User login
European Committee for Treatment and Research in Multiple Sclerosis - ECTRIMS 2018
Escalate treatment to avoid MS relapses
BERLIN – Escalating treatment to a “highly effective” disease-modifying treatment (DMT) results in fewer relapses in patients with relapsing-remitting multiple sclerosis (RRMS) than does switching to another “moderately effective” therapy, according to data from a Danish cohort study.
The annualized relapse rate (ARR) was 0.23 for patients who switched to a highly effective DMT, defined as either natalizumab (Tysabri) or fingolimod (Gilenya), whereas the ARR was 0.35 in those who were switched to a moderately effective DMT, defined as an interferon-beta, glatiramer acetate (Copaxone), teriflunomide (Aubagio), or dimethyl fumarate (Tecfidera).
This resulted in a relapse-rate ratio of 0.67 (95% confidence interval [CI], 0.55-0.83) comparing high to moderate DMT, or a 33% lower relapse rate in the high DMT group, Thor Ameri Chalmer, MD, PhD, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Dr. Chalmer, who works at the Danish Multiple Sclerosis Center at Rigshospitalet, the University of Copenhagen, reported that the time to first relapse and the likelihood for having recurrent relapses were all lowered by escalating treatment rather than switching treatment. Indeed, there was a 38% increase in the time to first relapse (hazard ratio [HR] = 0.62; 95% CI, 0.50-0.76) and a 31% reduction in recurrent relapses (HR = 0.69; 95% CI, 0.57-0.83).
However, there were “no clear differences” in the time to 3-month confirmed Expanded Disability Status Scale (EDSS) worsening and improvement, Dr. Chalmer said. The HR for time to first worsening in the 3-month confirmed EDSS was 0.86, and for recurrent worsening it was 0.86, but the 95% CI in both cases crossed over from 1.0 (0.65-1.14 and 0.71-1.05, respectively). There was no difference in the time to first improvement (HR = 1.23; 95% CI, 0.95-1.60).
“The aim of this study was to use data from the [Danish] MS Registry, find the patients who started on what we define as moderately effective DMT for the first time, and on this treatment experienced a disease breakthrough and then either switched to another moderately effective DMT or escalated to a highly effective DMT,” Dr. Chalmer explained.
Disease breakthrough was defined as at least one relapse occurring within 12 months of the treatment switch, or the treating neurologist defined the reason for switching as disease breakthrough. Dr. Chalmer acknowledged that this was one of the limitations of the observational study as patients could have been misclassified and switched treatment for another reason. The severity of the relapse was not recorded.
Data on more than 5,000 patients enrolled in the Danish Multiple Sclerosis Registry (DMSR) were considered, with a final propensity-match population of 788 included in the analysis; half had received highly effective DMT and half moderately effective DMT.
The DMSR contains data on virtually all patients with MS treated in Denmark, Dr. Chalmer observed; treatment with DMT is free of charge and it can be prescribed only in public MS clinics, he explained. Furthermore, all MS clinics are required to register information about treatment response at each clinical visit.
The mean age of patients in the study was 39 years, around 70% were female, and average disease duration was 5 years.
“I don’t see in your study what is really new,” Gilles Edan, MD, observed during a discussion. “We know that using more active, more efficient drugs gives more control on relapse.”
Dr. Edan, professor and head of the neurosciences department of University Hospital Pontchaillou, Rennes (France), added that these data “confirmed what has already been observed in the clinical trials.”
It is important to consider the safety and efficacy concerns on an individual level, Dr. Edan argued, questioning whether the more highly active drugs should be systematically used first-line rather than second-line in all patients with MS. He also noted that of course patients would need to be treated for very long periods.
Dr. Chalmer responded: “I agree some of the randomized trials have touched upon on this as well, but I think it’s really important to not just rely on one or two trials but to keep on doing the trials over and over again so that we show that we have the right results.”
Dr. Chalmer added that the present study looked only at efficacy and that the median follow-up time was 3.2 years. “Safety is important of course, but it was not the aim of this study.” Perhaps longer follow-up might have detected more differences in the EDSS outcomes, he added.
The study was funded by the Danish Multiple Sclerosis Society, the Foundation for Research in Neurology, Ejnar Jonassen, and Gangstedfonden. Dr. Chalmer disclosed he had received support for congress participation from Merck, Biogen, and Roche.
SOURCE: Chalmer T et al. Mult Scler. 2018;24(S2):99. Abstract 263.
BERLIN – Escalating treatment to a “highly effective” disease-modifying treatment (DMT) results in fewer relapses in patients with relapsing-remitting multiple sclerosis (RRMS) than does switching to another “moderately effective” therapy, according to data from a Danish cohort study.
The annualized relapse rate (ARR) was 0.23 for patients who switched to a highly effective DMT, defined as either natalizumab (Tysabri) or fingolimod (Gilenya), whereas the ARR was 0.35 in those who were switched to a moderately effective DMT, defined as an interferon-beta, glatiramer acetate (Copaxone), teriflunomide (Aubagio), or dimethyl fumarate (Tecfidera).
This resulted in a relapse-rate ratio of 0.67 (95% confidence interval [CI], 0.55-0.83) comparing high to moderate DMT, or a 33% lower relapse rate in the high DMT group, Thor Ameri Chalmer, MD, PhD, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Dr. Chalmer, who works at the Danish Multiple Sclerosis Center at Rigshospitalet, the University of Copenhagen, reported that the time to first relapse and the likelihood for having recurrent relapses were all lowered by escalating treatment rather than switching treatment. Indeed, there was a 38% increase in the time to first relapse (hazard ratio [HR] = 0.62; 95% CI, 0.50-0.76) and a 31% reduction in recurrent relapses (HR = 0.69; 95% CI, 0.57-0.83).
However, there were “no clear differences” in the time to 3-month confirmed Expanded Disability Status Scale (EDSS) worsening and improvement, Dr. Chalmer said. The HR for time to first worsening in the 3-month confirmed EDSS was 0.86, and for recurrent worsening it was 0.86, but the 95% CI in both cases crossed over from 1.0 (0.65-1.14 and 0.71-1.05, respectively). There was no difference in the time to first improvement (HR = 1.23; 95% CI, 0.95-1.60).
“The aim of this study was to use data from the [Danish] MS Registry, find the patients who started on what we define as moderately effective DMT for the first time, and on this treatment experienced a disease breakthrough and then either switched to another moderately effective DMT or escalated to a highly effective DMT,” Dr. Chalmer explained.
Disease breakthrough was defined as at least one relapse occurring within 12 months of the treatment switch, or the treating neurologist defined the reason for switching as disease breakthrough. Dr. Chalmer acknowledged that this was one of the limitations of the observational study as patients could have been misclassified and switched treatment for another reason. The severity of the relapse was not recorded.
Data on more than 5,000 patients enrolled in the Danish Multiple Sclerosis Registry (DMSR) were considered, with a final propensity-match population of 788 included in the analysis; half had received highly effective DMT and half moderately effective DMT.
The DMSR contains data on virtually all patients with MS treated in Denmark, Dr. Chalmer observed; treatment with DMT is free of charge and it can be prescribed only in public MS clinics, he explained. Furthermore, all MS clinics are required to register information about treatment response at each clinical visit.
The mean age of patients in the study was 39 years, around 70% were female, and average disease duration was 5 years.
“I don’t see in your study what is really new,” Gilles Edan, MD, observed during a discussion. “We know that using more active, more efficient drugs gives more control on relapse.”
Dr. Edan, professor and head of the neurosciences department of University Hospital Pontchaillou, Rennes (France), added that these data “confirmed what has already been observed in the clinical trials.”
It is important to consider the safety and efficacy concerns on an individual level, Dr. Edan argued, questioning whether the more highly active drugs should be systematically used first-line rather than second-line in all patients with MS. He also noted that of course patients would need to be treated for very long periods.
Dr. Chalmer responded: “I agree some of the randomized trials have touched upon on this as well, but I think it’s really important to not just rely on one or two trials but to keep on doing the trials over and over again so that we show that we have the right results.”
Dr. Chalmer added that the present study looked only at efficacy and that the median follow-up time was 3.2 years. “Safety is important of course, but it was not the aim of this study.” Perhaps longer follow-up might have detected more differences in the EDSS outcomes, he added.
The study was funded by the Danish Multiple Sclerosis Society, the Foundation for Research in Neurology, Ejnar Jonassen, and Gangstedfonden. Dr. Chalmer disclosed he had received support for congress participation from Merck, Biogen, and Roche.
SOURCE: Chalmer T et al. Mult Scler. 2018;24(S2):99. Abstract 263.
BERLIN – Escalating treatment to a “highly effective” disease-modifying treatment (DMT) results in fewer relapses in patients with relapsing-remitting multiple sclerosis (RRMS) than does switching to another “moderately effective” therapy, according to data from a Danish cohort study.
The annualized relapse rate (ARR) was 0.23 for patients who switched to a highly effective DMT, defined as either natalizumab (Tysabri) or fingolimod (Gilenya), whereas the ARR was 0.35 in those who were switched to a moderately effective DMT, defined as an interferon-beta, glatiramer acetate (Copaxone), teriflunomide (Aubagio), or dimethyl fumarate (Tecfidera).
This resulted in a relapse-rate ratio of 0.67 (95% confidence interval [CI], 0.55-0.83) comparing high to moderate DMT, or a 33% lower relapse rate in the high DMT group, Thor Ameri Chalmer, MD, PhD, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Dr. Chalmer, who works at the Danish Multiple Sclerosis Center at Rigshospitalet, the University of Copenhagen, reported that the time to first relapse and the likelihood for having recurrent relapses were all lowered by escalating treatment rather than switching treatment. Indeed, there was a 38% increase in the time to first relapse (hazard ratio [HR] = 0.62; 95% CI, 0.50-0.76) and a 31% reduction in recurrent relapses (HR = 0.69; 95% CI, 0.57-0.83).
However, there were “no clear differences” in the time to 3-month confirmed Expanded Disability Status Scale (EDSS) worsening and improvement, Dr. Chalmer said. The HR for time to first worsening in the 3-month confirmed EDSS was 0.86, and for recurrent worsening it was 0.86, but the 95% CI in both cases crossed over from 1.0 (0.65-1.14 and 0.71-1.05, respectively). There was no difference in the time to first improvement (HR = 1.23; 95% CI, 0.95-1.60).
“The aim of this study was to use data from the [Danish] MS Registry, find the patients who started on what we define as moderately effective DMT for the first time, and on this treatment experienced a disease breakthrough and then either switched to another moderately effective DMT or escalated to a highly effective DMT,” Dr. Chalmer explained.
Disease breakthrough was defined as at least one relapse occurring within 12 months of the treatment switch, or the treating neurologist defined the reason for switching as disease breakthrough. Dr. Chalmer acknowledged that this was one of the limitations of the observational study as patients could have been misclassified and switched treatment for another reason. The severity of the relapse was not recorded.
Data on more than 5,000 patients enrolled in the Danish Multiple Sclerosis Registry (DMSR) were considered, with a final propensity-match population of 788 included in the analysis; half had received highly effective DMT and half moderately effective DMT.
The DMSR contains data on virtually all patients with MS treated in Denmark, Dr. Chalmer observed; treatment with DMT is free of charge and it can be prescribed only in public MS clinics, he explained. Furthermore, all MS clinics are required to register information about treatment response at each clinical visit.
The mean age of patients in the study was 39 years, around 70% were female, and average disease duration was 5 years.
“I don’t see in your study what is really new,” Gilles Edan, MD, observed during a discussion. “We know that using more active, more efficient drugs gives more control on relapse.”
Dr. Edan, professor and head of the neurosciences department of University Hospital Pontchaillou, Rennes (France), added that these data “confirmed what has already been observed in the clinical trials.”
It is important to consider the safety and efficacy concerns on an individual level, Dr. Edan argued, questioning whether the more highly active drugs should be systematically used first-line rather than second-line in all patients with MS. He also noted that of course patients would need to be treated for very long periods.
Dr. Chalmer responded: “I agree some of the randomized trials have touched upon on this as well, but I think it’s really important to not just rely on one or two trials but to keep on doing the trials over and over again so that we show that we have the right results.”
Dr. Chalmer added that the present study looked only at efficacy and that the median follow-up time was 3.2 years. “Safety is important of course, but it was not the aim of this study.” Perhaps longer follow-up might have detected more differences in the EDSS outcomes, he added.
The study was funded by the Danish Multiple Sclerosis Society, the Foundation for Research in Neurology, Ejnar Jonassen, and Gangstedfonden. Dr. Chalmer disclosed he had received support for congress participation from Merck, Biogen, and Roche.
SOURCE: Chalmer T et al. Mult Scler. 2018;24(S2):99. Abstract 263.
REPORTING FROM ECTRIMS 2018
Retinal thinning in aquaporin-4-positive NMOSD may occur without optic neuritis
BERLIN – Retinal thinning related to ganglion loss may be independent of optic neuritis attacks in patients with neuromyelitis optica spectrum disorders who have anti–aquaporin-4 antibodies.
These eyes exhibited an annual retinal volume loss of about 0.6 micrometers – 80 times higher than that of normal controls – even though they did not have a history of optic neuritis (ON), Frederike C. Oertel said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“The most likely explanation for this seems to be a disease-related primary retinopathy due to the high density of astrocytic cells in the retina and the afferent visual system,” said Ms. Oertel, a doctoral student at NeuroCure Clinical Research Center, Berlin.
The study appeared in the Journal of Neurology, Neurosurgery & Psychiatry (J Neurol Neurosurg Psychiatry. 2018 Jun 19. doi: 10.1136/jnnp-2018-318382).
A previous cross-sectional study by her group found retinal thinning and an alteration of foveal shape in anti–aquaporin-4 (anti-AQP4) positive patients with neuromyelitis optica spectrum disorders (NMOSD) independent of whether they had experienced a clinical attack of optic neuritis (Neurol Neuroimmunol Neuroinflamm. 2017 May;4[3]:e334). In these patients, the fovea changed shape from a characteristic steeply angled “V” to a broader, flatter “U” shape, she said.
In that 2017 paper, Ms. Oertel and her colleagues theorized that the relationship between the water-channel regulator AQP4 and astrocytes could be the root cause of these microstructural alterations.
“The parafoveal area is characterized by a high density of retinal astrocytic Müller cells, which express AQP4 and may thus serve as retinal targets in NMOSD,” they wrote. “Müller cells regulate the retinal water balance and have a relevant role in neurotransmitter and photopigment recycling, as well as in energy and lipid metabolism. Müller cell dysfunction or degeneration could thus lead to impaired retinal function including changes in water homeostasis. Of interest, both the initial cohort and the confirmatory cohort showed a mild increase of peripapillary retinal nerve fiber layer thickness, which could indicate tissue swelling. These findings are supported by animal studies showing retraction of astrocytic end feet in some and astrocyte death in other cases, suggesting a primary astrocytoma in NMOSD also outside acute lesions.”
The study Ms. Oertel presented at ECTRIMS looked at full retinal thickness using the same imaging tool, optical coherence tomography (OCT). The longitudinal cohort comprised 94 eyes in 51 anti–AQP4-IgG seropositive patients who had NMOSD; 60 of these eyes had experienced an optic neuritis attack and 34 had not. Most of the patients were female; the mean age was 47 years. They were compared against 28 age- and sex-matched healthy controls.
OCT measured combined ganglion cell and inner plexiform layer (GCIP), the peripapillary retinal nerve fiber layer (pRNFL), fovea thickness (FT), inner nuclear layer (INL), and total macular volume (TMV).
At baseline, ON eyes already displayed reduced GCIP, FT, and TMV, compared with healthy controls – but so had eyes that had not had ON. Over the follow-up period, eyes without ON continued to show thinning, even in the absence of a clinical attack. Although visual acuity didn’t change over time, the retinas continued to thin, losing an average of 0.6 micrometers each year, a rate 80 times greater than that seen in the control group.
“We saw this significant loss of the ganglion cell layer volume independent of ON, suggesting that retinal neurodegeneration is not dependent on ON in these patients,” Ms. Oertel said.
The results fit well into the group’s prior theory of astrocytic involvement. However, she added, “We still have to think about an alternative theory of drug-induced neuroaxonal damage and retrograde neuroaxonal degeneration.”
The project was supported with grants from the German Ministry for Education and Research. Ms. Oertel had no financial disclosures relevant to the work, but many coauthors reported financial relationships with industry.
BERLIN – Retinal thinning related to ganglion loss may be independent of optic neuritis attacks in patients with neuromyelitis optica spectrum disorders who have anti–aquaporin-4 antibodies.
These eyes exhibited an annual retinal volume loss of about 0.6 micrometers – 80 times higher than that of normal controls – even though they did not have a history of optic neuritis (ON), Frederike C. Oertel said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“The most likely explanation for this seems to be a disease-related primary retinopathy due to the high density of astrocytic cells in the retina and the afferent visual system,” said Ms. Oertel, a doctoral student at NeuroCure Clinical Research Center, Berlin.
The study appeared in the Journal of Neurology, Neurosurgery & Psychiatry (J Neurol Neurosurg Psychiatry. 2018 Jun 19. doi: 10.1136/jnnp-2018-318382).
A previous cross-sectional study by her group found retinal thinning and an alteration of foveal shape in anti–aquaporin-4 (anti-AQP4) positive patients with neuromyelitis optica spectrum disorders (NMOSD) independent of whether they had experienced a clinical attack of optic neuritis (Neurol Neuroimmunol Neuroinflamm. 2017 May;4[3]:e334). In these patients, the fovea changed shape from a characteristic steeply angled “V” to a broader, flatter “U” shape, she said.
In that 2017 paper, Ms. Oertel and her colleagues theorized that the relationship between the water-channel regulator AQP4 and astrocytes could be the root cause of these microstructural alterations.
“The parafoveal area is characterized by a high density of retinal astrocytic Müller cells, which express AQP4 and may thus serve as retinal targets in NMOSD,” they wrote. “Müller cells regulate the retinal water balance and have a relevant role in neurotransmitter and photopigment recycling, as well as in energy and lipid metabolism. Müller cell dysfunction or degeneration could thus lead to impaired retinal function including changes in water homeostasis. Of interest, both the initial cohort and the confirmatory cohort showed a mild increase of peripapillary retinal nerve fiber layer thickness, which could indicate tissue swelling. These findings are supported by animal studies showing retraction of astrocytic end feet in some and astrocyte death in other cases, suggesting a primary astrocytoma in NMOSD also outside acute lesions.”
The study Ms. Oertel presented at ECTRIMS looked at full retinal thickness using the same imaging tool, optical coherence tomography (OCT). The longitudinal cohort comprised 94 eyes in 51 anti–AQP4-IgG seropositive patients who had NMOSD; 60 of these eyes had experienced an optic neuritis attack and 34 had not. Most of the patients were female; the mean age was 47 years. They were compared against 28 age- and sex-matched healthy controls.
OCT measured combined ganglion cell and inner plexiform layer (GCIP), the peripapillary retinal nerve fiber layer (pRNFL), fovea thickness (FT), inner nuclear layer (INL), and total macular volume (TMV).
At baseline, ON eyes already displayed reduced GCIP, FT, and TMV, compared with healthy controls – but so had eyes that had not had ON. Over the follow-up period, eyes without ON continued to show thinning, even in the absence of a clinical attack. Although visual acuity didn’t change over time, the retinas continued to thin, losing an average of 0.6 micrometers each year, a rate 80 times greater than that seen in the control group.
“We saw this significant loss of the ganglion cell layer volume independent of ON, suggesting that retinal neurodegeneration is not dependent on ON in these patients,” Ms. Oertel said.
The results fit well into the group’s prior theory of astrocytic involvement. However, she added, “We still have to think about an alternative theory of drug-induced neuroaxonal damage and retrograde neuroaxonal degeneration.”
The project was supported with grants from the German Ministry for Education and Research. Ms. Oertel had no financial disclosures relevant to the work, but many coauthors reported financial relationships with industry.
BERLIN – Retinal thinning related to ganglion loss may be independent of optic neuritis attacks in patients with neuromyelitis optica spectrum disorders who have anti–aquaporin-4 antibodies.
These eyes exhibited an annual retinal volume loss of about 0.6 micrometers – 80 times higher than that of normal controls – even though they did not have a history of optic neuritis (ON), Frederike C. Oertel said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“The most likely explanation for this seems to be a disease-related primary retinopathy due to the high density of astrocytic cells in the retina and the afferent visual system,” said Ms. Oertel, a doctoral student at NeuroCure Clinical Research Center, Berlin.
The study appeared in the Journal of Neurology, Neurosurgery & Psychiatry (J Neurol Neurosurg Psychiatry. 2018 Jun 19. doi: 10.1136/jnnp-2018-318382).
A previous cross-sectional study by her group found retinal thinning and an alteration of foveal shape in anti–aquaporin-4 (anti-AQP4) positive patients with neuromyelitis optica spectrum disorders (NMOSD) independent of whether they had experienced a clinical attack of optic neuritis (Neurol Neuroimmunol Neuroinflamm. 2017 May;4[3]:e334). In these patients, the fovea changed shape from a characteristic steeply angled “V” to a broader, flatter “U” shape, she said.
In that 2017 paper, Ms. Oertel and her colleagues theorized that the relationship between the water-channel regulator AQP4 and astrocytes could be the root cause of these microstructural alterations.
“The parafoveal area is characterized by a high density of retinal astrocytic Müller cells, which express AQP4 and may thus serve as retinal targets in NMOSD,” they wrote. “Müller cells regulate the retinal water balance and have a relevant role in neurotransmitter and photopigment recycling, as well as in energy and lipid metabolism. Müller cell dysfunction or degeneration could thus lead to impaired retinal function including changes in water homeostasis. Of interest, both the initial cohort and the confirmatory cohort showed a mild increase of peripapillary retinal nerve fiber layer thickness, which could indicate tissue swelling. These findings are supported by animal studies showing retraction of astrocytic end feet in some and astrocyte death in other cases, suggesting a primary astrocytoma in NMOSD also outside acute lesions.”
The study Ms. Oertel presented at ECTRIMS looked at full retinal thickness using the same imaging tool, optical coherence tomography (OCT). The longitudinal cohort comprised 94 eyes in 51 anti–AQP4-IgG seropositive patients who had NMOSD; 60 of these eyes had experienced an optic neuritis attack and 34 had not. Most of the patients were female; the mean age was 47 years. They were compared against 28 age- and sex-matched healthy controls.
OCT measured combined ganglion cell and inner plexiform layer (GCIP), the peripapillary retinal nerve fiber layer (pRNFL), fovea thickness (FT), inner nuclear layer (INL), and total macular volume (TMV).
At baseline, ON eyes already displayed reduced GCIP, FT, and TMV, compared with healthy controls – but so had eyes that had not had ON. Over the follow-up period, eyes without ON continued to show thinning, even in the absence of a clinical attack. Although visual acuity didn’t change over time, the retinas continued to thin, losing an average of 0.6 micrometers each year, a rate 80 times greater than that seen in the control group.
“We saw this significant loss of the ganglion cell layer volume independent of ON, suggesting that retinal neurodegeneration is not dependent on ON in these patients,” Ms. Oertel said.
The results fit well into the group’s prior theory of astrocytic involvement. However, she added, “We still have to think about an alternative theory of drug-induced neuroaxonal damage and retrograde neuroaxonal degeneration.”
The project was supported with grants from the German Ministry for Education and Research. Ms. Oertel had no financial disclosures relevant to the work, but many coauthors reported financial relationships with industry.
REPORTING FROM ECTRIMS 2018
Key clinical point:
Major finding: Over 2.5 years retinas thinned an average of 0.6 micrometers annually.
Study details: The longitudinal study comprised 94 eyes.
Disclosures: The project was supported with grants from the German Ministry for Education and Research. Dr. Oertel had no conflicts of interest, but many coauthors reported financial relationships with industry.
Source: Oertel FC et al. ECTRIMS 2018, Abstract 212.
Investigational BTK inhibitor for relapsing MS advances on positive phase 2 data
BERLIN – Evobrutinib, an investigational inhibitor of Bruton’s tyrosine kinase (BTK), significantly reduced the number of new T1 gadolinium-enhancing lesions at 24 weeks compared with placebo in patients with relapsing multiples sclerosis (MS).
However, the molecule was also associated with grade 3 and 4 elevations in alanine aminotransferase – a troubling finding, Xavier Montalban, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“Fortunately, all patients were asymptomatic, and the elevations were completely reversible. The results of this trial do support further development of this molecule,” said Dr. Montalban, director of the Multiple Sclerosis Centre of Catalonia at the Vall d’Hebron University Hospital in Barcelona.
Evobrutinib exerts a dual action in MS, Dr. Montalban said. By inhibiting BTK, the drug blocks B-cell activation and interaction between B and T cells. It also inhibits macrophage survival and dampens cytokine release, he said.
The study randomized 213 patients with relapsing MS to placebo or to evobrutinib in three daily doses: 25 mg, 75 mg, or 150 mg. A control arm of 54 additional patients received treatment with dimethyl fumarate. After 24 weeks of randomized treatment, patients who got placebo switched to 25 mg per day; everyone else continued in their assigned groups for another 24 weeks. The study concluded with an open-label extension phase during which everyone took 75 mg daily.
Dr. Montalban reported the primary 24-week analysis. The remainder of the data has not been analyzed yet, he said. The primary endpoint was the total number of T1 gadolinium-enhancing lesions at weeks 12, 16, 20, and 24. Secondary endpoints included the 24-week annualized relapse rate and safety signals. Patients were a mean of 41 years old, with a mean disease duration of 10 years. They had experienced a mean of two relapses in the prior 2 years. About 20% had gadolinium-enhancing lesions at baseline.
Compared with placebo and with the 25-mg dose, evobrutinib 75 mg and 150 mg significantly reduced the number of new enhancing lesions at 24 weeks. There was evidence of a dose-response effect, Dr. Montalban said. Patients taking placebo developed a mean of 3.8 new lesions, while those on 75 mg developed a mean of 1.69 and those taking 150 mg, a mean of 1.15. Patients in the 25-mg group developed a mean of four new lesions – not significantly different than placebo.
Both the 75-mg and 150-mg doses decreased the annualized relapse rate, compared with placebo but missed statistical significance, with P values of 0.90 and 0.63, respectively.
These two doses also conferred significant benefit on two other secondary endpoints, significantly reducing the number of new or enlarging T2 lesions and reducing the total T2 lesion volume, compared with placebo.
The safety profile was relatively benign, with no infections, including no opportunistic infections, and no neoplasms. About 7% of the highest-dose group experienced nausea, and the same number, arthralgia. Seven patients taking evobrutinib experienced grade 1 lymphopenia, compared with three patients taking placebo; grade 2 lymphopenia developed in one patient in the highest-dose group.
ALT elevation was the most concerning adverse event, Dr. Montalban said. Grade 1 elevations developed in 17% of the low-dose group and about 22% of the other two active groups (11 patients each), compared with 7% of the placebo group. Grade 2 elevations developed in three placebo patients and in two taking the highest dose of evobrutinib. There was one grade 3 elevation, which occurred in a patient in the highest-dose group. These were asymptomatic and resolved after discontinuing the medication. Lipase and aspartate transaminase elevations were also associated with evobrutinib, but Dr. Montalban did not provide these details.
He has been a paid consultant for Merck Serono, which is developing evobrutinib.
SOURCE: Montalban X et al. ECTRIMS 2018. Abstract 322.
BERLIN – Evobrutinib, an investigational inhibitor of Bruton’s tyrosine kinase (BTK), significantly reduced the number of new T1 gadolinium-enhancing lesions at 24 weeks compared with placebo in patients with relapsing multiples sclerosis (MS).
However, the molecule was also associated with grade 3 and 4 elevations in alanine aminotransferase – a troubling finding, Xavier Montalban, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“Fortunately, all patients were asymptomatic, and the elevations were completely reversible. The results of this trial do support further development of this molecule,” said Dr. Montalban, director of the Multiple Sclerosis Centre of Catalonia at the Vall d’Hebron University Hospital in Barcelona.
Evobrutinib exerts a dual action in MS, Dr. Montalban said. By inhibiting BTK, the drug blocks B-cell activation and interaction between B and T cells. It also inhibits macrophage survival and dampens cytokine release, he said.
The study randomized 213 patients with relapsing MS to placebo or to evobrutinib in three daily doses: 25 mg, 75 mg, or 150 mg. A control arm of 54 additional patients received treatment with dimethyl fumarate. After 24 weeks of randomized treatment, patients who got placebo switched to 25 mg per day; everyone else continued in their assigned groups for another 24 weeks. The study concluded with an open-label extension phase during which everyone took 75 mg daily.
Dr. Montalban reported the primary 24-week analysis. The remainder of the data has not been analyzed yet, he said. The primary endpoint was the total number of T1 gadolinium-enhancing lesions at weeks 12, 16, 20, and 24. Secondary endpoints included the 24-week annualized relapse rate and safety signals. Patients were a mean of 41 years old, with a mean disease duration of 10 years. They had experienced a mean of two relapses in the prior 2 years. About 20% had gadolinium-enhancing lesions at baseline.
Compared with placebo and with the 25-mg dose, evobrutinib 75 mg and 150 mg significantly reduced the number of new enhancing lesions at 24 weeks. There was evidence of a dose-response effect, Dr. Montalban said. Patients taking placebo developed a mean of 3.8 new lesions, while those on 75 mg developed a mean of 1.69 and those taking 150 mg, a mean of 1.15. Patients in the 25-mg group developed a mean of four new lesions – not significantly different than placebo.
Both the 75-mg and 150-mg doses decreased the annualized relapse rate, compared with placebo but missed statistical significance, with P values of 0.90 and 0.63, respectively.
These two doses also conferred significant benefit on two other secondary endpoints, significantly reducing the number of new or enlarging T2 lesions and reducing the total T2 lesion volume, compared with placebo.
The safety profile was relatively benign, with no infections, including no opportunistic infections, and no neoplasms. About 7% of the highest-dose group experienced nausea, and the same number, arthralgia. Seven patients taking evobrutinib experienced grade 1 lymphopenia, compared with three patients taking placebo; grade 2 lymphopenia developed in one patient in the highest-dose group.
ALT elevation was the most concerning adverse event, Dr. Montalban said. Grade 1 elevations developed in 17% of the low-dose group and about 22% of the other two active groups (11 patients each), compared with 7% of the placebo group. Grade 2 elevations developed in three placebo patients and in two taking the highest dose of evobrutinib. There was one grade 3 elevation, which occurred in a patient in the highest-dose group. These were asymptomatic and resolved after discontinuing the medication. Lipase and aspartate transaminase elevations were also associated with evobrutinib, but Dr. Montalban did not provide these details.
He has been a paid consultant for Merck Serono, which is developing evobrutinib.
SOURCE: Montalban X et al. ECTRIMS 2018. Abstract 322.
BERLIN – Evobrutinib, an investigational inhibitor of Bruton’s tyrosine kinase (BTK), significantly reduced the number of new T1 gadolinium-enhancing lesions at 24 weeks compared with placebo in patients with relapsing multiples sclerosis (MS).
However, the molecule was also associated with grade 3 and 4 elevations in alanine aminotransferase – a troubling finding, Xavier Montalban, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“Fortunately, all patients were asymptomatic, and the elevations were completely reversible. The results of this trial do support further development of this molecule,” said Dr. Montalban, director of the Multiple Sclerosis Centre of Catalonia at the Vall d’Hebron University Hospital in Barcelona.
Evobrutinib exerts a dual action in MS, Dr. Montalban said. By inhibiting BTK, the drug blocks B-cell activation and interaction between B and T cells. It also inhibits macrophage survival and dampens cytokine release, he said.
The study randomized 213 patients with relapsing MS to placebo or to evobrutinib in three daily doses: 25 mg, 75 mg, or 150 mg. A control arm of 54 additional patients received treatment with dimethyl fumarate. After 24 weeks of randomized treatment, patients who got placebo switched to 25 mg per day; everyone else continued in their assigned groups for another 24 weeks. The study concluded with an open-label extension phase during which everyone took 75 mg daily.
Dr. Montalban reported the primary 24-week analysis. The remainder of the data has not been analyzed yet, he said. The primary endpoint was the total number of T1 gadolinium-enhancing lesions at weeks 12, 16, 20, and 24. Secondary endpoints included the 24-week annualized relapse rate and safety signals. Patients were a mean of 41 years old, with a mean disease duration of 10 years. They had experienced a mean of two relapses in the prior 2 years. About 20% had gadolinium-enhancing lesions at baseline.
Compared with placebo and with the 25-mg dose, evobrutinib 75 mg and 150 mg significantly reduced the number of new enhancing lesions at 24 weeks. There was evidence of a dose-response effect, Dr. Montalban said. Patients taking placebo developed a mean of 3.8 new lesions, while those on 75 mg developed a mean of 1.69 and those taking 150 mg, a mean of 1.15. Patients in the 25-mg group developed a mean of four new lesions – not significantly different than placebo.
Both the 75-mg and 150-mg doses decreased the annualized relapse rate, compared with placebo but missed statistical significance, with P values of 0.90 and 0.63, respectively.
These two doses also conferred significant benefit on two other secondary endpoints, significantly reducing the number of new or enlarging T2 lesions and reducing the total T2 lesion volume, compared with placebo.
The safety profile was relatively benign, with no infections, including no opportunistic infections, and no neoplasms. About 7% of the highest-dose group experienced nausea, and the same number, arthralgia. Seven patients taking evobrutinib experienced grade 1 lymphopenia, compared with three patients taking placebo; grade 2 lymphopenia developed in one patient in the highest-dose group.
ALT elevation was the most concerning adverse event, Dr. Montalban said. Grade 1 elevations developed in 17% of the low-dose group and about 22% of the other two active groups (11 patients each), compared with 7% of the placebo group. Grade 2 elevations developed in three placebo patients and in two taking the highest dose of evobrutinib. There was one grade 3 elevation, which occurred in a patient in the highest-dose group. These were asymptomatic and resolved after discontinuing the medication. Lipase and aspartate transaminase elevations were also associated with evobrutinib, but Dr. Montalban did not provide these details.
He has been a paid consultant for Merck Serono, which is developing evobrutinib.
SOURCE: Montalban X et al. ECTRIMS 2018. Abstract 322.
REPORTING FROM ECTRIMS 2018
Key clinical point: Evobrutinib reduced the number of new T1 gadolinium-enhancing lesions.
Major finding: At 24 weeks, the 150-mg group had a mean of 1.15 new lesions vs. 3.8 in the placebo group.
Study details: The phase 2 study randomized 213 patients.
Disclosures: Dr. Montalban has been a paid consultant for Merck Serono, which is developing the molecule.
Source: Montalban X et al. ECTRIMS 2018.Abstract 322.
MS cognitive decline buffered by early high vitamin D levels
BERLIN – , according to a recent study.
“Higher vitamin D in the first years after [clinically isolated syndrome] was associated with better cognitive function and lower neuronal injury at year 11,” said Marianna Cortese, MD, presenting her findings during a late-breaking abstracts session at the annual congress of the European Society for Education and Treatment in Multiple Sclerosis.
“Vitamin D supplementation during the early years with the disease might be neuroprotective,” she said.
According to Dr. Cortese, 40%-70% of patients with MS will experience cognitive decline across their disease course; there is no currently known specific treatment for cognitive decline.
Smoking, low levels of vitamin D [as 25(OH)D], and Epstein-Barr virus (EBV) seropositivity are known risk factors for MS, and have been associated with more active MS and progressive disease, but whether these factors predict cognitive status had not been known, said Dr. Cortese of the Harvard T.H. Chan School of Public Health.
Accordingly, she said, investigators in the BENEFIT-11 trial sought to determine whether low vitamin D levels, smoking status, and EBV seropositivity detected early after the first disease manifestation in MS would affect later cognitive function.
The study is an observational study that followed 278 participants with clinically isolated syndrome (CIS) in the original BENEFIT trial, which was a randomized, double-blind, placebo-controlled trial of interferon beta-1b for early treatment of clinically isolated syndrome. The primary goal of BENEFIT-11, said Dr. Cortese, was to assess the effects of early treatment on long-term outcomes.
“To minimize reverse causation, we used exposure status in the first 2 years after CIS to predict progression outcomes at year 11,” explained Dr. Cortese. The investigators obtained biomarkers at baseline, and at study months 6, 12, and 24. Cotinine was used as a biomarker for current or recent nicotine exposure. Serum 25(OH)D levels were used to determine vitamin D levels, and immunoglobulin G levels for EBV antigen-1 were used for EBV seropositivity.
In terms of outcome measurements, the cognitive performance measure used in the study was the Paced Auditory Serial Addition Test, a validated test of processing speed, attention, and working memory, said Dr. Cortese. This test was performed at enrollment, and at study years 1, 2, 5, and 11. At study year 11, neuroaxonal injury was measured using serum neurofilament light chain levels.
In multivariable analysis, the study design adjusted for baseline age and sex, treatment allocation at baseline, unifocal versus multifocal disease seen on baseline magnetic resonance imaging, body mass index, and whether the patient was treated with steroids during the initial CIS.
“Higher quintiles of mean vitamin D levels during the first 2 years were associated with lower odds of scoring worse on the PASAT at year 11,” said Dr. Cortese (P-trend = .028). The significant trend across the quintiles “suggests a dose-response relationship,” she said.* For vitamin D levels over the first 5 years, the P-trend was .049. Dr. Cortese explained that “scoring worse” meant scoring below the median.
Looking at the effect of early vitamin D levels another way, incremental increases of 50 nmol/L of mean 25(OH)D in study months 6-24 predicted 65% lower odds of having a PASAT score below the median at year 11 (P = .027). “Within-person increases in vitamin D during the study were also significantly associated with a better PASAT score when we used the repeated measurement in a linear mixed model,” said Dr. Cortese.
Turning to the effect of smoking on cognitive function at year 11, Dr. Cortese explained that cotinine levels obtained during the first 2 years were all used to determine smoking status. If all levels were below 10 ng/mL, the participant was designated a nonsmoker (N = 125). If any levels were above 25 ng/mL, that patient was classified as a smoker. The investigators also looked at the small number of patients (N = 9) who were very heavy smokers, with cotinine levels over 191 ng/mL.
“Smokers – compared to nonsmokers – had a significantly lower standardized PASAT score at year 11,” said Dr. Cortese (P trend = .042 in age- and sex-adjusted analysis; P-trend = .056 in full multivariable analysis). “Actually, smokers had an up to 0.6-standard deviation-lower PASAT score at year 11 when we looked at heavy smokers. ...This difference corresponds to about 5 points of the PASAT, so I would say [the score is] clinically meaningful.”
Dr. Cortese pointed out that early smoking, again, showed a dose-response relationship with later cognitive status. “It continues to be important to encourage smoking cessation for patients.”
Epstein-Barr antibodies were not associated with cognitive function at year 11, according to the analysis (P-trend = .93).
“The findings of neuroaxonal injury at year 11 using serum neurofilament light-chain measures corroborated the main findings on cognitive function at year 11,” said Dr. Cortese.
For a 50-nmol higher vitamin D level within the first 5 years, neurofilament light chain levels at year 11 were 20% lower, said Dr. Cortese. Conversely, patients who had cotinine levels higher than 25 ng/mL during the first 5 years had neurofilament light chain levels 20% higher than other participants: “So they did worse. They had more neuroaxonal loss,” said Dr. Cortese. No association was seen between neurofilament light chain levels at year 11 and early EBV status, she said.
Though just cognitive function data from BENEFIT-11 were reported by Dr. Cortese, she said that radiologic and other clinical data are also being studied and will be reported in the future.
Dr. Cortese reported that she had no conflicts of interest. Several coauthors reported financial relationships with multiple pharmaceutical companies. The study was supported by the National Institutes of Health and the National Multiple Sclerosis Society, with clinical support from Bayer HealthCare.
SOURCE: Cortese M et al. ECTRIMS 2018, Late breaking abstracts session.
*Correction, 10/25/18: An earlier version of this article mischaracterized the relationship between vitamin D scores during the first 2 years and PASAT scores at year 11.
BERLIN – , according to a recent study.
“Higher vitamin D in the first years after [clinically isolated syndrome] was associated with better cognitive function and lower neuronal injury at year 11,” said Marianna Cortese, MD, presenting her findings during a late-breaking abstracts session at the annual congress of the European Society for Education and Treatment in Multiple Sclerosis.
“Vitamin D supplementation during the early years with the disease might be neuroprotective,” she said.
According to Dr. Cortese, 40%-70% of patients with MS will experience cognitive decline across their disease course; there is no currently known specific treatment for cognitive decline.
Smoking, low levels of vitamin D [as 25(OH)D], and Epstein-Barr virus (EBV) seropositivity are known risk factors for MS, and have been associated with more active MS and progressive disease, but whether these factors predict cognitive status had not been known, said Dr. Cortese of the Harvard T.H. Chan School of Public Health.
Accordingly, she said, investigators in the BENEFIT-11 trial sought to determine whether low vitamin D levels, smoking status, and EBV seropositivity detected early after the first disease manifestation in MS would affect later cognitive function.
The study is an observational study that followed 278 participants with clinically isolated syndrome (CIS) in the original BENEFIT trial, which was a randomized, double-blind, placebo-controlled trial of interferon beta-1b for early treatment of clinically isolated syndrome. The primary goal of BENEFIT-11, said Dr. Cortese, was to assess the effects of early treatment on long-term outcomes.
“To minimize reverse causation, we used exposure status in the first 2 years after CIS to predict progression outcomes at year 11,” explained Dr. Cortese. The investigators obtained biomarkers at baseline, and at study months 6, 12, and 24. Cotinine was used as a biomarker for current or recent nicotine exposure. Serum 25(OH)D levels were used to determine vitamin D levels, and immunoglobulin G levels for EBV antigen-1 were used for EBV seropositivity.
In terms of outcome measurements, the cognitive performance measure used in the study was the Paced Auditory Serial Addition Test, a validated test of processing speed, attention, and working memory, said Dr. Cortese. This test was performed at enrollment, and at study years 1, 2, 5, and 11. At study year 11, neuroaxonal injury was measured using serum neurofilament light chain levels.
In multivariable analysis, the study design adjusted for baseline age and sex, treatment allocation at baseline, unifocal versus multifocal disease seen on baseline magnetic resonance imaging, body mass index, and whether the patient was treated with steroids during the initial CIS.
“Higher quintiles of mean vitamin D levels during the first 2 years were associated with lower odds of scoring worse on the PASAT at year 11,” said Dr. Cortese (P-trend = .028). The significant trend across the quintiles “suggests a dose-response relationship,” she said.* For vitamin D levels over the first 5 years, the P-trend was .049. Dr. Cortese explained that “scoring worse” meant scoring below the median.
Looking at the effect of early vitamin D levels another way, incremental increases of 50 nmol/L of mean 25(OH)D in study months 6-24 predicted 65% lower odds of having a PASAT score below the median at year 11 (P = .027). “Within-person increases in vitamin D during the study were also significantly associated with a better PASAT score when we used the repeated measurement in a linear mixed model,” said Dr. Cortese.
Turning to the effect of smoking on cognitive function at year 11, Dr. Cortese explained that cotinine levels obtained during the first 2 years were all used to determine smoking status. If all levels were below 10 ng/mL, the participant was designated a nonsmoker (N = 125). If any levels were above 25 ng/mL, that patient was classified as a smoker. The investigators also looked at the small number of patients (N = 9) who were very heavy smokers, with cotinine levels over 191 ng/mL.
“Smokers – compared to nonsmokers – had a significantly lower standardized PASAT score at year 11,” said Dr. Cortese (P trend = .042 in age- and sex-adjusted analysis; P-trend = .056 in full multivariable analysis). “Actually, smokers had an up to 0.6-standard deviation-lower PASAT score at year 11 when we looked at heavy smokers. ...This difference corresponds to about 5 points of the PASAT, so I would say [the score is] clinically meaningful.”
Dr. Cortese pointed out that early smoking, again, showed a dose-response relationship with later cognitive status. “It continues to be important to encourage smoking cessation for patients.”
Epstein-Barr antibodies were not associated with cognitive function at year 11, according to the analysis (P-trend = .93).
“The findings of neuroaxonal injury at year 11 using serum neurofilament light-chain measures corroborated the main findings on cognitive function at year 11,” said Dr. Cortese.
For a 50-nmol higher vitamin D level within the first 5 years, neurofilament light chain levels at year 11 were 20% lower, said Dr. Cortese. Conversely, patients who had cotinine levels higher than 25 ng/mL during the first 5 years had neurofilament light chain levels 20% higher than other participants: “So they did worse. They had more neuroaxonal loss,” said Dr. Cortese. No association was seen between neurofilament light chain levels at year 11 and early EBV status, she said.
Though just cognitive function data from BENEFIT-11 were reported by Dr. Cortese, she said that radiologic and other clinical data are also being studied and will be reported in the future.
Dr. Cortese reported that she had no conflicts of interest. Several coauthors reported financial relationships with multiple pharmaceutical companies. The study was supported by the National Institutes of Health and the National Multiple Sclerosis Society, with clinical support from Bayer HealthCare.
SOURCE: Cortese M et al. ECTRIMS 2018, Late breaking abstracts session.
*Correction, 10/25/18: An earlier version of this article mischaracterized the relationship between vitamin D scores during the first 2 years and PASAT scores at year 11.
BERLIN – , according to a recent study.
“Higher vitamin D in the first years after [clinically isolated syndrome] was associated with better cognitive function and lower neuronal injury at year 11,” said Marianna Cortese, MD, presenting her findings during a late-breaking abstracts session at the annual congress of the European Society for Education and Treatment in Multiple Sclerosis.
“Vitamin D supplementation during the early years with the disease might be neuroprotective,” she said.
According to Dr. Cortese, 40%-70% of patients with MS will experience cognitive decline across their disease course; there is no currently known specific treatment for cognitive decline.
Smoking, low levels of vitamin D [as 25(OH)D], and Epstein-Barr virus (EBV) seropositivity are known risk factors for MS, and have been associated with more active MS and progressive disease, but whether these factors predict cognitive status had not been known, said Dr. Cortese of the Harvard T.H. Chan School of Public Health.
Accordingly, she said, investigators in the BENEFIT-11 trial sought to determine whether low vitamin D levels, smoking status, and EBV seropositivity detected early after the first disease manifestation in MS would affect later cognitive function.
The study is an observational study that followed 278 participants with clinically isolated syndrome (CIS) in the original BENEFIT trial, which was a randomized, double-blind, placebo-controlled trial of interferon beta-1b for early treatment of clinically isolated syndrome. The primary goal of BENEFIT-11, said Dr. Cortese, was to assess the effects of early treatment on long-term outcomes.
“To minimize reverse causation, we used exposure status in the first 2 years after CIS to predict progression outcomes at year 11,” explained Dr. Cortese. The investigators obtained biomarkers at baseline, and at study months 6, 12, and 24. Cotinine was used as a biomarker for current or recent nicotine exposure. Serum 25(OH)D levels were used to determine vitamin D levels, and immunoglobulin G levels for EBV antigen-1 were used for EBV seropositivity.
In terms of outcome measurements, the cognitive performance measure used in the study was the Paced Auditory Serial Addition Test, a validated test of processing speed, attention, and working memory, said Dr. Cortese. This test was performed at enrollment, and at study years 1, 2, 5, and 11. At study year 11, neuroaxonal injury was measured using serum neurofilament light chain levels.
In multivariable analysis, the study design adjusted for baseline age and sex, treatment allocation at baseline, unifocal versus multifocal disease seen on baseline magnetic resonance imaging, body mass index, and whether the patient was treated with steroids during the initial CIS.
“Higher quintiles of mean vitamin D levels during the first 2 years were associated with lower odds of scoring worse on the PASAT at year 11,” said Dr. Cortese (P-trend = .028). The significant trend across the quintiles “suggests a dose-response relationship,” she said.* For vitamin D levels over the first 5 years, the P-trend was .049. Dr. Cortese explained that “scoring worse” meant scoring below the median.
Looking at the effect of early vitamin D levels another way, incremental increases of 50 nmol/L of mean 25(OH)D in study months 6-24 predicted 65% lower odds of having a PASAT score below the median at year 11 (P = .027). “Within-person increases in vitamin D during the study were also significantly associated with a better PASAT score when we used the repeated measurement in a linear mixed model,” said Dr. Cortese.
Turning to the effect of smoking on cognitive function at year 11, Dr. Cortese explained that cotinine levels obtained during the first 2 years were all used to determine smoking status. If all levels were below 10 ng/mL, the participant was designated a nonsmoker (N = 125). If any levels were above 25 ng/mL, that patient was classified as a smoker. The investigators also looked at the small number of patients (N = 9) who were very heavy smokers, with cotinine levels over 191 ng/mL.
“Smokers – compared to nonsmokers – had a significantly lower standardized PASAT score at year 11,” said Dr. Cortese (P trend = .042 in age- and sex-adjusted analysis; P-trend = .056 in full multivariable analysis). “Actually, smokers had an up to 0.6-standard deviation-lower PASAT score at year 11 when we looked at heavy smokers. ...This difference corresponds to about 5 points of the PASAT, so I would say [the score is] clinically meaningful.”
Dr. Cortese pointed out that early smoking, again, showed a dose-response relationship with later cognitive status. “It continues to be important to encourage smoking cessation for patients.”
Epstein-Barr antibodies were not associated with cognitive function at year 11, according to the analysis (P-trend = .93).
“The findings of neuroaxonal injury at year 11 using serum neurofilament light-chain measures corroborated the main findings on cognitive function at year 11,” said Dr. Cortese.
For a 50-nmol higher vitamin D level within the first 5 years, neurofilament light chain levels at year 11 were 20% lower, said Dr. Cortese. Conversely, patients who had cotinine levels higher than 25 ng/mL during the first 5 years had neurofilament light chain levels 20% higher than other participants: “So they did worse. They had more neuroaxonal loss,” said Dr. Cortese. No association was seen between neurofilament light chain levels at year 11 and early EBV status, she said.
Though just cognitive function data from BENEFIT-11 were reported by Dr. Cortese, she said that radiologic and other clinical data are also being studied and will be reported in the future.
Dr. Cortese reported that she had no conflicts of interest. Several coauthors reported financial relationships with multiple pharmaceutical companies. The study was supported by the National Institutes of Health and the National Multiple Sclerosis Society, with clinical support from Bayer HealthCare.
SOURCE: Cortese M et al. ECTRIMS 2018, Late breaking abstracts session.
*Correction, 10/25/18: An earlier version of this article mischaracterized the relationship between vitamin D scores during the first 2 years and PASAT scores at year 11.
REPORTING FROM ECTRIMS 2018
Key clinical point: Higher early levels of vitamin D were associated with better later cognitive status in MS.
Major finding: Higher quintiles of baseline 25(OH)D were associated with higher PASAT scores (P-trend = .028).
Study details: Longitudinal observational study of 278 BENEFIT participants with CIS.
Disclosures: Dr. Cortese reported that she had no conflicts of interest. Several coauthors reported financial relationships with multiple pharmaceutical companies. The study was supported by the National Institutes of Health and the National Multiple Sclerosis Society, with clinical support from Bayer HealthCare.
Source: Cortese M et al. ECTRIMS 2018, Late breaking abstracts session.
Novel IL-6 antibody slashes relapse rates in neuromyelitis optica
BERLIN – The monoclonal antibody satralizumab reduced by 62% relapses of neuromyelitis optica spectrum disorder (NMOSD) over 24 weeks, as compared with placebo.
Chugai Pharmaceuticals of Tokyo and Roche are codeveloping the molecule. Called a “recycling” antibody, it has been designed to have extended circulation in plasma, Dr. Yamamura said.
The SAkuraSky study randomized 83 patients to placebo or to subcutaneous satralizumab 120 mg at baseline and weeks 2 and 4, and then once a month for 20 months.
Patients in the study had either aquaporin-4–positive NMOSD or neuromyelitis optica with or without aquaporin-4 antibodies. They also had to have experienced at least two relapses in the past 2 years, at least one of which occurred in the last year. The primary endpoint was time to first relapse during the randomized phase.
Patients were a mean of about 42 years old. A total of 64% were diagnosed with neuromyelitis optica and the remainder with NMOSD, with a mean disease duration of about 5 years. Aquaporin-4 antibodies were present in 67%. The baseline annualized relapse rate was 1.4. Baseline medications included azathioprine, mycophenolate, and oral corticosteroids. Patients stayed on these throughout the study.
Relapse curves separated significantly by 36 weeks, with 89% of treated patients being relapse-free vs. 66% of placebo patients. At 96 weeks, the curves still favored satralizumab, with 77.6% vs. 58.7% without relapse. The trajectories held steady until the end of follow-up at 216 weeks (relapse-free rates 60% vs. 30%; HR 0.38). The difference amounted to a risk reduction of 62%.
The antibody was even more effective for aquaporin-4–positive patients. By 48 weeks, the relapse-free rates were 91.5% vs. 60%. By week 96, 91.5% of treated patients were still without relapse compared to 53.3% of placebo patients. By week 216, those numbers were about 70% vs. 20%, for a 79% risk reduction. Treatment was still significantly better than placebo for aquaporin negative patients, but the benefit was less dramatic (67% vs. 56%; RR 34%).
The rate of serious infections was similar between placebo and satralizumab (62% vs. 68%) with no serious opportunistic infections in either group. Injection site reactions were more common among patients taking satralizumab (12% vs. 5%). Neoplasms occurred in 7% of each group.
Development of the molecule will continue, Dr. Yamamura said.
Chugai Pharmaceuticals sponsored the study. Dr. Yamamura has served as a consultant for the company and reported financial ties with numerous other drug manufacturers.
SOURCE: Yamamura T et al. ECTRIMS 2018, Oral abstract 323
BERLIN – The monoclonal antibody satralizumab reduced by 62% relapses of neuromyelitis optica spectrum disorder (NMOSD) over 24 weeks, as compared with placebo.
Chugai Pharmaceuticals of Tokyo and Roche are codeveloping the molecule. Called a “recycling” antibody, it has been designed to have extended circulation in plasma, Dr. Yamamura said.
The SAkuraSky study randomized 83 patients to placebo or to subcutaneous satralizumab 120 mg at baseline and weeks 2 and 4, and then once a month for 20 months.
Patients in the study had either aquaporin-4–positive NMOSD or neuromyelitis optica with or without aquaporin-4 antibodies. They also had to have experienced at least two relapses in the past 2 years, at least one of which occurred in the last year. The primary endpoint was time to first relapse during the randomized phase.
Patients were a mean of about 42 years old. A total of 64% were diagnosed with neuromyelitis optica and the remainder with NMOSD, with a mean disease duration of about 5 years. Aquaporin-4 antibodies were present in 67%. The baseline annualized relapse rate was 1.4. Baseline medications included azathioprine, mycophenolate, and oral corticosteroids. Patients stayed on these throughout the study.
Relapse curves separated significantly by 36 weeks, with 89% of treated patients being relapse-free vs. 66% of placebo patients. At 96 weeks, the curves still favored satralizumab, with 77.6% vs. 58.7% without relapse. The trajectories held steady until the end of follow-up at 216 weeks (relapse-free rates 60% vs. 30%; HR 0.38). The difference amounted to a risk reduction of 62%.
The antibody was even more effective for aquaporin-4–positive patients. By 48 weeks, the relapse-free rates were 91.5% vs. 60%. By week 96, 91.5% of treated patients were still without relapse compared to 53.3% of placebo patients. By week 216, those numbers were about 70% vs. 20%, for a 79% risk reduction. Treatment was still significantly better than placebo for aquaporin negative patients, but the benefit was less dramatic (67% vs. 56%; RR 34%).
The rate of serious infections was similar between placebo and satralizumab (62% vs. 68%) with no serious opportunistic infections in either group. Injection site reactions were more common among patients taking satralizumab (12% vs. 5%). Neoplasms occurred in 7% of each group.
Development of the molecule will continue, Dr. Yamamura said.
Chugai Pharmaceuticals sponsored the study. Dr. Yamamura has served as a consultant for the company and reported financial ties with numerous other drug manufacturers.
SOURCE: Yamamura T et al. ECTRIMS 2018, Oral abstract 323
BERLIN – The monoclonal antibody satralizumab reduced by 62% relapses of neuromyelitis optica spectrum disorder (NMOSD) over 24 weeks, as compared with placebo.
Chugai Pharmaceuticals of Tokyo and Roche are codeveloping the molecule. Called a “recycling” antibody, it has been designed to have extended circulation in plasma, Dr. Yamamura said.
The SAkuraSky study randomized 83 patients to placebo or to subcutaneous satralizumab 120 mg at baseline and weeks 2 and 4, and then once a month for 20 months.
Patients in the study had either aquaporin-4–positive NMOSD or neuromyelitis optica with or without aquaporin-4 antibodies. They also had to have experienced at least two relapses in the past 2 years, at least one of which occurred in the last year. The primary endpoint was time to first relapse during the randomized phase.
Patients were a mean of about 42 years old. A total of 64% were diagnosed with neuromyelitis optica and the remainder with NMOSD, with a mean disease duration of about 5 years. Aquaporin-4 antibodies were present in 67%. The baseline annualized relapse rate was 1.4. Baseline medications included azathioprine, mycophenolate, and oral corticosteroids. Patients stayed on these throughout the study.
Relapse curves separated significantly by 36 weeks, with 89% of treated patients being relapse-free vs. 66% of placebo patients. At 96 weeks, the curves still favored satralizumab, with 77.6% vs. 58.7% without relapse. The trajectories held steady until the end of follow-up at 216 weeks (relapse-free rates 60% vs. 30%; HR 0.38). The difference amounted to a risk reduction of 62%.
The antibody was even more effective for aquaporin-4–positive patients. By 48 weeks, the relapse-free rates were 91.5% vs. 60%. By week 96, 91.5% of treated patients were still without relapse compared to 53.3% of placebo patients. By week 216, those numbers were about 70% vs. 20%, for a 79% risk reduction. Treatment was still significantly better than placebo for aquaporin negative patients, but the benefit was less dramatic (67% vs. 56%; RR 34%).
The rate of serious infections was similar between placebo and satralizumab (62% vs. 68%) with no serious opportunistic infections in either group. Injection site reactions were more common among patients taking satralizumab (12% vs. 5%). Neoplasms occurred in 7% of each group.
Development of the molecule will continue, Dr. Yamamura said.
Chugai Pharmaceuticals sponsored the study. Dr. Yamamura has served as a consultant for the company and reported financial ties with numerous other drug manufacturers.
SOURCE: Yamamura T et al. ECTRIMS 2018, Oral abstract 323
REPORTING FROM ECTRIMS 2018
Key clinical point: Satralizumab decreased relapse in all patients, but was more effective in those positive for aquaporin-4 antibodies.
Major finding: Compared with placebo, the antibody decreased relapse by 62% overall, and by 79% in aquaporin-4–positive patients.
Study details: A randomized, placebo-controlled study of 83 patients.
Disclosures: Chugai Pharmaceuticals sponsored the study. Dr. Yamamura has served as a consultant for the company and reported financial ties with numerous other drug manufacturers.
Source: Yamamura T et al. ECTRIMS 2018, Oral abstract 323.
Nf-L levels predictive of brain atrophy, disability in progressive MS
BERLIN – Neurofilament light chain (Nf-L) levels are higher in the plasma of patients with secondary progressive multiple sclerosis (SPMS) than primary progressive multiple sclerosis (PPMS) irrespective of age, according to an analysis of blood samples from two large phase 3 trials.
“Our data suggest that Nf-L should be considered as an informative endpoint for phase 2 studies in SPMS,” said the presenting study author Ludwig Kappos, MD, at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Much of the research on using Nf-L as a biomarker in MS to date has looked at patients with relapsing-remitting MS and the researchers wanted to see if Nf-L might be a useful biomarker in progressive MS because drug development in this area needs long-term and large trials to show an effect of a drug on disability. Conventional magnetic resonance imaging measures show only a modest association with disease evolution in SPMS and PPMS, and, as Nf-L is specific to neuronal damage, it should reflect damage to the brain and spinal cord, Dr. Kappos explained.
The aim of the study was to compare Nf-L levels in the two progressive subtypes of MS – SPMS and PPMS – and to see if it had any predictive value in determining the degree of brain atrophy or disability. Other objectives were to measure the sensitivity for Nf-L to detect treatment effects, and to estimate how big a sample size would be needed in a phase 2 study if it was used as a primary endpoint.
Blood samples from 1,830 patients who had participated in one of two phase 3 studies of siponimod in SPMS (EXPAND) and fingolimod (Gilyena) in PPMS (INFORMS). Nf-L levels were measured retrospectively in plasma using the SIMOA Nf-L immunoassay and categorized as being low (less than 30 pg/mL), medium (30-60 pg/mL), or high (greater than 60 pg/mL). Brain volume change on MRI was calculated using the SIENA (Structural Image Evaluation, using Normalization, of Atrophy) method, and disability changes assessed were evaluated by the Expanded Disability Status Scale (EDSS) score
“One of the confounders of measuring Nf-L is age,” Dr. Kappos acknowledged, “but we see a difference between SPMS and PPMS that is robust along the spectrum of ages.” The geometric mean of Nf-L at baseline was 32.1 pg/mL in patients with SPMS (n = 1,452) and 22.0 pg/mL in those with PPMS (n = 378).
Multiple regression analysis showed that, in both SPMS and PPMS patients, higher Nf-L levels were associated with older age and higher disease activity (increased EDSS score, more gadolinium-enhancing (Gd+) lesions and higher T2 lesion load).
Greater brain loss was seen at both 12 and 24 months in patients with high versus low Nf-L levels at baseline in both the SPMS and PPMS groups. For example, comparing high versus low Nf-L in SPMS, the mean brain volume change from baseline was –0.8% vs. –0.2% (P less than .0001) at 12 months and –1.5% vs. –0.5% at 24 months (P less than .0001). Corresponding values for PPMS were –0.8% vs. –0.4% (P = .0044) and –1.9% vs. –0.8% (P less than .0001).
Nf-L levels of 30 pg/mL were associated with a 32% increased risk of disability progression in patients with SPMS (P = .0055) and a 49% increased risk of disability progression in patients with PPMS (P = .0268).
In both groups of progressive MS patients, Nf-L levels were reduced in response to treatment at both 12 and 24 months, which remained significant.
“So, what about sample size calculation for a 1-year, phase 2 study with Nf-L as a primary endpoint?” Dr. Kappos queried. Assuming a reduction in Nf-L of 20% with a test drug, such a study would be likely to need to include 188 patients, or 94 patients per single arm to have 80% statistical power. To see a 30% reduction in Nf-L, fewer total and single-arm numbers would be needed, at 74 and 37 participants, respectively.
The study was funded by Novartis Pharma AG, Basel, Switzerland. Dr. Kappos disclosed that his institution (University Hospital Basel) had received steering committee, advisory board, and consultancy fees in the last 3 years that had been used exclusively for research support at the department from Novartis and a number of other pharmaceutical manufacturers. The Research of the MS Centre in Basel has been supported by grants from Bayer, Biogen, Novartis, the Swiss MS Society, the Swiss National Research Foundation, the European Union, and Roche Research Foundations.
SOURCE: Kuhle J et al. ECTRIMS 2018. Mult Scler. 2018;24(Suppl 2):111, Abstract 286.
BERLIN – Neurofilament light chain (Nf-L) levels are higher in the plasma of patients with secondary progressive multiple sclerosis (SPMS) than primary progressive multiple sclerosis (PPMS) irrespective of age, according to an analysis of blood samples from two large phase 3 trials.
“Our data suggest that Nf-L should be considered as an informative endpoint for phase 2 studies in SPMS,” said the presenting study author Ludwig Kappos, MD, at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Much of the research on using Nf-L as a biomarker in MS to date has looked at patients with relapsing-remitting MS and the researchers wanted to see if Nf-L might be a useful biomarker in progressive MS because drug development in this area needs long-term and large trials to show an effect of a drug on disability. Conventional magnetic resonance imaging measures show only a modest association with disease evolution in SPMS and PPMS, and, as Nf-L is specific to neuronal damage, it should reflect damage to the brain and spinal cord, Dr. Kappos explained.
The aim of the study was to compare Nf-L levels in the two progressive subtypes of MS – SPMS and PPMS – and to see if it had any predictive value in determining the degree of brain atrophy or disability. Other objectives were to measure the sensitivity for Nf-L to detect treatment effects, and to estimate how big a sample size would be needed in a phase 2 study if it was used as a primary endpoint.
Blood samples from 1,830 patients who had participated in one of two phase 3 studies of siponimod in SPMS (EXPAND) and fingolimod (Gilyena) in PPMS (INFORMS). Nf-L levels were measured retrospectively in plasma using the SIMOA Nf-L immunoassay and categorized as being low (less than 30 pg/mL), medium (30-60 pg/mL), or high (greater than 60 pg/mL). Brain volume change on MRI was calculated using the SIENA (Structural Image Evaluation, using Normalization, of Atrophy) method, and disability changes assessed were evaluated by the Expanded Disability Status Scale (EDSS) score
“One of the confounders of measuring Nf-L is age,” Dr. Kappos acknowledged, “but we see a difference between SPMS and PPMS that is robust along the spectrum of ages.” The geometric mean of Nf-L at baseline was 32.1 pg/mL in patients with SPMS (n = 1,452) and 22.0 pg/mL in those with PPMS (n = 378).
Multiple regression analysis showed that, in both SPMS and PPMS patients, higher Nf-L levels were associated with older age and higher disease activity (increased EDSS score, more gadolinium-enhancing (Gd+) lesions and higher T2 lesion load).
Greater brain loss was seen at both 12 and 24 months in patients with high versus low Nf-L levels at baseline in both the SPMS and PPMS groups. For example, comparing high versus low Nf-L in SPMS, the mean brain volume change from baseline was –0.8% vs. –0.2% (P less than .0001) at 12 months and –1.5% vs. –0.5% at 24 months (P less than .0001). Corresponding values for PPMS were –0.8% vs. –0.4% (P = .0044) and –1.9% vs. –0.8% (P less than .0001).
Nf-L levels of 30 pg/mL were associated with a 32% increased risk of disability progression in patients with SPMS (P = .0055) and a 49% increased risk of disability progression in patients with PPMS (P = .0268).
In both groups of progressive MS patients, Nf-L levels were reduced in response to treatment at both 12 and 24 months, which remained significant.
“So, what about sample size calculation for a 1-year, phase 2 study with Nf-L as a primary endpoint?” Dr. Kappos queried. Assuming a reduction in Nf-L of 20% with a test drug, such a study would be likely to need to include 188 patients, or 94 patients per single arm to have 80% statistical power. To see a 30% reduction in Nf-L, fewer total and single-arm numbers would be needed, at 74 and 37 participants, respectively.
The study was funded by Novartis Pharma AG, Basel, Switzerland. Dr. Kappos disclosed that his institution (University Hospital Basel) had received steering committee, advisory board, and consultancy fees in the last 3 years that had been used exclusively for research support at the department from Novartis and a number of other pharmaceutical manufacturers. The Research of the MS Centre in Basel has been supported by grants from Bayer, Biogen, Novartis, the Swiss MS Society, the Swiss National Research Foundation, the European Union, and Roche Research Foundations.
SOURCE: Kuhle J et al. ECTRIMS 2018. Mult Scler. 2018;24(Suppl 2):111, Abstract 286.
BERLIN – Neurofilament light chain (Nf-L) levels are higher in the plasma of patients with secondary progressive multiple sclerosis (SPMS) than primary progressive multiple sclerosis (PPMS) irrespective of age, according to an analysis of blood samples from two large phase 3 trials.
“Our data suggest that Nf-L should be considered as an informative endpoint for phase 2 studies in SPMS,” said the presenting study author Ludwig Kappos, MD, at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Much of the research on using Nf-L as a biomarker in MS to date has looked at patients with relapsing-remitting MS and the researchers wanted to see if Nf-L might be a useful biomarker in progressive MS because drug development in this area needs long-term and large trials to show an effect of a drug on disability. Conventional magnetic resonance imaging measures show only a modest association with disease evolution in SPMS and PPMS, and, as Nf-L is specific to neuronal damage, it should reflect damage to the brain and spinal cord, Dr. Kappos explained.
The aim of the study was to compare Nf-L levels in the two progressive subtypes of MS – SPMS and PPMS – and to see if it had any predictive value in determining the degree of brain atrophy or disability. Other objectives were to measure the sensitivity for Nf-L to detect treatment effects, and to estimate how big a sample size would be needed in a phase 2 study if it was used as a primary endpoint.
Blood samples from 1,830 patients who had participated in one of two phase 3 studies of siponimod in SPMS (EXPAND) and fingolimod (Gilyena) in PPMS (INFORMS). Nf-L levels were measured retrospectively in plasma using the SIMOA Nf-L immunoassay and categorized as being low (less than 30 pg/mL), medium (30-60 pg/mL), or high (greater than 60 pg/mL). Brain volume change on MRI was calculated using the SIENA (Structural Image Evaluation, using Normalization, of Atrophy) method, and disability changes assessed were evaluated by the Expanded Disability Status Scale (EDSS) score
“One of the confounders of measuring Nf-L is age,” Dr. Kappos acknowledged, “but we see a difference between SPMS and PPMS that is robust along the spectrum of ages.” The geometric mean of Nf-L at baseline was 32.1 pg/mL in patients with SPMS (n = 1,452) and 22.0 pg/mL in those with PPMS (n = 378).
Multiple regression analysis showed that, in both SPMS and PPMS patients, higher Nf-L levels were associated with older age and higher disease activity (increased EDSS score, more gadolinium-enhancing (Gd+) lesions and higher T2 lesion load).
Greater brain loss was seen at both 12 and 24 months in patients with high versus low Nf-L levels at baseline in both the SPMS and PPMS groups. For example, comparing high versus low Nf-L in SPMS, the mean brain volume change from baseline was –0.8% vs. –0.2% (P less than .0001) at 12 months and –1.5% vs. –0.5% at 24 months (P less than .0001). Corresponding values for PPMS were –0.8% vs. –0.4% (P = .0044) and –1.9% vs. –0.8% (P less than .0001).
Nf-L levels of 30 pg/mL were associated with a 32% increased risk of disability progression in patients with SPMS (P = .0055) and a 49% increased risk of disability progression in patients with PPMS (P = .0268).
In both groups of progressive MS patients, Nf-L levels were reduced in response to treatment at both 12 and 24 months, which remained significant.
“So, what about sample size calculation for a 1-year, phase 2 study with Nf-L as a primary endpoint?” Dr. Kappos queried. Assuming a reduction in Nf-L of 20% with a test drug, such a study would be likely to need to include 188 patients, or 94 patients per single arm to have 80% statistical power. To see a 30% reduction in Nf-L, fewer total and single-arm numbers would be needed, at 74 and 37 participants, respectively.
The study was funded by Novartis Pharma AG, Basel, Switzerland. Dr. Kappos disclosed that his institution (University Hospital Basel) had received steering committee, advisory board, and consultancy fees in the last 3 years that had been used exclusively for research support at the department from Novartis and a number of other pharmaceutical manufacturers. The Research of the MS Centre in Basel has been supported by grants from Bayer, Biogen, Novartis, the Swiss MS Society, the Swiss National Research Foundation, the European Union, and Roche Research Foundations.
SOURCE: Kuhle J et al. ECTRIMS 2018. Mult Scler. 2018;24(Suppl 2):111, Abstract 286.
REPORTING FROM ECTRIMS 2018
Key clinical point: Neurofilament light chain level was predictive of changes in brain atrophy, disability and sensitive to treatment effect in secondary progressive multiple sclerosis.
Major finding: Comparing high versus low baseline Nf-L in SPMS, the mean brain volume change from baseline was –0.8% vs. –0.2% (P less than .0001) at 12 months. Elevated Nf-L was associated with a 32% increase risk of disability progression.
Study details: Include study type and number of subjects.
Disclosures: The study was funded by Novartis Pharma AG, Basel, Switzerland. Dr. Kappos disclosed that his institution (University Hospital Basel) had received steering committee, advisory board, and consultancy fees in the last 3 years that had been used exclusively for research support at the department from Novartis and many other pharmaceutical manufacturers.
Source: Kuhle J et al. ECTRIMS 2018. Mult Scler. 2018;24(Suppl 2):111, Abstract 286.
Low spinal cord volume linked to higher MS disability
BERLIN – Spinal cord volume deficits in patients with multiple sclerosis may contribute to clinical disability that appears out of proportion to lesion load on brain imaging, according to new research.
In a pool of 362 patients with mild to moderate MS-related disability but identical white matter lesion load identified by MRI, those with higher disability had significantly lower spinal cord volumes when compared against those with disability scores in the mild range (P less than .001).
Though brain MRI is a key tool used to track disease severity and progression in MS, some patients have relatively high disability but a low burden of white matter intracerebral lesions on MRI. Little is known about spinal cord volume in MS patients with pronounced dissociation between intracerebral lesion load and disability, Michaela Andelova, MD, said in an interview during a poster session at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Dr. Andelova, of Charles University, Prague, said that she and her colleagues hypothesized that spinal cord volume would differ between patients who had varying levels of disability, despite identical white matter lesion load.
To test this, she and her colleagues looked at records of 1,245 patients with relapsing-remitting MS. They divided them into three groups by severity of clinical disability, and also by extent of cerebral T2 hyperintense lesion load. The investigators identified a group of patients (n = 53) whose total volume of T2-weighted hyperintense lesions was less than 3 mL, but whose Expanded Disability Status Scale (EDSS) scores were at least 3.5; this was the low lesion load/high disability (LLHD) group.
Dr. Andelova and her colleagues then identified another group of patients (n = 71) who had a volume of T2-weighted hyperintensities that was greater than 9 mL, but whose EDSS score was less than 1.5. This was the high lesion load/low disability (HLLD) group.
The remaining patients (n = 1,121), who did not have these paradoxical associations, were analyzed separately.
For all patients, mean upper cervical cord area (MUCCA) was also measured. Using images acquired by a 3 T MRI scanner, MUCCA was calculated as the mean sum of spinal cord area in 21 slices centered at the C3/4 intervertebral disk, using an in-house, semiautomated method.
“Despite higher disability, LLHD patients demonstrated significantly higher normalized total brain volume, higher normalized volumes of thalamus and callosum, and smaller lateral ventricles than [the] HLLD group,” wrote Dr. Andelova and her collaborators.
However, the LLHD patients had MUCCA values that were significantly lower than the other groups: The nonparadoxical group’s mean MUCCA was 84.02 mm2, while the HLLD group had a mean MUCCA of 85.75 mm2. This difference was not statistically significant. By contrast, the LLHD group’s mean MUCCA was significantly smaller, at 80.40 mm2 (P = .023 versus nonparadoxical patients, and P = .007 versus HLLD patients).
Looking at the data another way, Dr. Andelova and her colleagues compared 362 evenly divided patients with moderate disability (EDSS 3.5-6.5) with matched patients who had mild MS-related disability (EDSS less than 3) and identical cerebral lesion loads. They found that MUCCA was significantly smaller in the moderate disability group (78.86 versus 84.44 mm2; P less than .001).
In addition to having identical lesions loads, the mild and moderate disability groups didn’t differ significantly in normalized total brain volume or regional brain volumes. The group with moderate disability did have slightly less white matter volume (P = .039), Dr. Andelova pointed out.
All differences found between groups retained statistical significance even after adjustment for such potential confounders as age, sex, and duration of disease, Dr. Andelova said.
“Reduced spinal cord volume may explain part of the clinical-radiological paradox in patients who have high disability despite low intracranial lesion load,” Dr. Andelova and her collaborators wrote. “In line with this finding, relatively preserved spinal cord volume may be associated with functional reserve and less physical disability in patients with low disability despite high cerebral lesion load.”
Further work looking more precisely at cerebral lesion distribution and quantitative MRI investigation of lesion distribution is in the works for Dr. Andelova and her collaborators. They are hoping to see some association between various distribution patterns and accelerated spinal atrophy.
The research was supported by the Czech government. Dr. Andelova and several of her collaborators reported financial relationships with pharmaceutical companies.
SOURCE: Andelova M et al. Mult Scler. 2018;24(Suppl 2):211, Abstract P477.
BERLIN – Spinal cord volume deficits in patients with multiple sclerosis may contribute to clinical disability that appears out of proportion to lesion load on brain imaging, according to new research.
In a pool of 362 patients with mild to moderate MS-related disability but identical white matter lesion load identified by MRI, those with higher disability had significantly lower spinal cord volumes when compared against those with disability scores in the mild range (P less than .001).
Though brain MRI is a key tool used to track disease severity and progression in MS, some patients have relatively high disability but a low burden of white matter intracerebral lesions on MRI. Little is known about spinal cord volume in MS patients with pronounced dissociation between intracerebral lesion load and disability, Michaela Andelova, MD, said in an interview during a poster session at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Dr. Andelova, of Charles University, Prague, said that she and her colleagues hypothesized that spinal cord volume would differ between patients who had varying levels of disability, despite identical white matter lesion load.
To test this, she and her colleagues looked at records of 1,245 patients with relapsing-remitting MS. They divided them into three groups by severity of clinical disability, and also by extent of cerebral T2 hyperintense lesion load. The investigators identified a group of patients (n = 53) whose total volume of T2-weighted hyperintense lesions was less than 3 mL, but whose Expanded Disability Status Scale (EDSS) scores were at least 3.5; this was the low lesion load/high disability (LLHD) group.
Dr. Andelova and her colleagues then identified another group of patients (n = 71) who had a volume of T2-weighted hyperintensities that was greater than 9 mL, but whose EDSS score was less than 1.5. This was the high lesion load/low disability (HLLD) group.
The remaining patients (n = 1,121), who did not have these paradoxical associations, were analyzed separately.
For all patients, mean upper cervical cord area (MUCCA) was also measured. Using images acquired by a 3 T MRI scanner, MUCCA was calculated as the mean sum of spinal cord area in 21 slices centered at the C3/4 intervertebral disk, using an in-house, semiautomated method.
“Despite higher disability, LLHD patients demonstrated significantly higher normalized total brain volume, higher normalized volumes of thalamus and callosum, and smaller lateral ventricles than [the] HLLD group,” wrote Dr. Andelova and her collaborators.
However, the LLHD patients had MUCCA values that were significantly lower than the other groups: The nonparadoxical group’s mean MUCCA was 84.02 mm2, while the HLLD group had a mean MUCCA of 85.75 mm2. This difference was not statistically significant. By contrast, the LLHD group’s mean MUCCA was significantly smaller, at 80.40 mm2 (P = .023 versus nonparadoxical patients, and P = .007 versus HLLD patients).
Looking at the data another way, Dr. Andelova and her colleagues compared 362 evenly divided patients with moderate disability (EDSS 3.5-6.5) with matched patients who had mild MS-related disability (EDSS less than 3) and identical cerebral lesion loads. They found that MUCCA was significantly smaller in the moderate disability group (78.86 versus 84.44 mm2; P less than .001).
In addition to having identical lesions loads, the mild and moderate disability groups didn’t differ significantly in normalized total brain volume or regional brain volumes. The group with moderate disability did have slightly less white matter volume (P = .039), Dr. Andelova pointed out.
All differences found between groups retained statistical significance even after adjustment for such potential confounders as age, sex, and duration of disease, Dr. Andelova said.
“Reduced spinal cord volume may explain part of the clinical-radiological paradox in patients who have high disability despite low intracranial lesion load,” Dr. Andelova and her collaborators wrote. “In line with this finding, relatively preserved spinal cord volume may be associated with functional reserve and less physical disability in patients with low disability despite high cerebral lesion load.”
Further work looking more precisely at cerebral lesion distribution and quantitative MRI investigation of lesion distribution is in the works for Dr. Andelova and her collaborators. They are hoping to see some association between various distribution patterns and accelerated spinal atrophy.
The research was supported by the Czech government. Dr. Andelova and several of her collaborators reported financial relationships with pharmaceutical companies.
SOURCE: Andelova M et al. Mult Scler. 2018;24(Suppl 2):211, Abstract P477.
BERLIN – Spinal cord volume deficits in patients with multiple sclerosis may contribute to clinical disability that appears out of proportion to lesion load on brain imaging, according to new research.
In a pool of 362 patients with mild to moderate MS-related disability but identical white matter lesion load identified by MRI, those with higher disability had significantly lower spinal cord volumes when compared against those with disability scores in the mild range (P less than .001).
Though brain MRI is a key tool used to track disease severity and progression in MS, some patients have relatively high disability but a low burden of white matter intracerebral lesions on MRI. Little is known about spinal cord volume in MS patients with pronounced dissociation between intracerebral lesion load and disability, Michaela Andelova, MD, said in an interview during a poster session at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Dr. Andelova, of Charles University, Prague, said that she and her colleagues hypothesized that spinal cord volume would differ between patients who had varying levels of disability, despite identical white matter lesion load.
To test this, she and her colleagues looked at records of 1,245 patients with relapsing-remitting MS. They divided them into three groups by severity of clinical disability, and also by extent of cerebral T2 hyperintense lesion load. The investigators identified a group of patients (n = 53) whose total volume of T2-weighted hyperintense lesions was less than 3 mL, but whose Expanded Disability Status Scale (EDSS) scores were at least 3.5; this was the low lesion load/high disability (LLHD) group.
Dr. Andelova and her colleagues then identified another group of patients (n = 71) who had a volume of T2-weighted hyperintensities that was greater than 9 mL, but whose EDSS score was less than 1.5. This was the high lesion load/low disability (HLLD) group.
The remaining patients (n = 1,121), who did not have these paradoxical associations, were analyzed separately.
For all patients, mean upper cervical cord area (MUCCA) was also measured. Using images acquired by a 3 T MRI scanner, MUCCA was calculated as the mean sum of spinal cord area in 21 slices centered at the C3/4 intervertebral disk, using an in-house, semiautomated method.
“Despite higher disability, LLHD patients demonstrated significantly higher normalized total brain volume, higher normalized volumes of thalamus and callosum, and smaller lateral ventricles than [the] HLLD group,” wrote Dr. Andelova and her collaborators.
However, the LLHD patients had MUCCA values that were significantly lower than the other groups: The nonparadoxical group’s mean MUCCA was 84.02 mm2, while the HLLD group had a mean MUCCA of 85.75 mm2. This difference was not statistically significant. By contrast, the LLHD group’s mean MUCCA was significantly smaller, at 80.40 mm2 (P = .023 versus nonparadoxical patients, and P = .007 versus HLLD patients).
Looking at the data another way, Dr. Andelova and her colleagues compared 362 evenly divided patients with moderate disability (EDSS 3.5-6.5) with matched patients who had mild MS-related disability (EDSS less than 3) and identical cerebral lesion loads. They found that MUCCA was significantly smaller in the moderate disability group (78.86 versus 84.44 mm2; P less than .001).
In addition to having identical lesions loads, the mild and moderate disability groups didn’t differ significantly in normalized total brain volume or regional brain volumes. The group with moderate disability did have slightly less white matter volume (P = .039), Dr. Andelova pointed out.
All differences found between groups retained statistical significance even after adjustment for such potential confounders as age, sex, and duration of disease, Dr. Andelova said.
“Reduced spinal cord volume may explain part of the clinical-radiological paradox in patients who have high disability despite low intracranial lesion load,” Dr. Andelova and her collaborators wrote. “In line with this finding, relatively preserved spinal cord volume may be associated with functional reserve and less physical disability in patients with low disability despite high cerebral lesion load.”
Further work looking more precisely at cerebral lesion distribution and quantitative MRI investigation of lesion distribution is in the works for Dr. Andelova and her collaborators. They are hoping to see some association between various distribution patterns and accelerated spinal atrophy.
The research was supported by the Czech government. Dr. Andelova and several of her collaborators reported financial relationships with pharmaceutical companies.
SOURCE: Andelova M et al. Mult Scler. 2018;24(Suppl 2):211, Abstract P477.
REPORTING FROM ECTRIMS 2018
Key clinical point:
Major finding: Moderate disability patients had lower spinal cord volumes than did those with mild disability but a similar intracerebral lesion load.
Study details: Retrospective study of 1,245 patients with relapsing-remitting MS.
Disclosures: The study was sponsored by a grant from the Czech government. Several authors, including Dr. Andelova, reported multiple financial relationships with pharmaceutical companies.
Source: Andelova M et al. Mult Scler. 2018;24(Suppl 2):211, Abstract P477.
Oligoclonal bands, initial seizures increase risk of post-ADEM epilepsy in children
BERLIN – Children with acute disseminated encephalomyelitis have a significantly increased risk of subsequent epilepsy when it occurs with oligoclonal bands in cerebrospinal fluid and seizures at presentation, Thomas Rossor, MD, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
But fortunately, the seizures of postacute disseminated encephalomyelitis (post-ADEM) epilepsy are relatively easy to control and not clinically devastating, said Dr. Rossor of Great Ormond Street Hospital, London.
Of the 12 who developed epilepsy in Dr. Rossor’s retrospective, multicenter review of 74 children with ADEM, 11 were well controlled on one drug and 1 on two drugs.
Pediatric ADEM is usually monophasic with good clinical outcome, he said. But a benign course is not set in stone: Up to 40% of children experience seizures during the acute presentation. “In contrast,” Dr. Rossor said, “adult patients with relapsing-remitting multiple sclerosis have the same risk of developing epilepsy as the general population.” Among adults with cortical encephalitis, antibodies against myelin oligodendrocyte glycoprotein (MOG) have been associated with seizures and the need for antiepileptic medications, he added.
That finding was part of what spurred Dr. Rossor’s study, which aimed to identify predictors of relapse and post-ADEM epilepsy in children. The patients in the review had a median age of 4.5 years. All were tested for anti-MOG antibodies, and most (about 68%) were positive. Oligoclonal bands in cerebrospinal fluid (CSF) occurred in 22%. The median follow-up period was 5 years.
A total of 41% (n = 31) relapsed after the initial acute phase. Among these, the final diagnosis included multiphasic disseminated encephalomyelitis (n = 19); ADEM-optic neuritis (n = 3); and neuromyelitis optica spectrum disorder (n = 6).
Of the 74 patients, 16 (22%) had seizures during the acute phase, and 12 (16%) developed post-ADEM epilepsy at a median of 3 months. The most common clinical characteristics with post-ADEM epilepsy included oligoclonal bands (57% vs. 13%), anti-MOG antibodies (92% vs. 16%), and seizures at presentation (50% vs. 16%). When these were entered into a regression model, oligoclonal bands and initial seizures significantly predicted epilepsy, increasing the risk by 20.7 and 13.5 times, respectively.
Since relapse is known to be associated with post-ADEM epilepsy, Dr. Rossor first looked at relapse risk. He conducted a multivariate analysis that included several clinical characteristics: age, prodrome, increased CSF white cells and protein, oligoclonal bands, anti-MOG antibodies, and seizures both at presentation and after the acute phase.
Anti-MOG antibodies were significantly more common among the relapsed patients than among the monophasic patients (87% vs. 53%). Seizures at presentation also were more common among the relapsed patients (32% vs. 14%). These two factors were entered into a binary regression analysis; only anti-MOG antibodies remained significantly associated with relapse, increasing the risk fivefold (odds ratio = 5.4; P = .007).
Anti-MOG antibodies also were associated with both earlier and more relapses. Overall, 40% of anti–MOG-antibody–positive patients relapsed by 24 months. In contrast, only 20% of anti–MOG-antibody–negative patients had relapsed by 24 months, and this number remained steady throughout the follow-up period.
By 96 months, almost all the anti–MOG-antibody–positive patients had relapsed, and some experienced many relapses. “In the antibody-negative group, four patients did relapse, but they had relatively few relapses. In the antibody-positive group, some had relatively few relapses, but several had 15, 20, or 25 clinical relapses in the follow-up period,” he said.
Dr. Rossor and his coauthors had no financial disclosures.
SOURCE: Rossor T et al. Mult Scler. 2018;24(Suppl 2):27. Abstract 62.
BERLIN – Children with acute disseminated encephalomyelitis have a significantly increased risk of subsequent epilepsy when it occurs with oligoclonal bands in cerebrospinal fluid and seizures at presentation, Thomas Rossor, MD, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
But fortunately, the seizures of postacute disseminated encephalomyelitis (post-ADEM) epilepsy are relatively easy to control and not clinically devastating, said Dr. Rossor of Great Ormond Street Hospital, London.
Of the 12 who developed epilepsy in Dr. Rossor’s retrospective, multicenter review of 74 children with ADEM, 11 were well controlled on one drug and 1 on two drugs.
Pediatric ADEM is usually monophasic with good clinical outcome, he said. But a benign course is not set in stone: Up to 40% of children experience seizures during the acute presentation. “In contrast,” Dr. Rossor said, “adult patients with relapsing-remitting multiple sclerosis have the same risk of developing epilepsy as the general population.” Among adults with cortical encephalitis, antibodies against myelin oligodendrocyte glycoprotein (MOG) have been associated with seizures and the need for antiepileptic medications, he added.
That finding was part of what spurred Dr. Rossor’s study, which aimed to identify predictors of relapse and post-ADEM epilepsy in children. The patients in the review had a median age of 4.5 years. All were tested for anti-MOG antibodies, and most (about 68%) were positive. Oligoclonal bands in cerebrospinal fluid (CSF) occurred in 22%. The median follow-up period was 5 years.
A total of 41% (n = 31) relapsed after the initial acute phase. Among these, the final diagnosis included multiphasic disseminated encephalomyelitis (n = 19); ADEM-optic neuritis (n = 3); and neuromyelitis optica spectrum disorder (n = 6).
Of the 74 patients, 16 (22%) had seizures during the acute phase, and 12 (16%) developed post-ADEM epilepsy at a median of 3 months. The most common clinical characteristics with post-ADEM epilepsy included oligoclonal bands (57% vs. 13%), anti-MOG antibodies (92% vs. 16%), and seizures at presentation (50% vs. 16%). When these were entered into a regression model, oligoclonal bands and initial seizures significantly predicted epilepsy, increasing the risk by 20.7 and 13.5 times, respectively.
Since relapse is known to be associated with post-ADEM epilepsy, Dr. Rossor first looked at relapse risk. He conducted a multivariate analysis that included several clinical characteristics: age, prodrome, increased CSF white cells and protein, oligoclonal bands, anti-MOG antibodies, and seizures both at presentation and after the acute phase.
Anti-MOG antibodies were significantly more common among the relapsed patients than among the monophasic patients (87% vs. 53%). Seizures at presentation also were more common among the relapsed patients (32% vs. 14%). These two factors were entered into a binary regression analysis; only anti-MOG antibodies remained significantly associated with relapse, increasing the risk fivefold (odds ratio = 5.4; P = .007).
Anti-MOG antibodies also were associated with both earlier and more relapses. Overall, 40% of anti–MOG-antibody–positive patients relapsed by 24 months. In contrast, only 20% of anti–MOG-antibody–negative patients had relapsed by 24 months, and this number remained steady throughout the follow-up period.
By 96 months, almost all the anti–MOG-antibody–positive patients had relapsed, and some experienced many relapses. “In the antibody-negative group, four patients did relapse, but they had relatively few relapses. In the antibody-positive group, some had relatively few relapses, but several had 15, 20, or 25 clinical relapses in the follow-up period,” he said.
Dr. Rossor and his coauthors had no financial disclosures.
SOURCE: Rossor T et al. Mult Scler. 2018;24(Suppl 2):27. Abstract 62.
BERLIN – Children with acute disseminated encephalomyelitis have a significantly increased risk of subsequent epilepsy when it occurs with oligoclonal bands in cerebrospinal fluid and seizures at presentation, Thomas Rossor, MD, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
But fortunately, the seizures of postacute disseminated encephalomyelitis (post-ADEM) epilepsy are relatively easy to control and not clinically devastating, said Dr. Rossor of Great Ormond Street Hospital, London.
Of the 12 who developed epilepsy in Dr. Rossor’s retrospective, multicenter review of 74 children with ADEM, 11 were well controlled on one drug and 1 on two drugs.
Pediatric ADEM is usually monophasic with good clinical outcome, he said. But a benign course is not set in stone: Up to 40% of children experience seizures during the acute presentation. “In contrast,” Dr. Rossor said, “adult patients with relapsing-remitting multiple sclerosis have the same risk of developing epilepsy as the general population.” Among adults with cortical encephalitis, antibodies against myelin oligodendrocyte glycoprotein (MOG) have been associated with seizures and the need for antiepileptic medications, he added.
That finding was part of what spurred Dr. Rossor’s study, which aimed to identify predictors of relapse and post-ADEM epilepsy in children. The patients in the review had a median age of 4.5 years. All were tested for anti-MOG antibodies, and most (about 68%) were positive. Oligoclonal bands in cerebrospinal fluid (CSF) occurred in 22%. The median follow-up period was 5 years.
A total of 41% (n = 31) relapsed after the initial acute phase. Among these, the final diagnosis included multiphasic disseminated encephalomyelitis (n = 19); ADEM-optic neuritis (n = 3); and neuromyelitis optica spectrum disorder (n = 6).
Of the 74 patients, 16 (22%) had seizures during the acute phase, and 12 (16%) developed post-ADEM epilepsy at a median of 3 months. The most common clinical characteristics with post-ADEM epilepsy included oligoclonal bands (57% vs. 13%), anti-MOG antibodies (92% vs. 16%), and seizures at presentation (50% vs. 16%). When these were entered into a regression model, oligoclonal bands and initial seizures significantly predicted epilepsy, increasing the risk by 20.7 and 13.5 times, respectively.
Since relapse is known to be associated with post-ADEM epilepsy, Dr. Rossor first looked at relapse risk. He conducted a multivariate analysis that included several clinical characteristics: age, prodrome, increased CSF white cells and protein, oligoclonal bands, anti-MOG antibodies, and seizures both at presentation and after the acute phase.
Anti-MOG antibodies were significantly more common among the relapsed patients than among the monophasic patients (87% vs. 53%). Seizures at presentation also were more common among the relapsed patients (32% vs. 14%). These two factors were entered into a binary regression analysis; only anti-MOG antibodies remained significantly associated with relapse, increasing the risk fivefold (odds ratio = 5.4; P = .007).
Anti-MOG antibodies also were associated with both earlier and more relapses. Overall, 40% of anti–MOG-antibody–positive patients relapsed by 24 months. In contrast, only 20% of anti–MOG-antibody–negative patients had relapsed by 24 months, and this number remained steady throughout the follow-up period.
By 96 months, almost all the anti–MOG-antibody–positive patients had relapsed, and some experienced many relapses. “In the antibody-negative group, four patients did relapse, but they had relatively few relapses. In the antibody-positive group, some had relatively few relapses, but several had 15, 20, or 25 clinical relapses in the follow-up period,” he said.
Dr. Rossor and his coauthors had no financial disclosures.
SOURCE: Rossor T et al. Mult Scler. 2018;24(Suppl 2):27. Abstract 62.
REPORTING FROM ECTRIMS 2018
Key clinical point: .
Major finding: Oligoclonal bands in CSF increased the risk of post-ADEM epilepsy by more than 20 times.
Study details: The retrospective cohort review comprised 74 children.
Disclosures: Dr. Rossor and his coauthors had no financial disclosures.
Source: Rossor T et al. Mult Scler. 2018;24(Suppl 2):27. Abstract 62.
Relapsing-remitting MS best treated within 6 months of onset
BERLIN – according to real-world data from the Big Multiple Sclerosis Data Network.
Receiving disease-modifying treatments (DMTs) within 6 months of diagnosis was associated with a 28% reduction in the risk of reaching an Expanded Disability Status Scale score of 3.0 or more for the first time at 12 months versus receiving treatment after 6 months (hazard ratio, 0.72; 95% confidence interval, 0.59-0.90; P = .003).
Results were not significant, looking at all the other periods tested at 6-month intervals from 1 year up to 5 years after diagnosis. HRs (95% CIs) comparing a first DMT given at 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, and 5 years were a respective 0.90 (0.78-1.03), 0.89 (0.79-1.01), 0.99 (0.88-1.11), 0.95 (0.85-1.06), 1.01 (0.90-1.12), 0.97 (0.86-1.09), 1.09 (0.96-1.22), 1.11 (0.98-1.25), and 1.06 (0.93-1.20).
“To date, these data represent the largest RRMS cohort with the longest follow-up ever analyzed to determine the long-term effectiveness of the early start of DMTs,” said Pietro Iaffaldano, MD, at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“This study also provides evidence that data sharing from MS registries and databases is feasible,” noted Dr. Iaffaldano, who is assistant professor of neurology at the University of Bari (Italy). Such an approach can provide enough statistical power to detect the impact of treatment on disability outcomes in the long term, he suggested.
For the study, a cohort of 11,934 patients was obtained by screening more than 149,636 patients from five large registries and databases of MS patients – the Italian MS Registry, the Swedish MS Registry, the Danish MS Registry, OFSEP (Observatoire Français de al Sclérose en Plaques), and MSBase. Patients were included in the current analysis if they had at least 10 years of follow-up, had at least three EDSS evaluations, and at least one DMT prescription.
“It is well known that randomized, controlled trials support the early start of treatment in MS, but open-label extensions of the same trials reported inconsistent results about the long-term benefit on disability accumulation,” Dr. Iaffaldano explained. Further, recent observational studies have suggested that initiating DMTs early might not only delay the accumulation of disability but perhaps also death.
The aim of the research was thus to look at what effect the time interval from disease onset to the first administration of a DMT might have on long-term disability accumulation, as measured by the EDSS, in patients with RRMS.
The population of patients studied was mostly (71%) female, with a median age of 27 years at disease onset. The number of relapses prior to starting a DMT was two and the baseline EDSS was 2.0. In almost all (98.9%) cases, DMT was used as first-line treatment (second line in 1.1% of cases). The median follow-up was 13.2 years and cumulative DMT exposure was 10.5 years.
The work was supported by Biogen International on the basis of a sponsored research agreement with the Big Multiple Sclerosis Data Network. Dr. Iaffaldano has served on scientific advisory boards for and received funding for travel and/or speaker honoraria from Biogen and other companies that market DMTs for MS. Several study authors are employees of Biogen, and other study authors also reported financial ties to Biogen and other pharmaceutical companies.
SOURCE: Iaffaldano P et al. Mult Scler. 2018;24(Suppl 2):71-2, Abstract 204.
BERLIN – according to real-world data from the Big Multiple Sclerosis Data Network.
Receiving disease-modifying treatments (DMTs) within 6 months of diagnosis was associated with a 28% reduction in the risk of reaching an Expanded Disability Status Scale score of 3.0 or more for the first time at 12 months versus receiving treatment after 6 months (hazard ratio, 0.72; 95% confidence interval, 0.59-0.90; P = .003).
Results were not significant, looking at all the other periods tested at 6-month intervals from 1 year up to 5 years after diagnosis. HRs (95% CIs) comparing a first DMT given at 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, and 5 years were a respective 0.90 (0.78-1.03), 0.89 (0.79-1.01), 0.99 (0.88-1.11), 0.95 (0.85-1.06), 1.01 (0.90-1.12), 0.97 (0.86-1.09), 1.09 (0.96-1.22), 1.11 (0.98-1.25), and 1.06 (0.93-1.20).
“To date, these data represent the largest RRMS cohort with the longest follow-up ever analyzed to determine the long-term effectiveness of the early start of DMTs,” said Pietro Iaffaldano, MD, at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“This study also provides evidence that data sharing from MS registries and databases is feasible,” noted Dr. Iaffaldano, who is assistant professor of neurology at the University of Bari (Italy). Such an approach can provide enough statistical power to detect the impact of treatment on disability outcomes in the long term, he suggested.
For the study, a cohort of 11,934 patients was obtained by screening more than 149,636 patients from five large registries and databases of MS patients – the Italian MS Registry, the Swedish MS Registry, the Danish MS Registry, OFSEP (Observatoire Français de al Sclérose en Plaques), and MSBase. Patients were included in the current analysis if they had at least 10 years of follow-up, had at least three EDSS evaluations, and at least one DMT prescription.
“It is well known that randomized, controlled trials support the early start of treatment in MS, but open-label extensions of the same trials reported inconsistent results about the long-term benefit on disability accumulation,” Dr. Iaffaldano explained. Further, recent observational studies have suggested that initiating DMTs early might not only delay the accumulation of disability but perhaps also death.
The aim of the research was thus to look at what effect the time interval from disease onset to the first administration of a DMT might have on long-term disability accumulation, as measured by the EDSS, in patients with RRMS.
The population of patients studied was mostly (71%) female, with a median age of 27 years at disease onset. The number of relapses prior to starting a DMT was two and the baseline EDSS was 2.0. In almost all (98.9%) cases, DMT was used as first-line treatment (second line in 1.1% of cases). The median follow-up was 13.2 years and cumulative DMT exposure was 10.5 years.
The work was supported by Biogen International on the basis of a sponsored research agreement with the Big Multiple Sclerosis Data Network. Dr. Iaffaldano has served on scientific advisory boards for and received funding for travel and/or speaker honoraria from Biogen and other companies that market DMTs for MS. Several study authors are employees of Biogen, and other study authors also reported financial ties to Biogen and other pharmaceutical companies.
SOURCE: Iaffaldano P et al. Mult Scler. 2018;24(Suppl 2):71-2, Abstract 204.
BERLIN – according to real-world data from the Big Multiple Sclerosis Data Network.
Receiving disease-modifying treatments (DMTs) within 6 months of diagnosis was associated with a 28% reduction in the risk of reaching an Expanded Disability Status Scale score of 3.0 or more for the first time at 12 months versus receiving treatment after 6 months (hazard ratio, 0.72; 95% confidence interval, 0.59-0.90; P = .003).
Results were not significant, looking at all the other periods tested at 6-month intervals from 1 year up to 5 years after diagnosis. HRs (95% CIs) comparing a first DMT given at 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, and 5 years were a respective 0.90 (0.78-1.03), 0.89 (0.79-1.01), 0.99 (0.88-1.11), 0.95 (0.85-1.06), 1.01 (0.90-1.12), 0.97 (0.86-1.09), 1.09 (0.96-1.22), 1.11 (0.98-1.25), and 1.06 (0.93-1.20).
“To date, these data represent the largest RRMS cohort with the longest follow-up ever analyzed to determine the long-term effectiveness of the early start of DMTs,” said Pietro Iaffaldano, MD, at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“This study also provides evidence that data sharing from MS registries and databases is feasible,” noted Dr. Iaffaldano, who is assistant professor of neurology at the University of Bari (Italy). Such an approach can provide enough statistical power to detect the impact of treatment on disability outcomes in the long term, he suggested.
For the study, a cohort of 11,934 patients was obtained by screening more than 149,636 patients from five large registries and databases of MS patients – the Italian MS Registry, the Swedish MS Registry, the Danish MS Registry, OFSEP (Observatoire Français de al Sclérose en Plaques), and MSBase. Patients were included in the current analysis if they had at least 10 years of follow-up, had at least three EDSS evaluations, and at least one DMT prescription.
“It is well known that randomized, controlled trials support the early start of treatment in MS, but open-label extensions of the same trials reported inconsistent results about the long-term benefit on disability accumulation,” Dr. Iaffaldano explained. Further, recent observational studies have suggested that initiating DMTs early might not only delay the accumulation of disability but perhaps also death.
The aim of the research was thus to look at what effect the time interval from disease onset to the first administration of a DMT might have on long-term disability accumulation, as measured by the EDSS, in patients with RRMS.
The population of patients studied was mostly (71%) female, with a median age of 27 years at disease onset. The number of relapses prior to starting a DMT was two and the baseline EDSS was 2.0. In almost all (98.9%) cases, DMT was used as first-line treatment (second line in 1.1% of cases). The median follow-up was 13.2 years and cumulative DMT exposure was 10.5 years.
The work was supported by Biogen International on the basis of a sponsored research agreement with the Big Multiple Sclerosis Data Network. Dr. Iaffaldano has served on scientific advisory boards for and received funding for travel and/or speaker honoraria from Biogen and other companies that market DMTs for MS. Several study authors are employees of Biogen, and other study authors also reported financial ties to Biogen and other pharmaceutical companies.
SOURCE: Iaffaldano P et al. Mult Scler. 2018;24(Suppl 2):71-2, Abstract 204.
REPORTING FROM ECTRIMS 2018
Key clinical point: Less disease progression occurs if disease-modifying treatments (DMTs) are given early in relapsing-remitting multiple sclerosis (RRMS).
Major finding: DMTs within 6 months vs. later decreased the risk of confirmed first disability progression at 12 months by 28% (P = .003).
Study details: 11,934 patients with RRMS with at least 10 years’ follow-up, three or more Expanded Disability Status Scale evaluations, and at least one DMT prescription.
Disclosures: The work was supported by Biogen International on the basis of a sponsored research agreement with the Big Multiple Sclerosis Data Network. Dr. Iaffaldano has served on scientific advisory boards for and received funding for travel and/or speaker honoraria from Biogen and other companies that market DMTs for MS. Several study authors are employees of Biogen, and other study authors also reported financial ties to Biogen and other pharmaceutical companies.
Source: Iaffaldano P et al. Mult Scler. 2018;24(Suppl 2):71-2, Abstract 204.
Mood disorders worsen multiple sclerosis disability
BERLIN – Depression and bipolar disorder are major risk factors for worsening disability in people with multiple sclerosis, according to the results of a large Swedish registry-based study.
The presence of depression increased the risk of having a sustained Expanded Disability Status Scale (EDSS) score of 3.0 by 54% and 4.0 by 87%, and it doubled the risk of an EDSS of 6.0.
Selective serotonin reuptake inhibitor treatment also upped the risk of greater disability, with patients exposed to SSRIs having a 40% increased risk of a sustained EDSS of 3.0, a 97% chance of having a sustained EDSS of 4.0, and 2.2-fold increased risk of a sustained EDSS of 6.0.
“We know that mood disorders are highly prevalent in people with multiple sclerosis,” Stefanie Binzer, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. She gave her presentation at the meeting on Oct. 10, which was World Mental Health Day.
The presence of mood disorders is associated with reduced quality of life, said Dr. Binzer of the department of clinical neuroscience at the Karolinska Institute in Stockholm. Furthermore, depression is the major risk factor for suicidality in patients with MS. However, before this study the effect of having a comorbid mood disorder on MS patients’ disability levels had not been established.
The investigators analyzed data from 5,875 patients in the Swedish MS registry between 2001 and 2014. By matching these patients to records in the Swedish National Patient Registry and the Swedish National Prescribed Drug Registry, they found that 8.5% (n = 502) had an International Classification of Diseases, 10th revision (ICD-10), code for depression. Of these, 261 had received a diagnosis of depression before their diagnosis of MS.
Of 3,817 patients with MS onset between 2005 and 2014, 27.4% (n = 1,048) had collected at least one prescription for an SSRI.
“What we found was that MS patients with either an ICD code for depression or having been exposed to SSRIs had a significantly increased risk of reaching EDSS 3.0,” Dr. Binzer reported. The age at which patients reached these milestones were younger in both groups when compared with MS patients without depression, she observed.
“The difference between the groups [MS with and MS without depression] seemed to increased with EDSS,” Dr. Binzer said.
Although not statistically significant, there was a trend for patients with depression to be more likely to convert to secondary progressive MS, with a hazard ratio of 1.38 (95% confidence interval, 0.91-2.1).
“For a sensitivity analysis, we found that those who had depression prior to their first MS symptom, the median age when they reached EDSS 3.0 and 4.0 was reduced by 3 and 7 years, respectively,” Dr. Binzer said, adding that, unfortunately, there wasn’t enough power to look at the other endpoints.
In regard to bipolar disorder, 1.5% (n = 200) of 13,125 MS patients diagnosed between 1973 and 2014 were identified with this mood disorder. Its presence significantly increased the risk of MS patients reaching an EDSS score of 4.0 by 58% (95% CI, 1.1-2.28), but not EDSS 3.0 (HR = 1.34; 95% CI, 0.94-1.92) or 6.0 (HR = 1.16; 95% CI, 0.79-1.69). The latter could be due to smaller sample size, Dr. Binzer suggested.
The investigators’ analysis of the results stratified by sex, conducted because men tend to fare worse than women with MS and progress faster, showed that for both depression and bipolar disorder, men were at significantly higher risk of reaching sustained disability milestones. Indeed, compared with women, men with depression had a 61% increased risk and those with bipolar disorder a 31% increased risk of reaching an EDSS score of 6.0. They also had 51% and 32% increased risks of conversion to secondary progressive MS.
“We don’t know the mechanisms that underlie these associations,” Dr. Binzer noted. “Irrespective of the underlying mechanisms, [the study] clearly shows that it’s imperative that we recognize, early, mood disorders in MS patients, and manage them effectively in order to provide better care and hopefully reduce MS disability worsening.”
The research was funded by the Swedish Research Council and the Swedish Brain Foundation. Dr. Binzer has received speaker fees and travel grants from Biogen.
SOURCE: Binzer S et al. Mult Scler. 2018;24(Suppl 2):41. Abstract 99.
BERLIN – Depression and bipolar disorder are major risk factors for worsening disability in people with multiple sclerosis, according to the results of a large Swedish registry-based study.
The presence of depression increased the risk of having a sustained Expanded Disability Status Scale (EDSS) score of 3.0 by 54% and 4.0 by 87%, and it doubled the risk of an EDSS of 6.0.
Selective serotonin reuptake inhibitor treatment also upped the risk of greater disability, with patients exposed to SSRIs having a 40% increased risk of a sustained EDSS of 3.0, a 97% chance of having a sustained EDSS of 4.0, and 2.2-fold increased risk of a sustained EDSS of 6.0.
“We know that mood disorders are highly prevalent in people with multiple sclerosis,” Stefanie Binzer, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. She gave her presentation at the meeting on Oct. 10, which was World Mental Health Day.
The presence of mood disorders is associated with reduced quality of life, said Dr. Binzer of the department of clinical neuroscience at the Karolinska Institute in Stockholm. Furthermore, depression is the major risk factor for suicidality in patients with MS. However, before this study the effect of having a comorbid mood disorder on MS patients’ disability levels had not been established.
The investigators analyzed data from 5,875 patients in the Swedish MS registry between 2001 and 2014. By matching these patients to records in the Swedish National Patient Registry and the Swedish National Prescribed Drug Registry, they found that 8.5% (n = 502) had an International Classification of Diseases, 10th revision (ICD-10), code for depression. Of these, 261 had received a diagnosis of depression before their diagnosis of MS.
Of 3,817 patients with MS onset between 2005 and 2014, 27.4% (n = 1,048) had collected at least one prescription for an SSRI.
“What we found was that MS patients with either an ICD code for depression or having been exposed to SSRIs had a significantly increased risk of reaching EDSS 3.0,” Dr. Binzer reported. The age at which patients reached these milestones were younger in both groups when compared with MS patients without depression, she observed.
“The difference between the groups [MS with and MS without depression] seemed to increased with EDSS,” Dr. Binzer said.
Although not statistically significant, there was a trend for patients with depression to be more likely to convert to secondary progressive MS, with a hazard ratio of 1.38 (95% confidence interval, 0.91-2.1).
“For a sensitivity analysis, we found that those who had depression prior to their first MS symptom, the median age when they reached EDSS 3.0 and 4.0 was reduced by 3 and 7 years, respectively,” Dr. Binzer said, adding that, unfortunately, there wasn’t enough power to look at the other endpoints.
In regard to bipolar disorder, 1.5% (n = 200) of 13,125 MS patients diagnosed between 1973 and 2014 were identified with this mood disorder. Its presence significantly increased the risk of MS patients reaching an EDSS score of 4.0 by 58% (95% CI, 1.1-2.28), but not EDSS 3.0 (HR = 1.34; 95% CI, 0.94-1.92) or 6.0 (HR = 1.16; 95% CI, 0.79-1.69). The latter could be due to smaller sample size, Dr. Binzer suggested.
The investigators’ analysis of the results stratified by sex, conducted because men tend to fare worse than women with MS and progress faster, showed that for both depression and bipolar disorder, men were at significantly higher risk of reaching sustained disability milestones. Indeed, compared with women, men with depression had a 61% increased risk and those with bipolar disorder a 31% increased risk of reaching an EDSS score of 6.0. They also had 51% and 32% increased risks of conversion to secondary progressive MS.
“We don’t know the mechanisms that underlie these associations,” Dr. Binzer noted. “Irrespective of the underlying mechanisms, [the study] clearly shows that it’s imperative that we recognize, early, mood disorders in MS patients, and manage them effectively in order to provide better care and hopefully reduce MS disability worsening.”
The research was funded by the Swedish Research Council and the Swedish Brain Foundation. Dr. Binzer has received speaker fees and travel grants from Biogen.
SOURCE: Binzer S et al. Mult Scler. 2018;24(Suppl 2):41. Abstract 99.
BERLIN – Depression and bipolar disorder are major risk factors for worsening disability in people with multiple sclerosis, according to the results of a large Swedish registry-based study.
The presence of depression increased the risk of having a sustained Expanded Disability Status Scale (EDSS) score of 3.0 by 54% and 4.0 by 87%, and it doubled the risk of an EDSS of 6.0.
Selective serotonin reuptake inhibitor treatment also upped the risk of greater disability, with patients exposed to SSRIs having a 40% increased risk of a sustained EDSS of 3.0, a 97% chance of having a sustained EDSS of 4.0, and 2.2-fold increased risk of a sustained EDSS of 6.0.
“We know that mood disorders are highly prevalent in people with multiple sclerosis,” Stefanie Binzer, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. She gave her presentation at the meeting on Oct. 10, which was World Mental Health Day.
The presence of mood disorders is associated with reduced quality of life, said Dr. Binzer of the department of clinical neuroscience at the Karolinska Institute in Stockholm. Furthermore, depression is the major risk factor for suicidality in patients with MS. However, before this study the effect of having a comorbid mood disorder on MS patients’ disability levels had not been established.
The investigators analyzed data from 5,875 patients in the Swedish MS registry between 2001 and 2014. By matching these patients to records in the Swedish National Patient Registry and the Swedish National Prescribed Drug Registry, they found that 8.5% (n = 502) had an International Classification of Diseases, 10th revision (ICD-10), code for depression. Of these, 261 had received a diagnosis of depression before their diagnosis of MS.
Of 3,817 patients with MS onset between 2005 and 2014, 27.4% (n = 1,048) had collected at least one prescription for an SSRI.
“What we found was that MS patients with either an ICD code for depression or having been exposed to SSRIs had a significantly increased risk of reaching EDSS 3.0,” Dr. Binzer reported. The age at which patients reached these milestones were younger in both groups when compared with MS patients without depression, she observed.
“The difference between the groups [MS with and MS without depression] seemed to increased with EDSS,” Dr. Binzer said.
Although not statistically significant, there was a trend for patients with depression to be more likely to convert to secondary progressive MS, with a hazard ratio of 1.38 (95% confidence interval, 0.91-2.1).
“For a sensitivity analysis, we found that those who had depression prior to their first MS symptom, the median age when they reached EDSS 3.0 and 4.0 was reduced by 3 and 7 years, respectively,” Dr. Binzer said, adding that, unfortunately, there wasn’t enough power to look at the other endpoints.
In regard to bipolar disorder, 1.5% (n = 200) of 13,125 MS patients diagnosed between 1973 and 2014 were identified with this mood disorder. Its presence significantly increased the risk of MS patients reaching an EDSS score of 4.0 by 58% (95% CI, 1.1-2.28), but not EDSS 3.0 (HR = 1.34; 95% CI, 0.94-1.92) or 6.0 (HR = 1.16; 95% CI, 0.79-1.69). The latter could be due to smaller sample size, Dr. Binzer suggested.
The investigators’ analysis of the results stratified by sex, conducted because men tend to fare worse than women with MS and progress faster, showed that for both depression and bipolar disorder, men were at significantly higher risk of reaching sustained disability milestones. Indeed, compared with women, men with depression had a 61% increased risk and those with bipolar disorder a 31% increased risk of reaching an EDSS score of 6.0. They also had 51% and 32% increased risks of conversion to secondary progressive MS.
“We don’t know the mechanisms that underlie these associations,” Dr. Binzer noted. “Irrespective of the underlying mechanisms, [the study] clearly shows that it’s imperative that we recognize, early, mood disorders in MS patients, and manage them effectively in order to provide better care and hopefully reduce MS disability worsening.”
The research was funded by the Swedish Research Council and the Swedish Brain Foundation. Dr. Binzer has received speaker fees and travel grants from Biogen.
SOURCE: Binzer S et al. Mult Scler. 2018;24(Suppl 2):41. Abstract 99.
REPORTING FROM ECTRIMS 2018
Key clinical point:
Major finding: Depression and bipolar disorder increased the risk of reaching Expanded Disability Status Scale scores of 3.0, 4.0, and 6.0, particularly in men with MS.
Study details: Swedish registry study of nearly 6,000 individuals with confirmed MS, 8.5% of whom had depression and 1.5% of whom had bipolar disorder.
Disclosures: The research was funded by the Swedish Research Council and the Swedish Brain Foundation. Dr. Binzer has received speaker fees and travel grants from Biogen.
Source: Binzer S et al. Mult Scler. 2018;24(Suppl 2):41. Abstract 99.