treatment with phenytoin was associated with a decline of mean RNFL thickness in the affected eye from 130.62 μm at baseline to 81.46 μm at six months, compared with a decline from 125.20 μm to 74.29 μm in the placebo group, representing a statistically significant adjusted mean difference of 7.15 μm.
The researchers also noted a significant 34% reduction in macular volume loss in the treatment arm, compared with placebo, representing an adjusted mean difference of 0.20 mm3. However, the treatment had no significant effect on low-contrast visual acuity and visual evoked potentials.
The most common adverse event in the treatment arm was maculopapular rash, which was judged as severe in one patient treated with phenytoin.
“The absence of regular, early outcome assessments around one to two months after initiation of treatment makes it hard to interpret the results because they would have helped to rule out a primarily anti-inflammatory effect of the treatment by tracking RNFL swelling and possible optic nerve inflammation, especially given that there was higher baseline RNFL thickness and worse low-contrast visual acuity in the patients who received phenytoin,” said Shiv Saidha, MBBCh, Assistant Professor of Neurology, and Peter A. Calabresi, MD, Director of the Division of Neuroimmunology, both at Johns Hopkins University in Baltimore, in an accompanying editorial. “If the true RNFL thickness at baseline in the affected eye of patients in the phenytoin group was higher than those in the placebo group, it could have accounted for the findings, even though the investigators made a prespecified adjustment for it.
“Although the results of this study are a major advancement and undeniably encouraging, future studies need to include more frequent optical coherence tomography (OCT) sampling, as well as more detailed OCT-segmentation-derived retinal measures such as ganglion cell plus inner plexiform layer thickness, which do not swell during acute optic neuritis, mitigating the need for statistical corrections involving the unaffected eye,” they concluded.
—Bianca Nogrady
Suggested Reading
Raftopoulos R, Hickman SJ, Toosy A, et al. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016 Jan 25 [Epub ahead of print].
Saidha S, Calabresi PA. Phenytoin in acute optic neuritis: neuroprotective or not? Lancet Neurol. 2016 Jan 25 [Epub ahead of print].
Patients with acute demyelinating optic neuritis who received phenytoin lost 30% less of their retinal nerve fiber layer (RNFL) than did placebo-treated patients in a randomized phase II study published online ahead of print January 25 in Lancet Neurology. “The results of this clinical trial support the concept of neuroprotection using phenytoin to inhibit voltage-gated sodium channels in patients with acute optic neuritis,” said Rhian Raftopoulos, MD, of the National Hospital for Neurology and Neurosurgery in London, and coauthors.
In the study of 86 people with acute optic neuritis, investigators randomized 29 participants to receive 4 mg/kg/day of oral phenytoin, 13 participants to receive 6 mg/kg/day of oral phenytoin, and 44 participants to receive placebo for three months. All participants were randomized within 14 days of vision loss. One-third of the patients had previously been diagnosed with multiple sclerosis or was diagnosed at presentation, and 74% had at least one brain lesion on MRI.
Treatment with phenytoin was associated with a decline of mean RNFL thickness in the affected eye from 130.62 μm at baseline to 81.46 μm at six months, compared with a decline from 125.20 μm to 74.29 μm in the placebo group, representing a statistically significant adjusted mean difference of 7.15 μm.
The researchers also noted a significant 34% reduction in macular volume loss in the treatment arm, compared with placebo, representing an adjusted mean difference of 0.20 mm3. However, the treatment had no significant effect on low-contrast visual acuity and visual evoked potentials.
The most common adverse event in the treatment arm was maculopapular rash, which was judged as severe in one patient treated with phenytoin.
“The absence of regular, early outcome assessments around one to two months after initiation of treatment makes it hard to interpret the results because they would have helped to rule out a primarily anti-inflammatory effect of the treatment by tracking RNFL swelling and possible optic nerve inflammation, especially given that there was higher baseline RNFL thickness and worse low-contrast visual acuity in the patients who received phenytoin,” said Shiv Saidha, MBBCh, Assistant Professor of Neurology, and Peter A. Calabresi, MD, Director of the Division of Neuroimmunology, both at Johns Hopkins University in Baltimore, in an accompanying editorial. “If the true RNFL thickness at baseline in the affected eye of patients in the phenytoin group was higher than those in the placebo group, it could have accounted for the findings, even though the investigators made a prespecified adjustment for it.
“Although the results of this study are a major advancement and undeniably encouraging, future studies need to include more frequent optical coherence tomography (OCT) sampling, as well as more detailed OCT-segmentation-derived retinal measures such as ganglion cell plus inner plexiform layer thickness, which do not swell during acute optic neuritis, mitigating the need for statistical corrections involving the unaffected eye,” they concluded.
—Bianca Nogrady
Patients with acute demyelinating optic neuritis who received phenytoin lost 30% less of their retinal nerve fiber layer (RNFL) than did placebo-treated patients in a randomized phase II study published online ahead of print January 25 in Lancet Neurology. “The results of this clinical trial support the concept of neuroprotection using phenytoin to inhibit voltage-gated sodium channels in patients with acute optic neuritis,” said Rhian Raftopoulos, MD, of the National Hospital for Neurology and Neurosurgery in London, and coauthors.
In the study of 86 people with acute optic neuritis, investigators randomized 29 participants to receive 4 mg/kg/day of oral phenytoin, 13 participants to receive 6 mg/kg/day of oral phenytoin, and 44 participants to receive placebo for three months. All participants were randomized within 14 days of vision loss. One-third of the patients had previously been diagnosed with multiple sclerosis or was diagnosed at presentation, and 74% had at least one brain lesion on MRI.
Treatment with phenytoin was associated with a decline of mean RNFL thickness in the affected eye from 130.62 μm at baseline to 81.46 μm at six months, compared with a decline from 125.20 μm to 74.29 μm in the placebo group, representing a statistically significant adjusted mean difference of 7.15 μm.
The researchers also noted a significant 34% reduction in macular volume loss in the treatment arm, compared with placebo, representing an adjusted mean difference of 0.20 mm3. However, the treatment had no significant effect on low-contrast visual acuity and visual evoked potentials.
The most common adverse event in the treatment arm was maculopapular rash, which was judged as severe in one patient treated with phenytoin.
“The absence of regular, early outcome assessments around one to two months after initiation of treatment makes it hard to interpret the results because they would have helped to rule out a primarily anti-inflammatory effect of the treatment by tracking RNFL swelling and possible optic nerve inflammation, especially given that there was higher baseline RNFL thickness and worse low-contrast visual acuity in the patients who received phenytoin,” said Shiv Saidha, MBBCh, Assistant Professor of Neurology, and Peter A. Calabresi, MD, Director of the Division of Neuroimmunology, both at Johns Hopkins University in Baltimore, in an accompanying editorial. “If the true RNFL thickness at baseline in the affected eye of patients in the phenytoin group was higher than those in the placebo group, it could have accounted for the findings, even though the investigators made a prespecified adjustment for it.
“Although the results of this study are a major advancement and undeniably encouraging, future studies need to include more frequent optical coherence tomography (OCT) sampling, as well as more detailed OCT-segmentation-derived retinal measures such as ganglion cell plus inner plexiform layer thickness, which do not swell during acute optic neuritis, mitigating the need for statistical corrections involving the unaffected eye,” they concluded.
—Bianca Nogrady
Suggested Reading
Raftopoulos R, Hickman SJ, Toosy A, et al. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016 Jan 25 [Epub ahead of print].
Saidha S, Calabresi PA. Phenytoin in acute optic neuritis: neuroprotective or not? Lancet Neurol. 2016 Jan 25 [Epub ahead of print].
Suggested Reading
Raftopoulos R, Hickman SJ, Toosy A, et al. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016 Jan 25 [Epub ahead of print].
Saidha S, Calabresi PA. Phenytoin in acute optic neuritis: neuroprotective or not? Lancet Neurol. 2016 Jan 25 [Epub ahead of print].
Natalizumab May Increase Risk of JCV Seroconversion
Patients with multiple sclerosis (MS) who receive natalizumab may have as much as a 10-fold greater risk of seroconversion to John Cunningham virus (JCV)-positive status, according to a study published online January 27 in Neurology Neuroimmunology & Neuroinflammation.
“An increase in the levels of anti-JCV antibodies could signify an increased risk of progressive multifocal leukoencephalopathy (PML),” said the study’s senior author, Heinz Wiendl, MD, Professor of Neurology at the University of Münster in Germany.
Dr. Wiendl and colleagues performed a longitudinal analysis of 525 German patients with MS and 711 French patients with MS, all of whom were treated with natalizumab, to assess whether the therapy influenced JCV seroconversion or JCV index value (ie, the level of anti-JCV antibody titers). An independent contractor processed and analyzed sera samples with the second-generation enzyme-linked immunosorbent assay kit STRATIFY JCV DxSelect.
Seroconversion and Increasing Index Value
Of the 525 German patients, 296 (56.4%) were JCV-negative throughout the observation period, and 171 were JCV-positive (32.6%). Forty-three patients changed from being JCV-negative to JCV-positive (8.2%), and 15 patients changed from being JCV-positive to JCV-negative (2.9%). When the authors used JCV serostatus to determine seroconversion, the longitudinal assessment started out with 339 initially JCV-negative patients. The serostatus of 43 of these initially JCV-negative patients changed to JCV-positive, which is a rate of 12.7% in 14.8 months (10.3% per year).
Of the 711 French patients, 243 initially were JCV-negative. The serostatus of 20 (8.2%) of these latter patients changed to JCV-positive in their first year of treatment, and 21 (8.6%) of the patients became JCV-positive in their second year of treatment. In all, the serostatus of 41 of 243 patients (16.9%) changed to JCV-positive in the first two years of natalizumab treatment (8.5% per year).
In addition, JCV index values changed in 525 patients during the observation period. The proportion of patients with an index value less than 0.4 was reduced by 20 patients (ie, from 65.1% to 61.3%), and the group of patients with low risk (ie, values between 0.4 and 0.9) was reduced by one patient to 7.8%. The patient groups with medium (ie, 0.9–1.5) and high risk (ie, greater than 1.5) increased by seven patients from 4.6% to 5.9% and by 14 patients from 22.3% to 25%, respectively.Furthermore, 161 of 201 JCV-positive patients (80%) had stable JCV index values over time. The remaining 40 patients (20%) had fluctuations of more than 30% in 14.8 months. Six of these patients (3%) had decreasing index values, and 34 (17%) had increasing index values (mean, 200.8%). Overall, the index value of all JCV-positive patients increased by an average of 15.9% in 14.8 months (12.9% per year).
Increased Index May Not Indicate Imminent PML
The high rate of seroconversion that the investigators observed “clearly supports the facilitation by treatment with natalizumab,” said Dr. Wiendl. “Our observed seroconversion of 8% to 10% per year and the rise in seroprevalence of 5% to 6% in 15 to 24 months is at least eight to 10 times as much as would be expected by age.” The study results imply that not every patient with MS is susceptible to JCV seroconversion by treatment, but natalizumab might facilitate seroconversion in patients who are susceptible.
No research has examined the influence of other MS treatments on JCV index values, and the investigators thus cannot be certain that natalizumab treatment caused the increase in index values observed in the study. But because there was no correlation between age and index value in JCV-positive patients, it is valid to speculate that natalizumab treatment induces rising JCV index values.
“If the hypothesis that treatment with natalizumab is associated with enhanced JCV seroconversion and higher index values is proven, it would also be important to determine whether cessation of natalizumab therapy (or perhaps prolonged infusion intervals) could lead to lower JCV index values as well,” Dr. Wiendl continued. The association “does not diminish [natalizumab’s] clinical efficacy, but calls for more elaborate strategies for PML risk stratification according to current scientific developments, also regarding patients with prior use of immunosuppressants, where the JCV index is not helpful.
“It is important that people with MS taking natalizumab speak with their doctor before making any changes to their treatment,” Dr. Wiendl added. “Still, this study shows anti-JCV antibodies may serve as a useful biomarker…. The results of this study underscore the need for frequent monitoring of anti-JCV antibodies in people who are being treated with natalizumab for MS.”
JCV serology, however, should not be the only PML risk biomarker to stratify patients treated with natalizumab, said Dr. Wiendl. Neurologists should explore and potentially apply additional biomarkers such as CD62L in peripheral blood or IgM bands in CSF. Together, all of these biomarkers may provide more accurate information about patients’ PML risk and help reduce the incidence of PML.
The investigators’ data extend earlier paired, longitudinal studies in various countries of patients treated with natalizumab who had similarly high rates of conversion and a rise in titers, said Adil Javed, MD, PhD, Associate Professor of Neurology, and Anthony T. Reder, MD, Professor of Neurology, both at the University of Chicago, in an accompanying editorial. Although the JCV index appears to be a valid serum marker of risk for PML, “risk is relative,” they said. “Despite a higher JCV replication state, an increase in JCV-antibody index does not necessarily mean that PML infection is imminent…. Schwab et al extend growing observations that JCV-antibody index values need to be monitored and that seroconversion or rising JCV-antibody titers alter the risk of PML in patients treated with natalizumab.”
—Erik Greb
Suggested Reading
Schwab N, Schneider-Hohendorf T, Pignolet B, et al. Therapy with natalizumab is associated with high JCV seroconversion and rising JCV index values. Neurol Neuroimmunol Neuroinflamm. 2016;3(1):e195.
Javed A, Reder AT. Rising JCV-Ab index during natalizumab therapy for MS: Inauspicious for a highly efficacious drug. Neurol Neuroimmunol Neuroinflamm. 2016;3(1):e199.
Patients with multiple sclerosis (MS) who receive natalizumab may have as much as a 10-fold greater risk of seroconversion to John Cunningham virus (JCV)-positive status, according to a study published online January 27 in Neurology Neuroimmunology & Neuroinflammation.
“An increase in the levels of anti-JCV antibodies could signify an increased risk of progressive multifocal leukoencephalopathy (PML),” said the study’s senior author, Heinz Wiendl, MD, Professor of Neurology at the University of Münster in Germany.
Dr. Wiendl and colleagues performed a longitudinal analysis of 525 German patients with MS and 711 French patients with MS, all of whom were treated with natalizumab, to assess whether the therapy influenced JCV seroconversion or JCV index value (ie, the level of anti-JCV antibody titers). An independent contractor processed and analyzed sera samples with the second-generation enzyme-linked immunosorbent assay kit STRATIFY JCV DxSelect.
Seroconversion and Increasing Index Value
Of the 525 German patients, 296 (56.4%) were JCV-negative throughout the observation period, and 171 were JCV-positive (32.6%). Forty-three patients changed from being JCV-negative to JCV-positive (8.2%), and 15 patients changed from being JCV-positive to JCV-negative (2.9%). When the authors used JCV serostatus to determine seroconversion, the longitudinal assessment started out with 339 initially JCV-negative patients. The serostatus of 43 of these initially JCV-negative patients changed to JCV-positive, which is a rate of 12.7% in 14.8 months (10.3% per year).
Of the 711 French patients, 243 initially were JCV-negative. The serostatus of 20 (8.2%) of these latter patients changed to JCV-positive in their first year of treatment, and 21 (8.6%) of the patients became JCV-positive in their second year of treatment. In all, the serostatus of 41 of 243 patients (16.9%) changed to JCV-positive in the first two years of natalizumab treatment (8.5% per year).
In addition, JCV index values changed in 525 patients during the observation period. The proportion of patients with an index value less than 0.4 was reduced by 20 patients (ie, from 65.1% to 61.3%), and the group of patients with low risk (ie, values between 0.4 and 0.9) was reduced by one patient to 7.8%. The patient groups with medium (ie, 0.9–1.5) and high risk (ie, greater than 1.5) increased by seven patients from 4.6% to 5.9% and by 14 patients from 22.3% to 25%, respectively.Furthermore, 161 of 201 JCV-positive patients (80%) had stable JCV index values over time. The remaining 40 patients (20%) had fluctuations of more than 30% in 14.8 months. Six of these patients (3%) had decreasing index values, and 34 (17%) had increasing index values (mean, 200.8%). Overall, the index value of all JCV-positive patients increased by an average of 15.9% in 14.8 months (12.9% per year).
Increased Index May Not Indicate Imminent PML
The high rate of seroconversion that the investigators observed “clearly supports the facilitation by treatment with natalizumab,” said Dr. Wiendl. “Our observed seroconversion of 8% to 10% per year and the rise in seroprevalence of 5% to 6% in 15 to 24 months is at least eight to 10 times as much as would be expected by age.” The study results imply that not every patient with MS is susceptible to JCV seroconversion by treatment, but natalizumab might facilitate seroconversion in patients who are susceptible.
No research has examined the influence of other MS treatments on JCV index values, and the investigators thus cannot be certain that natalizumab treatment caused the increase in index values observed in the study. But because there was no correlation between age and index value in JCV-positive patients, it is valid to speculate that natalizumab treatment induces rising JCV index values.
“If the hypothesis that treatment with natalizumab is associated with enhanced JCV seroconversion and higher index values is proven, it would also be important to determine whether cessation of natalizumab therapy (or perhaps prolonged infusion intervals) could lead to lower JCV index values as well,” Dr. Wiendl continued. The association “does not diminish [natalizumab’s] clinical efficacy, but calls for more elaborate strategies for PML risk stratification according to current scientific developments, also regarding patients with prior use of immunosuppressants, where the JCV index is not helpful.
“It is important that people with MS taking natalizumab speak with their doctor before making any changes to their treatment,” Dr. Wiendl added. “Still, this study shows anti-JCV antibodies may serve as a useful biomarker…. The results of this study underscore the need for frequent monitoring of anti-JCV antibodies in people who are being treated with natalizumab for MS.”
JCV serology, however, should not be the only PML risk biomarker to stratify patients treated with natalizumab, said Dr. Wiendl. Neurologists should explore and potentially apply additional biomarkers such as CD62L in peripheral blood or IgM bands in CSF. Together, all of these biomarkers may provide more accurate information about patients’ PML risk and help reduce the incidence of PML.
The investigators’ data extend earlier paired, longitudinal studies in various countries of patients treated with natalizumab who had similarly high rates of conversion and a rise in titers, said Adil Javed, MD, PhD, Associate Professor of Neurology, and Anthony T. Reder, MD, Professor of Neurology, both at the University of Chicago, in an accompanying editorial. Although the JCV index appears to be a valid serum marker of risk for PML, “risk is relative,” they said. “Despite a higher JCV replication state, an increase in JCV-antibody index does not necessarily mean that PML infection is imminent…. Schwab et al extend growing observations that JCV-antibody index values need to be monitored and that seroconversion or rising JCV-antibody titers alter the risk of PML in patients treated with natalizumab.”
—Erik Greb
Patients with multiple sclerosis (MS) who receive natalizumab may have as much as a 10-fold greater risk of seroconversion to John Cunningham virus (JCV)-positive status, according to a study published online January 27 in Neurology Neuroimmunology & Neuroinflammation.
“An increase in the levels of anti-JCV antibodies could signify an increased risk of progressive multifocal leukoencephalopathy (PML),” said the study’s senior author, Heinz Wiendl, MD, Professor of Neurology at the University of Münster in Germany.
Dr. Wiendl and colleagues performed a longitudinal analysis of 525 German patients with MS and 711 French patients with MS, all of whom were treated with natalizumab, to assess whether the therapy influenced JCV seroconversion or JCV index value (ie, the level of anti-JCV antibody titers). An independent contractor processed and analyzed sera samples with the second-generation enzyme-linked immunosorbent assay kit STRATIFY JCV DxSelect.
Seroconversion and Increasing Index Value
Of the 525 German patients, 296 (56.4%) were JCV-negative throughout the observation period, and 171 were JCV-positive (32.6%). Forty-three patients changed from being JCV-negative to JCV-positive (8.2%), and 15 patients changed from being JCV-positive to JCV-negative (2.9%). When the authors used JCV serostatus to determine seroconversion, the longitudinal assessment started out with 339 initially JCV-negative patients. The serostatus of 43 of these initially JCV-negative patients changed to JCV-positive, which is a rate of 12.7% in 14.8 months (10.3% per year).
Of the 711 French patients, 243 initially were JCV-negative. The serostatus of 20 (8.2%) of these latter patients changed to JCV-positive in their first year of treatment, and 21 (8.6%) of the patients became JCV-positive in their second year of treatment. In all, the serostatus of 41 of 243 patients (16.9%) changed to JCV-positive in the first two years of natalizumab treatment (8.5% per year).
In addition, JCV index values changed in 525 patients during the observation period. The proportion of patients with an index value less than 0.4 was reduced by 20 patients (ie, from 65.1% to 61.3%), and the group of patients with low risk (ie, values between 0.4 and 0.9) was reduced by one patient to 7.8%. The patient groups with medium (ie, 0.9–1.5) and high risk (ie, greater than 1.5) increased by seven patients from 4.6% to 5.9% and by 14 patients from 22.3% to 25%, respectively.Furthermore, 161 of 201 JCV-positive patients (80%) had stable JCV index values over time. The remaining 40 patients (20%) had fluctuations of more than 30% in 14.8 months. Six of these patients (3%) had decreasing index values, and 34 (17%) had increasing index values (mean, 200.8%). Overall, the index value of all JCV-positive patients increased by an average of 15.9% in 14.8 months (12.9% per year).
Increased Index May Not Indicate Imminent PML
The high rate of seroconversion that the investigators observed “clearly supports the facilitation by treatment with natalizumab,” said Dr. Wiendl. “Our observed seroconversion of 8% to 10% per year and the rise in seroprevalence of 5% to 6% in 15 to 24 months is at least eight to 10 times as much as would be expected by age.” The study results imply that not every patient with MS is susceptible to JCV seroconversion by treatment, but natalizumab might facilitate seroconversion in patients who are susceptible.
No research has examined the influence of other MS treatments on JCV index values, and the investigators thus cannot be certain that natalizumab treatment caused the increase in index values observed in the study. But because there was no correlation between age and index value in JCV-positive patients, it is valid to speculate that natalizumab treatment induces rising JCV index values.
“If the hypothesis that treatment with natalizumab is associated with enhanced JCV seroconversion and higher index values is proven, it would also be important to determine whether cessation of natalizumab therapy (or perhaps prolonged infusion intervals) could lead to lower JCV index values as well,” Dr. Wiendl continued. The association “does not diminish [natalizumab’s] clinical efficacy, but calls for more elaborate strategies for PML risk stratification according to current scientific developments, also regarding patients with prior use of immunosuppressants, where the JCV index is not helpful.
“It is important that people with MS taking natalizumab speak with their doctor before making any changes to their treatment,” Dr. Wiendl added. “Still, this study shows anti-JCV antibodies may serve as a useful biomarker…. The results of this study underscore the need for frequent monitoring of anti-JCV antibodies in people who are being treated with natalizumab for MS.”
JCV serology, however, should not be the only PML risk biomarker to stratify patients treated with natalizumab, said Dr. Wiendl. Neurologists should explore and potentially apply additional biomarkers such as CD62L in peripheral blood or IgM bands in CSF. Together, all of these biomarkers may provide more accurate information about patients’ PML risk and help reduce the incidence of PML.
The investigators’ data extend earlier paired, longitudinal studies in various countries of patients treated with natalizumab who had similarly high rates of conversion and a rise in titers, said Adil Javed, MD, PhD, Associate Professor of Neurology, and Anthony T. Reder, MD, Professor of Neurology, both at the University of Chicago, in an accompanying editorial. Although the JCV index appears to be a valid serum marker of risk for PML, “risk is relative,” they said. “Despite a higher JCV replication state, an increase in JCV-antibody index does not necessarily mean that PML infection is imminent…. Schwab et al extend growing observations that JCV-antibody index values need to be monitored and that seroconversion or rising JCV-antibody titers alter the risk of PML in patients treated with natalizumab.”
—Erik Greb
Suggested Reading
Schwab N, Schneider-Hohendorf T, Pignolet B, et al. Therapy with natalizumab is associated with high JCV seroconversion and rising JCV index values. Neurol Neuroimmunol Neuroinflamm. 2016;3(1):e195.
Javed A, Reder AT. Rising JCV-Ab index during natalizumab therapy for MS: Inauspicious for a highly efficacious drug. Neurol Neuroimmunol Neuroinflamm. 2016;3(1):e199.
Suggested Reading
Schwab N, Schneider-Hohendorf T, Pignolet B, et al. Therapy with natalizumab is associated with high JCV seroconversion and rising JCV index values. Neurol Neuroimmunol Neuroinflamm. 2016;3(1):e195.
Javed A, Reder AT. Rising JCV-Ab index during natalizumab therapy for MS: Inauspicious for a highly efficacious drug. Neurol Neuroimmunol Neuroinflamm. 2016;3(1):e199.
Stem cell therapy for MS: Steady progress but not ready for general use
NEW ORLEANS – Stem cell-mediated functional regeneration continues to attract interest in the treatment of multiple sclerosis (MS). The reality, however, is daunting.
“Several types of cell-based therapeutic strategies are under investigation, with different risks, benefits, and goals. Some of these strategies show promise but significant methodological questions need to be answered,” Dr. Andrew D. Goodman said at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
The present reality is that stem cell transplantation is not yet ready for general use to treat MS. Yet, the possible benefits of the approach demand further exploration, including clinical trials, according to Dr. Goodman, professor of neurology, chief of the neuroimmunology unit, and director of the multiple sclerosis center at the University of Rochester (N.Y.).
MS stem cell therapy hinges on the pluripotent nature of stem cells, particularly mesenchymal stem cells (MSCs) and hematopoietic stem cells. MS therapy would involve regeneration of nerve cell myelin in the brain and/or spinal cord and possibly suppression of inflammation.
Autologous HSC transplantation
Immunoablation followed by the autologous HSC transplantation (HSCT) has been explored in the ASTIMS phase II randomized trials (Neurology. Mar 10;84[10]:981-8 and HALT-MS, JAMA Neurol. 2015 Feb;72[2]:159-69), and in a Northwestern University case series (JAMA. 2015 Jan 20;313[3]:275-84).
ASTIMS compared high-dose chemotherapy followed by autologous HSCT with mitoxantrone (which is no longer used). Only 22% percent of patients had relapsing-remitting MS (RRMS; the one where HSCT generally works) and 78% had primary progressive MS (where HSCT generally does not work well or is not optimal). Yet, HSCT worked, with new T2 lesions reduced by 79%. No difference in disability progression was evident. Interim (3-year) results of HALT-MS were encouraging, with sustained remission of active RRMS and improved neurologic function. The Northwestern case series also documented improvements in neurologic disability and other clinical outcomes.
“The available data suggest that immunoablation and HSCT is highly effective in active RRMS. Patients most likely to benefit are young and still ambulatory with a relatively recent disease onset featuring highly active MS with MRI lesion activity and continued activity despite first- and second-line agents,” Dr. Goodman said.
While encouraging, the small patient numbers of the two trials and uncontrolled nature of the case series prevent conclusions concerning the therapeutic use of autologous HSCT in RRMS. Furthermore, risks of the approach include MS relapse, treatment-related adverse effects, adverse effects due to myelosuppression and immunoablation, and secondary autoimmune disorders that may arise at a later time.
Mesenchymal stem cell transplantation
MSCs offer the advantages of a variety of sources in adult tissue, established methods of culture, and either local or peripheral administration. Their finite capacity for proliferation is a drawback. Studies to date of MSC transplantation in MS have involved about 100 patients, so it is much too early to consider MSC use. Even if therapy is contemplated, whether it should be directed at quelling inflammation or to promote repair is undecided. As well, cell production and delivery issues need to be addressed, Dr. Goodman said.
Human oligodendrocyte progenitor cell transplantation
The implantation of CD 140a+ cell populations containing human oligodendrocyte progenitor cells (hOPCs) into the cerebral hemispheres of patients with non-relapsing secondary progressive MS as a means of stabilizing or improving neurological function is being planned. The NYSTEM project, with Dr. Goodman as a lead investigator, will first seek to identify the maximum tolerated dose of hOPCs.
The study is planned with the knowledge of safety issues that include cancer tumorigenesis. Yet exploration of the possible benefits will be evident only by testing in humans. “I don’t know of any way to find out except by trying,” Dr. Goodman said.
Dr. Goodman disclosed receiving research support and/or serving as a consultant to Avanir, Teva, Genzyme/Sanofi, Sun Pharma, Ono, Roche, AbbVie, Biogen, Novartis, Acorda, Purdue, and EMD Serono.
NEW ORLEANS – Stem cell-mediated functional regeneration continues to attract interest in the treatment of multiple sclerosis (MS). The reality, however, is daunting.
“Several types of cell-based therapeutic strategies are under investigation, with different risks, benefits, and goals. Some of these strategies show promise but significant methodological questions need to be answered,” Dr. Andrew D. Goodman said at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
The present reality is that stem cell transplantation is not yet ready for general use to treat MS. Yet, the possible benefits of the approach demand further exploration, including clinical trials, according to Dr. Goodman, professor of neurology, chief of the neuroimmunology unit, and director of the multiple sclerosis center at the University of Rochester (N.Y.).
MS stem cell therapy hinges on the pluripotent nature of stem cells, particularly mesenchymal stem cells (MSCs) and hematopoietic stem cells. MS therapy would involve regeneration of nerve cell myelin in the brain and/or spinal cord and possibly suppression of inflammation.
Autologous HSC transplantation
Immunoablation followed by the autologous HSC transplantation (HSCT) has been explored in the ASTIMS phase II randomized trials (Neurology. Mar 10;84[10]:981-8 and HALT-MS, JAMA Neurol. 2015 Feb;72[2]:159-69), and in a Northwestern University case series (JAMA. 2015 Jan 20;313[3]:275-84).
ASTIMS compared high-dose chemotherapy followed by autologous HSCT with mitoxantrone (which is no longer used). Only 22% percent of patients had relapsing-remitting MS (RRMS; the one where HSCT generally works) and 78% had primary progressive MS (where HSCT generally does not work well or is not optimal). Yet, HSCT worked, with new T2 lesions reduced by 79%. No difference in disability progression was evident. Interim (3-year) results of HALT-MS were encouraging, with sustained remission of active RRMS and improved neurologic function. The Northwestern case series also documented improvements in neurologic disability and other clinical outcomes.
“The available data suggest that immunoablation and HSCT is highly effective in active RRMS. Patients most likely to benefit are young and still ambulatory with a relatively recent disease onset featuring highly active MS with MRI lesion activity and continued activity despite first- and second-line agents,” Dr. Goodman said.
While encouraging, the small patient numbers of the two trials and uncontrolled nature of the case series prevent conclusions concerning the therapeutic use of autologous HSCT in RRMS. Furthermore, risks of the approach include MS relapse, treatment-related adverse effects, adverse effects due to myelosuppression and immunoablation, and secondary autoimmune disorders that may arise at a later time.
Mesenchymal stem cell transplantation
MSCs offer the advantages of a variety of sources in adult tissue, established methods of culture, and either local or peripheral administration. Their finite capacity for proliferation is a drawback. Studies to date of MSC transplantation in MS have involved about 100 patients, so it is much too early to consider MSC use. Even if therapy is contemplated, whether it should be directed at quelling inflammation or to promote repair is undecided. As well, cell production and delivery issues need to be addressed, Dr. Goodman said.
Human oligodendrocyte progenitor cell transplantation
The implantation of CD 140a+ cell populations containing human oligodendrocyte progenitor cells (hOPCs) into the cerebral hemispheres of patients with non-relapsing secondary progressive MS as a means of stabilizing or improving neurological function is being planned. The NYSTEM project, with Dr. Goodman as a lead investigator, will first seek to identify the maximum tolerated dose of hOPCs.
The study is planned with the knowledge of safety issues that include cancer tumorigenesis. Yet exploration of the possible benefits will be evident only by testing in humans. “I don’t know of any way to find out except by trying,” Dr. Goodman said.
Dr. Goodman disclosed receiving research support and/or serving as a consultant to Avanir, Teva, Genzyme/Sanofi, Sun Pharma, Ono, Roche, AbbVie, Biogen, Novartis, Acorda, Purdue, and EMD Serono.
NEW ORLEANS – Stem cell-mediated functional regeneration continues to attract interest in the treatment of multiple sclerosis (MS). The reality, however, is daunting.
“Several types of cell-based therapeutic strategies are under investigation, with different risks, benefits, and goals. Some of these strategies show promise but significant methodological questions need to be answered,” Dr. Andrew D. Goodman said at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
The present reality is that stem cell transplantation is not yet ready for general use to treat MS. Yet, the possible benefits of the approach demand further exploration, including clinical trials, according to Dr. Goodman, professor of neurology, chief of the neuroimmunology unit, and director of the multiple sclerosis center at the University of Rochester (N.Y.).
MS stem cell therapy hinges on the pluripotent nature of stem cells, particularly mesenchymal stem cells (MSCs) and hematopoietic stem cells. MS therapy would involve regeneration of nerve cell myelin in the brain and/or spinal cord and possibly suppression of inflammation.
Autologous HSC transplantation
Immunoablation followed by the autologous HSC transplantation (HSCT) has been explored in the ASTIMS phase II randomized trials (Neurology. Mar 10;84[10]:981-8 and HALT-MS, JAMA Neurol. 2015 Feb;72[2]:159-69), and in a Northwestern University case series (JAMA. 2015 Jan 20;313[3]:275-84).
ASTIMS compared high-dose chemotherapy followed by autologous HSCT with mitoxantrone (which is no longer used). Only 22% percent of patients had relapsing-remitting MS (RRMS; the one where HSCT generally works) and 78% had primary progressive MS (where HSCT generally does not work well or is not optimal). Yet, HSCT worked, with new T2 lesions reduced by 79%. No difference in disability progression was evident. Interim (3-year) results of HALT-MS were encouraging, with sustained remission of active RRMS and improved neurologic function. The Northwestern case series also documented improvements in neurologic disability and other clinical outcomes.
“The available data suggest that immunoablation and HSCT is highly effective in active RRMS. Patients most likely to benefit are young and still ambulatory with a relatively recent disease onset featuring highly active MS with MRI lesion activity and continued activity despite first- and second-line agents,” Dr. Goodman said.
While encouraging, the small patient numbers of the two trials and uncontrolled nature of the case series prevent conclusions concerning the therapeutic use of autologous HSCT in RRMS. Furthermore, risks of the approach include MS relapse, treatment-related adverse effects, adverse effects due to myelosuppression and immunoablation, and secondary autoimmune disorders that may arise at a later time.
Mesenchymal stem cell transplantation
MSCs offer the advantages of a variety of sources in adult tissue, established methods of culture, and either local or peripheral administration. Their finite capacity for proliferation is a drawback. Studies to date of MSC transplantation in MS have involved about 100 patients, so it is much too early to consider MSC use. Even if therapy is contemplated, whether it should be directed at quelling inflammation or to promote repair is undecided. As well, cell production and delivery issues need to be addressed, Dr. Goodman said.
Human oligodendrocyte progenitor cell transplantation
The implantation of CD 140a+ cell populations containing human oligodendrocyte progenitor cells (hOPCs) into the cerebral hemispheres of patients with non-relapsing secondary progressive MS as a means of stabilizing or improving neurological function is being planned. The NYSTEM project, with Dr. Goodman as a lead investigator, will first seek to identify the maximum tolerated dose of hOPCs.
The study is planned with the knowledge of safety issues that include cancer tumorigenesis. Yet exploration of the possible benefits will be evident only by testing in humans. “I don’t know of any way to find out except by trying,” Dr. Goodman said.
Dr. Goodman disclosed receiving research support and/or serving as a consultant to Avanir, Teva, Genzyme/Sanofi, Sun Pharma, Ono, Roche, AbbVie, Biogen, Novartis, Acorda, Purdue, and EMD Serono.
EXPERT ANALYSIS FROM ACTRIMS FORUM 2016
Brain atrophy may be a clinically relevant measure in PPMS: Data from INFORMS
NEW ORLEANS – The recently published results of the INFORMS multicenter, double-blind, placebo-controlled parallel-group study (NCT00731692) that compared the efficacy of fingolimod in slowing disease progression in primary progressive multiple sclerosis (PPMS) with placebo proved disappointing. However, further scrutiny of the data has provided valuable insights, such as supportive evidence for brain atrophy as a clinically relevant measure in PPMS patients.
“The degree of clinical worsening was directly associated with patient’s extent of brain volume loss. Patients in the extreme category of disability progression had more brain volume loss than patients with only one progression or those who remained clinically stable,” wrote Dr. Jerry Wolinsky of the University of Texas Health Science Center at Houston and his colleagues in a poster presented Feb. 19 at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
In INFORMS, 970 patients with PPMS were randomly allocated (1:1) to receive oral fingolimod 0.5 mg or placebo for at least 36 months and for up to 5 years. The anti-inflammatory effects of fingolimod did not slow disease progression in PPMS.
While INFORMS did not pan out in terms of the primary endpoint, the long duration of the study, use of various progression measures, and rigorous patient selection offered the unique opportunity to assess the associations of magnetic resonance imaging of the brain over at least 3 years of the clinical progression occurring in patients with PPMS.
All patients had being clinically diagnosed with PPMS, with disease duration of 2-10 years and objective evidence of progression in disability in the prior 2 years. The composite endpoint of INFORMS based on the change in Expanded Disability Status Scale (EDSS), 25-Foot Timed Walk Test, or 9-Hole Peg Test was used to gauge 3-month confirmed disease progression (3CDP). The patients were classified according to EDSS-determined disease progression as extreme (more than one occurrence of 3CDP; n = 162), moderate (one occurrence of 3CDP; n = 309), and stable (no 3CDP; n = 499).
Mean age, % male, and baseline EDSS scores were similar across the three categories (whole population: 48.4 ± 8.4 years; 51.6%; and 4.7 ± 1.0, respectively). Mean number of gadolinium-positive lesions in the extreme and stable category was 0.39 ± 1.1 and 0.25 ± 1.0, respectively. Baseline T2 lesion volume was 10,160.8 ± 12,743.3 mm3 in extreme patients and 9,585.8 ± 12,421.6 mm3 in stable patients.
Patients in the extreme category displayed greater changes in the three endpoint measures than did the moderate and stable categories. At month 36, the mean change in brain volume, compared with baseline, was –1.76 ± 1.4 in the extreme group and –1.26 ± 0.9 in stable group. Corresponding values for mean number of gadolinium-positive lesions were 0.40 ± 1.4 and 0.10 ± 0.5. Corresponding numbers of new/newly enlarging T2 lesions from baseline to month 36 were 1.7 ± 4.6 and 0.9 ± 2.9.
Patients in the extreme category exceeded the recently proposed cut-off for pathologically increased brain volume loss by about 60%, compared with only about 14% for patients in the stable category.
The higher change in brain volume from baseline in patients who progressed to extreme disability “supports brain atrophy as a clinically relevant measure of neuroprotection in PPMS trials,” wrote Dr. Wolinsky and his colleagues.
The study was funded by Novartis Pharma AG. Dr. Wolinsky disclosed consulting fees from Genzyme/Sanofi, Hoffmann-La Roche/Genentech, Forward Pharma, Alkermes, AbbVie, Novartis Pharmaceuticals, Teva, and XenoPort and advisory board participation for Hoffman-La Roche/Genentech, Forward Pharma, EMD Serono, Actelion, Novartis Pharmaceuticals, Teva, and Xenoport. He performed contract research for Genzyme/Sanofi.
NEW ORLEANS – The recently published results of the INFORMS multicenter, double-blind, placebo-controlled parallel-group study (NCT00731692) that compared the efficacy of fingolimod in slowing disease progression in primary progressive multiple sclerosis (PPMS) with placebo proved disappointing. However, further scrutiny of the data has provided valuable insights, such as supportive evidence for brain atrophy as a clinically relevant measure in PPMS patients.
“The degree of clinical worsening was directly associated with patient’s extent of brain volume loss. Patients in the extreme category of disability progression had more brain volume loss than patients with only one progression or those who remained clinically stable,” wrote Dr. Jerry Wolinsky of the University of Texas Health Science Center at Houston and his colleagues in a poster presented Feb. 19 at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
In INFORMS, 970 patients with PPMS were randomly allocated (1:1) to receive oral fingolimod 0.5 mg or placebo for at least 36 months and for up to 5 years. The anti-inflammatory effects of fingolimod did not slow disease progression in PPMS.
While INFORMS did not pan out in terms of the primary endpoint, the long duration of the study, use of various progression measures, and rigorous patient selection offered the unique opportunity to assess the associations of magnetic resonance imaging of the brain over at least 3 years of the clinical progression occurring in patients with PPMS.
All patients had being clinically diagnosed with PPMS, with disease duration of 2-10 years and objective evidence of progression in disability in the prior 2 years. The composite endpoint of INFORMS based on the change in Expanded Disability Status Scale (EDSS), 25-Foot Timed Walk Test, or 9-Hole Peg Test was used to gauge 3-month confirmed disease progression (3CDP). The patients were classified according to EDSS-determined disease progression as extreme (more than one occurrence of 3CDP; n = 162), moderate (one occurrence of 3CDP; n = 309), and stable (no 3CDP; n = 499).
Mean age, % male, and baseline EDSS scores were similar across the three categories (whole population: 48.4 ± 8.4 years; 51.6%; and 4.7 ± 1.0, respectively). Mean number of gadolinium-positive lesions in the extreme and stable category was 0.39 ± 1.1 and 0.25 ± 1.0, respectively. Baseline T2 lesion volume was 10,160.8 ± 12,743.3 mm3 in extreme patients and 9,585.8 ± 12,421.6 mm3 in stable patients.
Patients in the extreme category displayed greater changes in the three endpoint measures than did the moderate and stable categories. At month 36, the mean change in brain volume, compared with baseline, was –1.76 ± 1.4 in the extreme group and –1.26 ± 0.9 in stable group. Corresponding values for mean number of gadolinium-positive lesions were 0.40 ± 1.4 and 0.10 ± 0.5. Corresponding numbers of new/newly enlarging T2 lesions from baseline to month 36 were 1.7 ± 4.6 and 0.9 ± 2.9.
Patients in the extreme category exceeded the recently proposed cut-off for pathologically increased brain volume loss by about 60%, compared with only about 14% for patients in the stable category.
The higher change in brain volume from baseline in patients who progressed to extreme disability “supports brain atrophy as a clinically relevant measure of neuroprotection in PPMS trials,” wrote Dr. Wolinsky and his colleagues.
The study was funded by Novartis Pharma AG. Dr. Wolinsky disclosed consulting fees from Genzyme/Sanofi, Hoffmann-La Roche/Genentech, Forward Pharma, Alkermes, AbbVie, Novartis Pharmaceuticals, Teva, and XenoPort and advisory board participation for Hoffman-La Roche/Genentech, Forward Pharma, EMD Serono, Actelion, Novartis Pharmaceuticals, Teva, and Xenoport. He performed contract research for Genzyme/Sanofi.
NEW ORLEANS – The recently published results of the INFORMS multicenter, double-blind, placebo-controlled parallel-group study (NCT00731692) that compared the efficacy of fingolimod in slowing disease progression in primary progressive multiple sclerosis (PPMS) with placebo proved disappointing. However, further scrutiny of the data has provided valuable insights, such as supportive evidence for brain atrophy as a clinically relevant measure in PPMS patients.
“The degree of clinical worsening was directly associated with patient’s extent of brain volume loss. Patients in the extreme category of disability progression had more brain volume loss than patients with only one progression or those who remained clinically stable,” wrote Dr. Jerry Wolinsky of the University of Texas Health Science Center at Houston and his colleagues in a poster presented Feb. 19 at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
In INFORMS, 970 patients with PPMS were randomly allocated (1:1) to receive oral fingolimod 0.5 mg or placebo for at least 36 months and for up to 5 years. The anti-inflammatory effects of fingolimod did not slow disease progression in PPMS.
While INFORMS did not pan out in terms of the primary endpoint, the long duration of the study, use of various progression measures, and rigorous patient selection offered the unique opportunity to assess the associations of magnetic resonance imaging of the brain over at least 3 years of the clinical progression occurring in patients with PPMS.
All patients had being clinically diagnosed with PPMS, with disease duration of 2-10 years and objective evidence of progression in disability in the prior 2 years. The composite endpoint of INFORMS based on the change in Expanded Disability Status Scale (EDSS), 25-Foot Timed Walk Test, or 9-Hole Peg Test was used to gauge 3-month confirmed disease progression (3CDP). The patients were classified according to EDSS-determined disease progression as extreme (more than one occurrence of 3CDP; n = 162), moderate (one occurrence of 3CDP; n = 309), and stable (no 3CDP; n = 499).
Mean age, % male, and baseline EDSS scores were similar across the three categories (whole population: 48.4 ± 8.4 years; 51.6%; and 4.7 ± 1.0, respectively). Mean number of gadolinium-positive lesions in the extreme and stable category was 0.39 ± 1.1 and 0.25 ± 1.0, respectively. Baseline T2 lesion volume was 10,160.8 ± 12,743.3 mm3 in extreme patients and 9,585.8 ± 12,421.6 mm3 in stable patients.
Patients in the extreme category displayed greater changes in the three endpoint measures than did the moderate and stable categories. At month 36, the mean change in brain volume, compared with baseline, was –1.76 ± 1.4 in the extreme group and –1.26 ± 0.9 in stable group. Corresponding values for mean number of gadolinium-positive lesions were 0.40 ± 1.4 and 0.10 ± 0.5. Corresponding numbers of new/newly enlarging T2 lesions from baseline to month 36 were 1.7 ± 4.6 and 0.9 ± 2.9.
Patients in the extreme category exceeded the recently proposed cut-off for pathologically increased brain volume loss by about 60%, compared with only about 14% for patients in the stable category.
The higher change in brain volume from baseline in patients who progressed to extreme disability “supports brain atrophy as a clinically relevant measure of neuroprotection in PPMS trials,” wrote Dr. Wolinsky and his colleagues.
The study was funded by Novartis Pharma AG. Dr. Wolinsky disclosed consulting fees from Genzyme/Sanofi, Hoffmann-La Roche/Genentech, Forward Pharma, Alkermes, AbbVie, Novartis Pharmaceuticals, Teva, and XenoPort and advisory board participation for Hoffman-La Roche/Genentech, Forward Pharma, EMD Serono, Actelion, Novartis Pharmaceuticals, Teva, and Xenoport. He performed contract research for Genzyme/Sanofi.
Key clinical point: Brain atrophy could be a clinically useful and relevant measure in primary progressing multiple sclerosis.
Major finding: Progression to extreme disability was associated with greater brain volume loss.
Data source: Data from the multinational, double-blind, placebo-controlled, parallel-group INFORMS trial.
Disclosures: The study was funded by Novartis Pharma AG. Dr. Wolinsky disclosed consulting fees from Genzyme/Sanofi, Hoffmann-La Roche/Genentech, Forward Pharma, Alkermes, AbbVie, Novartis Pharmaceuticals, Teva, and XenoPort, and advisory board participation for Hoffman-La Roche/Genentech, Forward Pharma, EMD Serono, Actelion, Novartis Pharmaceuticals, Teva, and Xenoport. He performed contract research for Genzyme/Sanofi.
Triage MS-related ED visits to reduce unnecessary treatment
NEW ORLEANS – The majority of multiple sclerosis–related emergency department visits in a recent chart review were related to pseudoflares or MS-related complications, rather than to true MS relapse.
The findings suggest that many diagnostic tests, treatments, and hospital admissions are unnecessary, Dr. Hesham Abboud of the Cleveland Clinic and his colleagues reported in a poster at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Of 97 MS-related visits among 75 patients, 33 were for new neurologic symptoms, 29 were for worsening of preexisting symptoms, and 36 were for MS-related complications. New relapse was diagnosed in only 27 visits (27.8%), and urinary tract infections were found in about one-third of patients presenting with either urinary or neurologic symptoms, the investigators said.
New MRIs were ordered in 37 patients (38.1%); 89 emergency department visits (91.7%) resulted in hospital admissions and 40.4% were related to neurology; and steroid treatment was used in 24 visits (24.7%), 7 of which were for worsening of preexisting symptoms, the investigators said.
Of the visits involving new neurologic symptoms, one-third were not from relapse; 59% of the MRIs done in those situations were positive for enhancing or new lesions. Of the visits with worsening preexisting symptoms, only 16.6% were associated with a new relapse, and 28.5% of MRIs done in those situations were positive, the investigators said.
Although many ED visits among MS patients are driven by neurologic complaints, true relapse is rarely present, and not all those with true relapse require hospital admission and steroid treatment, they noted, concluding that developing a care path and triaging system for MS patients in the ED could prevent unnecessary MRIs, steroid treatment, and hospital admissions.
The investigators reported having no disclosures.
NEW ORLEANS – The majority of multiple sclerosis–related emergency department visits in a recent chart review were related to pseudoflares or MS-related complications, rather than to true MS relapse.
The findings suggest that many diagnostic tests, treatments, and hospital admissions are unnecessary, Dr. Hesham Abboud of the Cleveland Clinic and his colleagues reported in a poster at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Of 97 MS-related visits among 75 patients, 33 were for new neurologic symptoms, 29 were for worsening of preexisting symptoms, and 36 were for MS-related complications. New relapse was diagnosed in only 27 visits (27.8%), and urinary tract infections were found in about one-third of patients presenting with either urinary or neurologic symptoms, the investigators said.
New MRIs were ordered in 37 patients (38.1%); 89 emergency department visits (91.7%) resulted in hospital admissions and 40.4% were related to neurology; and steroid treatment was used in 24 visits (24.7%), 7 of which were for worsening of preexisting symptoms, the investigators said.
Of the visits involving new neurologic symptoms, one-third were not from relapse; 59% of the MRIs done in those situations were positive for enhancing or new lesions. Of the visits with worsening preexisting symptoms, only 16.6% were associated with a new relapse, and 28.5% of MRIs done in those situations were positive, the investigators said.
Although many ED visits among MS patients are driven by neurologic complaints, true relapse is rarely present, and not all those with true relapse require hospital admission and steroid treatment, they noted, concluding that developing a care path and triaging system for MS patients in the ED could prevent unnecessary MRIs, steroid treatment, and hospital admissions.
The investigators reported having no disclosures.
NEW ORLEANS – The majority of multiple sclerosis–related emergency department visits in a recent chart review were related to pseudoflares or MS-related complications, rather than to true MS relapse.
The findings suggest that many diagnostic tests, treatments, and hospital admissions are unnecessary, Dr. Hesham Abboud of the Cleveland Clinic and his colleagues reported in a poster at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Of 97 MS-related visits among 75 patients, 33 were for new neurologic symptoms, 29 were for worsening of preexisting symptoms, and 36 were for MS-related complications. New relapse was diagnosed in only 27 visits (27.8%), and urinary tract infections were found in about one-third of patients presenting with either urinary or neurologic symptoms, the investigators said.
New MRIs were ordered in 37 patients (38.1%); 89 emergency department visits (91.7%) resulted in hospital admissions and 40.4% were related to neurology; and steroid treatment was used in 24 visits (24.7%), 7 of which were for worsening of preexisting symptoms, the investigators said.
Of the visits involving new neurologic symptoms, one-third were not from relapse; 59% of the MRIs done in those situations were positive for enhancing or new lesions. Of the visits with worsening preexisting symptoms, only 16.6% were associated with a new relapse, and 28.5% of MRIs done in those situations were positive, the investigators said.
Although many ED visits among MS patients are driven by neurologic complaints, true relapse is rarely present, and not all those with true relapse require hospital admission and steroid treatment, they noted, concluding that developing a care path and triaging system for MS patients in the ED could prevent unnecessary MRIs, steroid treatment, and hospital admissions.
The investigators reported having no disclosures.
AT ACTRIMS FORUM 2016
Key clinical point: The majority of multiple sclerosis–related emergency department visits in a recent chart review were related to pseudoflares or MS-related complications, rather than true MS relapse.
Major finding: New relapse was diagnosed in only 27 visits (27.8%).
Data source: A retrospective chart review of 75 patients with 97 MS-related ED visits.
Disclosures: The investigators reported having no disclosures.
