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Plasma exchange in natalizumab-related PML shows no benefit, possible harm
STOCKHOLM – Christopher McGuigan, MD, and colleagues reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“This is a very important issue for us as neurologists. I think this data suggests that plasma exchange does not seem to confer an advantage to our patients when it comes to mortality and – albeit with caveats – it actually seems to be associated with worsening of the disability level in survivors,” according to Dr. McGuigan, consultant neurologist at St. Vincent’s University Hospital in Dublin and clinical professor at University College Dublin.
Natalizumab is an effective treatment for patients with highly active MS, but its use is limited by the feared complication of PML. Plasma exchange to clear the drug from the patient’s system is a popular and biologically plausible therapy, but its impact on clinical outcomes had not been formally studied until now.
Examining a database of confirmed PML cases
Dr. McGuigan presented a retrospective study of 723 patients with confirmed PML included in the natalizumab pharmacovigilance database run by Biogen, which markets the drug. A total of 85% (616 patients) underwent plasma exchange. The study’s primary outcome was the survival rate 2 years after PML diagnosis in patients who received plasma exchange, compared with those who did not.
Since the viral load of John Cunningham (JC) virus is known to influence outcome in PML, Dr. McGuigan and coinvestigators stratified the primary outcome based on tertiles of baseline viral copy number (VCN). The key study finding was that, across the range of viral loads, plasma exchange was consistently associated with a numerically worse 2-year survival rate, although the difference did not reach statistical significance. Among patients with less than a log5 baseline JC virus VCN, 2-year survival was 88.2% in the plasma exchange group, compared with 89.3% in the patients who did not undergo plasma exchange. For patients with a JC virus VCN greater than log5 but not more than log7, the survival rate was 89.3% without plasma exchange versus 73.8% with the intervention. In the group with greater than a log7 VCN, the 2-year survival was 78.9% without plasma exchange and 68.2% with it.
Statistically significant covariates
In a multivariate Cox proportional hazards analysis, plasma exchange was associated with a statistically nonsignificant 44% increased risk of mortality at 2 years post PML diagnosis. However, several other covariates emerged as statistically significant independent predictors of 2-year mortality. These included age greater than 50 years at diagnosis of PML, with an associated hazard ratio of 1.56, compared with younger patients; male gender (HR, 1.48); a JC virus VCN greater than log 7, compared with log 5 or less (HR, 2.86); a VCN greater than log5 but not more than log7, compared with a VCN of log5 or less (HR, 2.11); and widespread as opposed to localized MRI brain lesions of PML (HR, 1.61). In contrast, an asymptomatic presentation of PML was protective, with an HR of 0.38, compared with patients with a symptomatic presentation.
The likelihood of survival at 2 years was not affected by the number of plasma exchange cycles utilized, the number of natalizumab infusions received prior to diagnosis of PML, or the time from the last natalizumab infusion to starting plasma exchange.
Additional analyses focused on functional ability and disability
A secondary analysis addressed the question of whether plasma exchange has a favorable impact on functional ability. This is an important issue because many MS patients who remain alive 2 years after diagnosis of PML are left with marked permanent disability. This analysis was restricted to the 523 MS patients with PML for whom Expanded Disability Status Scale (EDSS) scores were available 6 months or more after PML diagnosis. The key finding here was that, at 2 years, 62% of the plasma exchange group, but only 38% of non–plasma exchange controls, were either dead or had an EDSS score of 7 or greater, which is a degree of disability likely to render a patient unable to live independently.
Of note, the median EDSS score 6 months before diagnosis of PML was 3.5 in both groups. Moreover, the median EDSS score at the time of diagnosis was similar in the two groups as well: 4.0 in those who underwent plasma exchange and 4.5 in those who did not. So the physician decision to employ plasma exchange clearly was not driven by more-severe disability.
In a multivariate analysis, plasma exchange was independently associated with a 168% increased likelihood of death or an EDSS score of 7 or more at 2 years. A sensitivity analysis restricted to patients who fell into that category was supportive of the main analysis: it concluded that such patients were 159% more likely to have received plasma exchange than not.
Dr. McGuigan cited several study limitations, including possible selection bias, inability to assess the potential impact of other disease-modifying therapies utilized after PML diagnosis, the lack of baseline EDSS scores in a fair number of patients, and the necessity to evaluate all-cause mortality rather than death attributable to PML.
He made a plea for neurologists to diligently submit their own cases of natalizumab-associated PML in MS patients to the Biogen pharmacovigilance database, which is totally dependent upon voluntary physician reporting.
“This is the only tool by which we can get this information at present. It’s the best data we’re likely to be able to get,” he observed.
The study was funded by Biogen. Dr. McGuigan reported receiving research grants from and serving as an advisor to that company and several other pharmaceutical companies.
SOURCE: McGuigan C et al. ECTRIMS 2019, Abstract 63.
STOCKHOLM – Christopher McGuigan, MD, and colleagues reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“This is a very important issue for us as neurologists. I think this data suggests that plasma exchange does not seem to confer an advantage to our patients when it comes to mortality and – albeit with caveats – it actually seems to be associated with worsening of the disability level in survivors,” according to Dr. McGuigan, consultant neurologist at St. Vincent’s University Hospital in Dublin and clinical professor at University College Dublin.
Natalizumab is an effective treatment for patients with highly active MS, but its use is limited by the feared complication of PML. Plasma exchange to clear the drug from the patient’s system is a popular and biologically plausible therapy, but its impact on clinical outcomes had not been formally studied until now.
Examining a database of confirmed PML cases
Dr. McGuigan presented a retrospective study of 723 patients with confirmed PML included in the natalizumab pharmacovigilance database run by Biogen, which markets the drug. A total of 85% (616 patients) underwent plasma exchange. The study’s primary outcome was the survival rate 2 years after PML diagnosis in patients who received plasma exchange, compared with those who did not.
Since the viral load of John Cunningham (JC) virus is known to influence outcome in PML, Dr. McGuigan and coinvestigators stratified the primary outcome based on tertiles of baseline viral copy number (VCN). The key study finding was that, across the range of viral loads, plasma exchange was consistently associated with a numerically worse 2-year survival rate, although the difference did not reach statistical significance. Among patients with less than a log5 baseline JC virus VCN, 2-year survival was 88.2% in the plasma exchange group, compared with 89.3% in the patients who did not undergo plasma exchange. For patients with a JC virus VCN greater than log5 but not more than log7, the survival rate was 89.3% without plasma exchange versus 73.8% with the intervention. In the group with greater than a log7 VCN, the 2-year survival was 78.9% without plasma exchange and 68.2% with it.
Statistically significant covariates
In a multivariate Cox proportional hazards analysis, plasma exchange was associated with a statistically nonsignificant 44% increased risk of mortality at 2 years post PML diagnosis. However, several other covariates emerged as statistically significant independent predictors of 2-year mortality. These included age greater than 50 years at diagnosis of PML, with an associated hazard ratio of 1.56, compared with younger patients; male gender (HR, 1.48); a JC virus VCN greater than log 7, compared with log 5 or less (HR, 2.86); a VCN greater than log5 but not more than log7, compared with a VCN of log5 or less (HR, 2.11); and widespread as opposed to localized MRI brain lesions of PML (HR, 1.61). In contrast, an asymptomatic presentation of PML was protective, with an HR of 0.38, compared with patients with a symptomatic presentation.
The likelihood of survival at 2 years was not affected by the number of plasma exchange cycles utilized, the number of natalizumab infusions received prior to diagnosis of PML, or the time from the last natalizumab infusion to starting plasma exchange.
Additional analyses focused on functional ability and disability
A secondary analysis addressed the question of whether plasma exchange has a favorable impact on functional ability. This is an important issue because many MS patients who remain alive 2 years after diagnosis of PML are left with marked permanent disability. This analysis was restricted to the 523 MS patients with PML for whom Expanded Disability Status Scale (EDSS) scores were available 6 months or more after PML diagnosis. The key finding here was that, at 2 years, 62% of the plasma exchange group, but only 38% of non–plasma exchange controls, were either dead or had an EDSS score of 7 or greater, which is a degree of disability likely to render a patient unable to live independently.
Of note, the median EDSS score 6 months before diagnosis of PML was 3.5 in both groups. Moreover, the median EDSS score at the time of diagnosis was similar in the two groups as well: 4.0 in those who underwent plasma exchange and 4.5 in those who did not. So the physician decision to employ plasma exchange clearly was not driven by more-severe disability.
In a multivariate analysis, plasma exchange was independently associated with a 168% increased likelihood of death or an EDSS score of 7 or more at 2 years. A sensitivity analysis restricted to patients who fell into that category was supportive of the main analysis: it concluded that such patients were 159% more likely to have received plasma exchange than not.
Dr. McGuigan cited several study limitations, including possible selection bias, inability to assess the potential impact of other disease-modifying therapies utilized after PML diagnosis, the lack of baseline EDSS scores in a fair number of patients, and the necessity to evaluate all-cause mortality rather than death attributable to PML.
He made a plea for neurologists to diligently submit their own cases of natalizumab-associated PML in MS patients to the Biogen pharmacovigilance database, which is totally dependent upon voluntary physician reporting.
“This is the only tool by which we can get this information at present. It’s the best data we’re likely to be able to get,” he observed.
The study was funded by Biogen. Dr. McGuigan reported receiving research grants from and serving as an advisor to that company and several other pharmaceutical companies.
SOURCE: McGuigan C et al. ECTRIMS 2019, Abstract 63.
STOCKHOLM – Christopher McGuigan, MD, and colleagues reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“This is a very important issue for us as neurologists. I think this data suggests that plasma exchange does not seem to confer an advantage to our patients when it comes to mortality and – albeit with caveats – it actually seems to be associated with worsening of the disability level in survivors,” according to Dr. McGuigan, consultant neurologist at St. Vincent’s University Hospital in Dublin and clinical professor at University College Dublin.
Natalizumab is an effective treatment for patients with highly active MS, but its use is limited by the feared complication of PML. Plasma exchange to clear the drug from the patient’s system is a popular and biologically plausible therapy, but its impact on clinical outcomes had not been formally studied until now.
Examining a database of confirmed PML cases
Dr. McGuigan presented a retrospective study of 723 patients with confirmed PML included in the natalizumab pharmacovigilance database run by Biogen, which markets the drug. A total of 85% (616 patients) underwent plasma exchange. The study’s primary outcome was the survival rate 2 years after PML diagnosis in patients who received plasma exchange, compared with those who did not.
Since the viral load of John Cunningham (JC) virus is known to influence outcome in PML, Dr. McGuigan and coinvestigators stratified the primary outcome based on tertiles of baseline viral copy number (VCN). The key study finding was that, across the range of viral loads, plasma exchange was consistently associated with a numerically worse 2-year survival rate, although the difference did not reach statistical significance. Among patients with less than a log5 baseline JC virus VCN, 2-year survival was 88.2% in the plasma exchange group, compared with 89.3% in the patients who did not undergo plasma exchange. For patients with a JC virus VCN greater than log5 but not more than log7, the survival rate was 89.3% without plasma exchange versus 73.8% with the intervention. In the group with greater than a log7 VCN, the 2-year survival was 78.9% without plasma exchange and 68.2% with it.
Statistically significant covariates
In a multivariate Cox proportional hazards analysis, plasma exchange was associated with a statistically nonsignificant 44% increased risk of mortality at 2 years post PML diagnosis. However, several other covariates emerged as statistically significant independent predictors of 2-year mortality. These included age greater than 50 years at diagnosis of PML, with an associated hazard ratio of 1.56, compared with younger patients; male gender (HR, 1.48); a JC virus VCN greater than log 7, compared with log 5 or less (HR, 2.86); a VCN greater than log5 but not more than log7, compared with a VCN of log5 or less (HR, 2.11); and widespread as opposed to localized MRI brain lesions of PML (HR, 1.61). In contrast, an asymptomatic presentation of PML was protective, with an HR of 0.38, compared with patients with a symptomatic presentation.
The likelihood of survival at 2 years was not affected by the number of plasma exchange cycles utilized, the number of natalizumab infusions received prior to diagnosis of PML, or the time from the last natalizumab infusion to starting plasma exchange.
Additional analyses focused on functional ability and disability
A secondary analysis addressed the question of whether plasma exchange has a favorable impact on functional ability. This is an important issue because many MS patients who remain alive 2 years after diagnosis of PML are left with marked permanent disability. This analysis was restricted to the 523 MS patients with PML for whom Expanded Disability Status Scale (EDSS) scores were available 6 months or more after PML diagnosis. The key finding here was that, at 2 years, 62% of the plasma exchange group, but only 38% of non–plasma exchange controls, were either dead or had an EDSS score of 7 or greater, which is a degree of disability likely to render a patient unable to live independently.
Of note, the median EDSS score 6 months before diagnosis of PML was 3.5 in both groups. Moreover, the median EDSS score at the time of diagnosis was similar in the two groups as well: 4.0 in those who underwent plasma exchange and 4.5 in those who did not. So the physician decision to employ plasma exchange clearly was not driven by more-severe disability.
In a multivariate analysis, plasma exchange was independently associated with a 168% increased likelihood of death or an EDSS score of 7 or more at 2 years. A sensitivity analysis restricted to patients who fell into that category was supportive of the main analysis: it concluded that such patients were 159% more likely to have received plasma exchange than not.
Dr. McGuigan cited several study limitations, including possible selection bias, inability to assess the potential impact of other disease-modifying therapies utilized after PML diagnosis, the lack of baseline EDSS scores in a fair number of patients, and the necessity to evaluate all-cause mortality rather than death attributable to PML.
He made a plea for neurologists to diligently submit their own cases of natalizumab-associated PML in MS patients to the Biogen pharmacovigilance database, which is totally dependent upon voluntary physician reporting.
“This is the only tool by which we can get this information at present. It’s the best data we’re likely to be able to get,” he observed.
The study was funded by Biogen. Dr. McGuigan reported receiving research grants from and serving as an advisor to that company and several other pharmaceutical companies.
SOURCE: McGuigan C et al. ECTRIMS 2019, Abstract 63.
REPORTING FROM ECTRIMS 2019
Key clinical point: Plasma exchange has no clinical benefit in natalizumab-associated progressive multifocal leukoencephalopathy (PML).
Major finding: The risk of composite endpoint of death or an Expanded Disability Status Scale of 7.0 or more at follow-up 2 years after a natalizumab-associated PML diagnosis was an adjusted 168% greater in multiple sclerosis patients who underwent plasma exchange than in those who did not.
Study details: A retrospective analysis of the records of 723 multiple sclerosis patients with confirmed natalizumab-associated PML.
Disclosures: The study was funded by Biogen. The presenter reported receiving research grants from and serving as an advisor to Biogen and several other pharmaceutical companies.
Source: McGuigan C et al. ECTRIMS 2019, Abstract 63.
Ofatumumab has superior efficacy in relapsing-remitting MS, compared with teriflunomide
STOCKHOLM – (MS), according to research presented at the annual congress of the European Committee for Treatment and Research in MS. Ofatumumab also reduces the risk of 3-month and 6-month confirmed disability worsening, compared with teriflunomide. The former therapy has a favorable safety profile, and the investigators did not observe any unexpected safety findings.
Ofatumumab is a fully human anti-CD20 monoclonal antibody that Novartis is developing as a monthly 20-mg subcutaneous infusion. “Targeting CD20-bearing B-cells has been shown to be an effective therapeutic against MS,” said Stephen Hauser, MD, professor of neurology at the University of California, San Francisco. “CD20 targeting is very effective at nearly complete depletion of B-cells in the blood, but [performs] only partial depletion in lymph nodes. This may explain, in part, its safety profile.”
Two concurrent phase 3 trials
Dr. Hauser and colleagues conducted two contemporaneous phase 3 trials, ASCLEPIOS I and ASCLEPIOS II, to compare the efficacy and safety of ofatumumab with those of teriflunomide. The two multicenter trials were double blinded and had a parallel-group design. Eligible patients were between ages 18 and 55 years; had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5; and had had one or more relapse in the previous year, two or more relapses in the previous 2 years, or a positive gadolinium-enhancing MRI scan during the year before randomization. Patients with progressive MS, neuromyelitis optica, or progressive multifocal leukoencephalopathy were excluded.
The investigators randomized patients in equal groups to receive 20-mg subcutaneous injections of ofatumumab every 4 weeks (plus a daily oral placebo) or 14 mg/day of teriflunomide orally (plus placebo subcutaneous injections). Participants randomized to ofatumumab underwent an initial loading regimen of 20-mg subcutaneous doses on days 1, 7, and 14. The trials had flexible durations: The number of events determined the length of the studies, which could last for as long as 30 months. At study completion, participants were enrolled into an ongoing, open-label extension study.
The primary endpoint of both trials was the annualized relapse rate (ARR). Among the secondary endpoints were 3- and 6-month confirmed disability worsening, 6-month confirmed disability improvement, MRI-related outcomes, and serum neurofilament light chain (NfL) levels.
Ofatumumab improved clinical and imaging outcomes
In all, 927 patients were randomized in ASCLEPIOS I (462 to teriflunomide and 465 to ofatumumab), and 955 patients were randomized in ASCLEPIOS II (474 to teriflunomide and 481 to ofatumumab). The study completion rate was approximately 85% in ASCLEPIOS I and approximately 82% in ASCLEPIOS II. The two studies had similar populations, and the two treatment arms in each trial were well balanced. Overall, mean age was approximately 38 years, 68% of patients were female, mean disease duration was approximately 8 years, and mean EDSS score was about 3.
Compared with teriflunomide, ofatumumab reduced the ARR by 50.5% in ASCLEPIOS I and by 58.5% in ASCLEPIOS II. Ofatumumab reduced the risk of 3-month confirmed disability worsening by 34.4%, compared with teriflunomide, and reduced the risk of 6-month confirmed disability worsening by 32.5%, compared with teriflunomide. All of these differences were statistically significant. Ofatumumab tended to increase the likelihood of confirmed disability improvement, compared with teriflunomide, but the result was not statistically significant.
Ofatumumab was superior to teriflunomide on imaging and laboratory measures, as well. Compared with teriflunomide, ofatumumab significantly reduced gadolinium-enhancing T1 lesions by 97.5% in ASCLEPIOS I and by 93.8% in ASCLEPIOS II. In addition, ofatumumab significantly reduced new or enlarging T2 lesions by 82.0% in ASCLEPIOS I and by 84.5% in ASCLEPIOS II. At month 24, ofatumumab reduced serum NfL levels by 23% in ASCLEPIOS I and by 24% in ASCLEPIOS II, compared with teriflunomide.
In both studies, adverse events and serious adverse events were well balanced between treatment groups. The ofatumumab groups had a slight increase in injection-related reactions, compared with the teriflunomide groups. Most systemic injection reactions were mild to moderate.
Novartis Pharma funded the research. Dr. Hauser has received travel reimbursement from F. Hoffmann-La Roche and Novartis for meetings and presentations related to anti-CD20 therapies.
STOCKHOLM – (MS), according to research presented at the annual congress of the European Committee for Treatment and Research in MS. Ofatumumab also reduces the risk of 3-month and 6-month confirmed disability worsening, compared with teriflunomide. The former therapy has a favorable safety profile, and the investigators did not observe any unexpected safety findings.
Ofatumumab is a fully human anti-CD20 monoclonal antibody that Novartis is developing as a monthly 20-mg subcutaneous infusion. “Targeting CD20-bearing B-cells has been shown to be an effective therapeutic against MS,” said Stephen Hauser, MD, professor of neurology at the University of California, San Francisco. “CD20 targeting is very effective at nearly complete depletion of B-cells in the blood, but [performs] only partial depletion in lymph nodes. This may explain, in part, its safety profile.”
Two concurrent phase 3 trials
Dr. Hauser and colleagues conducted two contemporaneous phase 3 trials, ASCLEPIOS I and ASCLEPIOS II, to compare the efficacy and safety of ofatumumab with those of teriflunomide. The two multicenter trials were double blinded and had a parallel-group design. Eligible patients were between ages 18 and 55 years; had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5; and had had one or more relapse in the previous year, two or more relapses in the previous 2 years, or a positive gadolinium-enhancing MRI scan during the year before randomization. Patients with progressive MS, neuromyelitis optica, or progressive multifocal leukoencephalopathy were excluded.
The investigators randomized patients in equal groups to receive 20-mg subcutaneous injections of ofatumumab every 4 weeks (plus a daily oral placebo) or 14 mg/day of teriflunomide orally (plus placebo subcutaneous injections). Participants randomized to ofatumumab underwent an initial loading regimen of 20-mg subcutaneous doses on days 1, 7, and 14. The trials had flexible durations: The number of events determined the length of the studies, which could last for as long as 30 months. At study completion, participants were enrolled into an ongoing, open-label extension study.
The primary endpoint of both trials was the annualized relapse rate (ARR). Among the secondary endpoints were 3- and 6-month confirmed disability worsening, 6-month confirmed disability improvement, MRI-related outcomes, and serum neurofilament light chain (NfL) levels.
Ofatumumab improved clinical and imaging outcomes
In all, 927 patients were randomized in ASCLEPIOS I (462 to teriflunomide and 465 to ofatumumab), and 955 patients were randomized in ASCLEPIOS II (474 to teriflunomide and 481 to ofatumumab). The study completion rate was approximately 85% in ASCLEPIOS I and approximately 82% in ASCLEPIOS II. The two studies had similar populations, and the two treatment arms in each trial were well balanced. Overall, mean age was approximately 38 years, 68% of patients were female, mean disease duration was approximately 8 years, and mean EDSS score was about 3.
Compared with teriflunomide, ofatumumab reduced the ARR by 50.5% in ASCLEPIOS I and by 58.5% in ASCLEPIOS II. Ofatumumab reduced the risk of 3-month confirmed disability worsening by 34.4%, compared with teriflunomide, and reduced the risk of 6-month confirmed disability worsening by 32.5%, compared with teriflunomide. All of these differences were statistically significant. Ofatumumab tended to increase the likelihood of confirmed disability improvement, compared with teriflunomide, but the result was not statistically significant.
Ofatumumab was superior to teriflunomide on imaging and laboratory measures, as well. Compared with teriflunomide, ofatumumab significantly reduced gadolinium-enhancing T1 lesions by 97.5% in ASCLEPIOS I and by 93.8% in ASCLEPIOS II. In addition, ofatumumab significantly reduced new or enlarging T2 lesions by 82.0% in ASCLEPIOS I and by 84.5% in ASCLEPIOS II. At month 24, ofatumumab reduced serum NfL levels by 23% in ASCLEPIOS I and by 24% in ASCLEPIOS II, compared with teriflunomide.
In both studies, adverse events and serious adverse events were well balanced between treatment groups. The ofatumumab groups had a slight increase in injection-related reactions, compared with the teriflunomide groups. Most systemic injection reactions were mild to moderate.
Novartis Pharma funded the research. Dr. Hauser has received travel reimbursement from F. Hoffmann-La Roche and Novartis for meetings and presentations related to anti-CD20 therapies.
STOCKHOLM – (MS), according to research presented at the annual congress of the European Committee for Treatment and Research in MS. Ofatumumab also reduces the risk of 3-month and 6-month confirmed disability worsening, compared with teriflunomide. The former therapy has a favorable safety profile, and the investigators did not observe any unexpected safety findings.
Ofatumumab is a fully human anti-CD20 monoclonal antibody that Novartis is developing as a monthly 20-mg subcutaneous infusion. “Targeting CD20-bearing B-cells has been shown to be an effective therapeutic against MS,” said Stephen Hauser, MD, professor of neurology at the University of California, San Francisco. “CD20 targeting is very effective at nearly complete depletion of B-cells in the blood, but [performs] only partial depletion in lymph nodes. This may explain, in part, its safety profile.”
Two concurrent phase 3 trials
Dr. Hauser and colleagues conducted two contemporaneous phase 3 trials, ASCLEPIOS I and ASCLEPIOS II, to compare the efficacy and safety of ofatumumab with those of teriflunomide. The two multicenter trials were double blinded and had a parallel-group design. Eligible patients were between ages 18 and 55 years; had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5; and had had one or more relapse in the previous year, two or more relapses in the previous 2 years, or a positive gadolinium-enhancing MRI scan during the year before randomization. Patients with progressive MS, neuromyelitis optica, or progressive multifocal leukoencephalopathy were excluded.
The investigators randomized patients in equal groups to receive 20-mg subcutaneous injections of ofatumumab every 4 weeks (plus a daily oral placebo) or 14 mg/day of teriflunomide orally (plus placebo subcutaneous injections). Participants randomized to ofatumumab underwent an initial loading regimen of 20-mg subcutaneous doses on days 1, 7, and 14. The trials had flexible durations: The number of events determined the length of the studies, which could last for as long as 30 months. At study completion, participants were enrolled into an ongoing, open-label extension study.
The primary endpoint of both trials was the annualized relapse rate (ARR). Among the secondary endpoints were 3- and 6-month confirmed disability worsening, 6-month confirmed disability improvement, MRI-related outcomes, and serum neurofilament light chain (NfL) levels.
Ofatumumab improved clinical and imaging outcomes
In all, 927 patients were randomized in ASCLEPIOS I (462 to teriflunomide and 465 to ofatumumab), and 955 patients were randomized in ASCLEPIOS II (474 to teriflunomide and 481 to ofatumumab). The study completion rate was approximately 85% in ASCLEPIOS I and approximately 82% in ASCLEPIOS II. The two studies had similar populations, and the two treatment arms in each trial were well balanced. Overall, mean age was approximately 38 years, 68% of patients were female, mean disease duration was approximately 8 years, and mean EDSS score was about 3.
Compared with teriflunomide, ofatumumab reduced the ARR by 50.5% in ASCLEPIOS I and by 58.5% in ASCLEPIOS II. Ofatumumab reduced the risk of 3-month confirmed disability worsening by 34.4%, compared with teriflunomide, and reduced the risk of 6-month confirmed disability worsening by 32.5%, compared with teriflunomide. All of these differences were statistically significant. Ofatumumab tended to increase the likelihood of confirmed disability improvement, compared with teriflunomide, but the result was not statistically significant.
Ofatumumab was superior to teriflunomide on imaging and laboratory measures, as well. Compared with teriflunomide, ofatumumab significantly reduced gadolinium-enhancing T1 lesions by 97.5% in ASCLEPIOS I and by 93.8% in ASCLEPIOS II. In addition, ofatumumab significantly reduced new or enlarging T2 lesions by 82.0% in ASCLEPIOS I and by 84.5% in ASCLEPIOS II. At month 24, ofatumumab reduced serum NfL levels by 23% in ASCLEPIOS I and by 24% in ASCLEPIOS II, compared with teriflunomide.
In both studies, adverse events and serious adverse events were well balanced between treatment groups. The ofatumumab groups had a slight increase in injection-related reactions, compared with the teriflunomide groups. Most systemic injection reactions were mild to moderate.
Novartis Pharma funded the research. Dr. Hauser has received travel reimbursement from F. Hoffmann-La Roche and Novartis for meetings and presentations related to anti-CD20 therapies.
REPORTING FROM ECTRIMS 2019
Average daily step count reflects disability in MS
STOCKHOLM – according to research presented at the annual congress of the European Committee for Treatment and Research in MS. Remote gait monitoring using a popular fitness tracker may offer a surrogate measure of MS disability in clinical trials, the researchers reported.
Many outcome measures in MS are evaluated in controlled contexts and do not indicate how patients are functioning outside of the clinical setting, said Valerie J. Block, PhD, from the Weill Institute for Neurosciences at the University of California, San Francisco. Patient-reported outcome measures are subject to recall bias and uneven perception of deficits. Remote ambulatory monitoring, on the other hand, could be a more objective measure that provides continuous information in the real-world setting, said Dr. Block. She and her colleagues have proposed remote ambulatory activity monitoring as an outcome measure for clinical trials.
The investigators chose this measure as an exploratory endpoint for SPI2, a phase 3 trial investigating the efficacy and safety of MD1003 (high-dose pharmaceutical-grade biotin) in patients with inactive primary progressive MS and secondary progressive MS. “To our knowledge, this is the first major clinical trial in progressive MS to include continuous remote step count monitoring as an exploratory endpoint,” said Dr. Block.
In the SPI2 study, patients received either MD1003 (300 mg/day) or placebo. To examine the relationship between ambulatory monitoring and clinical disability and MRI measures, the researchers remotely monitored participants’ ambulatory activity for 27 months using a fitness tracker. The investigators used the average daily step count from the first 30 days as the baseline activity measure. At first, they set a low daily step-count goal to minimize the influence of motivation on ambulatory activity. Participants later were taught how to change the goal independently.
Dr. Block and colleagues created LASSO subset selection regression models to correlate average daily step count with sex, age, disease duration, age at onset, disease course, and various MRI models (such as upper cervical cord area, gray matter volume, normalized brain volume, thalamic volume, and T1 and T2 lesion volumes). They performed least squares regression models on the subset selection results. Finally, the researchers calculated Spearman correlations between average daily step count and clinical disability, as measured by Expanded Disability Status Scale (EDSS) and timed 25-foot walk, and the Physical and Mental Health Composite measures of the MS Quality of Life scale (MSQoL-29).
As of April 23, 2019, the researchers had enrolled 492 patients (262 women) with full data at 90 centers (40 in the United States, 39 in Europe, 8 in Canada, and 3 in Australia). In all, 311 patients (63%) had secondary progressive MS, and 181 had primary progressive MS. Participants had moderate disability; the median EDSS score was 6.0. Median disease duration was 10.6 years. The mean daily step count during the first month was 3,699.
Greater step count was correlated with lower EDSS score, faster completion of the timed 25-foot walk, better Physical Health Composite score, better Symbol Digit Modalities Test score, and better Mental Health Composite score. Furthermore, greater mean daily step count also correlated with greater upper cervical cord area, greater normalized brain volume, greater gray matter volume, and lower T1 lesion volume. The correlations between step count and thalamic volume and T2 lesion volume were not significant. “These data support the study of steps as an exploratory outcome measure in clinical trials for progressive MS,” said Dr. Block.
Dr. Block received reimbursement for travel expenses related to this study from MedDay Pharmaceuticals. Coinvestigators received research support and compensation from companies such as Abbvie, Alexion, Biogen, Genentech, MedDay Pharmaceuticals, Novartis, and Sanofi Genzyme. One investigator is an employee of MedDay Pharmaceuticals.
SOURCE: Block V et al. ECTRIMS 2019, Abstract 217.
STOCKHOLM – according to research presented at the annual congress of the European Committee for Treatment and Research in MS. Remote gait monitoring using a popular fitness tracker may offer a surrogate measure of MS disability in clinical trials, the researchers reported.
Many outcome measures in MS are evaluated in controlled contexts and do not indicate how patients are functioning outside of the clinical setting, said Valerie J. Block, PhD, from the Weill Institute for Neurosciences at the University of California, San Francisco. Patient-reported outcome measures are subject to recall bias and uneven perception of deficits. Remote ambulatory monitoring, on the other hand, could be a more objective measure that provides continuous information in the real-world setting, said Dr. Block. She and her colleagues have proposed remote ambulatory activity monitoring as an outcome measure for clinical trials.
The investigators chose this measure as an exploratory endpoint for SPI2, a phase 3 trial investigating the efficacy and safety of MD1003 (high-dose pharmaceutical-grade biotin) in patients with inactive primary progressive MS and secondary progressive MS. “To our knowledge, this is the first major clinical trial in progressive MS to include continuous remote step count monitoring as an exploratory endpoint,” said Dr. Block.
In the SPI2 study, patients received either MD1003 (300 mg/day) or placebo. To examine the relationship between ambulatory monitoring and clinical disability and MRI measures, the researchers remotely monitored participants’ ambulatory activity for 27 months using a fitness tracker. The investigators used the average daily step count from the first 30 days as the baseline activity measure. At first, they set a low daily step-count goal to minimize the influence of motivation on ambulatory activity. Participants later were taught how to change the goal independently.
Dr. Block and colleagues created LASSO subset selection regression models to correlate average daily step count with sex, age, disease duration, age at onset, disease course, and various MRI models (such as upper cervical cord area, gray matter volume, normalized brain volume, thalamic volume, and T1 and T2 lesion volumes). They performed least squares regression models on the subset selection results. Finally, the researchers calculated Spearman correlations between average daily step count and clinical disability, as measured by Expanded Disability Status Scale (EDSS) and timed 25-foot walk, and the Physical and Mental Health Composite measures of the MS Quality of Life scale (MSQoL-29).
As of April 23, 2019, the researchers had enrolled 492 patients (262 women) with full data at 90 centers (40 in the United States, 39 in Europe, 8 in Canada, and 3 in Australia). In all, 311 patients (63%) had secondary progressive MS, and 181 had primary progressive MS. Participants had moderate disability; the median EDSS score was 6.0. Median disease duration was 10.6 years. The mean daily step count during the first month was 3,699.
Greater step count was correlated with lower EDSS score, faster completion of the timed 25-foot walk, better Physical Health Composite score, better Symbol Digit Modalities Test score, and better Mental Health Composite score. Furthermore, greater mean daily step count also correlated with greater upper cervical cord area, greater normalized brain volume, greater gray matter volume, and lower T1 lesion volume. The correlations between step count and thalamic volume and T2 lesion volume were not significant. “These data support the study of steps as an exploratory outcome measure in clinical trials for progressive MS,” said Dr. Block.
Dr. Block received reimbursement for travel expenses related to this study from MedDay Pharmaceuticals. Coinvestigators received research support and compensation from companies such as Abbvie, Alexion, Biogen, Genentech, MedDay Pharmaceuticals, Novartis, and Sanofi Genzyme. One investigator is an employee of MedDay Pharmaceuticals.
SOURCE: Block V et al. ECTRIMS 2019, Abstract 217.
STOCKHOLM – according to research presented at the annual congress of the European Committee for Treatment and Research in MS. Remote gait monitoring using a popular fitness tracker may offer a surrogate measure of MS disability in clinical trials, the researchers reported.
Many outcome measures in MS are evaluated in controlled contexts and do not indicate how patients are functioning outside of the clinical setting, said Valerie J. Block, PhD, from the Weill Institute for Neurosciences at the University of California, San Francisco. Patient-reported outcome measures are subject to recall bias and uneven perception of deficits. Remote ambulatory monitoring, on the other hand, could be a more objective measure that provides continuous information in the real-world setting, said Dr. Block. She and her colleagues have proposed remote ambulatory activity monitoring as an outcome measure for clinical trials.
The investigators chose this measure as an exploratory endpoint for SPI2, a phase 3 trial investigating the efficacy and safety of MD1003 (high-dose pharmaceutical-grade biotin) in patients with inactive primary progressive MS and secondary progressive MS. “To our knowledge, this is the first major clinical trial in progressive MS to include continuous remote step count monitoring as an exploratory endpoint,” said Dr. Block.
In the SPI2 study, patients received either MD1003 (300 mg/day) or placebo. To examine the relationship between ambulatory monitoring and clinical disability and MRI measures, the researchers remotely monitored participants’ ambulatory activity for 27 months using a fitness tracker. The investigators used the average daily step count from the first 30 days as the baseline activity measure. At first, they set a low daily step-count goal to minimize the influence of motivation on ambulatory activity. Participants later were taught how to change the goal independently.
Dr. Block and colleagues created LASSO subset selection regression models to correlate average daily step count with sex, age, disease duration, age at onset, disease course, and various MRI models (such as upper cervical cord area, gray matter volume, normalized brain volume, thalamic volume, and T1 and T2 lesion volumes). They performed least squares regression models on the subset selection results. Finally, the researchers calculated Spearman correlations between average daily step count and clinical disability, as measured by Expanded Disability Status Scale (EDSS) and timed 25-foot walk, and the Physical and Mental Health Composite measures of the MS Quality of Life scale (MSQoL-29).
As of April 23, 2019, the researchers had enrolled 492 patients (262 women) with full data at 90 centers (40 in the United States, 39 in Europe, 8 in Canada, and 3 in Australia). In all, 311 patients (63%) had secondary progressive MS, and 181 had primary progressive MS. Participants had moderate disability; the median EDSS score was 6.0. Median disease duration was 10.6 years. The mean daily step count during the first month was 3,699.
Greater step count was correlated with lower EDSS score, faster completion of the timed 25-foot walk, better Physical Health Composite score, better Symbol Digit Modalities Test score, and better Mental Health Composite score. Furthermore, greater mean daily step count also correlated with greater upper cervical cord area, greater normalized brain volume, greater gray matter volume, and lower T1 lesion volume. The correlations between step count and thalamic volume and T2 lesion volume were not significant. “These data support the study of steps as an exploratory outcome measure in clinical trials for progressive MS,” said Dr. Block.
Dr. Block received reimbursement for travel expenses related to this study from MedDay Pharmaceuticals. Coinvestigators received research support and compensation from companies such as Abbvie, Alexion, Biogen, Genentech, MedDay Pharmaceuticals, Novartis, and Sanofi Genzyme. One investigator is an employee of MedDay Pharmaceuticals.
SOURCE: Block V et al. ECTRIMS 2019, Abstract 217.
REPORTING FROM ECTRIMS 2019
In highly active MS, is skipping gadolinium an option?
STOCKHOLM – Further, lesions missed by skipping gadolinium would have changed treatment course for just 1 of the 84 patients in the study, said Lucia Gentili, MD, a neurologist in the department of medicine, section of neurology, at the University of Perugia (Italy), in an interview at the annual congress of the European Committee on Treatment and Research in Multiple Sclerosis.
“Postcontrast MRI might not be mandatory to detect signs of disease activity in patients with active MS,” she observed.
The question of the long-term effects of gadolinium deposition from serial scans in patients with MS is a hot topic among both patients and those caring for people with MS, said Dr. Gentili, so she and her associates decided to see how avoiding gadolinium exposure would affect lesion detection and patient management among their patient population.
For the retrospective study, the investigators looked at the records of 84 patients with relapsing remitting MS at two Italian MS centers over a 5-year time span. This was a cohort enriched for patients with highly active disease, said Dr. Gentili. A total of 45 patients, or over half of the cohort, had experienced at least one relapse in the preceding year.
The study included patients who were being screened for a second-line treatment and had evidence of brain or spinal cord contrast-enhancing lesions on MRI, if they also had a previous MRI of the brain and spinal cord performed on the same scanner.
The uniform protocol used for all MRIs included axial T2-weighted, fluid attenuated inversion recovery (FLAIR), and pre- and postcontrast T1-weighted sequences.
In all, the reference MRI scans picked up 164 contrast-enhancing lesions; of these, 151 (92.1%) were also seen on the T2/FLAIR sequences, showing up as new or enlarging lesions. Thirteen lesions were not visible on T2/FLAIR sequences when compared with the previous MRI, said Dr. Gentili.
Almost all patients in the cohort – a group with highly active disease, Dr. Gentili emphasized – also had new or enlarging lesions visible in T2 sequences. “Only two patients with MRI evidence of contrast-enhancing lesions showed no new or enlarged lesions in T2/FLAIR images,” she added. “Therefore, without gadolinium administration, only two patients in our cohort would have been incorrectly classified as radiologically stable.”
In reality, though, one of the two subjects whose disease activity was missed without gadolinium contrast had a relapse in the preceding 12 months, so clinical evidence of disease activity prompted attention to this individual. “Thus, only one subject in the entire cohort would have been incorrectly classified as stable,” Dr. Gentili and coauthors reported.
The results of this small study do not represent a case for abandoning gadolinium, Dr. Gentili stressed. “In our study, active lesions detected only by gadolinium enhancement, that is, without any evidence of new or enlarged lesions on T2/FLAIR, occurred in a limited but significant portion of contrast-enhancing lesions,” occurring in about 8% of the total lesions.
Rather, this study and other ongoing work represents a basis for shared decision making between persons with MS and those caring for them. Particularly for patients with highly active MS who can anticipate receiving a high burden of contrast to track disease activity, physicians can consider presenting them with the option to omit gadolinium contrast, she said.
Dr. Gentili reported receiving a travel grant from the ECTRIMS scientific program committee, and several coauthors reported relationships with multiple pharmaceutical companies. One coauthor received research funding from the Italian Multiple Sclerosis Society, the Italian Ministry of health, and the Italian Ministry of Education.
SOURCE: Gentili L et al. ECTRIMS 2019, Abstract P901.
STOCKHOLM – Further, lesions missed by skipping gadolinium would have changed treatment course for just 1 of the 84 patients in the study, said Lucia Gentili, MD, a neurologist in the department of medicine, section of neurology, at the University of Perugia (Italy), in an interview at the annual congress of the European Committee on Treatment and Research in Multiple Sclerosis.
“Postcontrast MRI might not be mandatory to detect signs of disease activity in patients with active MS,” she observed.
The question of the long-term effects of gadolinium deposition from serial scans in patients with MS is a hot topic among both patients and those caring for people with MS, said Dr. Gentili, so she and her associates decided to see how avoiding gadolinium exposure would affect lesion detection and patient management among their patient population.
For the retrospective study, the investigators looked at the records of 84 patients with relapsing remitting MS at two Italian MS centers over a 5-year time span. This was a cohort enriched for patients with highly active disease, said Dr. Gentili. A total of 45 patients, or over half of the cohort, had experienced at least one relapse in the preceding year.
The study included patients who were being screened for a second-line treatment and had evidence of brain or spinal cord contrast-enhancing lesions on MRI, if they also had a previous MRI of the brain and spinal cord performed on the same scanner.
The uniform protocol used for all MRIs included axial T2-weighted, fluid attenuated inversion recovery (FLAIR), and pre- and postcontrast T1-weighted sequences.
In all, the reference MRI scans picked up 164 contrast-enhancing lesions; of these, 151 (92.1%) were also seen on the T2/FLAIR sequences, showing up as new or enlarging lesions. Thirteen lesions were not visible on T2/FLAIR sequences when compared with the previous MRI, said Dr. Gentili.
Almost all patients in the cohort – a group with highly active disease, Dr. Gentili emphasized – also had new or enlarging lesions visible in T2 sequences. “Only two patients with MRI evidence of contrast-enhancing lesions showed no new or enlarged lesions in T2/FLAIR images,” she added. “Therefore, without gadolinium administration, only two patients in our cohort would have been incorrectly classified as radiologically stable.”
In reality, though, one of the two subjects whose disease activity was missed without gadolinium contrast had a relapse in the preceding 12 months, so clinical evidence of disease activity prompted attention to this individual. “Thus, only one subject in the entire cohort would have been incorrectly classified as stable,” Dr. Gentili and coauthors reported.
The results of this small study do not represent a case for abandoning gadolinium, Dr. Gentili stressed. “In our study, active lesions detected only by gadolinium enhancement, that is, without any evidence of new or enlarged lesions on T2/FLAIR, occurred in a limited but significant portion of contrast-enhancing lesions,” occurring in about 8% of the total lesions.
Rather, this study and other ongoing work represents a basis for shared decision making between persons with MS and those caring for them. Particularly for patients with highly active MS who can anticipate receiving a high burden of contrast to track disease activity, physicians can consider presenting them with the option to omit gadolinium contrast, she said.
Dr. Gentili reported receiving a travel grant from the ECTRIMS scientific program committee, and several coauthors reported relationships with multiple pharmaceutical companies. One coauthor received research funding from the Italian Multiple Sclerosis Society, the Italian Ministry of health, and the Italian Ministry of Education.
SOURCE: Gentili L et al. ECTRIMS 2019, Abstract P901.
STOCKHOLM – Further, lesions missed by skipping gadolinium would have changed treatment course for just 1 of the 84 patients in the study, said Lucia Gentili, MD, a neurologist in the department of medicine, section of neurology, at the University of Perugia (Italy), in an interview at the annual congress of the European Committee on Treatment and Research in Multiple Sclerosis.
“Postcontrast MRI might not be mandatory to detect signs of disease activity in patients with active MS,” she observed.
The question of the long-term effects of gadolinium deposition from serial scans in patients with MS is a hot topic among both patients and those caring for people with MS, said Dr. Gentili, so she and her associates decided to see how avoiding gadolinium exposure would affect lesion detection and patient management among their patient population.
For the retrospective study, the investigators looked at the records of 84 patients with relapsing remitting MS at two Italian MS centers over a 5-year time span. This was a cohort enriched for patients with highly active disease, said Dr. Gentili. A total of 45 patients, or over half of the cohort, had experienced at least one relapse in the preceding year.
The study included patients who were being screened for a second-line treatment and had evidence of brain or spinal cord contrast-enhancing lesions on MRI, if they also had a previous MRI of the brain and spinal cord performed on the same scanner.
The uniform protocol used for all MRIs included axial T2-weighted, fluid attenuated inversion recovery (FLAIR), and pre- and postcontrast T1-weighted sequences.
In all, the reference MRI scans picked up 164 contrast-enhancing lesions; of these, 151 (92.1%) were also seen on the T2/FLAIR sequences, showing up as new or enlarging lesions. Thirteen lesions were not visible on T2/FLAIR sequences when compared with the previous MRI, said Dr. Gentili.
Almost all patients in the cohort – a group with highly active disease, Dr. Gentili emphasized – also had new or enlarging lesions visible in T2 sequences. “Only two patients with MRI evidence of contrast-enhancing lesions showed no new or enlarged lesions in T2/FLAIR images,” she added. “Therefore, without gadolinium administration, only two patients in our cohort would have been incorrectly classified as radiologically stable.”
In reality, though, one of the two subjects whose disease activity was missed without gadolinium contrast had a relapse in the preceding 12 months, so clinical evidence of disease activity prompted attention to this individual. “Thus, only one subject in the entire cohort would have been incorrectly classified as stable,” Dr. Gentili and coauthors reported.
The results of this small study do not represent a case for abandoning gadolinium, Dr. Gentili stressed. “In our study, active lesions detected only by gadolinium enhancement, that is, without any evidence of new or enlarged lesions on T2/FLAIR, occurred in a limited but significant portion of contrast-enhancing lesions,” occurring in about 8% of the total lesions.
Rather, this study and other ongoing work represents a basis for shared decision making between persons with MS and those caring for them. Particularly for patients with highly active MS who can anticipate receiving a high burden of contrast to track disease activity, physicians can consider presenting them with the option to omit gadolinium contrast, she said.
Dr. Gentili reported receiving a travel grant from the ECTRIMS scientific program committee, and several coauthors reported relationships with multiple pharmaceutical companies. One coauthor received research funding from the Italian Multiple Sclerosis Society, the Italian Ministry of health, and the Italian Ministry of Education.
SOURCE: Gentili L et al. ECTRIMS 2019, Abstract P901.
REPORTING FROM ECTRIMS 2019
Most patients with RIS develop MS within 10 years
STOCKHOLM – Christine Lebrun-Frenay, MD, PhD, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
She and her coinvestigators in the Radiologically Isolated Syndrome Consortium identified four significant risk factors for conversion. The likelihood of developing MS rose stepwise with the number of risk factors present at baseline such that patients possessing all four risk factors had an 87% conversion rate by 10 years.
The four significant risk factors that emerged from multivariate analysis were being age 37 years or younger at the time of the initial abnormal MRI, having spinal cord lesions on MRI, being cerebrospinal fluid positive for oligoclonal immunoglobulin bands and/or an elevated IgG index, and having infratentorial brain lesions on MRI.
Patients with none or one of the risk factors at baseline had a 29% conversion rate at 10 years. That risk climbed to 54% with two risk factors and 68% with any three, according to Dr. Lebrun-Frenay, head of the inflammatory neurologic disorders clinical research unit and MS Center at the University of Nice (France).
The new 10-year results expand upon the previously reported outcomes involving 5 years of prospective follow-up in the initial cohort of 451 RIS patients at participating MS centers in the United States, three European countries, and Turkey. At 5 years, 34% of subjects had converted to MS as defined by a first acute symptomatic clinical event involving CNS demyelination or 12 months of a progressive neurologic deficit (PLoS One. 2014 Mar 5;9[3]:e90509).
Of note, 17% of patients were treated off label with MS disease-modifying therapies, including natalizumab, injectables, or fingolimod, while they still had RIS, she noted.
RIS was defined on the basis of an incidentally identified CNS white-matter lesion meeting the 2009 Okuda criteria (Neurology. 2009 Mar 3;72[9]:800-5), which remain the only validated criteria for RIS.
Fourteen patients converted from RIS to primary progressive MS, indicating the existence of a previously unrecognized presymptomatic phase for this form of the disease.
The mounting conversions from RIS to MS over time suggest that RIS is part of the MS spectrum. In light of the RIS Consortium’s 10-year findings, Dr. Lebrun-Frenay and colleagues strongly recommended yearly monitoring of patients with RIS via a clinical visit including a neurologic examination and possibly a cognitive evaluation, as well as brain and spinal cord MRI scans.
Based on the observed conversion trajectory between 5 and 10 years, Dr. Lebrun-Frenay speculated that with further prospective follow-up eventually all of the RIS patients will develop MS. Despite this, she did not recommend prescribing disease-modifying therapies for these asymptomatic RIS patients. Dr. Lebrun-Frenay noted that there are two ongoing major randomized, phase 3, placebo-controlled clinical trials addressing this very question: the ARISE study of dimethyl fumarate in the United States, and the TERIS study of teriflunomide in Europe.
“It hasn’t been demonstrated yet that to give an active drug at this early stage is useful, so we have to wait a little bit for the results of these ongoing trials. I think we have to believe in evidence-based medicine. After all, 5 or 6 years ago we didn’t have any diagnostic criteria for RIS. We didn’t have any knowledge of this syndrome. Now we have to wait for maybe 2 years. It’s not too long to wait for the answer,” she said.
Dr. Lebrun-Frenay serves as a consultant to more than a half-dozen pharmaceutical companies but reported having no financial conflicts regarding the RIS Consortium study, which is being conducted without commercial support.
SOURCE: Lebrun-Frenay C et al. ECTRIMS 2019, Abstract 97.
STOCKHOLM – Christine Lebrun-Frenay, MD, PhD, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
She and her coinvestigators in the Radiologically Isolated Syndrome Consortium identified four significant risk factors for conversion. The likelihood of developing MS rose stepwise with the number of risk factors present at baseline such that patients possessing all four risk factors had an 87% conversion rate by 10 years.
The four significant risk factors that emerged from multivariate analysis were being age 37 years or younger at the time of the initial abnormal MRI, having spinal cord lesions on MRI, being cerebrospinal fluid positive for oligoclonal immunoglobulin bands and/or an elevated IgG index, and having infratentorial brain lesions on MRI.
Patients with none or one of the risk factors at baseline had a 29% conversion rate at 10 years. That risk climbed to 54% with two risk factors and 68% with any three, according to Dr. Lebrun-Frenay, head of the inflammatory neurologic disorders clinical research unit and MS Center at the University of Nice (France).
The new 10-year results expand upon the previously reported outcomes involving 5 years of prospective follow-up in the initial cohort of 451 RIS patients at participating MS centers in the United States, three European countries, and Turkey. At 5 years, 34% of subjects had converted to MS as defined by a first acute symptomatic clinical event involving CNS demyelination or 12 months of a progressive neurologic deficit (PLoS One. 2014 Mar 5;9[3]:e90509).
Of note, 17% of patients were treated off label with MS disease-modifying therapies, including natalizumab, injectables, or fingolimod, while they still had RIS, she noted.
RIS was defined on the basis of an incidentally identified CNS white-matter lesion meeting the 2009 Okuda criteria (Neurology. 2009 Mar 3;72[9]:800-5), which remain the only validated criteria for RIS.
Fourteen patients converted from RIS to primary progressive MS, indicating the existence of a previously unrecognized presymptomatic phase for this form of the disease.
The mounting conversions from RIS to MS over time suggest that RIS is part of the MS spectrum. In light of the RIS Consortium’s 10-year findings, Dr. Lebrun-Frenay and colleagues strongly recommended yearly monitoring of patients with RIS via a clinical visit including a neurologic examination and possibly a cognitive evaluation, as well as brain and spinal cord MRI scans.
Based on the observed conversion trajectory between 5 and 10 years, Dr. Lebrun-Frenay speculated that with further prospective follow-up eventually all of the RIS patients will develop MS. Despite this, she did not recommend prescribing disease-modifying therapies for these asymptomatic RIS patients. Dr. Lebrun-Frenay noted that there are two ongoing major randomized, phase 3, placebo-controlled clinical trials addressing this very question: the ARISE study of dimethyl fumarate in the United States, and the TERIS study of teriflunomide in Europe.
“It hasn’t been demonstrated yet that to give an active drug at this early stage is useful, so we have to wait a little bit for the results of these ongoing trials. I think we have to believe in evidence-based medicine. After all, 5 or 6 years ago we didn’t have any diagnostic criteria for RIS. We didn’t have any knowledge of this syndrome. Now we have to wait for maybe 2 years. It’s not too long to wait for the answer,” she said.
Dr. Lebrun-Frenay serves as a consultant to more than a half-dozen pharmaceutical companies but reported having no financial conflicts regarding the RIS Consortium study, which is being conducted without commercial support.
SOURCE: Lebrun-Frenay C et al. ECTRIMS 2019, Abstract 97.
STOCKHOLM – Christine Lebrun-Frenay, MD, PhD, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
She and her coinvestigators in the Radiologically Isolated Syndrome Consortium identified four significant risk factors for conversion. The likelihood of developing MS rose stepwise with the number of risk factors present at baseline such that patients possessing all four risk factors had an 87% conversion rate by 10 years.
The four significant risk factors that emerged from multivariate analysis were being age 37 years or younger at the time of the initial abnormal MRI, having spinal cord lesions on MRI, being cerebrospinal fluid positive for oligoclonal immunoglobulin bands and/or an elevated IgG index, and having infratentorial brain lesions on MRI.
Patients with none or one of the risk factors at baseline had a 29% conversion rate at 10 years. That risk climbed to 54% with two risk factors and 68% with any three, according to Dr. Lebrun-Frenay, head of the inflammatory neurologic disorders clinical research unit and MS Center at the University of Nice (France).
The new 10-year results expand upon the previously reported outcomes involving 5 years of prospective follow-up in the initial cohort of 451 RIS patients at participating MS centers in the United States, three European countries, and Turkey. At 5 years, 34% of subjects had converted to MS as defined by a first acute symptomatic clinical event involving CNS demyelination or 12 months of a progressive neurologic deficit (PLoS One. 2014 Mar 5;9[3]:e90509).
Of note, 17% of patients were treated off label with MS disease-modifying therapies, including natalizumab, injectables, or fingolimod, while they still had RIS, she noted.
RIS was defined on the basis of an incidentally identified CNS white-matter lesion meeting the 2009 Okuda criteria (Neurology. 2009 Mar 3;72[9]:800-5), which remain the only validated criteria for RIS.
Fourteen patients converted from RIS to primary progressive MS, indicating the existence of a previously unrecognized presymptomatic phase for this form of the disease.
The mounting conversions from RIS to MS over time suggest that RIS is part of the MS spectrum. In light of the RIS Consortium’s 10-year findings, Dr. Lebrun-Frenay and colleagues strongly recommended yearly monitoring of patients with RIS via a clinical visit including a neurologic examination and possibly a cognitive evaluation, as well as brain and spinal cord MRI scans.
Based on the observed conversion trajectory between 5 and 10 years, Dr. Lebrun-Frenay speculated that with further prospective follow-up eventually all of the RIS patients will develop MS. Despite this, she did not recommend prescribing disease-modifying therapies for these asymptomatic RIS patients. Dr. Lebrun-Frenay noted that there are two ongoing major randomized, phase 3, placebo-controlled clinical trials addressing this very question: the ARISE study of dimethyl fumarate in the United States, and the TERIS study of teriflunomide in Europe.
“It hasn’t been demonstrated yet that to give an active drug at this early stage is useful, so we have to wait a little bit for the results of these ongoing trials. I think we have to believe in evidence-based medicine. After all, 5 or 6 years ago we didn’t have any diagnostic criteria for RIS. We didn’t have any knowledge of this syndrome. Now we have to wait for maybe 2 years. It’s not too long to wait for the answer,” she said.
Dr. Lebrun-Frenay serves as a consultant to more than a half-dozen pharmaceutical companies but reported having no financial conflicts regarding the RIS Consortium study, which is being conducted without commercial support.
SOURCE: Lebrun-Frenay C et al. ECTRIMS 2019, Abstract 97.
REPORTING FROM ECTRIMS 2019
In MS, iron-ringed lesions may add to imaging toolkit
STOCKHOLM – , according to research presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Using a conventional 3 Tesla magnetic resonance imaging (MRI) scanner, Margareta Clarke, PhD, and colleagues were able to identify iron rings (also called iron rims) and the central vein sign, and saw that both lesion characteristics were more common in MS patients than in those without MS.
“Routine two-dimensional 3 Tesla MRI with susceptibility weighting can be used to successfully visualize central veins and iron rims,” said Dr. Clarke, speaking at an imaging-focused young investigators’ session at the meeting. “Also, the central vein sign findings from previous 3T studies are confirmed.”
Dr. Clarke, a research fellow at the Vall d’Hebron Research Institute in Barcelona, explained that iron is stored within oligodendrocytes and myelin within the brain. In up to 56% of MS lesions, a rim of iron is visible with susceptibility weighted MRI imaging, she said, adding that the iron rings around the lesions “are likely caused by iron-laden activated microglia and macrophages that accumulate on the edges of lesions.”
It had been known that when lesions are surrounded by iron rings, they are more likely to enlarge and become increasingly hypointense on T1 weighted MRI. In addition, patients with more disability are more likely to have iron-rimmed brain lesions, said Dr. Clarke, and iron rings are associated with chronic disease activity. “Iron rings are a proposed marker of continuing inflammation and tissue loss,” she added.
The cross-sectional, single-center study enrolled patients with clinically isolated syndrome (CIS), MS, and conditions which can mimic MS on MRI. Dr. Clarke and her coinvestigators looked at the frequency of lesions with the central vein sign, and with iron rings, in all patients.
An additional aim of the study was to compare how experienced and inexperienced raters fared in their identification of both central veins and iron rings in 25 scans randomly chosen from within the study population. Inter-rater reliability between experienced and inexperienced raters was assessed as good, with little difference between experience levels in detecting iron rings and central veins, said Dr. Clarke.
Criteria used for central vein determination were those established by the North American Imaging in MS initiative, said Dr. Clarke: The vein needs to be seen entering and/or exiting the lesion, and the vein must course through the lesion’s center. If lesions are confluent, each of the larger lesion’s “fingers” must be assessed individually.
Iron rings appear as a hypointense area rimming the lesion’s edge; for the study, an iron ring was considered present if it could be seen fully or partially encircling a lesion, and if the ring was visible on at least two slices.
The study enrolled 103 patients with relapsing-remitting MS, 49 with progressive MS, 112 with CIS, and 35 non-MS patients; about 60% of this latter group had either autoimmune or vascular disease.
The fewest white matter lesions – a median of 4 per patient - were seen in the CIS group, while the progressive MS and non-MS group each had a median of 7 lesions, and the relapsing-remitting MS group had a median of 10 lesions.
In all, 2,617 lesions were analyzed, and 1,352 were assessed as having the central vein sign. Patients with MS or CIS had central vein sign in more than 50% of their lesions, while the non-MS patients had fewer than 20% central vein–positive lesions. In CIS and MS patients, central vein–positive lesions occurred more frequently in the periventricular and subcortical regions, compared with other brain regions (P less than .001).
Iron rings were detected in 392 lesions; none of the non-MS patients had iron ring–positive lesions. In terms of the brain regions where iron rings were most likely to be seen, said Dr. Clarke, “Over half of all iron ring-positive lesions were periventricular.” This finding was statistically significant as well (P less than .001). At least one lesion with an iron ring was seen in 59% of relapsing-remitting MS patients, 39% of progressive MS patients, and 48% of CIS patients.
In terms of patient characteristics, men were 40% more likely to have iron ring–positive lesions, and patients with relapsing-remitting MS were 50% more likely than were patients with CIS to have iron rings. Iron rings became 3% less likely for each additional year of age, as well (P less than .01 for all comparisons).
“Our results show that iron ring numbers peak in relapsing-remitting MS and decrease with longer disease duration,” Dr. Clarke and colleagues reported.
Dr. Clarke acknowledged several limitations of the study, including its single-center and retrospective nature, as well as the relatively low numbers of non-MS patients and patients with progressive MS. She and her colleagues are planning larger studies using 5-year follow-up data, she said.
Dr. Clarke is an ECTRIMS-MAGNIMS fellow and reported a speaker honorarium from Novartis.
SOURCE: Clarke M et al. ECTRIMS 2019. Abstract 108.
STOCKHOLM – , according to research presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Using a conventional 3 Tesla magnetic resonance imaging (MRI) scanner, Margareta Clarke, PhD, and colleagues were able to identify iron rings (also called iron rims) and the central vein sign, and saw that both lesion characteristics were more common in MS patients than in those without MS.
“Routine two-dimensional 3 Tesla MRI with susceptibility weighting can be used to successfully visualize central veins and iron rims,” said Dr. Clarke, speaking at an imaging-focused young investigators’ session at the meeting. “Also, the central vein sign findings from previous 3T studies are confirmed.”
Dr. Clarke, a research fellow at the Vall d’Hebron Research Institute in Barcelona, explained that iron is stored within oligodendrocytes and myelin within the brain. In up to 56% of MS lesions, a rim of iron is visible with susceptibility weighted MRI imaging, she said, adding that the iron rings around the lesions “are likely caused by iron-laden activated microglia and macrophages that accumulate on the edges of lesions.”
It had been known that when lesions are surrounded by iron rings, they are more likely to enlarge and become increasingly hypointense on T1 weighted MRI. In addition, patients with more disability are more likely to have iron-rimmed brain lesions, said Dr. Clarke, and iron rings are associated with chronic disease activity. “Iron rings are a proposed marker of continuing inflammation and tissue loss,” she added.
The cross-sectional, single-center study enrolled patients with clinically isolated syndrome (CIS), MS, and conditions which can mimic MS on MRI. Dr. Clarke and her coinvestigators looked at the frequency of lesions with the central vein sign, and with iron rings, in all patients.
An additional aim of the study was to compare how experienced and inexperienced raters fared in their identification of both central veins and iron rings in 25 scans randomly chosen from within the study population. Inter-rater reliability between experienced and inexperienced raters was assessed as good, with little difference between experience levels in detecting iron rings and central veins, said Dr. Clarke.
Criteria used for central vein determination were those established by the North American Imaging in MS initiative, said Dr. Clarke: The vein needs to be seen entering and/or exiting the lesion, and the vein must course through the lesion’s center. If lesions are confluent, each of the larger lesion’s “fingers” must be assessed individually.
Iron rings appear as a hypointense area rimming the lesion’s edge; for the study, an iron ring was considered present if it could be seen fully or partially encircling a lesion, and if the ring was visible on at least two slices.
The study enrolled 103 patients with relapsing-remitting MS, 49 with progressive MS, 112 with CIS, and 35 non-MS patients; about 60% of this latter group had either autoimmune or vascular disease.
The fewest white matter lesions – a median of 4 per patient - were seen in the CIS group, while the progressive MS and non-MS group each had a median of 7 lesions, and the relapsing-remitting MS group had a median of 10 lesions.
In all, 2,617 lesions were analyzed, and 1,352 were assessed as having the central vein sign. Patients with MS or CIS had central vein sign in more than 50% of their lesions, while the non-MS patients had fewer than 20% central vein–positive lesions. In CIS and MS patients, central vein–positive lesions occurred more frequently in the periventricular and subcortical regions, compared with other brain regions (P less than .001).
Iron rings were detected in 392 lesions; none of the non-MS patients had iron ring–positive lesions. In terms of the brain regions where iron rings were most likely to be seen, said Dr. Clarke, “Over half of all iron ring-positive lesions were periventricular.” This finding was statistically significant as well (P less than .001). At least one lesion with an iron ring was seen in 59% of relapsing-remitting MS patients, 39% of progressive MS patients, and 48% of CIS patients.
In terms of patient characteristics, men were 40% more likely to have iron ring–positive lesions, and patients with relapsing-remitting MS were 50% more likely than were patients with CIS to have iron rings. Iron rings became 3% less likely for each additional year of age, as well (P less than .01 for all comparisons).
“Our results show that iron ring numbers peak in relapsing-remitting MS and decrease with longer disease duration,” Dr. Clarke and colleagues reported.
Dr. Clarke acknowledged several limitations of the study, including its single-center and retrospective nature, as well as the relatively low numbers of non-MS patients and patients with progressive MS. She and her colleagues are planning larger studies using 5-year follow-up data, she said.
Dr. Clarke is an ECTRIMS-MAGNIMS fellow and reported a speaker honorarium from Novartis.
SOURCE: Clarke M et al. ECTRIMS 2019. Abstract 108.
STOCKHOLM – , according to research presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Using a conventional 3 Tesla magnetic resonance imaging (MRI) scanner, Margareta Clarke, PhD, and colleagues were able to identify iron rings (also called iron rims) and the central vein sign, and saw that both lesion characteristics were more common in MS patients than in those without MS.
“Routine two-dimensional 3 Tesla MRI with susceptibility weighting can be used to successfully visualize central veins and iron rims,” said Dr. Clarke, speaking at an imaging-focused young investigators’ session at the meeting. “Also, the central vein sign findings from previous 3T studies are confirmed.”
Dr. Clarke, a research fellow at the Vall d’Hebron Research Institute in Barcelona, explained that iron is stored within oligodendrocytes and myelin within the brain. In up to 56% of MS lesions, a rim of iron is visible with susceptibility weighted MRI imaging, she said, adding that the iron rings around the lesions “are likely caused by iron-laden activated microglia and macrophages that accumulate on the edges of lesions.”
It had been known that when lesions are surrounded by iron rings, they are more likely to enlarge and become increasingly hypointense on T1 weighted MRI. In addition, patients with more disability are more likely to have iron-rimmed brain lesions, said Dr. Clarke, and iron rings are associated with chronic disease activity. “Iron rings are a proposed marker of continuing inflammation and tissue loss,” she added.
The cross-sectional, single-center study enrolled patients with clinically isolated syndrome (CIS), MS, and conditions which can mimic MS on MRI. Dr. Clarke and her coinvestigators looked at the frequency of lesions with the central vein sign, and with iron rings, in all patients.
An additional aim of the study was to compare how experienced and inexperienced raters fared in their identification of both central veins and iron rings in 25 scans randomly chosen from within the study population. Inter-rater reliability between experienced and inexperienced raters was assessed as good, with little difference between experience levels in detecting iron rings and central veins, said Dr. Clarke.
Criteria used for central vein determination were those established by the North American Imaging in MS initiative, said Dr. Clarke: The vein needs to be seen entering and/or exiting the lesion, and the vein must course through the lesion’s center. If lesions are confluent, each of the larger lesion’s “fingers” must be assessed individually.
Iron rings appear as a hypointense area rimming the lesion’s edge; for the study, an iron ring was considered present if it could be seen fully or partially encircling a lesion, and if the ring was visible on at least two slices.
The study enrolled 103 patients with relapsing-remitting MS, 49 with progressive MS, 112 with CIS, and 35 non-MS patients; about 60% of this latter group had either autoimmune or vascular disease.
The fewest white matter lesions – a median of 4 per patient - were seen in the CIS group, while the progressive MS and non-MS group each had a median of 7 lesions, and the relapsing-remitting MS group had a median of 10 lesions.
In all, 2,617 lesions were analyzed, and 1,352 were assessed as having the central vein sign. Patients with MS or CIS had central vein sign in more than 50% of their lesions, while the non-MS patients had fewer than 20% central vein–positive lesions. In CIS and MS patients, central vein–positive lesions occurred more frequently in the periventricular and subcortical regions, compared with other brain regions (P less than .001).
Iron rings were detected in 392 lesions; none of the non-MS patients had iron ring–positive lesions. In terms of the brain regions where iron rings were most likely to be seen, said Dr. Clarke, “Over half of all iron ring-positive lesions were periventricular.” This finding was statistically significant as well (P less than .001). At least one lesion with an iron ring was seen in 59% of relapsing-remitting MS patients, 39% of progressive MS patients, and 48% of CIS patients.
In terms of patient characteristics, men were 40% more likely to have iron ring–positive lesions, and patients with relapsing-remitting MS were 50% more likely than were patients with CIS to have iron rings. Iron rings became 3% less likely for each additional year of age, as well (P less than .01 for all comparisons).
“Our results show that iron ring numbers peak in relapsing-remitting MS and decrease with longer disease duration,” Dr. Clarke and colleagues reported.
Dr. Clarke acknowledged several limitations of the study, including its single-center and retrospective nature, as well as the relatively low numbers of non-MS patients and patients with progressive MS. She and her colleagues are planning larger studies using 5-year follow-up data, she said.
Dr. Clarke is an ECTRIMS-MAGNIMS fellow and reported a speaker honorarium from Novartis.
SOURCE: Clarke M et al. ECTRIMS 2019. Abstract 108.
REPORTING FROM ECTRIMS 2019
Ponesimod reduces annualized relapse rate, compared with teriflunomide
STOCKHOLM – according to research presented at ECTRIMS 2019. Ponesimod also reduces fatigue and the number of active lesions, compared with teriflunomide.
Ponesimod selectively modulates the sphingosine-1-phosphate receptor 1 (S1P1). The drug is administered orally and reduces circulating lymphocyte counts by inducing a rapid, dose-dependent, and reversible sequestration of lymphocytes in lymphoid organs. This effect decreases the number of immune cells available for inflammatory attacks in the CNS, said Ludwig Kappos, MD, head of the department of neurology at University Hospital Basel (Switzerland). The drug has no active metabolites, and its effects on the immune system are reversible.
Dr. Kappos and colleagues conducted the OPTIMUM phase 3 study to assess the efficacy and safety of oral ponesimod, compared with those of teriflunomide. They enrolled patients between ages 18 and 55 years with an established diagnosis of MS according to the 2010 McDonald criteria with a relapsing course from onset into the multicenter, randomized, double-blind, superiority study. Eligible patients had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5 inclusive and recent clinical or MRI disease activity. Dr. Kappos and colleagues randomized participants in equal groups to receive ponesimod (20 mg/day) or teriflunomide (14 mg/day) and the respective placebo for 108 weeks. To mitigate the potential effects on heart rate that are associated with S1P1 modulators, patients were titrated gradually from 2 mg/day to the target dose over 14 days.
The trial’s primary endpoint was the annualized relapse rate over 108 weeks. Secondary endpoints were the effect on fatigue-related symptoms, as assessed with Fatigue Symptom and Impact Questionnaire-Relapsing MS (FSIQ-RMS); active lesions on MRI to week 108; and time to 12- and 24-week confirmed disability accumulation to end of study. The investigators also assessed the drugs’ safety and tolerability.
Dr. Kappos and colleagues randomized 1,133 patients at 162 sites in 28 countries. They stratified randomization according to whether participants had received prior disease-modifying treatment in the previous 2 years (39.4% had, and 60.6% had not) and EDSS score at baseline (83.4% had a score of 3.5 or lower, and 16.6% had a score above 3.5). The population’s mean age was 36.7 years, and 65% of participants were female. Most patients were recruited in Europe, and 51% came from E.U. countries. Patients’ mean baseline EDSS score was 2.6, and mean disease duration was 7.6 years. The mean prestudy 12-month relapse rate was 1.3, and 483 (42.7%) patients had one or more gadolinium-enhancing T1 lesions on baseline MRI. The two treatment groups were well balanced. The rate of treatment discontinuation was 16.6% for ponesimod and 16.4% on teriflunomide.
At the end of the study, the annualized relapse rate was 0.202 in the ponesimod group and 0.290 in the teriflunomide group. Compared with teriflunomide, ponesimod significantly reduced the annualized relapse rate by 30.5%. Fatigue remained stable in the ponesimod group, but worsened in the teriflunomide group: The mean difference in FSIQ-RMS score between the arms at week 108 was 3.57, and this result was statistically significant. In addition, ponesimod significantly reduced the number of active lesions by 56%, compared with teriflunomide. The risk for 12- and 24- week confirmed disability were lower with ponesimod, compared with teriflunomide, but the difference was not statistically significant.
The rates of treatment-emergent adverse events were approximately 89% for the ponesimod arm and 88% for teriflunomide. The rates of serious adverse events were about 9% for ponesimod and about 8% for teriflunomide. Respiratory events and laboratory values prompted slightly more study discontinuations in the ponesimod group than in the teriflunomide group.
This research represents the first controlled study to show superior efficacy of oral ponesimod, compared with an approved oral compound, said Dr. Kappos. “The overall profile suggests that [ponesimod] may be a valuable addition to our armamentarium in treating patients with relapsing forms of MS,” he concluded.
The study was supported by Actelion Pharmaceuticals. University Hospital Basel, where Dr. Kappos works, received steering committee, advisory board, and consultancy fees from Actelion and other companies.
SOURCE: Kappos L et al. ECTRIMS 2019, Abstract 93.
STOCKHOLM – according to research presented at ECTRIMS 2019. Ponesimod also reduces fatigue and the number of active lesions, compared with teriflunomide.
Ponesimod selectively modulates the sphingosine-1-phosphate receptor 1 (S1P1). The drug is administered orally and reduces circulating lymphocyte counts by inducing a rapid, dose-dependent, and reversible sequestration of lymphocytes in lymphoid organs. This effect decreases the number of immune cells available for inflammatory attacks in the CNS, said Ludwig Kappos, MD, head of the department of neurology at University Hospital Basel (Switzerland). The drug has no active metabolites, and its effects on the immune system are reversible.
Dr. Kappos and colleagues conducted the OPTIMUM phase 3 study to assess the efficacy and safety of oral ponesimod, compared with those of teriflunomide. They enrolled patients between ages 18 and 55 years with an established diagnosis of MS according to the 2010 McDonald criteria with a relapsing course from onset into the multicenter, randomized, double-blind, superiority study. Eligible patients had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5 inclusive and recent clinical or MRI disease activity. Dr. Kappos and colleagues randomized participants in equal groups to receive ponesimod (20 mg/day) or teriflunomide (14 mg/day) and the respective placebo for 108 weeks. To mitigate the potential effects on heart rate that are associated with S1P1 modulators, patients were titrated gradually from 2 mg/day to the target dose over 14 days.
The trial’s primary endpoint was the annualized relapse rate over 108 weeks. Secondary endpoints were the effect on fatigue-related symptoms, as assessed with Fatigue Symptom and Impact Questionnaire-Relapsing MS (FSIQ-RMS); active lesions on MRI to week 108; and time to 12- and 24-week confirmed disability accumulation to end of study. The investigators also assessed the drugs’ safety and tolerability.
Dr. Kappos and colleagues randomized 1,133 patients at 162 sites in 28 countries. They stratified randomization according to whether participants had received prior disease-modifying treatment in the previous 2 years (39.4% had, and 60.6% had not) and EDSS score at baseline (83.4% had a score of 3.5 or lower, and 16.6% had a score above 3.5). The population’s mean age was 36.7 years, and 65% of participants were female. Most patients were recruited in Europe, and 51% came from E.U. countries. Patients’ mean baseline EDSS score was 2.6, and mean disease duration was 7.6 years. The mean prestudy 12-month relapse rate was 1.3, and 483 (42.7%) patients had one or more gadolinium-enhancing T1 lesions on baseline MRI. The two treatment groups were well balanced. The rate of treatment discontinuation was 16.6% for ponesimod and 16.4% on teriflunomide.
At the end of the study, the annualized relapse rate was 0.202 in the ponesimod group and 0.290 in the teriflunomide group. Compared with teriflunomide, ponesimod significantly reduced the annualized relapse rate by 30.5%. Fatigue remained stable in the ponesimod group, but worsened in the teriflunomide group: The mean difference in FSIQ-RMS score between the arms at week 108 was 3.57, and this result was statistically significant. In addition, ponesimod significantly reduced the number of active lesions by 56%, compared with teriflunomide. The risk for 12- and 24- week confirmed disability were lower with ponesimod, compared with teriflunomide, but the difference was not statistically significant.
The rates of treatment-emergent adverse events were approximately 89% for the ponesimod arm and 88% for teriflunomide. The rates of serious adverse events were about 9% for ponesimod and about 8% for teriflunomide. Respiratory events and laboratory values prompted slightly more study discontinuations in the ponesimod group than in the teriflunomide group.
This research represents the first controlled study to show superior efficacy of oral ponesimod, compared with an approved oral compound, said Dr. Kappos. “The overall profile suggests that [ponesimod] may be a valuable addition to our armamentarium in treating patients with relapsing forms of MS,” he concluded.
The study was supported by Actelion Pharmaceuticals. University Hospital Basel, where Dr. Kappos works, received steering committee, advisory board, and consultancy fees from Actelion and other companies.
SOURCE: Kappos L et al. ECTRIMS 2019, Abstract 93.
STOCKHOLM – according to research presented at ECTRIMS 2019. Ponesimod also reduces fatigue and the number of active lesions, compared with teriflunomide.
Ponesimod selectively modulates the sphingosine-1-phosphate receptor 1 (S1P1). The drug is administered orally and reduces circulating lymphocyte counts by inducing a rapid, dose-dependent, and reversible sequestration of lymphocytes in lymphoid organs. This effect decreases the number of immune cells available for inflammatory attacks in the CNS, said Ludwig Kappos, MD, head of the department of neurology at University Hospital Basel (Switzerland). The drug has no active metabolites, and its effects on the immune system are reversible.
Dr. Kappos and colleagues conducted the OPTIMUM phase 3 study to assess the efficacy and safety of oral ponesimod, compared with those of teriflunomide. They enrolled patients between ages 18 and 55 years with an established diagnosis of MS according to the 2010 McDonald criteria with a relapsing course from onset into the multicenter, randomized, double-blind, superiority study. Eligible patients had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5 inclusive and recent clinical or MRI disease activity. Dr. Kappos and colleagues randomized participants in equal groups to receive ponesimod (20 mg/day) or teriflunomide (14 mg/day) and the respective placebo for 108 weeks. To mitigate the potential effects on heart rate that are associated with S1P1 modulators, patients were titrated gradually from 2 mg/day to the target dose over 14 days.
The trial’s primary endpoint was the annualized relapse rate over 108 weeks. Secondary endpoints were the effect on fatigue-related symptoms, as assessed with Fatigue Symptom and Impact Questionnaire-Relapsing MS (FSIQ-RMS); active lesions on MRI to week 108; and time to 12- and 24-week confirmed disability accumulation to end of study. The investigators also assessed the drugs’ safety and tolerability.
Dr. Kappos and colleagues randomized 1,133 patients at 162 sites in 28 countries. They stratified randomization according to whether participants had received prior disease-modifying treatment in the previous 2 years (39.4% had, and 60.6% had not) and EDSS score at baseline (83.4% had a score of 3.5 or lower, and 16.6% had a score above 3.5). The population’s mean age was 36.7 years, and 65% of participants were female. Most patients were recruited in Europe, and 51% came from E.U. countries. Patients’ mean baseline EDSS score was 2.6, and mean disease duration was 7.6 years. The mean prestudy 12-month relapse rate was 1.3, and 483 (42.7%) patients had one or more gadolinium-enhancing T1 lesions on baseline MRI. The two treatment groups were well balanced. The rate of treatment discontinuation was 16.6% for ponesimod and 16.4% on teriflunomide.
At the end of the study, the annualized relapse rate was 0.202 in the ponesimod group and 0.290 in the teriflunomide group. Compared with teriflunomide, ponesimod significantly reduced the annualized relapse rate by 30.5%. Fatigue remained stable in the ponesimod group, but worsened in the teriflunomide group: The mean difference in FSIQ-RMS score between the arms at week 108 was 3.57, and this result was statistically significant. In addition, ponesimod significantly reduced the number of active lesions by 56%, compared with teriflunomide. The risk for 12- and 24- week confirmed disability were lower with ponesimod, compared with teriflunomide, but the difference was not statistically significant.
The rates of treatment-emergent adverse events were approximately 89% for the ponesimod arm and 88% for teriflunomide. The rates of serious adverse events were about 9% for ponesimod and about 8% for teriflunomide. Respiratory events and laboratory values prompted slightly more study discontinuations in the ponesimod group than in the teriflunomide group.
This research represents the first controlled study to show superior efficacy of oral ponesimod, compared with an approved oral compound, said Dr. Kappos. “The overall profile suggests that [ponesimod] may be a valuable addition to our armamentarium in treating patients with relapsing forms of MS,” he concluded.
The study was supported by Actelion Pharmaceuticals. University Hospital Basel, where Dr. Kappos works, received steering committee, advisory board, and consultancy fees from Actelion and other companies.
SOURCE: Kappos L et al. ECTRIMS 2019, Abstract 93.
REPORTING FROM ECTRIMS 2019
Key clinical point: Ponesimod reduces the number of confirmed MS relapses, compared with teriflunomide.
Major finding: Annualized relapse rate was 30.5% lower with ponesimod, compared with teriflunomide.
Study details: A randomized, double-blind, superiority study of 1,133 patients with relapsing-remitting MS.
Disclosures: Actelion Pharmaceuticals sponsored the study.
Source: Kappos L et al. ECTRIMS 2019, Abstract 93.
Continuous treatment reduces risk of confirmed disability progression in MS
STOCKHOLM – (CDP), according to an investigation presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Using several confirmation points for Expanded Disability Status Scale (EDSS) progression (e.g., 12 months and 24 months), researchers detected a clear gradient of treatment effect. Identification of the most reliable outcome definitions will require further investigations, they said.
“The ultimate goal of MS treatment is the prevention of long-term disability accumulation,” said Giuseppe Lucisano, a biostatistician at the Center for Outcomes Research and Clinical Epidemiology in Pescara, Italy. “Continuous DMT exposure can impact long-term disability accumulation in MS, but it has not been definitively demonstrated yet.”
Registries and clinical databases provide the opportunity to collect longitudinal data for treated and untreated patients as a means of investigating questions such as this one, the researchers said. The Danish, Italian, and Swedish national MS registries, MSBase, and the Observatoire of MS (OFSEP) merged their data in the Big Multiple Sclerosis Data (BMSD) Network, which includes approximately 150,000 patients and more than 470,000 EDSS evaluations. The result is a large dataset suitable for long-term longitudinal studies.
Mr. Lucisano and colleagues sought to examine the long-term effect of DMTs on CDP and irreversible disability milestones (i.e., EDSS scores of 4 and 6) in relapsing-remitting MS. The researchers used marginal structural proportional models, a novel technique that enables them to correct modeling for confounders that vary with time in longitudinal observational studies. Such confounders include treatment switches, on-treatment relapses, and treatment gaps.
The investigators selected patients with 10 or more years’ follow-up and one or more EDSS score evaluations per year from the BMSD pooled cohort. Using marginal structural proportional models, the investigators evaluated cumulative hazards of 3-, 12- and 24-month CDP (i.e., CDP3, CDP12, CDP24) events in 6-month periods. They created stabilized inverse probability of treatment weights (IPTWs) at each 6-month period using survival models according to treatment status (i.e., treated versus untreated). Treatment status was assigned for each patient according to the percentage of time that he or she spent receiving DMT in each 6-month period. A patient who received treatment for 70% or more of the period studied was considered treated; patients who did not meet this threshold were considered untreated. The weights were calculated on the basis of sex, age, occurrence of relapse, EDSS score, and registry source. Finally, the researchers used Cox regression models estimating the effect of DMTs on the risk of reaching CDP3, CDP12, and CDP24, adjusted by the IPTWs, to compare cohorts that remained treated or untreated throughout follow-up.
The investigators identified a cohort of 15,602 patients with relapsing-remitting MS, and this group had 312,040 EDSS score evaluations. Approximately 28% of patients were male. Median age at disease onset was 28.3 years, and median disease duration was 18.7 years. Median follow-up duration was 13.8 years.
During follow-up, 43.3% of patients had CDP3, 27.7% had CDP12, and 14.4% had CDP24 events. In addition, 23.6% of patients reached an EDSS score of 4, and 11.2% reached an EDSS score of 6.
Cox models adjusted by IPTW demonstrated increasing positive evidence of the effect of cumulative treatment exposure, compared with cumulative untreated epochs, according to the length of confirmation time used for defining the CDP. The investigators did not observe an effect of treatment on the probability of reaching CDP3 (hazard ratio [HR], 1.02), but treatment had a protective effect on CDP12 (HR, 0.90) and CDP24 (HR, 0.65) endpoints. During treated epochs, the HR of EDSS 4 was 0.89, and the HR of EDSS 6 was 0.86. Sensitivity analyses largely confirmed the results of the main analysis.
Two of the researchers are employees of Biogen International, which supported the research. Several investigators received compensation or funding from various pharmaceutical companies.
STOCKHOLM – (CDP), according to an investigation presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Using several confirmation points for Expanded Disability Status Scale (EDSS) progression (e.g., 12 months and 24 months), researchers detected a clear gradient of treatment effect. Identification of the most reliable outcome definitions will require further investigations, they said.
“The ultimate goal of MS treatment is the prevention of long-term disability accumulation,” said Giuseppe Lucisano, a biostatistician at the Center for Outcomes Research and Clinical Epidemiology in Pescara, Italy. “Continuous DMT exposure can impact long-term disability accumulation in MS, but it has not been definitively demonstrated yet.”
Registries and clinical databases provide the opportunity to collect longitudinal data for treated and untreated patients as a means of investigating questions such as this one, the researchers said. The Danish, Italian, and Swedish national MS registries, MSBase, and the Observatoire of MS (OFSEP) merged their data in the Big Multiple Sclerosis Data (BMSD) Network, which includes approximately 150,000 patients and more than 470,000 EDSS evaluations. The result is a large dataset suitable for long-term longitudinal studies.
Mr. Lucisano and colleagues sought to examine the long-term effect of DMTs on CDP and irreversible disability milestones (i.e., EDSS scores of 4 and 6) in relapsing-remitting MS. The researchers used marginal structural proportional models, a novel technique that enables them to correct modeling for confounders that vary with time in longitudinal observational studies. Such confounders include treatment switches, on-treatment relapses, and treatment gaps.
The investigators selected patients with 10 or more years’ follow-up and one or more EDSS score evaluations per year from the BMSD pooled cohort. Using marginal structural proportional models, the investigators evaluated cumulative hazards of 3-, 12- and 24-month CDP (i.e., CDP3, CDP12, CDP24) events in 6-month periods. They created stabilized inverse probability of treatment weights (IPTWs) at each 6-month period using survival models according to treatment status (i.e., treated versus untreated). Treatment status was assigned for each patient according to the percentage of time that he or she spent receiving DMT in each 6-month period. A patient who received treatment for 70% or more of the period studied was considered treated; patients who did not meet this threshold were considered untreated. The weights were calculated on the basis of sex, age, occurrence of relapse, EDSS score, and registry source. Finally, the researchers used Cox regression models estimating the effect of DMTs on the risk of reaching CDP3, CDP12, and CDP24, adjusted by the IPTWs, to compare cohorts that remained treated or untreated throughout follow-up.
The investigators identified a cohort of 15,602 patients with relapsing-remitting MS, and this group had 312,040 EDSS score evaluations. Approximately 28% of patients were male. Median age at disease onset was 28.3 years, and median disease duration was 18.7 years. Median follow-up duration was 13.8 years.
During follow-up, 43.3% of patients had CDP3, 27.7% had CDP12, and 14.4% had CDP24 events. In addition, 23.6% of patients reached an EDSS score of 4, and 11.2% reached an EDSS score of 6.
Cox models adjusted by IPTW demonstrated increasing positive evidence of the effect of cumulative treatment exposure, compared with cumulative untreated epochs, according to the length of confirmation time used for defining the CDP. The investigators did not observe an effect of treatment on the probability of reaching CDP3 (hazard ratio [HR], 1.02), but treatment had a protective effect on CDP12 (HR, 0.90) and CDP24 (HR, 0.65) endpoints. During treated epochs, the HR of EDSS 4 was 0.89, and the HR of EDSS 6 was 0.86. Sensitivity analyses largely confirmed the results of the main analysis.
Two of the researchers are employees of Biogen International, which supported the research. Several investigators received compensation or funding from various pharmaceutical companies.
STOCKHOLM – (CDP), according to an investigation presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Using several confirmation points for Expanded Disability Status Scale (EDSS) progression (e.g., 12 months and 24 months), researchers detected a clear gradient of treatment effect. Identification of the most reliable outcome definitions will require further investigations, they said.
“The ultimate goal of MS treatment is the prevention of long-term disability accumulation,” said Giuseppe Lucisano, a biostatistician at the Center for Outcomes Research and Clinical Epidemiology in Pescara, Italy. “Continuous DMT exposure can impact long-term disability accumulation in MS, but it has not been definitively demonstrated yet.”
Registries and clinical databases provide the opportunity to collect longitudinal data for treated and untreated patients as a means of investigating questions such as this one, the researchers said. The Danish, Italian, and Swedish national MS registries, MSBase, and the Observatoire of MS (OFSEP) merged their data in the Big Multiple Sclerosis Data (BMSD) Network, which includes approximately 150,000 patients and more than 470,000 EDSS evaluations. The result is a large dataset suitable for long-term longitudinal studies.
Mr. Lucisano and colleagues sought to examine the long-term effect of DMTs on CDP and irreversible disability milestones (i.e., EDSS scores of 4 and 6) in relapsing-remitting MS. The researchers used marginal structural proportional models, a novel technique that enables them to correct modeling for confounders that vary with time in longitudinal observational studies. Such confounders include treatment switches, on-treatment relapses, and treatment gaps.
The investigators selected patients with 10 or more years’ follow-up and one or more EDSS score evaluations per year from the BMSD pooled cohort. Using marginal structural proportional models, the investigators evaluated cumulative hazards of 3-, 12- and 24-month CDP (i.e., CDP3, CDP12, CDP24) events in 6-month periods. They created stabilized inverse probability of treatment weights (IPTWs) at each 6-month period using survival models according to treatment status (i.e., treated versus untreated). Treatment status was assigned for each patient according to the percentage of time that he or she spent receiving DMT in each 6-month period. A patient who received treatment for 70% or more of the period studied was considered treated; patients who did not meet this threshold were considered untreated. The weights were calculated on the basis of sex, age, occurrence of relapse, EDSS score, and registry source. Finally, the researchers used Cox regression models estimating the effect of DMTs on the risk of reaching CDP3, CDP12, and CDP24, adjusted by the IPTWs, to compare cohorts that remained treated or untreated throughout follow-up.
The investigators identified a cohort of 15,602 patients with relapsing-remitting MS, and this group had 312,040 EDSS score evaluations. Approximately 28% of patients were male. Median age at disease onset was 28.3 years, and median disease duration was 18.7 years. Median follow-up duration was 13.8 years.
During follow-up, 43.3% of patients had CDP3, 27.7% had CDP12, and 14.4% had CDP24 events. In addition, 23.6% of patients reached an EDSS score of 4, and 11.2% reached an EDSS score of 6.
Cox models adjusted by IPTW demonstrated increasing positive evidence of the effect of cumulative treatment exposure, compared with cumulative untreated epochs, according to the length of confirmation time used for defining the CDP. The investigators did not observe an effect of treatment on the probability of reaching CDP3 (hazard ratio [HR], 1.02), but treatment had a protective effect on CDP12 (HR, 0.90) and CDP24 (HR, 0.65) endpoints. During treated epochs, the HR of EDSS 4 was 0.89, and the HR of EDSS 6 was 0.86. Sensitivity analyses largely confirmed the results of the main analysis.
Two of the researchers are employees of Biogen International, which supported the research. Several investigators received compensation or funding from various pharmaceutical companies.
REPORTING FROM ECTRIMS 2019
Neurologists need not discourage breastfeeding in women with MS
STOCKHOLM – Most neurologists are overly conservative when it comes to advising women with multiple sclerosis (MS) about breastfeeding, discouraging this broadly beneficial practice in favor of early resumption of treatment post pregnancy, Kerstin Hellwig, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“We should change our behavior, and I predict we will change it so that more women are breastfeeding while under MS medication within the next couple years. ,” said Dr. Hellwig, senior consultant and MS specialist in the department of neurology at St. Josef Hospital/Ruhr University in Bochum, Germany.
She was a coauthor of a groundbreaking 2012 meta-analysis that concluded that breastfeeding by MS patients is not harmful (J Neurol. 2012 Oct;259[10]:2246-8), a finding since confirmed in multiple additional studies.
“Women with MS who want to breastfeed should be supported in doing so,” Dr. Hellwig said.
In this regard, many neurologists are out of step with their colleagues in rheumatology and gastroenterology, who commonly endorse breastfeeding by their patients while on monoclonal antibodies for other autoimmune diseases, according to Dr. Hellwig.
It is important to recognize that most women of reproductive age with MS have milder forms of the disease, she said. They can safely breastfeed without being on any MS medications at all for the duration.
For women who want to breastfeed and have more-active disease where early treatment resumption is warranted, the key is to select a breastfeeding-compatible medication. The main determinant of whether a drug will enter the mother’s breast milk is the size of the drug molecule, with large molecules being unlikely to make their way into breast milk in anything approaching clinically meaningful amounts. The injectable first-line disease-modifying drugs are good options: For example, interferon-beta is a very large molecule which has been detected in breast milk at 0.0006% of the relative infant dose. That’s reassuring, Dr. Hellwig said, since anything less than a relative infant dose of 10% is generally considered to be safe for a baby. And while glatiramer acetate, another injectable, has not been tested, it is metabolized so rapidly that it is unlikely to be detectable in breast milk, according to Dr. Hellwig.
Monoclonal antibodies are also compatible with breastfeeding. Rituximab has been detected in breast milk at 1/240th of the maternal serum level, and natalizumab at less than 1/200th. These are large molecules with a low likelihood of infant absorption, since they are probably destroyed in the child’s gastrointestinal tract. Ocrelizumab has not been studied in breast milk, but it is an IgG1 monoclonal antibody, as is rituximab, and so should likewise pose “exceedingly low risk,” Dr. Hellwig said.
At last year’s ECTRIMS conference, she presented reassuring 1-year follow-up data on a cohort of infants breastfed by mothers with MS while on interferon-beta. “We do not see any growth disturbances, any severe infections, hospitalizations, excess antibiotic use, or postponed reaching of developmental milestones in babies being breastfed under the injectables,” she said.
Dr. Hellwig has served on scientific advisory board for Bayer, Biogen, Genzyme Sanofi, Teva, Roche, Novartis, and Merck. She has received speaker honoraria and research support from Bayer, Biogen, Merck, Novartis, SanofiGenzyme, and Teva, and has received support for congress participation from Bayer, Biogen, Genzyme, Teva, Roche, and Merck.
STOCKHOLM – Most neurologists are overly conservative when it comes to advising women with multiple sclerosis (MS) about breastfeeding, discouraging this broadly beneficial practice in favor of early resumption of treatment post pregnancy, Kerstin Hellwig, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“We should change our behavior, and I predict we will change it so that more women are breastfeeding while under MS medication within the next couple years. ,” said Dr. Hellwig, senior consultant and MS specialist in the department of neurology at St. Josef Hospital/Ruhr University in Bochum, Germany.
She was a coauthor of a groundbreaking 2012 meta-analysis that concluded that breastfeeding by MS patients is not harmful (J Neurol. 2012 Oct;259[10]:2246-8), a finding since confirmed in multiple additional studies.
“Women with MS who want to breastfeed should be supported in doing so,” Dr. Hellwig said.
In this regard, many neurologists are out of step with their colleagues in rheumatology and gastroenterology, who commonly endorse breastfeeding by their patients while on monoclonal antibodies for other autoimmune diseases, according to Dr. Hellwig.
It is important to recognize that most women of reproductive age with MS have milder forms of the disease, she said. They can safely breastfeed without being on any MS medications at all for the duration.
For women who want to breastfeed and have more-active disease where early treatment resumption is warranted, the key is to select a breastfeeding-compatible medication. The main determinant of whether a drug will enter the mother’s breast milk is the size of the drug molecule, with large molecules being unlikely to make their way into breast milk in anything approaching clinically meaningful amounts. The injectable first-line disease-modifying drugs are good options: For example, interferon-beta is a very large molecule which has been detected in breast milk at 0.0006% of the relative infant dose. That’s reassuring, Dr. Hellwig said, since anything less than a relative infant dose of 10% is generally considered to be safe for a baby. And while glatiramer acetate, another injectable, has not been tested, it is metabolized so rapidly that it is unlikely to be detectable in breast milk, according to Dr. Hellwig.
Monoclonal antibodies are also compatible with breastfeeding. Rituximab has been detected in breast milk at 1/240th of the maternal serum level, and natalizumab at less than 1/200th. These are large molecules with a low likelihood of infant absorption, since they are probably destroyed in the child’s gastrointestinal tract. Ocrelizumab has not been studied in breast milk, but it is an IgG1 monoclonal antibody, as is rituximab, and so should likewise pose “exceedingly low risk,” Dr. Hellwig said.
At last year’s ECTRIMS conference, she presented reassuring 1-year follow-up data on a cohort of infants breastfed by mothers with MS while on interferon-beta. “We do not see any growth disturbances, any severe infections, hospitalizations, excess antibiotic use, or postponed reaching of developmental milestones in babies being breastfed under the injectables,” she said.
Dr. Hellwig has served on scientific advisory board for Bayer, Biogen, Genzyme Sanofi, Teva, Roche, Novartis, and Merck. She has received speaker honoraria and research support from Bayer, Biogen, Merck, Novartis, SanofiGenzyme, and Teva, and has received support for congress participation from Bayer, Biogen, Genzyme, Teva, Roche, and Merck.
STOCKHOLM – Most neurologists are overly conservative when it comes to advising women with multiple sclerosis (MS) about breastfeeding, discouraging this broadly beneficial practice in favor of early resumption of treatment post pregnancy, Kerstin Hellwig, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“We should change our behavior, and I predict we will change it so that more women are breastfeeding while under MS medication within the next couple years. ,” said Dr. Hellwig, senior consultant and MS specialist in the department of neurology at St. Josef Hospital/Ruhr University in Bochum, Germany.
She was a coauthor of a groundbreaking 2012 meta-analysis that concluded that breastfeeding by MS patients is not harmful (J Neurol. 2012 Oct;259[10]:2246-8), a finding since confirmed in multiple additional studies.
“Women with MS who want to breastfeed should be supported in doing so,” Dr. Hellwig said.
In this regard, many neurologists are out of step with their colleagues in rheumatology and gastroenterology, who commonly endorse breastfeeding by their patients while on monoclonal antibodies for other autoimmune diseases, according to Dr. Hellwig.
It is important to recognize that most women of reproductive age with MS have milder forms of the disease, she said. They can safely breastfeed without being on any MS medications at all for the duration.
For women who want to breastfeed and have more-active disease where early treatment resumption is warranted, the key is to select a breastfeeding-compatible medication. The main determinant of whether a drug will enter the mother’s breast milk is the size of the drug molecule, with large molecules being unlikely to make their way into breast milk in anything approaching clinically meaningful amounts. The injectable first-line disease-modifying drugs are good options: For example, interferon-beta is a very large molecule which has been detected in breast milk at 0.0006% of the relative infant dose. That’s reassuring, Dr. Hellwig said, since anything less than a relative infant dose of 10% is generally considered to be safe for a baby. And while glatiramer acetate, another injectable, has not been tested, it is metabolized so rapidly that it is unlikely to be detectable in breast milk, according to Dr. Hellwig.
Monoclonal antibodies are also compatible with breastfeeding. Rituximab has been detected in breast milk at 1/240th of the maternal serum level, and natalizumab at less than 1/200th. These are large molecules with a low likelihood of infant absorption, since they are probably destroyed in the child’s gastrointestinal tract. Ocrelizumab has not been studied in breast milk, but it is an IgG1 monoclonal antibody, as is rituximab, and so should likewise pose “exceedingly low risk,” Dr. Hellwig said.
At last year’s ECTRIMS conference, she presented reassuring 1-year follow-up data on a cohort of infants breastfed by mothers with MS while on interferon-beta. “We do not see any growth disturbances, any severe infections, hospitalizations, excess antibiotic use, or postponed reaching of developmental milestones in babies being breastfed under the injectables,” she said.
Dr. Hellwig has served on scientific advisory board for Bayer, Biogen, Genzyme Sanofi, Teva, Roche, Novartis, and Merck. She has received speaker honoraria and research support from Bayer, Biogen, Merck, Novartis, SanofiGenzyme, and Teva, and has received support for congress participation from Bayer, Biogen, Genzyme, Teva, Roche, and Merck.
EXPERT ANALYSIS FROM ECTRIMS 2019
Vaccination is not associated with increased risk of MS
(MS), according to an analysis published July 30 in Neurology. Although the results suggest that vaccination is associated with a lower likelihood of incident MS within the following 5 years, “these data alone do not allow for any conclusion regarding a possible protective effect of vaccinations regarding the development of MS,” wrote Alexander Hapfelmeier, PhD, of the Technical University of Munich and colleagues.
In recent years, researchers have proposed and investigated various potential environmental risk factors for the development of MS. Vaccination is one proposed environmental risk factor, but case reports and small studies have yielded conflicting results about its association with incident MS.
To examine this question more closely, Dr. Hapfelmeier and colleagues performed a systematic retrospective analysis of ambulatory claims data held by the Bavarian Association of Statutory Health Insurance Physicians. They reviewed the data to identify patients with new-onset MS and at least two ICD-10 diagnoses of the disorder. They next identified two control cohorts of participants diagnosed with other autoimmune diseases: Crohn’s disease and psoriasis. Finally, they randomly selected a third control cohort of patients without any of these diagnoses and matched them by age, sex, and district to patients with MS in a 5:1 ratio. Eligible participants were younger than 70 years.
Dr. Hapfelmeier and colleagues reviewed the incidence and frequency of vaccinations (such as those targeting tick-borne encephalitis, human papillomavirus, and influenza virus) in all cohorts. They created unconditional logistic regression models to assess the association between vaccination and MS. They also created separate models to contrast the MS cohort with each of the control cohorts.
The researchers included 12,262 patients with MS, 19,296 patients with Crohn’s disease, 112,292 patients with psoriasis, and 79,185 participants without these autoimmune diseases in their analysis. They found 456 participants with Crohn’s disease and psoriasis, 216 participants with MS and psoriasis, 48 participants with Crohn’s disease and MS, and 2 participants with Crohn’s disease, psoriasis, and MS. Dr. Hapfelmeier and colleagues allocated these participants to each of the respective cohorts and did not analyze them differently because of the comparatively small sample sizes.
The investigators analyzed the occurrence of vaccination in all participants during the 5 years before first diagnosis. Among patients who received vaccination, the odds ratio of MS was 0.870 in participants without autoimmune disease, 0.919 in participants with Crohn’s disease, and 0.973 in participants with psoriasis. Decreased risk of MS was most notable for vaccinations against influenza and tick-borne encephalitis. The results were consistent regardless of time frame, control cohort, and definition of MS.
The subjective definition of the MS cohort was a limitation of the study, but the authors addressed it by also using several strict definitions of that cohort. Another limitation is that the source data may reflect entry errors and incorrect coding.
A grant from the German Federal Ministry of Education and Research Competence Network MS supported the study. The authors had no conflicts that were relevant to the topic of the study.
SOURCE: Hapfelmeier A et al. Neurology. 2019 Jul 30. doi: 10.1212/WNL.0000000000008012.
The analysis by Hapfelmeier et al. provides important evidence that vaccinations are not associated with multiple sclerosis (MS), said E. Ann Yeh, MD, a neurologist at the Hospital for Sick Children in Toronto, and Jennifer Graves, MD, PhD, a neurologist at the University of California, San Diego, in an accompanying editorial. On the contrary, the evidence supports a potential protective effect of vaccines on the risk of developing MS, they said.
“The reasons for this [finding] cannot be gleaned from this study and may range from biological to sociocultural/demographic reasons,” the authors added. “Infection, rather than vaccination, may be an MS trigger, or individuals obtaining vaccinations may be practicing other healthy behaviors protective for MS. These possibilities should be the subject of future studies.”
Until future studies are completed and their results published, the findings of Hapfelmeier et al. offer “strong evidence to share with worried patients and families when faced with the question of whether a vaccine in the recent or relatively distant past triggered the individual’s MS,” said Dr. Yeh and Dr. Graves.
The authors had various relationships with industry, including serving on advisory boards for and receiving funding from pharmaceutical companies.
The analysis by Hapfelmeier et al. provides important evidence that vaccinations are not associated with multiple sclerosis (MS), said E. Ann Yeh, MD, a neurologist at the Hospital for Sick Children in Toronto, and Jennifer Graves, MD, PhD, a neurologist at the University of California, San Diego, in an accompanying editorial. On the contrary, the evidence supports a potential protective effect of vaccines on the risk of developing MS, they said.
“The reasons for this [finding] cannot be gleaned from this study and may range from biological to sociocultural/demographic reasons,” the authors added. “Infection, rather than vaccination, may be an MS trigger, or individuals obtaining vaccinations may be practicing other healthy behaviors protective for MS. These possibilities should be the subject of future studies.”
Until future studies are completed and their results published, the findings of Hapfelmeier et al. offer “strong evidence to share with worried patients and families when faced with the question of whether a vaccine in the recent or relatively distant past triggered the individual’s MS,” said Dr. Yeh and Dr. Graves.
The authors had various relationships with industry, including serving on advisory boards for and receiving funding from pharmaceutical companies.
The analysis by Hapfelmeier et al. provides important evidence that vaccinations are not associated with multiple sclerosis (MS), said E. Ann Yeh, MD, a neurologist at the Hospital for Sick Children in Toronto, and Jennifer Graves, MD, PhD, a neurologist at the University of California, San Diego, in an accompanying editorial. On the contrary, the evidence supports a potential protective effect of vaccines on the risk of developing MS, they said.
“The reasons for this [finding] cannot be gleaned from this study and may range from biological to sociocultural/demographic reasons,” the authors added. “Infection, rather than vaccination, may be an MS trigger, or individuals obtaining vaccinations may be practicing other healthy behaviors protective for MS. These possibilities should be the subject of future studies.”
Until future studies are completed and their results published, the findings of Hapfelmeier et al. offer “strong evidence to share with worried patients and families when faced with the question of whether a vaccine in the recent or relatively distant past triggered the individual’s MS,” said Dr. Yeh and Dr. Graves.
The authors had various relationships with industry, including serving on advisory boards for and receiving funding from pharmaceutical companies.
(MS), according to an analysis published July 30 in Neurology. Although the results suggest that vaccination is associated with a lower likelihood of incident MS within the following 5 years, “these data alone do not allow for any conclusion regarding a possible protective effect of vaccinations regarding the development of MS,” wrote Alexander Hapfelmeier, PhD, of the Technical University of Munich and colleagues.
In recent years, researchers have proposed and investigated various potential environmental risk factors for the development of MS. Vaccination is one proposed environmental risk factor, but case reports and small studies have yielded conflicting results about its association with incident MS.
To examine this question more closely, Dr. Hapfelmeier and colleagues performed a systematic retrospective analysis of ambulatory claims data held by the Bavarian Association of Statutory Health Insurance Physicians. They reviewed the data to identify patients with new-onset MS and at least two ICD-10 diagnoses of the disorder. They next identified two control cohorts of participants diagnosed with other autoimmune diseases: Crohn’s disease and psoriasis. Finally, they randomly selected a third control cohort of patients without any of these diagnoses and matched them by age, sex, and district to patients with MS in a 5:1 ratio. Eligible participants were younger than 70 years.
Dr. Hapfelmeier and colleagues reviewed the incidence and frequency of vaccinations (such as those targeting tick-borne encephalitis, human papillomavirus, and influenza virus) in all cohorts. They created unconditional logistic regression models to assess the association between vaccination and MS. They also created separate models to contrast the MS cohort with each of the control cohorts.
The researchers included 12,262 patients with MS, 19,296 patients with Crohn’s disease, 112,292 patients with psoriasis, and 79,185 participants without these autoimmune diseases in their analysis. They found 456 participants with Crohn’s disease and psoriasis, 216 participants with MS and psoriasis, 48 participants with Crohn’s disease and MS, and 2 participants with Crohn’s disease, psoriasis, and MS. Dr. Hapfelmeier and colleagues allocated these participants to each of the respective cohorts and did not analyze them differently because of the comparatively small sample sizes.
The investigators analyzed the occurrence of vaccination in all participants during the 5 years before first diagnosis. Among patients who received vaccination, the odds ratio of MS was 0.870 in participants without autoimmune disease, 0.919 in participants with Crohn’s disease, and 0.973 in participants with psoriasis. Decreased risk of MS was most notable for vaccinations against influenza and tick-borne encephalitis. The results were consistent regardless of time frame, control cohort, and definition of MS.
The subjective definition of the MS cohort was a limitation of the study, but the authors addressed it by also using several strict definitions of that cohort. Another limitation is that the source data may reflect entry errors and incorrect coding.
A grant from the German Federal Ministry of Education and Research Competence Network MS supported the study. The authors had no conflicts that were relevant to the topic of the study.
SOURCE: Hapfelmeier A et al. Neurology. 2019 Jul 30. doi: 10.1212/WNL.0000000000008012.
(MS), according to an analysis published July 30 in Neurology. Although the results suggest that vaccination is associated with a lower likelihood of incident MS within the following 5 years, “these data alone do not allow for any conclusion regarding a possible protective effect of vaccinations regarding the development of MS,” wrote Alexander Hapfelmeier, PhD, of the Technical University of Munich and colleagues.
In recent years, researchers have proposed and investigated various potential environmental risk factors for the development of MS. Vaccination is one proposed environmental risk factor, but case reports and small studies have yielded conflicting results about its association with incident MS.
To examine this question more closely, Dr. Hapfelmeier and colleagues performed a systematic retrospective analysis of ambulatory claims data held by the Bavarian Association of Statutory Health Insurance Physicians. They reviewed the data to identify patients with new-onset MS and at least two ICD-10 diagnoses of the disorder. They next identified two control cohorts of participants diagnosed with other autoimmune diseases: Crohn’s disease and psoriasis. Finally, they randomly selected a third control cohort of patients without any of these diagnoses and matched them by age, sex, and district to patients with MS in a 5:1 ratio. Eligible participants were younger than 70 years.
Dr. Hapfelmeier and colleagues reviewed the incidence and frequency of vaccinations (such as those targeting tick-borne encephalitis, human papillomavirus, and influenza virus) in all cohorts. They created unconditional logistic regression models to assess the association between vaccination and MS. They also created separate models to contrast the MS cohort with each of the control cohorts.
The researchers included 12,262 patients with MS, 19,296 patients with Crohn’s disease, 112,292 patients with psoriasis, and 79,185 participants without these autoimmune diseases in their analysis. They found 456 participants with Crohn’s disease and psoriasis, 216 participants with MS and psoriasis, 48 participants with Crohn’s disease and MS, and 2 participants with Crohn’s disease, psoriasis, and MS. Dr. Hapfelmeier and colleagues allocated these participants to each of the respective cohorts and did not analyze them differently because of the comparatively small sample sizes.
The investigators analyzed the occurrence of vaccination in all participants during the 5 years before first diagnosis. Among patients who received vaccination, the odds ratio of MS was 0.870 in participants without autoimmune disease, 0.919 in participants with Crohn’s disease, and 0.973 in participants with psoriasis. Decreased risk of MS was most notable for vaccinations against influenza and tick-borne encephalitis. The results were consistent regardless of time frame, control cohort, and definition of MS.
The subjective definition of the MS cohort was a limitation of the study, but the authors addressed it by also using several strict definitions of that cohort. Another limitation is that the source data may reflect entry errors and incorrect coding.
A grant from the German Federal Ministry of Education and Research Competence Network MS supported the study. The authors had no conflicts that were relevant to the topic of the study.
SOURCE: Hapfelmeier A et al. Neurology. 2019 Jul 30. doi: 10.1212/WNL.0000000000008012.
FROM NEUROLOGY