Multiple Sclerosis Hub

VANCOUVER – Three types of drugs commonly used to treat multiple sclerosis (MS) appear to have a generally good safety profile when administered before and during early pregnancy, suggest a trio of studies reported at the annual meeting of the American Academy of Neurology.

Exposure to interferon-beta during the first trimester did not increase the risks of miscarriage, congenital anomalies, or birth weight. And although use of natalizumab led to higher odds of spontaneous abortion as compared with interferon-beta or no therapy, the absolute rate still fell within that of the general population. Pregnancies occurring weeks to years after treatment with alemtuzumab also had rates of spontaneous abortion, birth defects, and stillbirth on par with population values.

All three drugs fall in a gray area when it comes to use in pregnancy, with a Food and Drug Administration designation of category C, indicating that animal studies have shown adverse effects on the fetus and adequate, quality human data are lacking, but potential benefits may outweigh potential harms in pregnancy. The studies’ findings are therefore likely to be informative to women of reproductive age, a group disproportionately affected by MS.

“It’s very important to collect as much data as possible about potential exposure risks with disease-modifying therapy in pregnancy,” session comoderator Dr. Jennifer Graves, a neurologist at the Multiple Sclerosis Center at University of California–San Francisco Medical Center and UCSF Benioff Children’s Hospital, San Francisco, said in an interview.

“However, all studies have the limitation of sample size,” she added. “The majority of serious adverse effects – teratogenicity, major birth defects – may be less than 1 in 500 [in frequency]. So this is something that puts all of these studies into context because we just don’t have that many pregnancies that have been exposed to some of these agents.” The method whereby miscarriages are ascertained can also influence findings.

Nonetheless, this research is critical for women and their physicians when it comes to making decisions about treatment, Dr. Graves maintained. “Although pregnancy may be protective for many women with MS, many do need treatment during their pregnancy to prevent severe relapses due to various factors. Collecting this type of information is important.”

Interferon-beta safety

In the first study, investigators led by Dr. Sandra Thiel of Ruhr University Bochum and the Heinrich Heine University Düsseldorf, both in Germany, analyzed data from the German Multiple Sclerosis and Pregnancy Registry.

They studied pregnancies among women who had at least 12 months of postpartum follow-up. Exposure to interferon-beta (brand names Rebif, Avonex, Betaseron, and Extavia) was defined as injection of the drug at any time after the last menstrual period.

In all, 251 pregnancies exposed to interferon-beta were compared with 194 pregnancies not exposed to any disease-modifying drugs. The median duration of exposure in the former group was 32 days, indicating that most women stopped the drug soon after discovering they were pregnant, Dr. Thiel noted.

Study results, reported at the meeting and recently published (Mult Scler. 2016 Feb 26. doi: 10.1177/1352458516634872), showed that the rate of miscarriage was 9.96% in the exposed group and 7.73% in the unexposed group, and the rate of congenital anomalies among live births was 3.08% and 5.52%.

In analyses using propensity score adjustment, there were no significant differences between groups in the odds of live birth, spontaneous abortion, congenital anomalies, preterm birth, cesarean section, or small for gestational age, or in mean infant birth weight.

Of note, the women whose pregnancies were not exposed to any disease-modifying therapy had a higher rate of relapse during pregnancy when compared with counterparts whose pregnancies were exposed to interferon-beta (27.3% vs. 14.3%).

“Taken together with the existing literature, our study provides further reassurance that interferon-beta treatment can be safely continued up until the time when women with MS become pregnant,” Dr. Thiel concluded. The safety profile seen “is consistent with the pharmacologically plausible safety of interferon-beta, as interferon-beta is a huge molecule that cannot pass the placental barrier.”

“Since the vast majority of women stopped the interferon-beta treatment during the first trimester of pregnancy, we cannot draw any conclusions about the safety of interferon-beta later in pregnancy,” she cautioned. “Another limitation is the variability in the gestational week of entry into the cohort, as later than first-trimester inclusion can lead to an underestimation of early events, particularly spontaneous abortions.”

Natalizumab safety

In the second study, Dr. Maria Pia Amato, Department of NEUROFARBA, Section of Neurosciences, University of Florence, Italy, and her colleagues with the Italian MS Study Group assessed pregnancy outcomes after exposure to natalizumab (Tysabri). This antibody targets alpha-4 integrins, which play a role in a variety of pregnancy processes and in fetal hematopoiesis and cardiac development, she noted.

They identified women for the study using two sources: the prospective Italian Pregnancy Dataset of consecutive female patients with MS referred to 25 centers and a cohort of women from an Italian interferon-beta study.

In all, they compared 65 pregnancies exposed to natalizumab (any treatment from 8 weeks before the start of the last menstrual period onward), 88 exposed to interferon-beta as a control, and 339 not exposed to either. The mean duration of natalizumab exposure was 1.16 weeks, and the mean duration of interferon-beta exposure was 4.6 weeks.

Results showed that the rate of spontaneous abortion was higher for natalizumab-exposed pregnancies, at 18.5%, than for interferon-beta–exposed pregnancies, at 8%, and for nonexposed pregnancies, at 6.5% (P = .006). But the timing of these abortions was similar, at about 8 weeks of gestation.

In adjusted analyses, natalizumab exposure was still associated with an elevated risk of spontaneous abortion when compared with interferon-beta or no exposure (odds ratio, 3.9). However, the 18.5% rate seen with the antibody fell within the range for the Italian general population of 4.8% to 21.1%.

Infants in the natalizumab group had the lowest birth weight and length, while infants in the interferon-beta group had the youngest gestational age. The groups did not differ significantly with respect to the incidence of birth defects; however, with a single defect seen in each, the study was underpowered to assess differences in this outcome.

Data additionally showed that discontinuation of natalizumab in advance of pregnancy led to an uptick in relapses, with 30% of women having a relapse, according to Dr. Amato. “This increase started during the first trimester of pregnancy and culminated in the second trimester of pregnancy. All the women were retreated soon after delivery with natalizumab, and disease activity returned to the pre-pregnancy period level with resumption of the drug.”

“Patients and clinicians should discuss together and balance the potential risks to the fetus with natalizumab exposure with the potential risks to the mother of disease reactivation during pregnancy,” she recommended, cautioning that the findings were based on first-trimester exposure of short duration. “Decisions should be made case by case on the basis of the disease activity in a specific patient and the availability of alternative treatment, and whether to use a conservative approach, stopping the drug and respecting the washout period, or in a few cases, an active approach, continuing the drug till conception or even discuss continuing the drug during pregnancy.”

Alemtuzumab safety

In the third study, investigators led by Dr. Jiwon Oh of the division of neurology at the University of Toronto analyzed outcomes of pregnancies among women who had been treated with alemtuzumab (Lemtrada), an antibody that targets CD52.

Treatment with alemtuzumab leads to depletion of lymphocytes followed by reconstitution of the immune system with a less inflammatory profile. “This is thought to contribute to the durable efficacy in the absence of continuous treatment with alemtuzumab,” she explained. “This durable efficacy and the fact that you may not need to redose is relevant when you are thinking about pregnancy in patients with MS, just because this is a drug that is given in two different cycles and may not need to be readministered.”

Although the antibody becomes undetectable in serum about 30 days after administration, it is unclear whether the ongoing immune reconstitution has any impact on subsequent pregnancy, Dr. Oh said.

The investigators pooled data from the phase II CAMMS223 trial and the phase III CARE-MS I and CARE-MS II trials of alemtuzumab and their extension phases. Women enrolled in the trials were required to use effective contraception during treatment and for the next 6 months.

Dr. Oh reported interim results based on 200 pregnancies among 137 women. Most pregnancies occurred at least 4 months after the last dose of alemtuzumab; only four occurred within 1 month and another four occurred 1 to 3 months after the last dose.

Among the 181 completed pregnancies with known outcomes, 67.4% resulted in live births. Another 21.5% ended in spontaneous abortion. “Although this is on the higher end of normal, it is still in keeping with what is seen in the general population,” Dr. Oh noted.

The rate of stillbirth was 0.6%, also at the upper end of the range seen for the general population. Finally, 10.5% of the pregnancies ended in elective abortion.

There were no congenital anomalies or birth defects among the live-born infants. One was seen in an electively terminated pregnancy (26 months after the last dose), and another was seen in a stillbirth (4 years after the last dose).

“Two out of 200 is 1%, and this is actually lower than what is normally seen in the general population, approximately 3% to 7%,” Dr. Oh commented.

“To date, there is no indication of an increased risk for congenital anomalies or birth defects in infants,” she summarized. “There has also been no indication of increased rates of spontaneous abortion in women who become pregnant, but obviously, these data are limited because we don’t necessarily have a control group.”

“Based on the pharmacokinetics of alemtuzumab and labeling guidelines, women of childbearing potential should continue to use contraception for 4 months after receiving a course of alemtuzumab,” Dr. Oh concluded. “There is an international Alemtuzumab Pregnancy Exposure Registry that is open and enrolling patients who become pregnant between the first dose of alemtuzumab and 4 months after the last infusion, and hopefully this will give us more information to confirm some of the observations that we see here.”

Dr. Thiel disclosed that she had no relevant conflicts of interest; the German Multiple Sclerosis and Pregnancy registry was partly supported by Bayer Healthcare, Biogen Idec Germany, Merck Serono, Novartis Pharma, Teva Pharma, and Sanofi-Aventis/Genzyme Pharmaceuticals. Dr. Amato disclosed that she has received research grants and honoraria as a speaker from and is a member of advisory boards for Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, Teva, Almirall, and Roche; the study did not receive any financial support. Dr. Oh disclosed that she serves on the scientific advisory boards or is a speaker for Biogen Idec, EMD Serono, Genzyme, Novartis, Roche, and Teva; the study was supported by Genzyme and Bayer Healthcare.

VANCOUVER – Three types of drugs commonly used to treat multiple sclerosis (MS) appear to have a generally good safety profile when administered before and during early pregnancy, suggest a trio of studies reported at the annual meeting of the American Academy of Neurology.

Exposure to interferon-beta during the first trimester did not increase the risks of miscarriage, congenital anomalies, or birth weight. And although use of natalizumab led to higher odds of spontaneous abortion as compared with interferon-beta or no therapy, the absolute rate still fell within that of the general population. Pregnancies occurring weeks to years after treatment with alemtuzumab also had rates of spontaneous abortion, birth defects, and stillbirth on par with population values.

All three drugs fall in a gray area when it comes to use in pregnancy, with a Food and Drug Administration designation of category C, indicating that animal studies have shown adverse effects on the fetus and adequate, quality human data are lacking, but potential benefits may outweigh potential harms in pregnancy. The studies’ findings are therefore likely to be informative to women of reproductive age, a group disproportionately affected by MS.

“It’s very important to collect as much data as possible about potential exposure risks with disease-modifying therapy in pregnancy,” session comoderator Dr. Jennifer Graves, a neurologist at the Multiple Sclerosis Center at University of California–San Francisco Medical Center and UCSF Benioff Children’s Hospital, San Francisco, said in an interview.

“However, all studies have the limitation of sample size,” she added. “The majority of serious adverse effects – teratogenicity, major birth defects – may be less than 1 in 500 [in frequency]. So this is something that puts all of these studies into context because we just don’t have that many pregnancies that have been exposed to some of these agents.” The method whereby miscarriages are ascertained can also influence findings.

Nonetheless, this research is critical for women and their physicians when it comes to making decisions about treatment, Dr. Graves maintained. “Although pregnancy may be protective for many women with MS, many do need treatment during their pregnancy to prevent severe relapses due to various factors. Collecting this type of information is important.”

Interferon-beta safety

In the first study, investigators led by Dr. Sandra Thiel of Ruhr University Bochum and the Heinrich Heine University Düsseldorf, both in Germany, analyzed data from the German Multiple Sclerosis and Pregnancy Registry.

They studied pregnancies among women who had at least 12 months of postpartum follow-up. Exposure to interferon-beta (brand names Rebif, Avonex, Betaseron, and Extavia) was defined as injection of the drug at any time after the last menstrual period.

In all, 251 pregnancies exposed to interferon-beta were compared with 194 pregnancies not exposed to any disease-modifying drugs. The median duration of exposure in the former group was 32 days, indicating that most women stopped the drug soon after discovering they were pregnant, Dr. Thiel noted.

Study results, reported at the meeting and recently published (Mult Scler. 2016 Feb 26. doi: 10.1177/1352458516634872), showed that the rate of miscarriage was 9.96% in the exposed group and 7.73% in the unexposed group, and the rate of congenital anomalies among live births was 3.08% and 5.52%.

In analyses using propensity score adjustment, there were no significant differences between groups in the odds of live birth, spontaneous abortion, congenital anomalies, preterm birth, cesarean section, or small for gestational age, or in mean infant birth weight.

Of note, the women whose pregnancies were not exposed to any disease-modifying therapy had a higher rate of relapse during pregnancy when compared with counterparts whose pregnancies were exposed to interferon-beta (27.3% vs. 14.3%).

“Taken together with the existing literature, our study provides further reassurance that interferon-beta treatment can be safely continued up until the time when women with MS become pregnant,” Dr. Thiel concluded. The safety profile seen “is consistent with the pharmacologically plausible safety of interferon-beta, as interferon-beta is a huge molecule that cannot pass the placental barrier.”

“Since the vast majority of women stopped the interferon-beta treatment during the first trimester of pregnancy, we cannot draw any conclusions about the safety of interferon-beta later in pregnancy,” she cautioned. “Another limitation is the variability in the gestational week of entry into the cohort, as later than first-trimester inclusion can lead to an underestimation of early events, particularly spontaneous abortions.”

Natalizumab safety

In the second study, Dr. Maria Pia Amato, Department of NEUROFARBA, Section of Neurosciences, University of Florence, Italy, and her colleagues with the Italian MS Study Group assessed pregnancy outcomes after exposure to natalizumab (Tysabri). This antibody targets alpha-4 integrins, which play a role in a variety of pregnancy processes and in fetal hematopoiesis and cardiac development, she noted.

They identified women for the study using two sources: the prospective Italian Pregnancy Dataset of consecutive female patients with MS referred to 25 centers and a cohort of women from an Italian interferon-beta study.

In all, they compared 65 pregnancies exposed to natalizumab (any treatment from 8 weeks before the start of the last menstrual period onward), 88 exposed to interferon-beta as a control, and 339 not exposed to either. The mean duration of natalizumab exposure was 1.16 weeks, and the mean duration of interferon-beta exposure was 4.6 weeks.

Results showed that the rate of spontaneous abortion was higher for natalizumab-exposed pregnancies, at 18.5%, than for interferon-beta–exposed pregnancies, at 8%, and for nonexposed pregnancies, at 6.5% (P = .006). But the timing of these abortions was similar, at about 8 weeks of gestation.

In adjusted analyses, natalizumab exposure was still associated with an elevated risk of spontaneous abortion when compared with interferon-beta or no exposure (odds ratio, 3.9). However, the 18.5% rate seen with the antibody fell within the range for the Italian general population of 4.8% to 21.1%.

Infants in the natalizumab group had the lowest birth weight and length, while infants in the interferon-beta group had the youngest gestational age. The groups did not differ significantly with respect to the incidence of birth defects; however, with a single defect seen in each, the study was underpowered to assess differences in this outcome.

Data additionally showed that discontinuation of natalizumab in advance of pregnancy led to an uptick in relapses, with 30% of women having a relapse, according to Dr. Amato. “This increase started during the first trimester of pregnancy and culminated in the second trimester of pregnancy. All the women were retreated soon after delivery with natalizumab, and disease activity returned to the pre-pregnancy period level with resumption of the drug.”

“Patients and clinicians should discuss together and balance the potential risks to the fetus with natalizumab exposure with the potential risks to the mother of disease reactivation during pregnancy,” she recommended, cautioning that the findings were based on first-trimester exposure of short duration. “Decisions should be made case by case on the basis of the disease activity in a specific patient and the availability of alternative treatment, and whether to use a conservative approach, stopping the drug and respecting the washout period, or in a few cases, an active approach, continuing the drug till conception or even discuss continuing the drug during pregnancy.”

Alemtuzumab safety

In the third study, investigators led by Dr. Jiwon Oh of the division of neurology at the University of Toronto analyzed outcomes of pregnancies among women who had been treated with alemtuzumab (Lemtrada), an antibody that targets CD52.

Treatment with alemtuzumab leads to depletion of lymphocytes followed by reconstitution of the immune system with a less inflammatory profile. “This is thought to contribute to the durable efficacy in the absence of continuous treatment with alemtuzumab,” she explained. “This durable efficacy and the fact that you may not need to redose is relevant when you are thinking about pregnancy in patients with MS, just because this is a drug that is given in two different cycles and may not need to be readministered.”

Although the antibody becomes undetectable in serum about 30 days after administration, it is unclear whether the ongoing immune reconstitution has any impact on subsequent pregnancy, Dr. Oh said.

The investigators pooled data from the phase II CAMMS223 trial and the phase III CARE-MS I and CARE-MS II trials of alemtuzumab and their extension phases. Women enrolled in the trials were required to use effective contraception during treatment and for the next 6 months.

Dr. Oh reported interim results based on 200 pregnancies among 137 women. Most pregnancies occurred at least 4 months after the last dose of alemtuzumab; only four occurred within 1 month and another four occurred 1 to 3 months after the last dose.

Among the 181 completed pregnancies with known outcomes, 67.4% resulted in live births. Another 21.5% ended in spontaneous abortion. “Although this is on the higher end of normal, it is still in keeping with what is seen in the general population,” Dr. Oh noted.

The rate of stillbirth was 0.6%, also at the upper end of the range seen for the general population. Finally, 10.5% of the pregnancies ended in elective abortion.

There were no congenital anomalies or birth defects among the live-born infants. One was seen in an electively terminated pregnancy (26 months after the last dose), and another was seen in a stillbirth (4 years after the last dose).

“Two out of 200 is 1%, and this is actually lower than what is normally seen in the general population, approximately 3% to 7%,” Dr. Oh commented.

“To date, there is no indication of an increased risk for congenital anomalies or birth defects in infants,” she summarized. “There has also been no indication of increased rates of spontaneous abortion in women who become pregnant, but obviously, these data are limited because we don’t necessarily have a control group.”

“Based on the pharmacokinetics of alemtuzumab and labeling guidelines, women of childbearing potential should continue to use contraception for 4 months after receiving a course of alemtuzumab,” Dr. Oh concluded. “There is an international Alemtuzumab Pregnancy Exposure Registry that is open and enrolling patients who become pregnant between the first dose of alemtuzumab and 4 months after the last infusion, and hopefully this will give us more information to confirm some of the observations that we see here.”

Dr. Thiel disclosed that she had no relevant conflicts of interest; the German Multiple Sclerosis and Pregnancy registry was partly supported by Bayer Healthcare, Biogen Idec Germany, Merck Serono, Novartis Pharma, Teva Pharma, and Sanofi-Aventis/Genzyme Pharmaceuticals. Dr. Amato disclosed that she has received research grants and honoraria as a speaker from and is a member of advisory boards for Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, Teva, Almirall, and Roche; the study did not receive any financial support. Dr. Oh disclosed that she serves on the scientific advisory boards or is a speaker for Biogen Idec, EMD Serono, Genzyme, Novartis, Roche, and Teva; the study was supported by Genzyme and Bayer Healthcare.

VANCOUVER – Three types of drugs commonly used to treat multiple sclerosis (MS) appear to have a generally good safety profile when administered before and during early pregnancy, suggest a trio of studies reported at the annual meeting of the American Academy of Neurology.

Exposure to interferon-beta during the first trimester did not increase the risks of miscarriage, congenital anomalies, or birth weight. And although use of natalizumab led to higher odds of spontaneous abortion as compared with interferon-beta or no therapy, the absolute rate still fell within that of the general population. Pregnancies occurring weeks to years after treatment with alemtuzumab also had rates of spontaneous abortion, birth defects, and stillbirth on par with population values.

All three drugs fall in a gray area when it comes to use in pregnancy, with a Food and Drug Administration designation of category C, indicating that animal studies have shown adverse effects on the fetus and adequate, quality human data are lacking, but potential benefits may outweigh potential harms in pregnancy. The studies’ findings are therefore likely to be informative to women of reproductive age, a group disproportionately affected by MS.

“It’s very important to collect as much data as possible about potential exposure risks with disease-modifying therapy in pregnancy,” session comoderator Dr. Jennifer Graves, a neurologist at the Multiple Sclerosis Center at University of California–San Francisco Medical Center and UCSF Benioff Children’s Hospital, San Francisco, said in an interview.

“However, all studies have the limitation of sample size,” she added. “The majority of serious adverse effects – teratogenicity, major birth defects – may be less than 1 in 500 [in frequency]. So this is something that puts all of these studies into context because we just don’t have that many pregnancies that have been exposed to some of these agents.” The method whereby miscarriages are ascertained can also influence findings.

Nonetheless, this research is critical for women and their physicians when it comes to making decisions about treatment, Dr. Graves maintained. “Although pregnancy may be protective for many women with MS, many do need treatment during their pregnancy to prevent severe relapses due to various factors. Collecting this type of information is important.”

Interferon-beta safety

In the first study, investigators led by Dr. Sandra Thiel of Ruhr University Bochum and the Heinrich Heine University Düsseldorf, both in Germany, analyzed data from the German Multiple Sclerosis and Pregnancy Registry.

They studied pregnancies among women who had at least 12 months of postpartum follow-up. Exposure to interferon-beta (brand names Rebif, Avonex, Betaseron, and Extavia) was defined as injection of the drug at any time after the last menstrual period.

In all, 251 pregnancies exposed to interferon-beta were compared with 194 pregnancies not exposed to any disease-modifying drugs. The median duration of exposure in the former group was 32 days, indicating that most women stopped the drug soon after discovering they were pregnant, Dr. Thiel noted.

Study results, reported at the meeting and recently published (Mult Scler. 2016 Feb 26. doi: 10.1177/1352458516634872), showed that the rate of miscarriage was 9.96% in the exposed group and 7.73% in the unexposed group, and the rate of congenital anomalies among live births was 3.08% and 5.52%.

In analyses using propensity score adjustment, there were no significant differences between groups in the odds of live birth, spontaneous abortion, congenital anomalies, preterm birth, cesarean section, or small for gestational age, or in mean infant birth weight.

Of note, the women whose pregnancies were not exposed to any disease-modifying therapy had a higher rate of relapse during pregnancy when compared with counterparts whose pregnancies were exposed to interferon-beta (27.3% vs. 14.3%).

“Taken together with the existing literature, our study provides further reassurance that interferon-beta treatment can be safely continued up until the time when women with MS become pregnant,” Dr. Thiel concluded. The safety profile seen “is consistent with the pharmacologically plausible safety of interferon-beta, as interferon-beta is a huge molecule that cannot pass the placental barrier.”

“Since the vast majority of women stopped the interferon-beta treatment during the first trimester of pregnancy, we cannot draw any conclusions about the safety of interferon-beta later in pregnancy,” she cautioned. “Another limitation is the variability in the gestational week of entry into the cohort, as later than first-trimester inclusion can lead to an underestimation of early events, particularly spontaneous abortions.”

Natalizumab safety

In the second study, Dr. Maria Pia Amato, Department of NEUROFARBA, Section of Neurosciences, University of Florence, Italy, and her colleagues with the Italian MS Study Group assessed pregnancy outcomes after exposure to natalizumab (Tysabri). This antibody targets alpha-4 integrins, which play a role in a variety of pregnancy processes and in fetal hematopoiesis and cardiac development, she noted.

They identified women for the study using two sources: the prospective Italian Pregnancy Dataset of consecutive female patients with MS referred to 25 centers and a cohort of women from an Italian interferon-beta study.

In all, they compared 65 pregnancies exposed to natalizumab (any treatment from 8 weeks before the start of the last menstrual period onward), 88 exposed to interferon-beta as a control, and 339 not exposed to either. The mean duration of natalizumab exposure was 1.16 weeks, and the mean duration of interferon-beta exposure was 4.6 weeks.

Results showed that the rate of spontaneous abortion was higher for natalizumab-exposed pregnancies, at 18.5%, than for interferon-beta–exposed pregnancies, at 8%, and for nonexposed pregnancies, at 6.5% (P = .006). But the timing of these abortions was similar, at about 8 weeks of gestation.

In adjusted analyses, natalizumab exposure was still associated with an elevated risk of spontaneous abortion when compared with interferon-beta or no exposure (odds ratio, 3.9). However, the 18.5% rate seen with the antibody fell within the range for the Italian general population of 4.8% to 21.1%.

Infants in the natalizumab group had the lowest birth weight and length, while infants in the interferon-beta group had the youngest gestational age. The groups did not differ significantly with respect to the incidence of birth defects; however, with a single defect seen in each, the study was underpowered to assess differences in this outcome.

Data additionally showed that discontinuation of natalizumab in advance of pregnancy led to an uptick in relapses, with 30% of women having a relapse, according to Dr. Amato. “This increase started during the first trimester of pregnancy and culminated in the second trimester of pregnancy. All the women were retreated soon after delivery with natalizumab, and disease activity returned to the pre-pregnancy period level with resumption of the drug.”

“Patients and clinicians should discuss together and balance the potential risks to the fetus with natalizumab exposure with the potential risks to the mother of disease reactivation during pregnancy,” she recommended, cautioning that the findings were based on first-trimester exposure of short duration. “Decisions should be made case by case on the basis of the disease activity in a specific patient and the availability of alternative treatment, and whether to use a conservative approach, stopping the drug and respecting the washout period, or in a few cases, an active approach, continuing the drug till conception or even discuss continuing the drug during pregnancy.”

Alemtuzumab safety

In the third study, investigators led by Dr. Jiwon Oh of the division of neurology at the University of Toronto analyzed outcomes of pregnancies among women who had been treated with alemtuzumab (Lemtrada), an antibody that targets CD52.

Treatment with alemtuzumab leads to depletion of lymphocytes followed by reconstitution of the immune system with a less inflammatory profile. “This is thought to contribute to the durable efficacy in the absence of continuous treatment with alemtuzumab,” she explained. “This durable efficacy and the fact that you may not need to redose is relevant when you are thinking about pregnancy in patients with MS, just because this is a drug that is given in two different cycles and may not need to be readministered.”

Although the antibody becomes undetectable in serum about 30 days after administration, it is unclear whether the ongoing immune reconstitution has any impact on subsequent pregnancy, Dr. Oh said.

The investigators pooled data from the phase II CAMMS223 trial and the phase III CARE-MS I and CARE-MS II trials of alemtuzumab and their extension phases. Women enrolled in the trials were required to use effective contraception during treatment and for the next 6 months.

Dr. Oh reported interim results based on 200 pregnancies among 137 women. Most pregnancies occurred at least 4 months after the last dose of alemtuzumab; only four occurred within 1 month and another four occurred 1 to 3 months after the last dose.

Among the 181 completed pregnancies with known outcomes, 67.4% resulted in live births. Another 21.5% ended in spontaneous abortion. “Although this is on the higher end of normal, it is still in keeping with what is seen in the general population,” Dr. Oh noted.

The rate of stillbirth was 0.6%, also at the upper end of the range seen for the general population. Finally, 10.5% of the pregnancies ended in elective abortion.

There were no congenital anomalies or birth defects among the live-born infants. One was seen in an electively terminated pregnancy (26 months after the last dose), and another was seen in a stillbirth (4 years after the last dose).

“Two out of 200 is 1%, and this is actually lower than what is normally seen in the general population, approximately 3% to 7%,” Dr. Oh commented.

“To date, there is no indication of an increased risk for congenital anomalies or birth defects in infants,” she summarized. “There has also been no indication of increased rates of spontaneous abortion in women who become pregnant, but obviously, these data are limited because we don’t necessarily have a control group.”

“Based on the pharmacokinetics of alemtuzumab and labeling guidelines, women of childbearing potential should continue to use contraception for 4 months after receiving a course of alemtuzumab,” Dr. Oh concluded. “There is an international Alemtuzumab Pregnancy Exposure Registry that is open and enrolling patients who become pregnant between the first dose of alemtuzumab and 4 months after the last infusion, and hopefully this will give us more information to confirm some of the observations that we see here.”

Dr. Thiel disclosed that she had no relevant conflicts of interest; the German Multiple Sclerosis and Pregnancy registry was partly supported by Bayer Healthcare, Biogen Idec Germany, Merck Serono, Novartis Pharma, Teva Pharma, and Sanofi-Aventis/Genzyme Pharmaceuticals. Dr. Amato disclosed that she has received research grants and honoraria as a speaker from and is a member of advisory boards for Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, Teva, Almirall, and Roche; the study did not receive any financial support. Dr. Oh disclosed that she serves on the scientific advisory boards or is a speaker for Biogen Idec, EMD Serono, Genzyme, Novartis, Roche, and Teva; the study was supported by Genzyme and Bayer Healthcare.

NEW ORLEANS—In an uncontrolled, prospective study, repeated intrathecal administration of autologous mesenchymal bone marrow–derived stromal stem cells to treat multiple sclerosis was safe and induced accelerated beneficial effects in some patients.

Of 28 patients with either secondary progressive or relapsing-progressive multiple sclerosis who were experiencing severe clinical deterioration and failure to respond to first- and second-line immunomodulatory treatments, 25 experienced either stable or improved Expanded Disability Status Scale (EDSS) scores following autologous mesenchymal stem cell (MSC) injections. The mean score decreased from 6.76 at study entry to 6.57 at a mean follow-up of 3.6 years, Panayiota Petrou, MD, of Hadassah University Hospital in Jerusalem, and her colleagues reported at the ACTRIMS 2016 Forum.

In addition, 17 patients experienced improvements in at least one functional system of the EDSS, including 14 who experienced improved motor function, five who experienced improved speech or bulbar functions, four who experienced improved urinary function, and six who experienced improved cerebellar function. Eight patients remained stable during the entire follow-up period.

In a prior pilot trial, intrathecal administration of MSCs was shown to be safe and provided “some indications of potentially clinically meaningful beneficial effects on the progression of the disease,” said the investigators.

The current study provides further support for those findings. It included patients who experienced severe clinical deterioration of at least 0.5 points on the EDSS during the year prior to study enrollment, or who had at least one major relapse without sufficient recovery following steroid treatment. Study subjects had a mean age of 56 and mean disease duration of 15.4 years. They received at least two courses and up to 10 injections with 1 million cells/kg; most patients received two injections (eight patients) or three injections (nine patients), and the participants were followed for up to six years. No serious side effects were observed during long-term follow-up. Eight patients experienced headaches or fever in the hours and days after injection; two patients experienced symptoms of encephalopathy that resolved within a few hours. One patient experienced back pain, and one patient had neck rigidity. No long-term side effects were reported.

Immunologic follow-up showed a transient up-regulation of regulatory T cells and down-regulation of the proliferative ability of lymphocytes and of several immune activation surface markers for up to three months.

—Sharon Worcester

NEW ORLEANS—In an uncontrolled, prospective study, repeated intrathecal administration of autologous mesenchymal bone marrow–derived stromal stem cells to treat multiple sclerosis was safe and induced accelerated beneficial effects in some patients.

Of 28 patients with either secondary progressive or relapsing-progressive multiple sclerosis who were experiencing severe clinical deterioration and failure to respond to first- and second-line immunomodulatory treatments, 25 experienced either stable or improved Expanded Disability Status Scale (EDSS) scores following autologous mesenchymal stem cell (MSC) injections. The mean score decreased from 6.76 at study entry to 6.57 at a mean follow-up of 3.6 years, Panayiota Petrou, MD, of Hadassah University Hospital in Jerusalem, and her colleagues reported at the ACTRIMS 2016 Forum.

In addition, 17 patients experienced improvements in at least one functional system of the EDSS, including 14 who experienced improved motor function, five who experienced improved speech or bulbar functions, four who experienced improved urinary function, and six who experienced improved cerebellar function. Eight patients remained stable during the entire follow-up period.

In a prior pilot trial, intrathecal administration of MSCs was shown to be safe and provided “some indications of potentially clinically meaningful beneficial effects on the progression of the disease,” said the investigators.

The current study provides further support for those findings. It included patients who experienced severe clinical deterioration of at least 0.5 points on the EDSS during the year prior to study enrollment, or who had at least one major relapse without sufficient recovery following steroid treatment. Study subjects had a mean age of 56 and mean disease duration of 15.4 years. They received at least two courses and up to 10 injections with 1 million cells/kg; most patients received two injections (eight patients) or three injections (nine patients), and the participants were followed for up to six years. No serious side effects were observed during long-term follow-up. Eight patients experienced headaches or fever in the hours and days after injection; two patients experienced symptoms of encephalopathy that resolved within a few hours. One patient experienced back pain, and one patient had neck rigidity. No long-term side effects were reported.

Immunologic follow-up showed a transient up-regulation of regulatory T cells and down-regulation of the proliferative ability of lymphocytes and of several immune activation surface markers for up to three months.

—Sharon Worcester

NEW ORLEANS—In an uncontrolled, prospective study, repeated intrathecal administration of autologous mesenchymal bone marrow–derived stromal stem cells to treat multiple sclerosis was safe and induced accelerated beneficial effects in some patients.

Of 28 patients with either secondary progressive or relapsing-progressive multiple sclerosis who were experiencing severe clinical deterioration and failure to respond to first- and second-line immunomodulatory treatments, 25 experienced either stable or improved Expanded Disability Status Scale (EDSS) scores following autologous mesenchymal stem cell (MSC) injections. The mean score decreased from 6.76 at study entry to 6.57 at a mean follow-up of 3.6 years, Panayiota Petrou, MD, of Hadassah University Hospital in Jerusalem, and her colleagues reported at the ACTRIMS 2016 Forum.

In addition, 17 patients experienced improvements in at least one functional system of the EDSS, including 14 who experienced improved motor function, five who experienced improved speech or bulbar functions, four who experienced improved urinary function, and six who experienced improved cerebellar function. Eight patients remained stable during the entire follow-up period.

In a prior pilot trial, intrathecal administration of MSCs was shown to be safe and provided “some indications of potentially clinically meaningful beneficial effects on the progression of the disease,” said the investigators.

The current study provides further support for those findings. It included patients who experienced severe clinical deterioration of at least 0.5 points on the EDSS during the year prior to study enrollment, or who had at least one major relapse without sufficient recovery following steroid treatment. Study subjects had a mean age of 56 and mean disease duration of 15.4 years. They received at least two courses and up to 10 injections with 1 million cells/kg; most patients received two injections (eight patients) or three injections (nine patients), and the participants were followed for up to six years. No serious side effects were observed during long-term follow-up. Eight patients experienced headaches or fever in the hours and days after injection; two patients experienced symptoms of encephalopathy that resolved within a few hours. One patient experienced back pain, and one patient had neck rigidity. No long-term side effects were reported.

Immunologic follow-up showed a transient up-regulation of regulatory T cells and down-regulation of the proliferative ability of lymphocytes and of several immune activation surface markers for up to three months.

—Sharon Worcester

VANCOUVER – Multiple sclerosis patients discontinued treatment and relapsed earlier with dimethyl fumarate (Tecfidera) than with fingolimod (Gilenya), and had more gadolinium-enhancing lesions at 12 months, in a propensity score matching analysis involving 775 patients at the Cleveland Clinic.

“Based on these data, I now [favor] Gilenya over Tecfidera; Gilenya works a little bit better,” lead investigator and staff neurologist Carrie Hersh said at the annual meeting of the American Academy of Neurology.

The two drugs performed about equally in clinical trials, but Dr. Hersh and her colleagues said fingolimod seems to have the edge in clinical practice; they wanted to see if that hunch held up to scrutiny.

In the single-center cohort study, about 30% of the 458 dimethyl fumarate patients discontinued the drug after an average of 4 months, and about 14% relapsed within a year of starting it. About a quarter of the 317 fingolimod patients discontinued at an average of 6.5 months, and 11% relapsed. About 9% of dimethyl fumarate patients, but 6% of fingolimod patients, had new gadolinium-enhancing (GdE) brain lesions at 12 months.

A propensity score analysis was performed to control for confounders; patients were matched one to one for baseline demographics and clinical and MRI characteristics. Dimethyl fumarate patients were almost three times more likely than fingolimod patients to have new GdE lesions after a year (odds ratio, 2.90; 95% confidence interval, 1.24-6.57). They also had an earlier time to discontinuation (OR, 1.35; 95% CI, 1.05-1.74) and clinical relapse (OR, 1.64; 95% CI, 1.10-2.46). The study included patients with secondary progressive disease. Results were the same when the analysis was limited to relapsing-remitting multiple sclerosis.

The investigators concluded that “dimethyl fumarate and fingolimod have comparable annualized relapse rates, overall brain MRI activity, and discontinuation at 12 months.” However, “dimethyl fumarate may have greater GdE lesions and side effects early after treatment initiation, leading to early discontinuation and relapses.

“This makes sense from what we are seeing in the clinic. We know Tecfidera patients have tolerability issues,” especially with gastrointestinal and flushing events, “so they discontinue earlier or might not be as adherent, and so they relapse earlier. The new enhancing lesions might be a difference in efficacy,” Dr. Hersh said.

Patients treated with fingolimod were more likely to be white (91% vs. 83%), have a longer disease duration (16 vs. 14 years), have a higher proportion of relapsing-remitting disease (82% vs. 74%), and have more severe baseline brain lesion burden (15% vs. 8%). The subjects had tried interferon, glatiramer acetate (Copaxone), natalizumab (Tysabri), or other options before being switched to the study medications because of disease activity or intolerability. Patients were in their 40s, on average, and about 70% were women.

Data are now being collected for a 2-year analysis.

There was no industry funding for the work, and Dr. Hersh had no disclosures. Other investigators reported ties to both Novartis, the maker of Gilenya, and Biogen, the maker of Tecfidera.

aotto@frontlinemedcom.com

VANCOUVER – Multiple sclerosis patients discontinued treatment and relapsed earlier with dimethyl fumarate (Tecfidera) than with fingolimod (Gilenya), and had more gadolinium-enhancing lesions at 12 months, in a propensity score matching analysis involving 775 patients at the Cleveland Clinic.

“Based on these data, I now [favor] Gilenya over Tecfidera; Gilenya works a little bit better,” lead investigator and staff neurologist Carrie Hersh said at the annual meeting of the American Academy of Neurology.

The two drugs performed about equally in clinical trials, but Dr. Hersh and her colleagues said fingolimod seems to have the edge in clinical practice; they wanted to see if that hunch held up to scrutiny.

In the single-center cohort study, about 30% of the 458 dimethyl fumarate patients discontinued the drug after an average of 4 months, and about 14% relapsed within a year of starting it. About a quarter of the 317 fingolimod patients discontinued at an average of 6.5 months, and 11% relapsed. About 9% of dimethyl fumarate patients, but 6% of fingolimod patients, had new gadolinium-enhancing (GdE) brain lesions at 12 months.

A propensity score analysis was performed to control for confounders; patients were matched one to one for baseline demographics and clinical and MRI characteristics. Dimethyl fumarate patients were almost three times more likely than fingolimod patients to have new GdE lesions after a year (odds ratio, 2.90; 95% confidence interval, 1.24-6.57). They also had an earlier time to discontinuation (OR, 1.35; 95% CI, 1.05-1.74) and clinical relapse (OR, 1.64; 95% CI, 1.10-2.46). The study included patients with secondary progressive disease. Results were the same when the analysis was limited to relapsing-remitting multiple sclerosis.

The investigators concluded that “dimethyl fumarate and fingolimod have comparable annualized relapse rates, overall brain MRI activity, and discontinuation at 12 months.” However, “dimethyl fumarate may have greater GdE lesions and side effects early after treatment initiation, leading to early discontinuation and relapses.

“This makes sense from what we are seeing in the clinic. We know Tecfidera patients have tolerability issues,” especially with gastrointestinal and flushing events, “so they discontinue earlier or might not be as adherent, and so they relapse earlier. The new enhancing lesions might be a difference in efficacy,” Dr. Hersh said.

Patients treated with fingolimod were more likely to be white (91% vs. 83%), have a longer disease duration (16 vs. 14 years), have a higher proportion of relapsing-remitting disease (82% vs. 74%), and have more severe baseline brain lesion burden (15% vs. 8%). The subjects had tried interferon, glatiramer acetate (Copaxone), natalizumab (Tysabri), or other options before being switched to the study medications because of disease activity or intolerability. Patients were in their 40s, on average, and about 70% were women.

Data are now being collected for a 2-year analysis.

There was no industry funding for the work, and Dr. Hersh had no disclosures. Other investigators reported ties to both Novartis, the maker of Gilenya, and Biogen, the maker of Tecfidera.

aotto@frontlinemedcom.com

VANCOUVER – Multiple sclerosis patients discontinued treatment and relapsed earlier with dimethyl fumarate (Tecfidera) than with fingolimod (Gilenya), and had more gadolinium-enhancing lesions at 12 months, in a propensity score matching analysis involving 775 patients at the Cleveland Clinic.

“Based on these data, I now [favor] Gilenya over Tecfidera; Gilenya works a little bit better,” lead investigator and staff neurologist Carrie Hersh said at the annual meeting of the American Academy of Neurology.

The two drugs performed about equally in clinical trials, but Dr. Hersh and her colleagues said fingolimod seems to have the edge in clinical practice; they wanted to see if that hunch held up to scrutiny.

In the single-center cohort study, about 30% of the 458 dimethyl fumarate patients discontinued the drug after an average of 4 months, and about 14% relapsed within a year of starting it. About a quarter of the 317 fingolimod patients discontinued at an average of 6.5 months, and 11% relapsed. About 9% of dimethyl fumarate patients, but 6% of fingolimod patients, had new gadolinium-enhancing (GdE) brain lesions at 12 months.

A propensity score analysis was performed to control for confounders; patients were matched one to one for baseline demographics and clinical and MRI characteristics. Dimethyl fumarate patients were almost three times more likely than fingolimod patients to have new GdE lesions after a year (odds ratio, 2.90; 95% confidence interval, 1.24-6.57). They also had an earlier time to discontinuation (OR, 1.35; 95% CI, 1.05-1.74) and clinical relapse (OR, 1.64; 95% CI, 1.10-2.46). The study included patients with secondary progressive disease. Results were the same when the analysis was limited to relapsing-remitting multiple sclerosis.

The investigators concluded that “dimethyl fumarate and fingolimod have comparable annualized relapse rates, overall brain MRI activity, and discontinuation at 12 months.” However, “dimethyl fumarate may have greater GdE lesions and side effects early after treatment initiation, leading to early discontinuation and relapses.

“This makes sense from what we are seeing in the clinic. We know Tecfidera patients have tolerability issues,” especially with gastrointestinal and flushing events, “so they discontinue earlier or might not be as adherent, and so they relapse earlier. The new enhancing lesions might be a difference in efficacy,” Dr. Hersh said.

Patients treated with fingolimod were more likely to be white (91% vs. 83%), have a longer disease duration (16 vs. 14 years), have a higher proportion of relapsing-remitting disease (82% vs. 74%), and have more severe baseline brain lesion burden (15% vs. 8%). The subjects had tried interferon, glatiramer acetate (Copaxone), natalizumab (Tysabri), or other options before being switched to the study medications because of disease activity or intolerability. Patients were in their 40s, on average, and about 70% were women.

Data are now being collected for a 2-year analysis.

There was no industry funding for the work, and Dr. Hersh had no disclosures. Other investigators reported ties to both Novartis, the maker of Gilenya, and Biogen, the maker of Tecfidera.

aotto@frontlinemedcom.com

VANCOUVER—Among people with multiple sclerosis (MS) and chronic demyelinating optic neuropathy, clemastine fumarate reduces visual evoked potential latency delay, a putative biomarker for remyelination, according to a phase II study presented at the 68th Annual Meeting of the American Academy of Neurology.

"This is the first randomized controlled trial documenting efficacy for a candidate remyelinating agent in MS," said Ari Green, MD, Assistant Clinical Director of the Multiple Sclerosis Center at the University of California San Francisco (UCSF), and colleagues.

Ari Green, MD

Investigators at UCSF identified clemastine fumarate, an antihistamine that is available over the counter, as a potential remyelinating agent using an in vitro micropillar screen. In an animal model, the agent led to robust remyelination and appeared to protect axons, said Dr. Green.

To assess the efficacy of clemastine fumarate for remyelination in patients with MS and chronic optic neuropathy, Dr. Green and colleagues conducted a double-blind, randomized, placebo-controlled, crossover study.

They enrolled 50 participants who had a delay in transmission time greater than 118 ms in at least one eye. Patients had an average age of 40, Expanded Disability Status Scale score of 2.1, and disease duration of 5.1 years. The study period was 150 days.

Patients were grouped into two treatment arms. For the first treatment period, 25 patients received oral clemastine fumarate and 25 patients received placebo twice daily. The primary efficacy end point was change in latency delay on visual evoked potential.

Visual evoked potential latency delay was reduced by 1.9 ms per eye for the period on treatment. A strong trend for improvement of the secondary end point of low contrast visual acuity also was observed. Clemastine treatment was associated with mild worsening of fatigue on the Multidimensional Assessment of Fatigue, however.

Among patients who first received clemastine, the treatment effect was sustained "even into the second epoch, suggesting that we were in fact having a remyelinating effect, and not just a transient effect on ion channels," Dr. Green said.

Larger studies are needed before doctors can recommend clemastine fumarate for people with MS, Dr. Green said. New medications are in development, and researchers aim to improve the targeting and reduce the side effects from these drugs.

"While the improvement in vision appears modest, this study is promising because it is the first time a drug has been shown to possibly reverse the damage done by MS," said Dr. Green. "Findings are preliminary, but this study provides a framework for future MS repair studies and will hopefully herald discoveries that will enhance the brain's innate capacity for repair."

—Jake Remaly

VANCOUVER—Among people with multiple sclerosis (MS) and chronic demyelinating optic neuropathy, clemastine fumarate reduces visual evoked potential latency delay, a putative biomarker for remyelination, according to a phase II study presented at the 68th Annual Meeting of the American Academy of Neurology.

"This is the first randomized controlled trial documenting efficacy for a candidate remyelinating agent in MS," said Ari Green, MD, Assistant Clinical Director of the Multiple Sclerosis Center at the University of California San Francisco (UCSF), and colleagues.

Ari Green, MD

Investigators at UCSF identified clemastine fumarate, an antihistamine that is available over the counter, as a potential remyelinating agent using an in vitro micropillar screen. In an animal model, the agent led to robust remyelination and appeared to protect axons, said Dr. Green.

To assess the efficacy of clemastine fumarate for remyelination in patients with MS and chronic optic neuropathy, Dr. Green and colleagues conducted a double-blind, randomized, placebo-controlled, crossover study.

They enrolled 50 participants who had a delay in transmission time greater than 118 ms in at least one eye. Patients had an average age of 40, Expanded Disability Status Scale score of 2.1, and disease duration of 5.1 years. The study period was 150 days.

Patients were grouped into two treatment arms. For the first treatment period, 25 patients received oral clemastine fumarate and 25 patients received placebo twice daily. The primary efficacy end point was change in latency delay on visual evoked potential.

Visual evoked potential latency delay was reduced by 1.9 ms per eye for the period on treatment. A strong trend for improvement of the secondary end point of low contrast visual acuity also was observed. Clemastine treatment was associated with mild worsening of fatigue on the Multidimensional Assessment of Fatigue, however.

Among patients who first received clemastine, the treatment effect was sustained "even into the second epoch, suggesting that we were in fact having a remyelinating effect, and not just a transient effect on ion channels," Dr. Green said.

Larger studies are needed before doctors can recommend clemastine fumarate for people with MS, Dr. Green said. New medications are in development, and researchers aim to improve the targeting and reduce the side effects from these drugs.

"While the improvement in vision appears modest, this study is promising because it is the first time a drug has been shown to possibly reverse the damage done by MS," said Dr. Green. "Findings are preliminary, but this study provides a framework for future MS repair studies and will hopefully herald discoveries that will enhance the brain's innate capacity for repair."

—Jake Remaly

VANCOUVER—Among people with multiple sclerosis (MS) and chronic demyelinating optic neuropathy, clemastine fumarate reduces visual evoked potential latency delay, a putative biomarker for remyelination, according to a phase II study presented at the 68th Annual Meeting of the American Academy of Neurology.

"This is the first randomized controlled trial documenting efficacy for a candidate remyelinating agent in MS," said Ari Green, MD, Assistant Clinical Director of the Multiple Sclerosis Center at the University of California San Francisco (UCSF), and colleagues.

Ari Green, MD

Investigators at UCSF identified clemastine fumarate, an antihistamine that is available over the counter, as a potential remyelinating agent using an in vitro micropillar screen. In an animal model, the agent led to robust remyelination and appeared to protect axons, said Dr. Green.

To assess the efficacy of clemastine fumarate for remyelination in patients with MS and chronic optic neuropathy, Dr. Green and colleagues conducted a double-blind, randomized, placebo-controlled, crossover study.

They enrolled 50 participants who had a delay in transmission time greater than 118 ms in at least one eye. Patients had an average age of 40, Expanded Disability Status Scale score of 2.1, and disease duration of 5.1 years. The study period was 150 days.

Patients were grouped into two treatment arms. For the first treatment period, 25 patients received oral clemastine fumarate and 25 patients received placebo twice daily. The primary efficacy end point was change in latency delay on visual evoked potential.

Visual evoked potential latency delay was reduced by 1.9 ms per eye for the period on treatment. A strong trend for improvement of the secondary end point of low contrast visual acuity also was observed. Clemastine treatment was associated with mild worsening of fatigue on the Multidimensional Assessment of Fatigue, however.

Among patients who first received clemastine, the treatment effect was sustained "even into the second epoch, suggesting that we were in fact having a remyelinating effect, and not just a transient effect on ion channels," Dr. Green said.

Larger studies are needed before doctors can recommend clemastine fumarate for people with MS, Dr. Green said. New medications are in development, and researchers aim to improve the targeting and reduce the side effects from these drugs.

"While the improvement in vision appears modest, this study is promising because it is the first time a drug has been shown to possibly reverse the damage done by MS," said Dr. Green. "Findings are preliminary, but this study provides a framework for future MS repair studies and will hopefully herald discoveries that will enhance the brain's innate capacity for repair."

—Jake Remaly

VANCOUVER – Certain patient and disease characteristics may help guide decisions about starting and stopping therapy in progressive multiple sclerosis, according to a pair of longitudinal cohort studies reported at the annual meeting of the American Academy of Neurology.

In a cohort of patients transitioning from relapsing-remitting to progressive multiple sclerosis (MS), the age at onset of progression predicted the likelihood of subsequent relapses. The absolute lifetime risk ranged from 18% for patients younger than 35 years at the time to just 5% for those aged 55 years or older at the time.

And in a cohort of patients with secondary progressive MS, the annual rate of clinical relapse fell in the third year after immunomodulator discontinuation. Overall, 35% had a clinical relapse or radiologic disease activity. Patients had a lower risk of this outcome if they had greater disability at the time of discontinuation or if they had not had any radiologic disease activity in the antecedent years.

“These studies address a very important question, because not many people talk about stopping drugs,” commented session comoderator Helen Tremlett, Ph.D., of the division of neurology at the University of British Columbia, Vancouver, and the Canada Research Chair in Neuroepidemiology and Multiple Sclerosis. “I would like to see some of these findings validated in other cohorts. But I did like the questions they are asking.”

Age, risk of postprogression relapse

The first study focused on ongoing relapses in patients transitioning to progressive MS. “We have recently shown that these relapses indeed matter. People who continue to relapse after progressive MS onset develop a need for a cane 2 years earlier than those who don’t” continue to have relapses, explained senior author Dr. Orhun H. Kantarci of the department of neurology at the Mayo Clinic in Rochester, Minn. Therefore, continuation or initiation of disease-modifying drugs (DMDs) during this period of overlap may be beneficial.

Courtesy Mayo Clinic

He and his colleagues followed 946 patients with MS from a clinic- and population-based cohort, assessing the age at various disease landmarks.

Results showed the mean age at first relapse was 33 years, the mean age at the onset of progressive MS was 45 years, and the mean age at last relapse (whether it occurred before or after the onset of progressive disease) was 43 years.

The 95% overlap age range for age at first relapse and age at onset of progressive MS was 27-46 years, Dr. Kantarci reported. Therefore, DMDs would be expected to have a some impact during those years.

Further analyses showed that if the age of progressive MS onset was before 35 years, 35-44 years, 45-54 years, and 55 years or older, the absolute lifetime risk of relapse after progressive MS onset was 18%, 17%, 13%, and 5%, respectively. The corresponding last predicted relapse for these groups was before age 50, age 60, age 70, and age 70.

Taken together, the data suggest that in patients transitioning to progressive MS, initiation or continuation of a DMD is most likely to be beneficial if the patient is younger than 35, with some benefit, albeit less, up to the age of 54, according to Dr. Kantarci.

“But above 55, if a person has never been on a DMD, it is unlikely to be recommended, because I don’t expect it to do anything from the data we have,” he said. Furthermore, “DMD stopping can be offered to these patients. If a person is on a DMD and they are asking, ‘Can I stop it? I have been stable,’ and they are above age 55, it can be considered.”

The investigators are performing additional analyses of the data to assess the impact of DMDs on disease course, including the influence of initial and maintenance treatment choices, and factors that prompt physicians to switch treatments.

“What we haven’t done and will not be possible with this data ... the most interesting question is the impact of subclinical MRI disease, which is a different question,” Dr. Kantarci concluded. “And ultimately, we will have to have an actual stopping experiment and [assess] outcomes, which is an ongoing major planned effort.”

Outcomes after stopping immunomodulators

The second study assessed clinical and radiologic outcomes after discontinuation of immunomodulatory therapy in patients with secondary progressive MS.

“We have more and more patients [with secondary progressive disease] treated for several years, yet the natural history of the disease is less and less relapse, and progression of disability,” commented first author Dr. Julien Bonenfant, a neurologist at the Rennes University Hospital in France. Thus, the benefit of continuing treatment is unclear, especially given its cost and side effects.

He and his colleagues studied 106 consecutive patients with secondary progressive MS who had been on immunomodulators for at least 6 months, were taken off the immunomodulators, and were followed for a mean of 5 years.

Results showed that 16% of the patients had a clinical relapse after discontinuation, nearly all within the first 3 years. The annualized rate of clinical relapse actually fell from 0.13 in the 3 years before discontinuation to 0.07 in the 3 years afterward.

Overall, 35% of patients had either a clinical relapse and/or new contrast enhancement on MRI. Again, most of these events occurred within the first 3 years of discontinuation.

Patients had a lower risk of this outcome after treatment discontinuation if they had an Expanded Disability Status Scale (EDSS) score of 6 or greater at the time of discontinuation (hazard ratio, 0.4) and if they had not had any gadolinium enhancement on MRI in the 3 years before treatment discontinuation (HR, 0.4).

“Disease activity remained low after treatment withdrawal. We found no rebound of relapse rate in our population,” Dr. Bonenfant summarized. “There was no consequence on the slope of disability progression,” nor on the finding of enhancement on MRI alone.

Thirty patients were restarted on immunomodulators, about half of them solely because of MRI findings, he noted. This raises “the controversial question, is it relevant or not to resume treatment in these patients?”

“This study suggests that immunomodulatory treatment withdrawal seems reasonable for patients with advanced secondary progressive MS, especially with an EDSS of 6 or greater and no focal inflammatory disease [clinical or radiologic] at least in the past 3 years,” Dr. Bonenfant maintained. “It shows the importance of MRI monitoring to define the patients who are still in a focal immunoreactive state.”

“The results are far from being definitive, and further prospective studies are needed to provide evidence-based recommendations for clinical practice,” he concluded.

Dr. Kantarci disclosed that he has given scientific presentations at meetings supported by Novartis Pharmaceuticals and has presented as an invited speaker for Biogen but has received no personal compensation from either company. Dr. Bonenfant disclosed that he had no relevant conflicts of interest.

VANCOUVER – Certain patient and disease characteristics may help guide decisions about starting and stopping therapy in progressive multiple sclerosis, according to a pair of longitudinal cohort studies reported at the annual meeting of the American Academy of Neurology.

In a cohort of patients transitioning from relapsing-remitting to progressive multiple sclerosis (MS), the age at onset of progression predicted the likelihood of subsequent relapses. The absolute lifetime risk ranged from 18% for patients younger than 35 years at the time to just 5% for those aged 55 years or older at the time.

And in a cohort of patients with secondary progressive MS, the annual rate of clinical relapse fell in the third year after immunomodulator discontinuation. Overall, 35% had a clinical relapse or radiologic disease activity. Patients had a lower risk of this outcome if they had greater disability at the time of discontinuation or if they had not had any radiologic disease activity in the antecedent years.

“These studies address a very important question, because not many people talk about stopping drugs,” commented session comoderator Helen Tremlett, Ph.D., of the division of neurology at the University of British Columbia, Vancouver, and the Canada Research Chair in Neuroepidemiology and Multiple Sclerosis. “I would like to see some of these findings validated in other cohorts. But I did like the questions they are asking.”

Age, risk of postprogression relapse

The first study focused on ongoing relapses in patients transitioning to progressive MS. “We have recently shown that these relapses indeed matter. People who continue to relapse after progressive MS onset develop a need for a cane 2 years earlier than those who don’t” continue to have relapses, explained senior author Dr. Orhun H. Kantarci of the department of neurology at the Mayo Clinic in Rochester, Minn. Therefore, continuation or initiation of disease-modifying drugs (DMDs) during this period of overlap may be beneficial.

Courtesy Mayo Clinic

He and his colleagues followed 946 patients with MS from a clinic- and population-based cohort, assessing the age at various disease landmarks.

Results showed the mean age at first relapse was 33 years, the mean age at the onset of progressive MS was 45 years, and the mean age at last relapse (whether it occurred before or after the onset of progressive disease) was 43 years.

The 95% overlap age range for age at first relapse and age at onset of progressive MS was 27-46 years, Dr. Kantarci reported. Therefore, DMDs would be expected to have a some impact during those years.

Further analyses showed that if the age of progressive MS onset was before 35 years, 35-44 years, 45-54 years, and 55 years or older, the absolute lifetime risk of relapse after progressive MS onset was 18%, 17%, 13%, and 5%, respectively. The corresponding last predicted relapse for these groups was before age 50, age 60, age 70, and age 70.

Taken together, the data suggest that in patients transitioning to progressive MS, initiation or continuation of a DMD is most likely to be beneficial if the patient is younger than 35, with some benefit, albeit less, up to the age of 54, according to Dr. Kantarci.

“But above 55, if a person has never been on a DMD, it is unlikely to be recommended, because I don’t expect it to do anything from the data we have,” he said. Furthermore, “DMD stopping can be offered to these patients. If a person is on a DMD and they are asking, ‘Can I stop it? I have been stable,’ and they are above age 55, it can be considered.”

The investigators are performing additional analyses of the data to assess the impact of DMDs on disease course, including the influence of initial and maintenance treatment choices, and factors that prompt physicians to switch treatments.

“What we haven’t done and will not be possible with this data ... the most interesting question is the impact of subclinical MRI disease, which is a different question,” Dr. Kantarci concluded. “And ultimately, we will have to have an actual stopping experiment and [assess] outcomes, which is an ongoing major planned effort.”

Outcomes after stopping immunomodulators

The second study assessed clinical and radiologic outcomes after discontinuation of immunomodulatory therapy in patients with secondary progressive MS.

“We have more and more patients [with secondary progressive disease] treated for several years, yet the natural history of the disease is less and less relapse, and progression of disability,” commented first author Dr. Julien Bonenfant, a neurologist at the Rennes University Hospital in France. Thus, the benefit of continuing treatment is unclear, especially given its cost and side effects.

He and his colleagues studied 106 consecutive patients with secondary progressive MS who had been on immunomodulators for at least 6 months, were taken off the immunomodulators, and were followed for a mean of 5 years.

Results showed that 16% of the patients had a clinical relapse after discontinuation, nearly all within the first 3 years. The annualized rate of clinical relapse actually fell from 0.13 in the 3 years before discontinuation to 0.07 in the 3 years afterward.

Overall, 35% of patients had either a clinical relapse and/or new contrast enhancement on MRI. Again, most of these events occurred within the first 3 years of discontinuation.

Patients had a lower risk of this outcome after treatment discontinuation if they had an Expanded Disability Status Scale (EDSS) score of 6 or greater at the time of discontinuation (hazard ratio, 0.4) and if they had not had any gadolinium enhancement on MRI in the 3 years before treatment discontinuation (HR, 0.4).

“Disease activity remained low after treatment withdrawal. We found no rebound of relapse rate in our population,” Dr. Bonenfant summarized. “There was no consequence on the slope of disability progression,” nor on the finding of enhancement on MRI alone.

Thirty patients were restarted on immunomodulators, about half of them solely because of MRI findings, he noted. This raises “the controversial question, is it relevant or not to resume treatment in these patients?”

“This study suggests that immunomodulatory treatment withdrawal seems reasonable for patients with advanced secondary progressive MS, especially with an EDSS of 6 or greater and no focal inflammatory disease [clinical or radiologic] at least in the past 3 years,” Dr. Bonenfant maintained. “It shows the importance of MRI monitoring to define the patients who are still in a focal immunoreactive state.”

“The results are far from being definitive, and further prospective studies are needed to provide evidence-based recommendations for clinical practice,” he concluded.

Dr. Kantarci disclosed that he has given scientific presentations at meetings supported by Novartis Pharmaceuticals and has presented as an invited speaker for Biogen but has received no personal compensation from either company. Dr. Bonenfant disclosed that he had no relevant conflicts of interest.

VANCOUVER – Certain patient and disease characteristics may help guide decisions about starting and stopping therapy in progressive multiple sclerosis, according to a pair of longitudinal cohort studies reported at the annual meeting of the American Academy of Neurology.

In a cohort of patients transitioning from relapsing-remitting to progressive multiple sclerosis (MS), the age at onset of progression predicted the likelihood of subsequent relapses. The absolute lifetime risk ranged from 18% for patients younger than 35 years at the time to just 5% for those aged 55 years or older at the time.

And in a cohort of patients with secondary progressive MS, the annual rate of clinical relapse fell in the third year after immunomodulator discontinuation. Overall, 35% had a clinical relapse or radiologic disease activity. Patients had a lower risk of this outcome if they had greater disability at the time of discontinuation or if they had not had any radiologic disease activity in the antecedent years.

“These studies address a very important question, because not many people talk about stopping drugs,” commented session comoderator Helen Tremlett, Ph.D., of the division of neurology at the University of British Columbia, Vancouver, and the Canada Research Chair in Neuroepidemiology and Multiple Sclerosis. “I would like to see some of these findings validated in other cohorts. But I did like the questions they are asking.”

Age, risk of postprogression relapse

The first study focused on ongoing relapses in patients transitioning to progressive MS. “We have recently shown that these relapses indeed matter. People who continue to relapse after progressive MS onset develop a need for a cane 2 years earlier than those who don’t” continue to have relapses, explained senior author Dr. Orhun H. Kantarci of the department of neurology at the Mayo Clinic in Rochester, Minn. Therefore, continuation or initiation of disease-modifying drugs (DMDs) during this period of overlap may be beneficial.

Courtesy Mayo Clinic

He and his colleagues followed 946 patients with MS from a clinic- and population-based cohort, assessing the age at various disease landmarks.

Results showed the mean age at first relapse was 33 years, the mean age at the onset of progressive MS was 45 years, and the mean age at last relapse (whether it occurred before or after the onset of progressive disease) was 43 years.

The 95% overlap age range for age at first relapse and age at onset of progressive MS was 27-46 years, Dr. Kantarci reported. Therefore, DMDs would be expected to have a some impact during those years.

Further analyses showed that if the age of progressive MS onset was before 35 years, 35-44 years, 45-54 years, and 55 years or older, the absolute lifetime risk of relapse after progressive MS onset was 18%, 17%, 13%, and 5%, respectively. The corresponding last predicted relapse for these groups was before age 50, age 60, age 70, and age 70.

Taken together, the data suggest that in patients transitioning to progressive MS, initiation or continuation of a DMD is most likely to be beneficial if the patient is younger than 35, with some benefit, albeit less, up to the age of 54, according to Dr. Kantarci.

“But above 55, if a person has never been on a DMD, it is unlikely to be recommended, because I don’t expect it to do anything from the data we have,” he said. Furthermore, “DMD stopping can be offered to these patients. If a person is on a DMD and they are asking, ‘Can I stop it? I have been stable,’ and they are above age 55, it can be considered.”

The investigators are performing additional analyses of the data to assess the impact of DMDs on disease course, including the influence of initial and maintenance treatment choices, and factors that prompt physicians to switch treatments.

“What we haven’t done and will not be possible with this data ... the most interesting question is the impact of subclinical MRI disease, which is a different question,” Dr. Kantarci concluded. “And ultimately, we will have to have an actual stopping experiment and [assess] outcomes, which is an ongoing major planned effort.”

Outcomes after stopping immunomodulators

The second study assessed clinical and radiologic outcomes after discontinuation of immunomodulatory therapy in patients with secondary progressive MS.

“We have more and more patients [with secondary progressive disease] treated for several years, yet the natural history of the disease is less and less relapse, and progression of disability,” commented first author Dr. Julien Bonenfant, a neurologist at the Rennes University Hospital in France. Thus, the benefit of continuing treatment is unclear, especially given its cost and side effects.

He and his colleagues studied 106 consecutive patients with secondary progressive MS who had been on immunomodulators for at least 6 months, were taken off the immunomodulators, and were followed for a mean of 5 years.

Results showed that 16% of the patients had a clinical relapse after discontinuation, nearly all within the first 3 years. The annualized rate of clinical relapse actually fell from 0.13 in the 3 years before discontinuation to 0.07 in the 3 years afterward.

Overall, 35% of patients had either a clinical relapse and/or new contrast enhancement on MRI. Again, most of these events occurred within the first 3 years of discontinuation.

Patients had a lower risk of this outcome after treatment discontinuation if they had an Expanded Disability Status Scale (EDSS) score of 6 or greater at the time of discontinuation (hazard ratio, 0.4) and if they had not had any gadolinium enhancement on MRI in the 3 years before treatment discontinuation (HR, 0.4).

“Disease activity remained low after treatment withdrawal. We found no rebound of relapse rate in our population,” Dr. Bonenfant summarized. “There was no consequence on the slope of disability progression,” nor on the finding of enhancement on MRI alone.

Thirty patients were restarted on immunomodulators, about half of them solely because of MRI findings, he noted. This raises “the controversial question, is it relevant or not to resume treatment in these patients?”

“This study suggests that immunomodulatory treatment withdrawal seems reasonable for patients with advanced secondary progressive MS, especially with an EDSS of 6 or greater and no focal inflammatory disease [clinical or radiologic] at least in the past 3 years,” Dr. Bonenfant maintained. “It shows the importance of MRI monitoring to define the patients who are still in a focal immunoreactive state.”

“The results are far from being definitive, and further prospective studies are needed to provide evidence-based recommendations for clinical practice,” he concluded.

Dr. Kantarci disclosed that he has given scientific presentations at meetings supported by Novartis Pharmaceuticals and has presented as an invited speaker for Biogen but has received no personal compensation from either company. Dr. Bonenfant disclosed that he had no relevant conflicts of interest.

For patients with relapsing-remitting multiple sclerosis (RRMS) switching to other therapies due to positive JC virus serology, treatment with rituximab resulted in a lower rate of clinical relapse as compared with fingolimod in a retrospective outcomes study of registry data from three Swedish MS centers, according to a report published online March 31 in Annals of Neurology.

Although natalizumab (Tysabri) is approved for the treatment of highly active RRMS, its long-term use can increase the risk of developing progressive multifocal leukoencephalopathy. Because this is a serious and potentially lethal condition associated with opportunistic brain infection with the JC virus, those patients testing positive for JC virus antibodies may require a switch to an alternative treatment, such as fingolimod (Gilenya), or off-label use of rituximab (Rituxan). The efficacy, safety, and tolerability associated with switching to either of these alternative therapies were compared by Peter Alping of the department of clinical neuroscience, Karolinska Institutet, Stockholm, and his associates (Ann Neurol. 2016 Mar 31. doi: 10.1002/ana.24651).

©solitude72/iStockphoto

Of the 256 patients included in the study, 142 (55%) were switched to fingolimod. The efficacy outcomes comparison showed a statistically significant difference in favor of rituximab, with which 2% of patients had a clinical relapse in the first 1.5 years of treatment after natalizumab cessation as opposed to 18% for fingolimod. This corresponded to an annual relapse rate of 0.02 and 0.16, respectively. Additionally, a review of patients’ contrast-enhancing lesions on MRI scans after at least 3 months of treatment indicated that disease progression was detected less frequently in patients switched to rituximab (1%) as opposed to those switched to fingolimod (16%).

The safety and tolerability data also indicated more favorable results for those patients switched to rituximab. For example, a significantly lower rate of adverse events was noted in the rituximab group (5%) when compared with the fingolimod group (21%). Similarly, a lower rate of treatment discontinuation was observed for those switched to rituximab (2%) when compared with those switched to fingolimod (28%).

The statistically significant differences found in the efficacy, safety, and tolerability data persisted even after adjusting for possible confounding factors including patient age, sex, disability status, time on natalizumab, washout time, follow-up time, and study center. Despite the differences noted in the safety findings, the authors said that both treatments seemed to be safe in general.

In most cases, natalizumab had been given 300 mg IV every 4 weeks. Fingolimod was given orally 0.5 mg once daily. Nearly all patients who received rituximab got a single IV infusion of 500 or 1,000 mg every 6 months, but in some cases the first infusion had been repeated after 2 weeks.

In the absence of formal randomized clinical trial data, the authors said that these findings support the use of rituximab over fingolimod in this particular population of MS patients.

This study was supported by the Swedish Medical Research council and the Stockholm County. First author Peter Alping declared no competing interests; several of his associates reported ties to numerous industry sources.

For patients with relapsing-remitting multiple sclerosis (RRMS) switching to other therapies due to positive JC virus serology, treatment with rituximab resulted in a lower rate of clinical relapse as compared with fingolimod in a retrospective outcomes study of registry data from three Swedish MS centers, according to a report published online March 31 in Annals of Neurology.

Although natalizumab (Tysabri) is approved for the treatment of highly active RRMS, its long-term use can increase the risk of developing progressive multifocal leukoencephalopathy. Because this is a serious and potentially lethal condition associated with opportunistic brain infection with the JC virus, those patients testing positive for JC virus antibodies may require a switch to an alternative treatment, such as fingolimod (Gilenya), or off-label use of rituximab (Rituxan). The efficacy, safety, and tolerability associated with switching to either of these alternative therapies were compared by Peter Alping of the department of clinical neuroscience, Karolinska Institutet, Stockholm, and his associates (Ann Neurol. 2016 Mar 31. doi: 10.1002/ana.24651).

©solitude72/iStockphoto

Of the 256 patients included in the study, 142 (55%) were switched to fingolimod. The efficacy outcomes comparison showed a statistically significant difference in favor of rituximab, with which 2% of patients had a clinical relapse in the first 1.5 years of treatment after natalizumab cessation as opposed to 18% for fingolimod. This corresponded to an annual relapse rate of 0.02 and 0.16, respectively. Additionally, a review of patients’ contrast-enhancing lesions on MRI scans after at least 3 months of treatment indicated that disease progression was detected less frequently in patients switched to rituximab (1%) as opposed to those switched to fingolimod (16%).

The safety and tolerability data also indicated more favorable results for those patients switched to rituximab. For example, a significantly lower rate of adverse events was noted in the rituximab group (5%) when compared with the fingolimod group (21%). Similarly, a lower rate of treatment discontinuation was observed for those switched to rituximab (2%) when compared with those switched to fingolimod (28%).

The statistically significant differences found in the efficacy, safety, and tolerability data persisted even after adjusting for possible confounding factors including patient age, sex, disability status, time on natalizumab, washout time, follow-up time, and study center. Despite the differences noted in the safety findings, the authors said that both treatments seemed to be safe in general.

In most cases, natalizumab had been given 300 mg IV every 4 weeks. Fingolimod was given orally 0.5 mg once daily. Nearly all patients who received rituximab got a single IV infusion of 500 or 1,000 mg every 6 months, but in some cases the first infusion had been repeated after 2 weeks.

In the absence of formal randomized clinical trial data, the authors said that these findings support the use of rituximab over fingolimod in this particular population of MS patients.

This study was supported by the Swedish Medical Research council and the Stockholm County. First author Peter Alping declared no competing interests; several of his associates reported ties to numerous industry sources.

For patients with relapsing-remitting multiple sclerosis (RRMS) switching to other therapies due to positive JC virus serology, treatment with rituximab resulted in a lower rate of clinical relapse as compared with fingolimod in a retrospective outcomes study of registry data from three Swedish MS centers, according to a report published online March 31 in Annals of Neurology.

Although natalizumab (Tysabri) is approved for the treatment of highly active RRMS, its long-term use can increase the risk of developing progressive multifocal leukoencephalopathy. Because this is a serious and potentially lethal condition associated with opportunistic brain infection with the JC virus, those patients testing positive for JC virus antibodies may require a switch to an alternative treatment, such as fingolimod (Gilenya), or off-label use of rituximab (Rituxan). The efficacy, safety, and tolerability associated with switching to either of these alternative therapies were compared by Peter Alping of the department of clinical neuroscience, Karolinska Institutet, Stockholm, and his associates (Ann Neurol. 2016 Mar 31. doi: 10.1002/ana.24651).

©solitude72/iStockphoto

Of the 256 patients included in the study, 142 (55%) were switched to fingolimod. The efficacy outcomes comparison showed a statistically significant difference in favor of rituximab, with which 2% of patients had a clinical relapse in the first 1.5 years of treatment after natalizumab cessation as opposed to 18% for fingolimod. This corresponded to an annual relapse rate of 0.02 and 0.16, respectively. Additionally, a review of patients’ contrast-enhancing lesions on MRI scans after at least 3 months of treatment indicated that disease progression was detected less frequently in patients switched to rituximab (1%) as opposed to those switched to fingolimod (16%).

The safety and tolerability data also indicated more favorable results for those patients switched to rituximab. For example, a significantly lower rate of adverse events was noted in the rituximab group (5%) when compared with the fingolimod group (21%). Similarly, a lower rate of treatment discontinuation was observed for those switched to rituximab (2%) when compared with those switched to fingolimod (28%).

The statistically significant differences found in the efficacy, safety, and tolerability data persisted even after adjusting for possible confounding factors including patient age, sex, disability status, time on natalizumab, washout time, follow-up time, and study center. Despite the differences noted in the safety findings, the authors said that both treatments seemed to be safe in general.

In most cases, natalizumab had been given 300 mg IV every 4 weeks. Fingolimod was given orally 0.5 mg once daily. Nearly all patients who received rituximab got a single IV infusion of 500 or 1,000 mg every 6 months, but in some cases the first infusion had been repeated after 2 weeks.

In the absence of formal randomized clinical trial data, the authors said that these findings support the use of rituximab over fingolimod in this particular population of MS patients.

This study was supported by the Swedish Medical Research council and the Stockholm County. First author Peter Alping declared no competing interests; several of his associates reported ties to numerous industry sources.

NEW ORLEANS—“Ocrelizumab is the first investigational treatment to reach primary and key secondary efficacy end points in a phase III primary progressive MS [PPMS] study,” reported Jerry S. Wolinsky, MD, Bartels Family Professor and Opal C. Rankin Professor in Neurology at the University of Texas Health Science Center at Houston. On behalf of his study collaborators, Dr. Wolinsky presented the results from a subgroup analysis of the ORATORIO study at the ACTRIMS 2016 Forum.

Consistent with other PPMS study populations, ORATORIO study patients included several individuals with T1 gadolinium-enhancing lesions at baseline. “The efficacy of ocrelizumab versus placebo in patients with and without gadolinium–positive lesions at baseline was consistent with what was seen in the overall study population,” Dr. Wolinsky concluded.

Ocrelizumab is a humanized monoclonal antibody that selectively targets and depletes CD20+ B cells. In ORATORIO, a randomized, double-blind, placebo-controlled phase III trial, ocrelizumab significantly reduced disease activity in patients with PPMS. Further, ORATORIO was the first major clinical trial in PPMS to achieve positive results. The main study results were reported in 2015 at the ECTRIMS meeting in Barcelona.

For the study reported at ACTRIMS, Dr. Wolinsky and his reseach colleagues sought to evaluate the efficacy of ocrelizumab in the ORATORIO patient subgroups with and without T1 gadolinium-enhancing lesions at baseline.

A total of 732 patients were randomized 2 to 1 to receive ocrelizumab (600 mg) or placebo as two 300-mg IV infusions 14 days apart every 24 weeks for at least 120 weeks and until a prespecified number of 12-week confirmed disability progression events occurred. Key eligibility criteria included age between 18 and 55, diagnosis of PPMS according to the 2005 revised McDonald criteria, Expanded Disability Status Scale (EDSS) score of 3 to 6.5, and documented history of elevated immunoglobulin index and/or presence of two or more oligoclonal bands in the CSF.

Although not powered for comparisons, prespecified subgroups included age (45 or younger vs older than 45), sex, BMI (less than 25 versus 25 or greater), weight (less than 75 kg vs 75 kg or more), region (US vs the rest of the world), treatment history, symptom duration, and disease activity (EDSS score of 5.5 or less vs more than 5 and presence or absence of T1 gadolinium-enhancing lesions) at baseline.

Efficacy of ocrelizumab on confirmed disability progression at 12 weeks or more and at 24 weeks or more, change in total T2 lesion volume at 120 weeks, and other secondary outcomes were evaluated in the subgroups with presence or absence of T1 gadolinium-enhancing lesions at baseline.

Compared with placebo, ocrelizumab significantly reduced the relative risk of 12-week confirmed disability progression by 24% (hazard ratio, 0.76) and 24-week confirmed disability progression by 25% (hazard ratio, 0.75). T1 gadolinium-enhancing lesions were present at baseline in 27.5% of ocrelizumab-treated patients versus 24.7% of placebo-treated patients. In patients with and without T1 gadolinium-enhancing lesions at baseline, respectively, ocrelizumab reduced the risk of 12-week confirmed disability progression by 35% (hazard ratio, 0.65) and 16% (hazard ratio, 0.84), the risk of 24-week confirmed disability progression by 33% (hazard ratio, 0.67) and 19% (hazard ratio, 0.81), and total T2 lesion volume by –3.8% versus +12.0% with placebo and by –3.1% versus +6.1% with placebo. Because of confidence intervals, not all of these end points analyses reached statistical significance.

“The study was in no way powered to approach this type of subgroup analysis. Rather, the analysis was an attempt to understand the data better,” said Dr. Wolinsky.

—Glenn S. Williams

NEW ORLEANS—“Ocrelizumab is the first investigational treatment to reach primary and key secondary efficacy end points in a phase III primary progressive MS [PPMS] study,” reported Jerry S. Wolinsky, MD, Bartels Family Professor and Opal C. Rankin Professor in Neurology at the University of Texas Health Science Center at Houston. On behalf of his study collaborators, Dr. Wolinsky presented the results from a subgroup analysis of the ORATORIO study at the ACTRIMS 2016 Forum.

Consistent with other PPMS study populations, ORATORIO study patients included several individuals with T1 gadolinium-enhancing lesions at baseline. “The efficacy of ocrelizumab versus placebo in patients with and without gadolinium–positive lesions at baseline was consistent with what was seen in the overall study population,” Dr. Wolinsky concluded.

Ocrelizumab is a humanized monoclonal antibody that selectively targets and depletes CD20+ B cells. In ORATORIO, a randomized, double-blind, placebo-controlled phase III trial, ocrelizumab significantly reduced disease activity in patients with PPMS. Further, ORATORIO was the first major clinical trial in PPMS to achieve positive results. The main study results were reported in 2015 at the ECTRIMS meeting in Barcelona.

For the study reported at ACTRIMS, Dr. Wolinsky and his reseach colleagues sought to evaluate the efficacy of ocrelizumab in the ORATORIO patient subgroups with and without T1 gadolinium-enhancing lesions at baseline.

A total of 732 patients were randomized 2 to 1 to receive ocrelizumab (600 mg) or placebo as two 300-mg IV infusions 14 days apart every 24 weeks for at least 120 weeks and until a prespecified number of 12-week confirmed disability progression events occurred. Key eligibility criteria included age between 18 and 55, diagnosis of PPMS according to the 2005 revised McDonald criteria, Expanded Disability Status Scale (EDSS) score of 3 to 6.5, and documented history of elevated immunoglobulin index and/or presence of two or more oligoclonal bands in the CSF.

Although not powered for comparisons, prespecified subgroups included age (45 or younger vs older than 45), sex, BMI (less than 25 versus 25 or greater), weight (less than 75 kg vs 75 kg or more), region (US vs the rest of the world), treatment history, symptom duration, and disease activity (EDSS score of 5.5 or less vs more than 5 and presence or absence of T1 gadolinium-enhancing lesions) at baseline.

Efficacy of ocrelizumab on confirmed disability progression at 12 weeks or more and at 24 weeks or more, change in total T2 lesion volume at 120 weeks, and other secondary outcomes were evaluated in the subgroups with presence or absence of T1 gadolinium-enhancing lesions at baseline.

Compared with placebo, ocrelizumab significantly reduced the relative risk of 12-week confirmed disability progression by 24% (hazard ratio, 0.76) and 24-week confirmed disability progression by 25% (hazard ratio, 0.75). T1 gadolinium-enhancing lesions were present at baseline in 27.5% of ocrelizumab-treated patients versus 24.7% of placebo-treated patients. In patients with and without T1 gadolinium-enhancing lesions at baseline, respectively, ocrelizumab reduced the risk of 12-week confirmed disability progression by 35% (hazard ratio, 0.65) and 16% (hazard ratio, 0.84), the risk of 24-week confirmed disability progression by 33% (hazard ratio, 0.67) and 19% (hazard ratio, 0.81), and total T2 lesion volume by –3.8% versus +12.0% with placebo and by –3.1% versus +6.1% with placebo. Because of confidence intervals, not all of these end points analyses reached statistical significance.

“The study was in no way powered to approach this type of subgroup analysis. Rather, the analysis was an attempt to understand the data better,” said Dr. Wolinsky.

—Glenn S. Williams

NEW ORLEANS—“Ocrelizumab is the first investigational treatment to reach primary and key secondary efficacy end points in a phase III primary progressive MS [PPMS] study,” reported Jerry S. Wolinsky, MD, Bartels Family Professor and Opal C. Rankin Professor in Neurology at the University of Texas Health Science Center at Houston. On behalf of his study collaborators, Dr. Wolinsky presented the results from a subgroup analysis of the ORATORIO study at the ACTRIMS 2016 Forum.

Consistent with other PPMS study populations, ORATORIO study patients included several individuals with T1 gadolinium-enhancing lesions at baseline. “The efficacy of ocrelizumab versus placebo in patients with and without gadolinium–positive lesions at baseline was consistent with what was seen in the overall study population,” Dr. Wolinsky concluded.

Ocrelizumab is a humanized monoclonal antibody that selectively targets and depletes CD20+ B cells. In ORATORIO, a randomized, double-blind, placebo-controlled phase III trial, ocrelizumab significantly reduced disease activity in patients with PPMS. Further, ORATORIO was the first major clinical trial in PPMS to achieve positive results. The main study results were reported in 2015 at the ECTRIMS meeting in Barcelona.

For the study reported at ACTRIMS, Dr. Wolinsky and his reseach colleagues sought to evaluate the efficacy of ocrelizumab in the ORATORIO patient subgroups with and without T1 gadolinium-enhancing lesions at baseline.

A total of 732 patients were randomized 2 to 1 to receive ocrelizumab (600 mg) or placebo as two 300-mg IV infusions 14 days apart every 24 weeks for at least 120 weeks and until a prespecified number of 12-week confirmed disability progression events occurred. Key eligibility criteria included age between 18 and 55, diagnosis of PPMS according to the 2005 revised McDonald criteria, Expanded Disability Status Scale (EDSS) score of 3 to 6.5, and documented history of elevated immunoglobulin index and/or presence of two or more oligoclonal bands in the CSF.

Although not powered for comparisons, prespecified subgroups included age (45 or younger vs older than 45), sex, BMI (less than 25 versus 25 or greater), weight (less than 75 kg vs 75 kg or more), region (US vs the rest of the world), treatment history, symptom duration, and disease activity (EDSS score of 5.5 or less vs more than 5 and presence or absence of T1 gadolinium-enhancing lesions) at baseline.

Efficacy of ocrelizumab on confirmed disability progression at 12 weeks or more and at 24 weeks or more, change in total T2 lesion volume at 120 weeks, and other secondary outcomes were evaluated in the subgroups with presence or absence of T1 gadolinium-enhancing lesions at baseline.

Compared with placebo, ocrelizumab significantly reduced the relative risk of 12-week confirmed disability progression by 24% (hazard ratio, 0.76) and 24-week confirmed disability progression by 25% (hazard ratio, 0.75). T1 gadolinium-enhancing lesions were present at baseline in 27.5% of ocrelizumab-treated patients versus 24.7% of placebo-treated patients. In patients with and without T1 gadolinium-enhancing lesions at baseline, respectively, ocrelizumab reduced the risk of 12-week confirmed disability progression by 35% (hazard ratio, 0.65) and 16% (hazard ratio, 0.84), the risk of 24-week confirmed disability progression by 33% (hazard ratio, 0.67) and 19% (hazard ratio, 0.81), and total T2 lesion volume by –3.8% versus +12.0% with placebo and by –3.1% versus +6.1% with placebo. Because of confidence intervals, not all of these end points analyses reached statistical significance.

“The study was in no way powered to approach this type of subgroup analysis. Rather, the analysis was an attempt to understand the data better,” said Dr. Wolinsky.

—Glenn S. Williams

High coffee consumption decreases the odds of developing multiple sclerosis (MS), according to two case–control studies published online ahead of print March 3 in the Journal of Neurology, Neurosurgery & Psychiatry. Anna K. Hedström, MD, PhD, a postdoctoral researcher at the Karolinska Institute, Stockholm, and her associates conducted the studies.

The investigators analyzed coffee consumption among 1,620 adults with MS and 2,788 healthy controls in the Swedish Epidemiological Investigation of Multiple Sclerosis (EIMS). They also examined coffee consumption in 1,159 adults with MS and 1,172 healthy controls in the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC).

In EIMS, the adjusted odds ratio (OR) for developing MS was 0.70 among participants who drank more than six cups of coffee (ie, greater than 900 mL) daily at the index year, which was defined as the year of the initial appearance of symptoms indicative of MS. The corresponding ORs for those who reported high coffee consumption at five or 10 years before the study were 0.72 and 0.71, respectively, but these results were not statistically significant.

In KPNC, those who consumed four or more cups of coffee (ie, more than 948 mL) daily were significantly less likely to develop MS than were those who never drank coffee (OR, 0.69). In addition, people who drank four or more cups of coffee daily at least five years prior to the index year had significantly reduced odds of MS (OR, 0.64).

A meta-analysis of the combined results of the two studies indicated a significant 29% reduction in the likelihood of developing MS among the people with the greatest coffee consumption (ie, greater than 900 mL daily in EIMS and greater than 948 mL in KPNC). The investigators adjusted all the analyses for many demographic and environmental risk factors for MS, including age, gender, residential area, ancestry, smoking habits, exposure to passive smoking, sun exposure habits, and BMI at age 20.

No evidence indicated any associations between increased amounts of tea or soda intake and MS.

“Further studies are required to establish if it is in fact caffeine, or if there is another molecule in coffee underlying the findings, to longitudinally assess the association between consumption of coffee and disease activity in MS, and to evaluate the mechanisms by which coffee may be acting, which could thus lead to new therapeutic targets,” the researchers concluded.

—Lori Laubach

High coffee consumption decreases the odds of developing multiple sclerosis (MS), according to two case–control studies published online ahead of print March 3 in the Journal of Neurology, Neurosurgery & Psychiatry. Anna K. Hedström, MD, PhD, a postdoctoral researcher at the Karolinska Institute, Stockholm, and her associates conducted the studies.

The investigators analyzed coffee consumption among 1,620 adults with MS and 2,788 healthy controls in the Swedish Epidemiological Investigation of Multiple Sclerosis (EIMS). They also examined coffee consumption in 1,159 adults with MS and 1,172 healthy controls in the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC).

In EIMS, the adjusted odds ratio (OR) for developing MS was 0.70 among participants who drank more than six cups of coffee (ie, greater than 900 mL) daily at the index year, which was defined as the year of the initial appearance of symptoms indicative of MS. The corresponding ORs for those who reported high coffee consumption at five or 10 years before the study were 0.72 and 0.71, respectively, but these results were not statistically significant.

In KPNC, those who consumed four or more cups of coffee (ie, more than 948 mL) daily were significantly less likely to develop MS than were those who never drank coffee (OR, 0.69). In addition, people who drank four or more cups of coffee daily at least five years prior to the index year had significantly reduced odds of MS (OR, 0.64).

A meta-analysis of the combined results of the two studies indicated a significant 29% reduction in the likelihood of developing MS among the people with the greatest coffee consumption (ie, greater than 900 mL daily in EIMS and greater than 948 mL in KPNC). The investigators adjusted all the analyses for many demographic and environmental risk factors for MS, including age, gender, residential area, ancestry, smoking habits, exposure to passive smoking, sun exposure habits, and BMI at age 20.

No evidence indicated any associations between increased amounts of tea or soda intake and MS.

“Further studies are required to establish if it is in fact caffeine, or if there is another molecule in coffee underlying the findings, to longitudinally assess the association between consumption of coffee and disease activity in MS, and to evaluate the mechanisms by which coffee may be acting, which could thus lead to new therapeutic targets,” the researchers concluded.

—Lori Laubach

High coffee consumption decreases the odds of developing multiple sclerosis (MS), according to two case–control studies published online ahead of print March 3 in the Journal of Neurology, Neurosurgery & Psychiatry. Anna K. Hedström, MD, PhD, a postdoctoral researcher at the Karolinska Institute, Stockholm, and her associates conducted the studies.

The investigators analyzed coffee consumption among 1,620 adults with MS and 2,788 healthy controls in the Swedish Epidemiological Investigation of Multiple Sclerosis (EIMS). They also examined coffee consumption in 1,159 adults with MS and 1,172 healthy controls in the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC).

In EIMS, the adjusted odds ratio (OR) for developing MS was 0.70 among participants who drank more than six cups of coffee (ie, greater than 900 mL) daily at the index year, which was defined as the year of the initial appearance of symptoms indicative of MS. The corresponding ORs for those who reported high coffee consumption at five or 10 years before the study were 0.72 and 0.71, respectively, but these results were not statistically significant.

In KPNC, those who consumed four or more cups of coffee (ie, more than 948 mL) daily were significantly less likely to develop MS than were those who never drank coffee (OR, 0.69). In addition, people who drank four or more cups of coffee daily at least five years prior to the index year had significantly reduced odds of MS (OR, 0.64).

A meta-analysis of the combined results of the two studies indicated a significant 29% reduction in the likelihood of developing MS among the people with the greatest coffee consumption (ie, greater than 900 mL daily in EIMS and greater than 948 mL in KPNC). The investigators adjusted all the analyses for many demographic and environmental risk factors for MS, including age, gender, residential area, ancestry, smoking habits, exposure to passive smoking, sun exposure habits, and BMI at age 20.

No evidence indicated any associations between increased amounts of tea or soda intake and MS.

“Further studies are required to establish if it is in fact caffeine, or if there is another molecule in coffee underlying the findings, to longitudinally assess the association between consumption of coffee and disease activity in MS, and to evaluate the mechanisms by which coffee may be acting, which could thus lead to new therapeutic targets,” the researchers concluded.

—Lori Laubach

NEW ORLEANS—The lack of a therapy that slows or stops disease progression represents the greatest unmet need among patients with progressive multiple sclerosis (MS), according to a lecture presented at the ACTRIMS 2016 Forum. Future therapeutics for progressive MS will need to address mechanisms such as microglial and macrophage-driven neurodegeneration, mitochondrial dysfunction, and oxidative stress, said Claudia F. Lucchinetti, MD, Professor of Neurology at Mayo Clinic in Rochester, Minnesota.

Research efforts should aim to develop drugs that treat smoldering plaques and meningeal inflammation, she added. Furthermore, patients need a therapy that protects axons and promotes remyelination. “Finally, our therapies are going to need to consider targeting both inflammation and neurodegeneration early and concurrently,” said Dr. Lucchinetti.

White Matter Plaques Indicate Disease Duration

MS progression generally affects the white matter, the axons, the cortex, the meninges, and the deep gray matter. As white matter undergoes demyelination, it may develop any of four types of plaques, including active, inactive, smoldering, and remyelinated shadow plaques. In 2015, Dr. Lucchinetti and colleagues studied autopsy results for 120 patients with MS who had 2,476 white-matter plaques. They found that most plaques in early MS were active, while inactive plaques predominated in chronic MS. Smoldering plaques were rare in early MS, but reached peak levels at 18 to 20 years’ disease duration, which is when many patients convert to secondary progressive MS. The frequency of shadow plaques was similar throughout the disease duration.

In addition, the investigators found that active plaques predominated among patients with ongoing relapses, indicating that the plaques may be “the substrate of the relapse itself,” said Dr. Lucchinetti. Active plaques were less frequent in secondary progressive MS without attacks and in primary progressive MS. Shadow plaques occurred in all clinical forms of the disease, but smoldering plaques occurred only in progressive MS.

Axonal Injury May Promote Progression

Axonal injury in MS mostly occurs in small axons. The main causes of axonal loss are repeated demyelination, lack of trophic support for myelin in oligodendrocytes, Wallerian degeneration, and acute and chronic mitochondrial dysfunction, which may result from enhanced production of reactive oxygen species in macrophages and active microglia.

Mitochondria are especially susceptible to oxidative damage, and microarray gene studies have found mitochondrial dysfunction in MS. Oxidized lipids are common within active plaques and promote calcium accumulation in the axon and, hence, axonal degeneration. In cells such as oligodendrocytes, injury to the mitochondria activates apoptosis-inducible factor, which can be transferred into the nucleus. MS also causes chronic energy failure in axons, which leak current when they have been demyelinated. In a compensatory response, sodium channels increase within the axon, and mitochondria are recruited, but this response eventually fails. Demyelinated axons subsequently undergo neurodegeneration and irreversible injury, potentially leading to disease progression.

Cortical Lesions Predict Disability

“Cortical lesion load is the strongest predictor of MS disability,” said Dr. Lucchinetti. Cortical lesion load correlates with cognitive dysfunction and is present early in the disease. Approximately 40% of patients with clinically isolated syndrome have cortical lesions, which include leukocortical, intracortical, and subpial plaques.

Dr. Lucchinetti and colleagues demonstrated in one investigation that early MS lesions in the cortex are inflammatory, unlike lesions found in chronic MS. Furthermore, they found myelinated macrophages in early cortical plaques. A finding of large numbers of CD68 and CD8 cells near neurons suggests that early neurodegeneration occurs against a background of inflammation, said Dr. Lucchinetti.

Demyelination in the cortex is extensive in chronic MS. It occurs in multiple gyri and mainly affects areas involved in cognition. Research indicates that areas of cortical demyelination often are topographically related to areas in which one finds follicular light structures. “This topographical association of meningeal inflammation and cortical demyelination is striking, and it also seems to be associated with microglial activation in the underlying cortex and neuritic damage, again pointing to the fact that there is a potential soluble myelinotoxic factor mediating this aspect of MS pathology,” said Dr. Lucchinetti.

Meningeal Inflammation and Aggressive Disease

Although meningeal infiltrates may not be true follicles, meningeal inflammation is associated with greater inflammation and a shorter, more aggressive disease course. Data suggest that patients have more aggressive disease and die sooner when they have more meningeal inflammation.

In 2015, Absinta et al found that 3-T postcontrast T2-weighted FLAIR MRI may identify areas of fixed leptomeningeal inflammation. Histopathology indicated that the inflammation included perivascular lymphocytic and mononuclear infiltration in association with nearby subpial cortical demyelination. “When they looked further within these areas, they found prominent, meningeal diffuse inflammation positive for CD45 and CD68 cells,” said Dr. Lucchinetti.

The results indicate that neurologists may now have a marker to track this aspect of MS pathology, she continued. Diffuse and focal meningeal inflammation is present within days to weeks of initial presentation. This inflammation increases the likelihood of cortical demyelination and may contribute to disease progression. In a cohort of patients with early MS, meningeal inflammation was associated with subpial demyelination, similar to the association in chronic MS.

Mainero et al found that sparse areas of abnormality within the upper 25% of the brain tissue correspond with focal myelin loss or iron loss. Deeper areas of the cortex have more extensive involvement (ie, prolonged T2), and these changes are strongly associated with Expanded Disability Status Scale score. This process begins early and is not associated with white matter lesion burden, thus “highlighting the importance of this pathology to some elements of disease progression,” said Dr. Lucchinetti.

Deep Gray Matter Damage

Damage to deep gray matter in MS is focused in the caudate and the hypothalamus. As the disease progresses, it may involve the deep gray matter more extensively. Atrophy of the third ventricle is one potential way to measure the degree to which MS affects the thalamus. This atrophy seems to be associated with cognitive decline, motor deficits, and fatigue. It correlates with cortical demyelination, but not white matter demyelination.

Current approved therapies “are really targeting what we can see, [such as] inflammation and white matter plaques, but there’s much more going on,” concluded Dr. Lucchinetti.

—Erik Greb

NEW ORLEANS—The lack of a therapy that slows or stops disease progression represents the greatest unmet need among patients with progressive multiple sclerosis (MS), according to a lecture presented at the ACTRIMS 2016 Forum. Future therapeutics for progressive MS will need to address mechanisms such as microglial and macrophage-driven neurodegeneration, mitochondrial dysfunction, and oxidative stress, said Claudia F. Lucchinetti, MD, Professor of Neurology at Mayo Clinic in Rochester, Minnesota.

Research efforts should aim to develop drugs that treat smoldering plaques and meningeal inflammation, she added. Furthermore, patients need a therapy that protects axons and promotes remyelination. “Finally, our therapies are going to need to consider targeting both inflammation and neurodegeneration early and concurrently,” said Dr. Lucchinetti.

White Matter Plaques Indicate Disease Duration

MS progression generally affects the white matter, the axons, the cortex, the meninges, and the deep gray matter. As white matter undergoes demyelination, it may develop any of four types of plaques, including active, inactive, smoldering, and remyelinated shadow plaques. In 2015, Dr. Lucchinetti and colleagues studied autopsy results for 120 patients with MS who had 2,476 white-matter plaques. They found that most plaques in early MS were active, while inactive plaques predominated in chronic MS. Smoldering plaques were rare in early MS, but reached peak levels at 18 to 20 years’ disease duration, which is when many patients convert to secondary progressive MS. The frequency of shadow plaques was similar throughout the disease duration.

In addition, the investigators found that active plaques predominated among patients with ongoing relapses, indicating that the plaques may be “the substrate of the relapse itself,” said Dr. Lucchinetti. Active plaques were less frequent in secondary progressive MS without attacks and in primary progressive MS. Shadow plaques occurred in all clinical forms of the disease, but smoldering plaques occurred only in progressive MS.

Axonal Injury May Promote Progression

Axonal injury in MS mostly occurs in small axons. The main causes of axonal loss are repeated demyelination, lack of trophic support for myelin in oligodendrocytes, Wallerian degeneration, and acute and chronic mitochondrial dysfunction, which may result from enhanced production of reactive oxygen species in macrophages and active microglia.

Mitochondria are especially susceptible to oxidative damage, and microarray gene studies have found mitochondrial dysfunction in MS. Oxidized lipids are common within active plaques and promote calcium accumulation in the axon and, hence, axonal degeneration. In cells such as oligodendrocytes, injury to the mitochondria activates apoptosis-inducible factor, which can be transferred into the nucleus. MS also causes chronic energy failure in axons, which leak current when they have been demyelinated. In a compensatory response, sodium channels increase within the axon, and mitochondria are recruited, but this response eventually fails. Demyelinated axons subsequently undergo neurodegeneration and irreversible injury, potentially leading to disease progression.

Cortical Lesions Predict Disability

“Cortical lesion load is the strongest predictor of MS disability,” said Dr. Lucchinetti. Cortical lesion load correlates with cognitive dysfunction and is present early in the disease. Approximately 40% of patients with clinically isolated syndrome have cortical lesions, which include leukocortical, intracortical, and subpial plaques.

Dr. Lucchinetti and colleagues demonstrated in one investigation that early MS lesions in the cortex are inflammatory, unlike lesions found in chronic MS. Furthermore, they found myelinated macrophages in early cortical plaques. A finding of large numbers of CD68 and CD8 cells near neurons suggests that early neurodegeneration occurs against a background of inflammation, said Dr. Lucchinetti.

Demyelination in the cortex is extensive in chronic MS. It occurs in multiple gyri and mainly affects areas involved in cognition. Research indicates that areas of cortical demyelination often are topographically related to areas in which one finds follicular light structures. “This topographical association of meningeal inflammation and cortical demyelination is striking, and it also seems to be associated with microglial activation in the underlying cortex and neuritic damage, again pointing to the fact that there is a potential soluble myelinotoxic factor mediating this aspect of MS pathology,” said Dr. Lucchinetti.

Meningeal Inflammation and Aggressive Disease

Although meningeal infiltrates may not be true follicles, meningeal inflammation is associated with greater inflammation and a shorter, more aggressive disease course. Data suggest that patients have more aggressive disease and die sooner when they have more meningeal inflammation.

In 2015, Absinta et al found that 3-T postcontrast T2-weighted FLAIR MRI may identify areas of fixed leptomeningeal inflammation. Histopathology indicated that the inflammation included perivascular lymphocytic and mononuclear infiltration in association with nearby subpial cortical demyelination. “When they looked further within these areas, they found prominent, meningeal diffuse inflammation positive for CD45 and CD68 cells,” said Dr. Lucchinetti.

The results indicate that neurologists may now have a marker to track this aspect of MS pathology, she continued. Diffuse and focal meningeal inflammation is present within days to weeks of initial presentation. This inflammation increases the likelihood of cortical demyelination and may contribute to disease progression. In a cohort of patients with early MS, meningeal inflammation was associated with subpial demyelination, similar to the association in chronic MS.

Mainero et al found that sparse areas of abnormality within the upper 25% of the brain tissue correspond with focal myelin loss or iron loss. Deeper areas of the cortex have more extensive involvement (ie, prolonged T2), and these changes are strongly associated with Expanded Disability Status Scale score. This process begins early and is not associated with white matter lesion burden, thus “highlighting the importance of this pathology to some elements of disease progression,” said Dr. Lucchinetti.

Deep Gray Matter Damage

Damage to deep gray matter in MS is focused in the caudate and the hypothalamus. As the disease progresses, it may involve the deep gray matter more extensively. Atrophy of the third ventricle is one potential way to measure the degree to which MS affects the thalamus. This atrophy seems to be associated with cognitive decline, motor deficits, and fatigue. It correlates with cortical demyelination, but not white matter demyelination.

Current approved therapies “are really targeting what we can see, [such as] inflammation and white matter plaques, but there’s much more going on,” concluded Dr. Lucchinetti.

—Erik Greb

NEW ORLEANS—The lack of a therapy that slows or stops disease progression represents the greatest unmet need among patients with progressive multiple sclerosis (MS), according to a lecture presented at the ACTRIMS 2016 Forum. Future therapeutics for progressive MS will need to address mechanisms such as microglial and macrophage-driven neurodegeneration, mitochondrial dysfunction, and oxidative stress, said Claudia F. Lucchinetti, MD, Professor of Neurology at Mayo Clinic in Rochester, Minnesota.

Research efforts should aim to develop drugs that treat smoldering plaques and meningeal inflammation, she added. Furthermore, patients need a therapy that protects axons and promotes remyelination. “Finally, our therapies are going to need to consider targeting both inflammation and neurodegeneration early and concurrently,” said Dr. Lucchinetti.

White Matter Plaques Indicate Disease Duration

MS progression generally affects the white matter, the axons, the cortex, the meninges, and the deep gray matter. As white matter undergoes demyelination, it may develop any of four types of plaques, including active, inactive, smoldering, and remyelinated shadow plaques. In 2015, Dr. Lucchinetti and colleagues studied autopsy results for 120 patients with MS who had 2,476 white-matter plaques. They found that most plaques in early MS were active, while inactive plaques predominated in chronic MS. Smoldering plaques were rare in early MS, but reached peak levels at 18 to 20 years’ disease duration, which is when many patients convert to secondary progressive MS. The frequency of shadow plaques was similar throughout the disease duration.

In addition, the investigators found that active plaques predominated among patients with ongoing relapses, indicating that the plaques may be “the substrate of the relapse itself,” said Dr. Lucchinetti. Active plaques were less frequent in secondary progressive MS without attacks and in primary progressive MS. Shadow plaques occurred in all clinical forms of the disease, but smoldering plaques occurred only in progressive MS.

Axonal Injury May Promote Progression

Axonal injury in MS mostly occurs in small axons. The main causes of axonal loss are repeated demyelination, lack of trophic support for myelin in oligodendrocytes, Wallerian degeneration, and acute and chronic mitochondrial dysfunction, which may result from enhanced production of reactive oxygen species in macrophages and active microglia.

Mitochondria are especially susceptible to oxidative damage, and microarray gene studies have found mitochondrial dysfunction in MS. Oxidized lipids are common within active plaques and promote calcium accumulation in the axon and, hence, axonal degeneration. In cells such as oligodendrocytes, injury to the mitochondria activates apoptosis-inducible factor, which can be transferred into the nucleus. MS also causes chronic energy failure in axons, which leak current when they have been demyelinated. In a compensatory response, sodium channels increase within the axon, and mitochondria are recruited, but this response eventually fails. Demyelinated axons subsequently undergo neurodegeneration and irreversible injury, potentially leading to disease progression.

Cortical Lesions Predict Disability

“Cortical lesion load is the strongest predictor of MS disability,” said Dr. Lucchinetti. Cortical lesion load correlates with cognitive dysfunction and is present early in the disease. Approximately 40% of patients with clinically isolated syndrome have cortical lesions, which include leukocortical, intracortical, and subpial plaques.

Dr. Lucchinetti and colleagues demonstrated in one investigation that early MS lesions in the cortex are inflammatory, unlike lesions found in chronic MS. Furthermore, they found myelinated macrophages in early cortical plaques. A finding of large numbers of CD68 and CD8 cells near neurons suggests that early neurodegeneration occurs against a background of inflammation, said Dr. Lucchinetti.

Demyelination in the cortex is extensive in chronic MS. It occurs in multiple gyri and mainly affects areas involved in cognition. Research indicates that areas of cortical demyelination often are topographically related to areas in which one finds follicular light structures. “This topographical association of meningeal inflammation and cortical demyelination is striking, and it also seems to be associated with microglial activation in the underlying cortex and neuritic damage, again pointing to the fact that there is a potential soluble myelinotoxic factor mediating this aspect of MS pathology,” said Dr. Lucchinetti.

Meningeal Inflammation and Aggressive Disease

Although meningeal infiltrates may not be true follicles, meningeal inflammation is associated with greater inflammation and a shorter, more aggressive disease course. Data suggest that patients have more aggressive disease and die sooner when they have more meningeal inflammation.

In 2015, Absinta et al found that 3-T postcontrast T2-weighted FLAIR MRI may identify areas of fixed leptomeningeal inflammation. Histopathology indicated that the inflammation included perivascular lymphocytic and mononuclear infiltration in association with nearby subpial cortical demyelination. “When they looked further within these areas, they found prominent, meningeal diffuse inflammation positive for CD45 and CD68 cells,” said Dr. Lucchinetti.

The results indicate that neurologists may now have a marker to track this aspect of MS pathology, she continued. Diffuse and focal meningeal inflammation is present within days to weeks of initial presentation. This inflammation increases the likelihood of cortical demyelination and may contribute to disease progression. In a cohort of patients with early MS, meningeal inflammation was associated with subpial demyelination, similar to the association in chronic MS.

Mainero et al found that sparse areas of abnormality within the upper 25% of the brain tissue correspond with focal myelin loss or iron loss. Deeper areas of the cortex have more extensive involvement (ie, prolonged T2), and these changes are strongly associated with Expanded Disability Status Scale score. This process begins early and is not associated with white matter lesion burden, thus “highlighting the importance of this pathology to some elements of disease progression,” said Dr. Lucchinetti.

Deep Gray Matter Damage

Damage to deep gray matter in MS is focused in the caudate and the hypothalamus. As the disease progresses, it may involve the deep gray matter more extensively. Atrophy of the third ventricle is one potential way to measure the degree to which MS affects the thalamus. This atrophy seems to be associated with cognitive decline, motor deficits, and fatigue. It correlates with cortical demyelination, but not white matter demyelination.

Current approved therapies “are really targeting what we can see, [such as] inflammation and white matter plaques, but there’s much more going on,” concluded Dr. Lucchinetti.

—Erik Greb

NEW ORLEANS – Repeated intrathecal administration of autologous mesenchymal bone marrow-derived stromal stem cells for the treatment of multiple sclerosis was safe and induced accelerated beneficial effects in some patients in an uncontrolled, prospective study.

Of 28 patients with either secondary progressive or relapsing-progressive MS who were experiencing severe clinical deterioration and failure to respond to first- and second-line immunomodulatory treatments, 25 experienced either stable or improved Expanded Disability Status Scale (EDSS) scores following autologous mesenchymal stem cell (MSC) injections. The mean score decreased from 6.76 at study entry to 6.57 at a mean follow-up of 3.6 years, Dr. Panayiota Petrou of Hadassah-Hebrew University Medical Center, Jerusalem, Israel, and her colleagues reported in a poster at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

©Zerbor/thinkstockphotos.com

In addition, 17 patients experienced improvements in at least one functional system of the EDSS, including 14 who experienced improved motor function, 5 who experienced improved speech/bulbar functions, 4 who experienced improved urinary functions, and 6 who experienced improved cerebellar function. Eight patients remained stable during the entire follow-up period.

In a prior pilot trial, intrathecal administration of MSCs was shown to be safe and provided “some indications of potentially clinically meaningful beneficial effects on the progression of the disease,” the investigators said.

The current study provides further support for those findings. It included patients who experienced severe clinical deterioration (at least 0.5-1 points in the EDSS) during the year prior to study enrollment, or who had at least one major relapse without sufficient recovery following steroid treatment. Study subjects had a mean age of 56 years and mean disease duration of 15.4 years. They received at least 2 courses and up to 10 injections with 1 million cells/kg; most received 2 (8 patients) or 3 (9 patients) injections, and they were followed for up to 6 years.

No serious side effects were observed during long-term follow-up after repeated intrathecal injections. Eight patients experienced headaches and/or fever in the hours and days after injection, and two experienced symptoms of encephalopathy, which resolved within a few hours. Also, one patient experienced back pain and one had neck rigidity, but no long-term side effects were reported, the investigators said.

Immunological follow-up showed a transient up-regulation of regulatory T cells and down-regulation of the proliferative ability of lymphocytes and of several immune activation surface markers for up to 3 months, they noted.

The investigators reported having no disclosures.

sworcester@frontlinemedcom.com

NEW ORLEANS – Repeated intrathecal administration of autologous mesenchymal bone marrow-derived stromal stem cells for the treatment of multiple sclerosis was safe and induced accelerated beneficial effects in some patients in an uncontrolled, prospective study.

Of 28 patients with either secondary progressive or relapsing-progressive MS who were experiencing severe clinical deterioration and failure to respond to first- and second-line immunomodulatory treatments, 25 experienced either stable or improved Expanded Disability Status Scale (EDSS) scores following autologous mesenchymal stem cell (MSC) injections. The mean score decreased from 6.76 at study entry to 6.57 at a mean follow-up of 3.6 years, Dr. Panayiota Petrou of Hadassah-Hebrew University Medical Center, Jerusalem, Israel, and her colleagues reported in a poster at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

©Zerbor/thinkstockphotos.com

In addition, 17 patients experienced improvements in at least one functional system of the EDSS, including 14 who experienced improved motor function, 5 who experienced improved speech/bulbar functions, 4 who experienced improved urinary functions, and 6 who experienced improved cerebellar function. Eight patients remained stable during the entire follow-up period.

In a prior pilot trial, intrathecal administration of MSCs was shown to be safe and provided “some indications of potentially clinically meaningful beneficial effects on the progression of the disease,” the investigators said.

The current study provides further support for those findings. It included patients who experienced severe clinical deterioration (at least 0.5-1 points in the EDSS) during the year prior to study enrollment, or who had at least one major relapse without sufficient recovery following steroid treatment. Study subjects had a mean age of 56 years and mean disease duration of 15.4 years. They received at least 2 courses and up to 10 injections with 1 million cells/kg; most received 2 (8 patients) or 3 (9 patients) injections, and they were followed for up to 6 years.

No serious side effects were observed during long-term follow-up after repeated intrathecal injections. Eight patients experienced headaches and/or fever in the hours and days after injection, and two experienced symptoms of encephalopathy, which resolved within a few hours. Also, one patient experienced back pain and one had neck rigidity, but no long-term side effects were reported, the investigators said.

Immunological follow-up showed a transient up-regulation of regulatory T cells and down-regulation of the proliferative ability of lymphocytes and of several immune activation surface markers for up to 3 months, they noted.

The investigators reported having no disclosures.

sworcester@frontlinemedcom.com

NEW ORLEANS – Repeated intrathecal administration of autologous mesenchymal bone marrow-derived stromal stem cells for the treatment of multiple sclerosis was safe and induced accelerated beneficial effects in some patients in an uncontrolled, prospective study.

Of 28 patients with either secondary progressive or relapsing-progressive MS who were experiencing severe clinical deterioration and failure to respond to first- and second-line immunomodulatory treatments, 25 experienced either stable or improved Expanded Disability Status Scale (EDSS) scores following autologous mesenchymal stem cell (MSC) injections. The mean score decreased from 6.76 at study entry to 6.57 at a mean follow-up of 3.6 years, Dr. Panayiota Petrou of Hadassah-Hebrew University Medical Center, Jerusalem, Israel, and her colleagues reported in a poster at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

©Zerbor/thinkstockphotos.com

In addition, 17 patients experienced improvements in at least one functional system of the EDSS, including 14 who experienced improved motor function, 5 who experienced improved speech/bulbar functions, 4 who experienced improved urinary functions, and 6 who experienced improved cerebellar function. Eight patients remained stable during the entire follow-up period.

In a prior pilot trial, intrathecal administration of MSCs was shown to be safe and provided “some indications of potentially clinically meaningful beneficial effects on the progression of the disease,” the investigators said.

The current study provides further support for those findings. It included patients who experienced severe clinical deterioration (at least 0.5-1 points in the EDSS) during the year prior to study enrollment, or who had at least one major relapse without sufficient recovery following steroid treatment. Study subjects had a mean age of 56 years and mean disease duration of 15.4 years. They received at least 2 courses and up to 10 injections with 1 million cells/kg; most received 2 (8 patients) or 3 (9 patients) injections, and they were followed for up to 6 years.

No serious side effects were observed during long-term follow-up after repeated intrathecal injections. Eight patients experienced headaches and/or fever in the hours and days after injection, and two experienced symptoms of encephalopathy, which resolved within a few hours. Also, one patient experienced back pain and one had neck rigidity, but no long-term side effects were reported, the investigators said.

Immunological follow-up showed a transient up-regulation of regulatory T cells and down-regulation of the proliferative ability of lymphocytes and of several immune activation surface markers for up to 3 months, they noted.

The investigators reported having no disclosures.

sworcester@frontlinemedcom.com