ICYMI Multiple Sclerosis

The humanized monoclonal antibody ocrelizumab became the first drug to receive approval from the Food and Drug Administration for the treatment of primary progressive multiple sclerosis in adults, according to a March 29 announcement from the agency that also said it is approved for relapsing-remitting disease in adults.

The drug has a mechanism of action similar to rituximab (Rituxan) through its selective targeting of CD20-positive B cells, which depletes them from circulation. CD20-positive B cells are thought to be a key contributor to myelin and axonal damage.

jevans@frontlinemedcom.com

The humanized monoclonal antibody ocrelizumab became the first drug to receive approval from the Food and Drug Administration for the treatment of primary progressive multiple sclerosis in adults, according to a March 29 announcement from the agency that also said it is approved for relapsing-remitting disease in adults.

The drug has a mechanism of action similar to rituximab (Rituxan) through its selective targeting of CD20-positive B cells, which depletes them from circulation. CD20-positive B cells are thought to be a key contributor to myelin and axonal damage.

jevans@frontlinemedcom.com

The humanized monoclonal antibody ocrelizumab became the first drug to receive approval from the Food and Drug Administration for the treatment of primary progressive multiple sclerosis in adults, according to a March 29 announcement from the agency that also said it is approved for relapsing-remitting disease in adults.

The drug has a mechanism of action similar to rituximab (Rituxan) through its selective targeting of CD20-positive B cells, which depletes them from circulation. CD20-positive B cells are thought to be a key contributor to myelin and axonal damage.

jevans@frontlinemedcom.com

ORLANDO—Probiotic treatment is associated with the induction of an anti-inflammatory peripheral immune profile in patients with multiple sclerosis (MS), and discontinuing probiotics is associated with a decrease in immune regulatory cells, according to pilot study results presented at the ACTRIMS 2017 Forum. The results suggest that probiotics may be applicable as a therapy for MS. More studies, including controlled clinical trials, are needed to guide treatment decisions, said Howard L. Weiner, MD, Director of the MS Program at Brigham and Women’s Hospital in Newton, Massachusetts, and Robert L. Kroc Professor of Neurology at Harvard Medical School in Boston.

The gut microbiome can modulate neuroimmune function, and studies have found that patients with MS have alterations in the gut microbiome, compared with healthy controls. These findings have led researchers to ask, “Can you treat MS by modulating the microbiome?” Dr. Weiner said. One way to modulate the microbiome is with probiotics, which can be taken as an oral, nontoxic treatment in combination with current therapies. He and his research colleagues conducted a pilot study to investigate the effect of probiotics in patients with MS. “We did not feel that we could do a clinically related study,” he said. Instead, the investigators focused on what happens to the gut microbiome and immune profiles in the blood of patients who receive probiotics.

Two Months of Treatment

The study included nine patients with MS and 13 controls. The investigators gave study participants the probiotic VSL#3. Some formulations of VSL#3 are available in stores. The company that markets the probiotic, Sigma-Tau HealthScience USA, based in Gaithersburg, Maryland, requires a prescription for VSL#3 DS, the double-strength formulation used in the study.

Prior studies of the probiotic have found that VSL#3 provides benefit in animal models of diabetes, colitis, and allergy. Kigerl et al reported that, in mice with spinal cord injury, dysbiosis induced by antibiotics exacerbates neurologic impairment and spinal cord pathology, whereas feeding mice VSL#3 enriched with lactic-acid-producing bacteria triggers a protective immune response, confers neuroprotection, and improves walking. In addition, some doctors prescribe VSL#3 to patients with ulcerative colitis, irritable bowel syndrome, and pouchitis, Dr. Weiner said.

In the pilot study, participants took VSL#3 DS sachets twice daily for two months. Researchers took blood and stool samples from participants before administering the probiotic, at discontinuation of therapy, and three months thereafter.

VSL#3 had no effect on alpha or phylogenetic diversity, but did change the gut microbiome composition. Researchers observed an increase in the relative abundance of specific organisms contained in the probiotic. Methanogens, which are increased in MS, decreased when patients received the probiotic. Administration of VSL#3 also was associated with a decrease in proinflammatory monocytes and decreased expression of activation markers on monocytes and dendritic cells.

When patients stopped probiotic treatment, the numbers of CD39 and IL10 T regulatory cells decreased, and proinflammatory monocytes increased. “We did see changes when you stop treatment, almost as if there is a rebound,” he said. “We are seeing an immune effect in the blood.”

The treatment was well tolerated. “I myself took some,” Dr. Weiner said. “It tastes a little chalky, but otherwise it is fine.” Some patients said they felt better after taking the probiotic. The study was not placebo-controlled, however. Future randomized clinical studies will include MRI scans, he said.

What should neurologists tell patients who want to take a probiotic and ask which probiotic they should take? “We are all asked those questions,” Dr. Weiner said. “I tell them, we really don’t know, but if you would like to take a probiotic, that is fine. But we have no particular recommendations at this time. We need a lot of science before we know what we are doing, as far as treatment, in this regard.”

Changes in the Gut Microbiome in MS

Prior to conducting the pilot study, Sushrut Jangi, MD, research fellow at Brigham and Women’s Hospital, Dr. Weiner, and colleagues studied the gut microbiome in 60 patients with MS and 43 healthy controls. They found that patients with MS had increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas, compared with controls. Methanobrevibacter produces methane, and in another cohort, the researchers detected more methane in the breath of patients with MS than in controls.

In addition, Prevotella and Sutterella were increased, and Sarcina was decreased in patients with MS who were treated with disease-modifying therapy, compared with untreated patients with MS. “It gives us a whole series of targets to try to understand,” he said. The gut microbiome alterations in patients with MS correlated with variations in the expression of genes in circulating T cells and monocytes that have been implicated in MS pathogenesis.

How Are the Gut Microbiome and MS Related?

The nature of the relationship between the gut microbiome and MS is unclear. One possibility is that “the gut could be the key to MS,” Dr. Weiner said. An organism in the gut may trigger MS, and that organism potentially could be altered or used in vaccinations to treat or prevent the disease. Alternatively, the gut microbiome might relate to MS susceptibility. Environmental factors, including diet and antibiotics, could affect the microbiome and MS risk. It is also possible that MS disease-modifying therapies act in part through the gut, Dr. Weiner said.

Various treatments targeting the microbiome are under investigation. For example, researchers are asking whether a particular bacteria or fecal microbiome transplants might help treat MS. “I am very interested in the concept of oral tolerance, where we trigger immune responses in the mucosa,” said Dr. Weiner. “We are beginning a trial of anti-CD3 [monoclonal antibodies], which will be given mucosally to stimulate the gut immune response.”

—Jake Remaly

Suggested Reading

Jangi S, Gandhi R, Cox LM, et al. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun. 2016;7:12015.

Kigerl KA, Hall JC, Wang L, et al. Gut dysbiosis impairs recovery after spinal cord injury. J Exp Med. 2016;213(12):2603-2620.

Kouchaki E, Tamtaji OR, Salami M, et al. Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: A randomized, double-blind, placebo-controlled trial. Clin Nutr. 2016 Sep 16 [Epub ahead of print].

Miyake S, Kim S, Suda W, et al. Dysbiosis in the gut microbiota of patients with multiple sclerosis, with a striking depletion of species belonging to Clostridia XIVa and IV clusters. PLoS One. 2015;10(9):e0137429.

Tremlett H, Waubant E. The multiple sclerosis microbiome? Ann Transl Med. 2017;5(3):53.

ORLANDO—Probiotic treatment is associated with the induction of an anti-inflammatory peripheral immune profile in patients with multiple sclerosis (MS), and discontinuing probiotics is associated with a decrease in immune regulatory cells, according to pilot study results presented at the ACTRIMS 2017 Forum. The results suggest that probiotics may be applicable as a therapy for MS. More studies, including controlled clinical trials, are needed to guide treatment decisions, said Howard L. Weiner, MD, Director of the MS Program at Brigham and Women’s Hospital in Newton, Massachusetts, and Robert L. Kroc Professor of Neurology at Harvard Medical School in Boston.

The gut microbiome can modulate neuroimmune function, and studies have found that patients with MS have alterations in the gut microbiome, compared with healthy controls. These findings have led researchers to ask, “Can you treat MS by modulating the microbiome?” Dr. Weiner said. One way to modulate the microbiome is with probiotics, which can be taken as an oral, nontoxic treatment in combination with current therapies. He and his research colleagues conducted a pilot study to investigate the effect of probiotics in patients with MS. “We did not feel that we could do a clinically related study,” he said. Instead, the investigators focused on what happens to the gut microbiome and immune profiles in the blood of patients who receive probiotics.

Two Months of Treatment

The study included nine patients with MS and 13 controls. The investigators gave study participants the probiotic VSL#3. Some formulations of VSL#3 are available in stores. The company that markets the probiotic, Sigma-Tau HealthScience USA, based in Gaithersburg, Maryland, requires a prescription for VSL#3 DS, the double-strength formulation used in the study.

Prior studies of the probiotic have found that VSL#3 provides benefit in animal models of diabetes, colitis, and allergy. Kigerl et al reported that, in mice with spinal cord injury, dysbiosis induced by antibiotics exacerbates neurologic impairment and spinal cord pathology, whereas feeding mice VSL#3 enriched with lactic-acid-producing bacteria triggers a protective immune response, confers neuroprotection, and improves walking. In addition, some doctors prescribe VSL#3 to patients with ulcerative colitis, irritable bowel syndrome, and pouchitis, Dr. Weiner said.

In the pilot study, participants took VSL#3 DS sachets twice daily for two months. Researchers took blood and stool samples from participants before administering the probiotic, at discontinuation of therapy, and three months thereafter.

VSL#3 had no effect on alpha or phylogenetic diversity, but did change the gut microbiome composition. Researchers observed an increase in the relative abundance of specific organisms contained in the probiotic. Methanogens, which are increased in MS, decreased when patients received the probiotic. Administration of VSL#3 also was associated with a decrease in proinflammatory monocytes and decreased expression of activation markers on monocytes and dendritic cells.

When patients stopped probiotic treatment, the numbers of CD39 and IL10 T regulatory cells decreased, and proinflammatory monocytes increased. “We did see changes when you stop treatment, almost as if there is a rebound,” he said. “We are seeing an immune effect in the blood.”

The treatment was well tolerated. “I myself took some,” Dr. Weiner said. “It tastes a little chalky, but otherwise it is fine.” Some patients said they felt better after taking the probiotic. The study was not placebo-controlled, however. Future randomized clinical studies will include MRI scans, he said.

What should neurologists tell patients who want to take a probiotic and ask which probiotic they should take? “We are all asked those questions,” Dr. Weiner said. “I tell them, we really don’t know, but if you would like to take a probiotic, that is fine. But we have no particular recommendations at this time. We need a lot of science before we know what we are doing, as far as treatment, in this regard.”

Changes in the Gut Microbiome in MS

Prior to conducting the pilot study, Sushrut Jangi, MD, research fellow at Brigham and Women’s Hospital, Dr. Weiner, and colleagues studied the gut microbiome in 60 patients with MS and 43 healthy controls. They found that patients with MS had increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas, compared with controls. Methanobrevibacter produces methane, and in another cohort, the researchers detected more methane in the breath of patients with MS than in controls.

In addition, Prevotella and Sutterella were increased, and Sarcina was decreased in patients with MS who were treated with disease-modifying therapy, compared with untreated patients with MS. “It gives us a whole series of targets to try to understand,” he said. The gut microbiome alterations in patients with MS correlated with variations in the expression of genes in circulating T cells and monocytes that have been implicated in MS pathogenesis.

How Are the Gut Microbiome and MS Related?

The nature of the relationship between the gut microbiome and MS is unclear. One possibility is that “the gut could be the key to MS,” Dr. Weiner said. An organism in the gut may trigger MS, and that organism potentially could be altered or used in vaccinations to treat or prevent the disease. Alternatively, the gut microbiome might relate to MS susceptibility. Environmental factors, including diet and antibiotics, could affect the microbiome and MS risk. It is also possible that MS disease-modifying therapies act in part through the gut, Dr. Weiner said.

Various treatments targeting the microbiome are under investigation. For example, researchers are asking whether a particular bacteria or fecal microbiome transplants might help treat MS. “I am very interested in the concept of oral tolerance, where we trigger immune responses in the mucosa,” said Dr. Weiner. “We are beginning a trial of anti-CD3 [monoclonal antibodies], which will be given mucosally to stimulate the gut immune response.”

—Jake Remaly

Suggested Reading

Jangi S, Gandhi R, Cox LM, et al. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun. 2016;7:12015.

Kigerl KA, Hall JC, Wang L, et al. Gut dysbiosis impairs recovery after spinal cord injury. J Exp Med. 2016;213(12):2603-2620.

Kouchaki E, Tamtaji OR, Salami M, et al. Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: A randomized, double-blind, placebo-controlled trial. Clin Nutr. 2016 Sep 16 [Epub ahead of print].

Miyake S, Kim S, Suda W, et al. Dysbiosis in the gut microbiota of patients with multiple sclerosis, with a striking depletion of species belonging to Clostridia XIVa and IV clusters. PLoS One. 2015;10(9):e0137429.

Tremlett H, Waubant E. The multiple sclerosis microbiome? Ann Transl Med. 2017;5(3):53.

ORLANDO—Probiotic treatment is associated with the induction of an anti-inflammatory peripheral immune profile in patients with multiple sclerosis (MS), and discontinuing probiotics is associated with a decrease in immune regulatory cells, according to pilot study results presented at the ACTRIMS 2017 Forum. The results suggest that probiotics may be applicable as a therapy for MS. More studies, including controlled clinical trials, are needed to guide treatment decisions, said Howard L. Weiner, MD, Director of the MS Program at Brigham and Women’s Hospital in Newton, Massachusetts, and Robert L. Kroc Professor of Neurology at Harvard Medical School in Boston.

The gut microbiome can modulate neuroimmune function, and studies have found that patients with MS have alterations in the gut microbiome, compared with healthy controls. These findings have led researchers to ask, “Can you treat MS by modulating the microbiome?” Dr. Weiner said. One way to modulate the microbiome is with probiotics, which can be taken as an oral, nontoxic treatment in combination with current therapies. He and his research colleagues conducted a pilot study to investigate the effect of probiotics in patients with MS. “We did not feel that we could do a clinically related study,” he said. Instead, the investigators focused on what happens to the gut microbiome and immune profiles in the blood of patients who receive probiotics.

Two Months of Treatment

The study included nine patients with MS and 13 controls. The investigators gave study participants the probiotic VSL#3. Some formulations of VSL#3 are available in stores. The company that markets the probiotic, Sigma-Tau HealthScience USA, based in Gaithersburg, Maryland, requires a prescription for VSL#3 DS, the double-strength formulation used in the study.

Prior studies of the probiotic have found that VSL#3 provides benefit in animal models of diabetes, colitis, and allergy. Kigerl et al reported that, in mice with spinal cord injury, dysbiosis induced by antibiotics exacerbates neurologic impairment and spinal cord pathology, whereas feeding mice VSL#3 enriched with lactic-acid-producing bacteria triggers a protective immune response, confers neuroprotection, and improves walking. In addition, some doctors prescribe VSL#3 to patients with ulcerative colitis, irritable bowel syndrome, and pouchitis, Dr. Weiner said.

In the pilot study, participants took VSL#3 DS sachets twice daily for two months. Researchers took blood and stool samples from participants before administering the probiotic, at discontinuation of therapy, and three months thereafter.

VSL#3 had no effect on alpha or phylogenetic diversity, but did change the gut microbiome composition. Researchers observed an increase in the relative abundance of specific organisms contained in the probiotic. Methanogens, which are increased in MS, decreased when patients received the probiotic. Administration of VSL#3 also was associated with a decrease in proinflammatory monocytes and decreased expression of activation markers on monocytes and dendritic cells.

When patients stopped probiotic treatment, the numbers of CD39 and IL10 T regulatory cells decreased, and proinflammatory monocytes increased. “We did see changes when you stop treatment, almost as if there is a rebound,” he said. “We are seeing an immune effect in the blood.”

The treatment was well tolerated. “I myself took some,” Dr. Weiner said. “It tastes a little chalky, but otherwise it is fine.” Some patients said they felt better after taking the probiotic. The study was not placebo-controlled, however. Future randomized clinical studies will include MRI scans, he said.

What should neurologists tell patients who want to take a probiotic and ask which probiotic they should take? “We are all asked those questions,” Dr. Weiner said. “I tell them, we really don’t know, but if you would like to take a probiotic, that is fine. But we have no particular recommendations at this time. We need a lot of science before we know what we are doing, as far as treatment, in this regard.”

Changes in the Gut Microbiome in MS

Prior to conducting the pilot study, Sushrut Jangi, MD, research fellow at Brigham and Women’s Hospital, Dr. Weiner, and colleagues studied the gut microbiome in 60 patients with MS and 43 healthy controls. They found that patients with MS had increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas, compared with controls. Methanobrevibacter produces methane, and in another cohort, the researchers detected more methane in the breath of patients with MS than in controls.

In addition, Prevotella and Sutterella were increased, and Sarcina was decreased in patients with MS who were treated with disease-modifying therapy, compared with untreated patients with MS. “It gives us a whole series of targets to try to understand,” he said. The gut microbiome alterations in patients with MS correlated with variations in the expression of genes in circulating T cells and monocytes that have been implicated in MS pathogenesis.

How Are the Gut Microbiome and MS Related?

The nature of the relationship between the gut microbiome and MS is unclear. One possibility is that “the gut could be the key to MS,” Dr. Weiner said. An organism in the gut may trigger MS, and that organism potentially could be altered or used in vaccinations to treat or prevent the disease. Alternatively, the gut microbiome might relate to MS susceptibility. Environmental factors, including diet and antibiotics, could affect the microbiome and MS risk. It is also possible that MS disease-modifying therapies act in part through the gut, Dr. Weiner said.

Various treatments targeting the microbiome are under investigation. For example, researchers are asking whether a particular bacteria or fecal microbiome transplants might help treat MS. “I am very interested in the concept of oral tolerance, where we trigger immune responses in the mucosa,” said Dr. Weiner. “We are beginning a trial of anti-CD3 [monoclonal antibodies], which will be given mucosally to stimulate the gut immune response.”

—Jake Remaly

Suggested Reading

Jangi S, Gandhi R, Cox LM, et al. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun. 2016;7:12015.

Kigerl KA, Hall JC, Wang L, et al. Gut dysbiosis impairs recovery after spinal cord injury. J Exp Med. 2016;213(12):2603-2620.

Kouchaki E, Tamtaji OR, Salami M, et al. Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: A randomized, double-blind, placebo-controlled trial. Clin Nutr. 2016 Sep 16 [Epub ahead of print].

Miyake S, Kim S, Suda W, et al. Dysbiosis in the gut microbiota of patients with multiple sclerosis, with a striking depletion of species belonging to Clostridia XIVa and IV clusters. PLoS One. 2015;10(9):e0137429.

Tremlett H, Waubant E. The multiple sclerosis microbiome? Ann Transl Med. 2017;5(3):53.

ORLANDO—Patients with multiple sclerosis (MS) have a 14-year reduction in median life expectancy from onset of the disease, compared with the general population, according to a 60-year Norwegian study presented at the ACTRIMS 2017 Forum. The standardized mortality ratio (SMR) may be nearly threefold higher in patients with MS, compared with controls, and sevenfold higher in patients who are the youngest at onset.

Approximately 1,388 patients with MS with onset between 1953 and 2012 in Hordaland County, Western Norway, participated in the study. Dr. Grytten and colleagues obtained information from patient records at Haukeland University Hospital, and it was linked to the Causes of Death Registry. They estimated survival from disease onset, adjusted for sex, age, and disease course, using the Kaplan-Meier analyses. In addition, researchers used the SMR to examine mortality and causes of death in MS.

In all, 291 patients died, primarily from MS. The median time to death from MS onset was 41 years for all patients, compared with 55 years for the general population. Women with MS had a 43-year median life expectancy from onset, compared with 56 years in the general female population. Men had a 36-year median life expectancy from MS onset, compared with 50 years in the general male population. Patients with relapsing-remitting MS had a 43-year median life expectancy from onset, and individuals with primary progressive MS had a 26-year median life expectancy from onset.

The SMR was 2.7 in the total MS population. SMR was 2.4 in patients with relapsing-remitting MS and 3.9 in patients with primary progressive MS. In addition, SMR was 2.9 in women with MS and 2.5 in men with MS. Patients with onset at age 20 or younger had an SMR of 7.3. For patients age 21 to 30 at onset, SMR was 4.0. SMR was 2.6 for patients age 31 to 40 at onset. SMR was 1.3 in patients who were age 60 or older at onset.

SMR from disease onset during the period from 1953 to 1974 was 3.1. SMR from disease onset between 1975 and 1996 was 2.6, and SMR from disease onset between 1997 and 2012 was 0.7. Among causes of death, the SMR for cancer was 5.4, that for respiratory causes and infections was 4.5, and that for coronary and cerebrovascular causes was 3.28. The SMR of causes of death indicated serious comorbid disease in MS, said the investigators.

Female patients with MS had a longer median time to death, compared with male patients, but had a higher risk of dying than did the general population. Investigators also observed a decrease in mortality throughout the study, which might be attributed to environmental factors such as lifestyle and treatment.

—Erica Tricarico

Suggested Reading

Grytten Torkildsen N, Lie SA, Aarseth JH, et al. Survival and cause of death in multiple sclerosis: results from a 50-year follow-up in Western Norway. Mult Scler. 2008; 14(9):1191-1198.

ORLANDO—Patients with multiple sclerosis (MS) have a 14-year reduction in median life expectancy from onset of the disease, compared with the general population, according to a 60-year Norwegian study presented at the ACTRIMS 2017 Forum. The standardized mortality ratio (SMR) may be nearly threefold higher in patients with MS, compared with controls, and sevenfold higher in patients who are the youngest at onset.

Approximately 1,388 patients with MS with onset between 1953 and 2012 in Hordaland County, Western Norway, participated in the study. Dr. Grytten and colleagues obtained information from patient records at Haukeland University Hospital, and it was linked to the Causes of Death Registry. They estimated survival from disease onset, adjusted for sex, age, and disease course, using the Kaplan-Meier analyses. In addition, researchers used the SMR to examine mortality and causes of death in MS.

In all, 291 patients died, primarily from MS. The median time to death from MS onset was 41 years for all patients, compared with 55 years for the general population. Women with MS had a 43-year median life expectancy from onset, compared with 56 years in the general female population. Men had a 36-year median life expectancy from MS onset, compared with 50 years in the general male population. Patients with relapsing-remitting MS had a 43-year median life expectancy from onset, and individuals with primary progressive MS had a 26-year median life expectancy from onset.

The SMR was 2.7 in the total MS population. SMR was 2.4 in patients with relapsing-remitting MS and 3.9 in patients with primary progressive MS. In addition, SMR was 2.9 in women with MS and 2.5 in men with MS. Patients with onset at age 20 or younger had an SMR of 7.3. For patients age 21 to 30 at onset, SMR was 4.0. SMR was 2.6 for patients age 31 to 40 at onset. SMR was 1.3 in patients who were age 60 or older at onset.

SMR from disease onset during the period from 1953 to 1974 was 3.1. SMR from disease onset between 1975 and 1996 was 2.6, and SMR from disease onset between 1997 and 2012 was 0.7. Among causes of death, the SMR for cancer was 5.4, that for respiratory causes and infections was 4.5, and that for coronary and cerebrovascular causes was 3.28. The SMR of causes of death indicated serious comorbid disease in MS, said the investigators.

Female patients with MS had a longer median time to death, compared with male patients, but had a higher risk of dying than did the general population. Investigators also observed a decrease in mortality throughout the study, which might be attributed to environmental factors such as lifestyle and treatment.

—Erica Tricarico

Suggested Reading

Grytten Torkildsen N, Lie SA, Aarseth JH, et al. Survival and cause of death in multiple sclerosis: results from a 50-year follow-up in Western Norway. Mult Scler. 2008; 14(9):1191-1198.

ORLANDO—Patients with multiple sclerosis (MS) have a 14-year reduction in median life expectancy from onset of the disease, compared with the general population, according to a 60-year Norwegian study presented at the ACTRIMS 2017 Forum. The standardized mortality ratio (SMR) may be nearly threefold higher in patients with MS, compared with controls, and sevenfold higher in patients who are the youngest at onset.

Approximately 1,388 patients with MS with onset between 1953 and 2012 in Hordaland County, Western Norway, participated in the study. Dr. Grytten and colleagues obtained information from patient records at Haukeland University Hospital, and it was linked to the Causes of Death Registry. They estimated survival from disease onset, adjusted for sex, age, and disease course, using the Kaplan-Meier analyses. In addition, researchers used the SMR to examine mortality and causes of death in MS.

In all, 291 patients died, primarily from MS. The median time to death from MS onset was 41 years for all patients, compared with 55 years for the general population. Women with MS had a 43-year median life expectancy from onset, compared with 56 years in the general female population. Men had a 36-year median life expectancy from MS onset, compared with 50 years in the general male population. Patients with relapsing-remitting MS had a 43-year median life expectancy from onset, and individuals with primary progressive MS had a 26-year median life expectancy from onset.

The SMR was 2.7 in the total MS population. SMR was 2.4 in patients with relapsing-remitting MS and 3.9 in patients with primary progressive MS. In addition, SMR was 2.9 in women with MS and 2.5 in men with MS. Patients with onset at age 20 or younger had an SMR of 7.3. For patients age 21 to 30 at onset, SMR was 4.0. SMR was 2.6 for patients age 31 to 40 at onset. SMR was 1.3 in patients who were age 60 or older at onset.

SMR from disease onset during the period from 1953 to 1974 was 3.1. SMR from disease onset between 1975 and 1996 was 2.6, and SMR from disease onset between 1997 and 2012 was 0.7. Among causes of death, the SMR for cancer was 5.4, that for respiratory causes and infections was 4.5, and that for coronary and cerebrovascular causes was 3.28. The SMR of causes of death indicated serious comorbid disease in MS, said the investigators.

Female patients with MS had a longer median time to death, compared with male patients, but had a higher risk of dying than did the general population. Investigators also observed a decrease in mortality throughout the study, which might be attributed to environmental factors such as lifestyle and treatment.

—Erica Tricarico

Suggested Reading

Grytten Torkildsen N, Lie SA, Aarseth JH, et al. Survival and cause of death in multiple sclerosis: results from a 50-year follow-up in Western Norway. Mult Scler. 2008; 14(9):1191-1198.

ORLANDO—A high-salt diet might be a key environmental risk factor for multiple sclerosis (MS), according to an overview presented at the ACTRIMS 2017 Forum. Since most research has been performed in vitro and in animal models, it remains unclear how a high-salt diet affects patients with MS. Researchers have found in experimental models, however, that salt induces inflammation by several mechanisms: it increases frequency of inflammatory TH17 cells, decreases function of suppressor cells, and increases inflammation of antigen-presenting cells.

“There’s been an epidemic of human autoimmune disease over the past 70 years,” said Dr. Hafler. Researchers are working to discover why there has been such a significant rise in cases. “Genetics cannot allow this to happen. There must be something in the environment,” said Dr. Hafler. He and his colleagues sought to understand how a high-salt diet affects MS.

“What we found is if you added sodium chloride to cultures of T cells, you have autoimmune increases in the frequency of TH17 cells,” he said. In addition, salt decreases function of suppressor cells, the Tregs, and increases inflammation of antigen-presenting cells of the immune system, said Dr. Hafler.

Previous research found that mice fed a high-salt diet were more prone to severe experimental autoimmune encephalomyelitis. When the mice were given a high-salt, high-fat diet that mimicked fast food and probiotics, researchers observed a decrease in inflammation.

“It is really surprising to me how diet can really influence the degree of inflammation in these animals,” said Dr. Hafler. “We do not know if this will work in humans, but probiotics may decrease inflammation. We have no information [on] whether a diet with a probiotic would help prevent or treat MS.”

According to Farez et al, a higher sodium intake is associated with increased clinical and radiological disease activity in patients with MS. Other studies have found that environmental factors such as smoking and low vitamin D levels are associated with MS risk, and the risk is genetically mediated. What may be an environmental risk for one individual may not be a risk for another individual, said Dr. Hafler. “It is unlikely that any of these factors by themselves—smoking, vitamin D, fat, and salt—would be critically important, but together, they might have a strong effect,” he said.

Since there is limited research on a high-salt diet in humans, Dr. Hafler does not recommend his patients with MS go on a strict low-salt diet. However, he does advise patients to stay away from processed foods and fast food. He also encourages patients to get most of their calories from fruits and vegetables.

“We are now doing studies in which we put patients and control subjects on a high-salt diet and low[-salt] diet to observe the direct effect in those individuals,” said Dr. Hafler.

—Erica Tricarico

Suggested Reading

Farez MF, Fiol MP, Gaitán MI, et al. Sodium intake is associated with increased disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2015;86(1):26-31.

Jörg S, Kissel J, Manzel A, et al. High salt drives Th17 responses in experimental autoimmune encephalomyelitis without impacting myeloid dendritic cells. Exp Neurol. 2016;279:212-222.

Kleinewietfeld M, Manzel A, Tize J, et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature. 2013;496(7446):518-522.

Paling D, Solanky BS, Riemer F, et al. Sodium accumulation is associated with disability and a progressive course in multiple sclerosis. Brain. 2013;136(Pt 7):2305-2317.

ORLANDO—A high-salt diet might be a key environmental risk factor for multiple sclerosis (MS), according to an overview presented at the ACTRIMS 2017 Forum. Since most research has been performed in vitro and in animal models, it remains unclear how a high-salt diet affects patients with MS. Researchers have found in experimental models, however, that salt induces inflammation by several mechanisms: it increases frequency of inflammatory TH17 cells, decreases function of suppressor cells, and increases inflammation of antigen-presenting cells.

“There’s been an epidemic of human autoimmune disease over the past 70 years,” said Dr. Hafler. Researchers are working to discover why there has been such a significant rise in cases. “Genetics cannot allow this to happen. There must be something in the environment,” said Dr. Hafler. He and his colleagues sought to understand how a high-salt diet affects MS.

“What we found is if you added sodium chloride to cultures of T cells, you have autoimmune increases in the frequency of TH17 cells,” he said. In addition, salt decreases function of suppressor cells, the Tregs, and increases inflammation of antigen-presenting cells of the immune system, said Dr. Hafler.

Previous research found that mice fed a high-salt diet were more prone to severe experimental autoimmune encephalomyelitis. When the mice were given a high-salt, high-fat diet that mimicked fast food and probiotics, researchers observed a decrease in inflammation.

“It is really surprising to me how diet can really influence the degree of inflammation in these animals,” said Dr. Hafler. “We do not know if this will work in humans, but probiotics may decrease inflammation. We have no information [on] whether a diet with a probiotic would help prevent or treat MS.”

According to Farez et al, a higher sodium intake is associated with increased clinical and radiological disease activity in patients with MS. Other studies have found that environmental factors such as smoking and low vitamin D levels are associated with MS risk, and the risk is genetically mediated. What may be an environmental risk for one individual may not be a risk for another individual, said Dr. Hafler. “It is unlikely that any of these factors by themselves—smoking, vitamin D, fat, and salt—would be critically important, but together, they might have a strong effect,” he said.

Since there is limited research on a high-salt diet in humans, Dr. Hafler does not recommend his patients with MS go on a strict low-salt diet. However, he does advise patients to stay away from processed foods and fast food. He also encourages patients to get most of their calories from fruits and vegetables.

“We are now doing studies in which we put patients and control subjects on a high-salt diet and low[-salt] diet to observe the direct effect in those individuals,” said Dr. Hafler.

—Erica Tricarico

Suggested Reading

Farez MF, Fiol MP, Gaitán MI, et al. Sodium intake is associated with increased disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2015;86(1):26-31.

Jörg S, Kissel J, Manzel A, et al. High salt drives Th17 responses in experimental autoimmune encephalomyelitis without impacting myeloid dendritic cells. Exp Neurol. 2016;279:212-222.

Kleinewietfeld M, Manzel A, Tize J, et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature. 2013;496(7446):518-522.

Paling D, Solanky BS, Riemer F, et al. Sodium accumulation is associated with disability and a progressive course in multiple sclerosis. Brain. 2013;136(Pt 7):2305-2317.

ORLANDO—A high-salt diet might be a key environmental risk factor for multiple sclerosis (MS), according to an overview presented at the ACTRIMS 2017 Forum. Since most research has been performed in vitro and in animal models, it remains unclear how a high-salt diet affects patients with MS. Researchers have found in experimental models, however, that salt induces inflammation by several mechanisms: it increases frequency of inflammatory TH17 cells, decreases function of suppressor cells, and increases inflammation of antigen-presenting cells.

“There’s been an epidemic of human autoimmune disease over the past 70 years,” said Dr. Hafler. Researchers are working to discover why there has been such a significant rise in cases. “Genetics cannot allow this to happen. There must be something in the environment,” said Dr. Hafler. He and his colleagues sought to understand how a high-salt diet affects MS.

“What we found is if you added sodium chloride to cultures of T cells, you have autoimmune increases in the frequency of TH17 cells,” he said. In addition, salt decreases function of suppressor cells, the Tregs, and increases inflammation of antigen-presenting cells of the immune system, said Dr. Hafler.

Previous research found that mice fed a high-salt diet were more prone to severe experimental autoimmune encephalomyelitis. When the mice were given a high-salt, high-fat diet that mimicked fast food and probiotics, researchers observed a decrease in inflammation.

“It is really surprising to me how diet can really influence the degree of inflammation in these animals,” said Dr. Hafler. “We do not know if this will work in humans, but probiotics may decrease inflammation. We have no information [on] whether a diet with a probiotic would help prevent or treat MS.”

According to Farez et al, a higher sodium intake is associated with increased clinical and radiological disease activity in patients with MS. Other studies have found that environmental factors such as smoking and low vitamin D levels are associated with MS risk, and the risk is genetically mediated. What may be an environmental risk for one individual may not be a risk for another individual, said Dr. Hafler. “It is unlikely that any of these factors by themselves—smoking, vitamin D, fat, and salt—would be critically important, but together, they might have a strong effect,” he said.

Since there is limited research on a high-salt diet in humans, Dr. Hafler does not recommend his patients with MS go on a strict low-salt diet. However, he does advise patients to stay away from processed foods and fast food. He also encourages patients to get most of their calories from fruits and vegetables.

“We are now doing studies in which we put patients and control subjects on a high-salt diet and low[-salt] diet to observe the direct effect in those individuals,” said Dr. Hafler.

—Erica Tricarico

Suggested Reading

Farez MF, Fiol MP, Gaitán MI, et al. Sodium intake is associated with increased disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2015;86(1):26-31.

Jörg S, Kissel J, Manzel A, et al. High salt drives Th17 responses in experimental autoimmune encephalomyelitis without impacting myeloid dendritic cells. Exp Neurol. 2016;279:212-222.

Kleinewietfeld M, Manzel A, Tize J, et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature. 2013;496(7446):518-522.

Paling D, Solanky BS, Riemer F, et al. Sodium accumulation is associated with disability and a progressive course in multiple sclerosis. Brain. 2013;136(Pt 7):2305-2317.

ORLANDO—Although multiple sclerosis (MS) is more common in women, when men develop MS, it tends to be worse. Studies indicate that MS in men is associated with a faster accrual of disability and worse relapse recovery. In addition, research suggests that male gender is a predictor for more severe forms of MS. Also, there appears to be a higher male-to-female ratio in primary progressive MS (PPMS), compared with relapsing forms of MS.

Role of Sex Chromosomes and Hormones

Studies suggest that women are predisposed to higher rates of MS relapses than men. Kalincik et al found that there was approximately a 1:1 male-to-female ratio in PPMS onset, compared with a 1:3 male-to-female ratio in relapsing-onset MS. “One of the interesting paradigms they looked at was the proportion of relapses or the relapse count over the course of 10 years and the female-to-male ratio and how it has increased to become predominately female with a higher relapse count. This certainly suggests that hormones and sex may be driving a relapsing phenotype,” said Dr. Chitnis.

Raghavan et al found that men appeared to have higher Expanded Disability Status Scale scores over disease duration in relapsing forms of MS compared with PPMS. In addition, when researchers observed optic neuritis as a model of relapse recovery, they found that male gender was associated with worse recovery from optic neuritis despite adjusting for disease severity as well as vitamin D levels.

Is Testosterone Neuroprotective?

Previous studies in MS suggest that low testosterone is associated with worse disability. Studies have also associated low testosterone levels with more cognitive decline in MS. Following up on these clinical observations, Dr. Chitnis and colleagues conducted the CLIMB study, a long-term study of how MS changes over time, to observe testosterone levels in men with MS. Data from the study, which involved nearly 100 men with MS, revealed that there were significantly reduced testosterone levels in a majority of the males.

Although lower levels of testosterone may be a risk factor for rapid disability accrual, testosterone supplementation appears to be neuroprotective. “There is a vast amount of literature now demonstrating in animal models particularly that testosterone does appear to be neuroprotective and anti-inflammatory,” said Dr. Chitnis.

According to Ziehn et al, testosterone seemed to be protective against synaptic preservation in animal models. In addition, research has elucidated that testosterone is able to cross the blood-brain barrier in its free form and directly influence neuronal cells. Other studies suggest that testosterone protects spinal cord neurons from glutamate toxicity, and protects from oxidative stress in neuronal cell lines.

Sex-Stratified MS Risk, Prenatal Exposure, and Puberty

To understand whether testosterone levels predispose men to MS, researchers studied a measure called the second-digit-fourth-digit ratio (2D:4D) and found that it was associated with MS in men. Researchers have also discovered that there may be prenatal risk factors that may increase susceptibility in men. While studies suggest that breast-feeding is associated with a reduced risk of MS in boys, maternal illness and pesticide exposure in pregnancy and during the prenatal stage were associated with an increased risk for pediatric-onset MS.

Puberty also may be a turning point for the initiation of MS in boys, said Dr. Chitnis. “Younger males with MS show evidence of earlier puberty than regional controls. It is unclear if they have lower testosterone, however, research does suggest a disturbance in sex hormones early on,” she said.

Testosterone as an MS Therapy?

Several benefits have been associated with testosterone as a potential therapy, such as improved libido, increased muscle strength, improved bone density, and potentially improved memory and other cognitive measures. However, there are serious risks associated with testosterone therapy such as an increased prostate specific antigen, increased susceptibility to cancer, emotional lability, hypertension, increased hemoglobin, and increased cardiovascular events.

There may be benefits with regard to slowing disease progression and cognitive decline that warrant further study, said Dr. Chitnis. She added that future studies should focus on “mechanisms and interactions of sex hormones and testosterone in boys with MS, as well as safety and efficacy of testosterone in men with MS.”

—Erica Tricarico

Suggested Reading

Bove R, Malik MT, Diaz-Cruz C, et al. The 2D:4D ratio, a proxy for prenatal androgen levels, differs in men with and without MS. Neurology. 2015;85(14):1209-1213.

Kalincik T, Vivek V, Jokubaitis V, et al. Sex as a determinant of relapse incidence and progressive course of multiple sclerosis. Brain. 2013;136(Pt 12):3609-3617.

Raghavan K, Healy BC, Carruthers RL, Chitnis T. Progression rates and sample size estimates for PPMS based on the CLIMB study population. Mult Scler. 2015;21(2):180-188.

Ziehn MO, Avedisian AA, Dervin SM, et al. Therapeutic testosterone administration preserves excitatory synaptic transmission in the hippocampus during autoimmune demyelinating disease. J Neurosci. 2012; 32(36):12312-12324.

ORLANDO—Although multiple sclerosis (MS) is more common in women, when men develop MS, it tends to be worse. Studies indicate that MS in men is associated with a faster accrual of disability and worse relapse recovery. In addition, research suggests that male gender is a predictor for more severe forms of MS. Also, there appears to be a higher male-to-female ratio in primary progressive MS (PPMS), compared with relapsing forms of MS.

Role of Sex Chromosomes and Hormones

Studies suggest that women are predisposed to higher rates of MS relapses than men. Kalincik et al found that there was approximately a 1:1 male-to-female ratio in PPMS onset, compared with a 1:3 male-to-female ratio in relapsing-onset MS. “One of the interesting paradigms they looked at was the proportion of relapses or the relapse count over the course of 10 years and the female-to-male ratio and how it has increased to become predominately female with a higher relapse count. This certainly suggests that hormones and sex may be driving a relapsing phenotype,” said Dr. Chitnis.

Raghavan et al found that men appeared to have higher Expanded Disability Status Scale scores over disease duration in relapsing forms of MS compared with PPMS. In addition, when researchers observed optic neuritis as a model of relapse recovery, they found that male gender was associated with worse recovery from optic neuritis despite adjusting for disease severity as well as vitamin D levels.

Is Testosterone Neuroprotective?

Previous studies in MS suggest that low testosterone is associated with worse disability. Studies have also associated low testosterone levels with more cognitive decline in MS. Following up on these clinical observations, Dr. Chitnis and colleagues conducted the CLIMB study, a long-term study of how MS changes over time, to observe testosterone levels in men with MS. Data from the study, which involved nearly 100 men with MS, revealed that there were significantly reduced testosterone levels in a majority of the males.

Although lower levels of testosterone may be a risk factor for rapid disability accrual, testosterone supplementation appears to be neuroprotective. “There is a vast amount of literature now demonstrating in animal models particularly that testosterone does appear to be neuroprotective and anti-inflammatory,” said Dr. Chitnis.

According to Ziehn et al, testosterone seemed to be protective against synaptic preservation in animal models. In addition, research has elucidated that testosterone is able to cross the blood-brain barrier in its free form and directly influence neuronal cells. Other studies suggest that testosterone protects spinal cord neurons from glutamate toxicity, and protects from oxidative stress in neuronal cell lines.

Sex-Stratified MS Risk, Prenatal Exposure, and Puberty

To understand whether testosterone levels predispose men to MS, researchers studied a measure called the second-digit-fourth-digit ratio (2D:4D) and found that it was associated with MS in men. Researchers have also discovered that there may be prenatal risk factors that may increase susceptibility in men. While studies suggest that breast-feeding is associated with a reduced risk of MS in boys, maternal illness and pesticide exposure in pregnancy and during the prenatal stage were associated with an increased risk for pediatric-onset MS.

Puberty also may be a turning point for the initiation of MS in boys, said Dr. Chitnis. “Younger males with MS show evidence of earlier puberty than regional controls. It is unclear if they have lower testosterone, however, research does suggest a disturbance in sex hormones early on,” she said.

Testosterone as an MS Therapy?

Several benefits have been associated with testosterone as a potential therapy, such as improved libido, increased muscle strength, improved bone density, and potentially improved memory and other cognitive measures. However, there are serious risks associated with testosterone therapy such as an increased prostate specific antigen, increased susceptibility to cancer, emotional lability, hypertension, increased hemoglobin, and increased cardiovascular events.

There may be benefits with regard to slowing disease progression and cognitive decline that warrant further study, said Dr. Chitnis. She added that future studies should focus on “mechanisms and interactions of sex hormones and testosterone in boys with MS, as well as safety and efficacy of testosterone in men with MS.”

—Erica Tricarico

Suggested Reading

Bove R, Malik MT, Diaz-Cruz C, et al. The 2D:4D ratio, a proxy for prenatal androgen levels, differs in men with and without MS. Neurology. 2015;85(14):1209-1213.

Kalincik T, Vivek V, Jokubaitis V, et al. Sex as a determinant of relapse incidence and progressive course of multiple sclerosis. Brain. 2013;136(Pt 12):3609-3617.

Raghavan K, Healy BC, Carruthers RL, Chitnis T. Progression rates and sample size estimates for PPMS based on the CLIMB study population. Mult Scler. 2015;21(2):180-188.

Ziehn MO, Avedisian AA, Dervin SM, et al. Therapeutic testosterone administration preserves excitatory synaptic transmission in the hippocampus during autoimmune demyelinating disease. J Neurosci. 2012; 32(36):12312-12324.

ORLANDO—Although multiple sclerosis (MS) is more common in women, when men develop MS, it tends to be worse. Studies indicate that MS in men is associated with a faster accrual of disability and worse relapse recovery. In addition, research suggests that male gender is a predictor for more severe forms of MS. Also, there appears to be a higher male-to-female ratio in primary progressive MS (PPMS), compared with relapsing forms of MS.

Role of Sex Chromosomes and Hormones

Studies suggest that women are predisposed to higher rates of MS relapses than men. Kalincik et al found that there was approximately a 1:1 male-to-female ratio in PPMS onset, compared with a 1:3 male-to-female ratio in relapsing-onset MS. “One of the interesting paradigms they looked at was the proportion of relapses or the relapse count over the course of 10 years and the female-to-male ratio and how it has increased to become predominately female with a higher relapse count. This certainly suggests that hormones and sex may be driving a relapsing phenotype,” said Dr. Chitnis.

Raghavan et al found that men appeared to have higher Expanded Disability Status Scale scores over disease duration in relapsing forms of MS compared with PPMS. In addition, when researchers observed optic neuritis as a model of relapse recovery, they found that male gender was associated with worse recovery from optic neuritis despite adjusting for disease severity as well as vitamin D levels.

Is Testosterone Neuroprotective?

Previous studies in MS suggest that low testosterone is associated with worse disability. Studies have also associated low testosterone levels with more cognitive decline in MS. Following up on these clinical observations, Dr. Chitnis and colleagues conducted the CLIMB study, a long-term study of how MS changes over time, to observe testosterone levels in men with MS. Data from the study, which involved nearly 100 men with MS, revealed that there were significantly reduced testosterone levels in a majority of the males.

Although lower levels of testosterone may be a risk factor for rapid disability accrual, testosterone supplementation appears to be neuroprotective. “There is a vast amount of literature now demonstrating in animal models particularly that testosterone does appear to be neuroprotective and anti-inflammatory,” said Dr. Chitnis.

According to Ziehn et al, testosterone seemed to be protective against synaptic preservation in animal models. In addition, research has elucidated that testosterone is able to cross the blood-brain barrier in its free form and directly influence neuronal cells. Other studies suggest that testosterone protects spinal cord neurons from glutamate toxicity, and protects from oxidative stress in neuronal cell lines.

Sex-Stratified MS Risk, Prenatal Exposure, and Puberty

To understand whether testosterone levels predispose men to MS, researchers studied a measure called the second-digit-fourth-digit ratio (2D:4D) and found that it was associated with MS in men. Researchers have also discovered that there may be prenatal risk factors that may increase susceptibility in men. While studies suggest that breast-feeding is associated with a reduced risk of MS in boys, maternal illness and pesticide exposure in pregnancy and during the prenatal stage were associated with an increased risk for pediatric-onset MS.

Puberty also may be a turning point for the initiation of MS in boys, said Dr. Chitnis. “Younger males with MS show evidence of earlier puberty than regional controls. It is unclear if they have lower testosterone, however, research does suggest a disturbance in sex hormones early on,” she said.

Testosterone as an MS Therapy?

Several benefits have been associated with testosterone as a potential therapy, such as improved libido, increased muscle strength, improved bone density, and potentially improved memory and other cognitive measures. However, there are serious risks associated with testosterone therapy such as an increased prostate specific antigen, increased susceptibility to cancer, emotional lability, hypertension, increased hemoglobin, and increased cardiovascular events.

There may be benefits with regard to slowing disease progression and cognitive decline that warrant further study, said Dr. Chitnis. She added that future studies should focus on “mechanisms and interactions of sex hormones and testosterone in boys with MS, as well as safety and efficacy of testosterone in men with MS.”

—Erica Tricarico

Suggested Reading

Bove R, Malik MT, Diaz-Cruz C, et al. The 2D:4D ratio, a proxy for prenatal androgen levels, differs in men with and without MS. Neurology. 2015;85(14):1209-1213.

Kalincik T, Vivek V, Jokubaitis V, et al. Sex as a determinant of relapse incidence and progressive course of multiple sclerosis. Brain. 2013;136(Pt 12):3609-3617.

Raghavan K, Healy BC, Carruthers RL, Chitnis T. Progression rates and sample size estimates for PPMS based on the CLIMB study population. Mult Scler. 2015;21(2):180-188.

Ziehn MO, Avedisian AA, Dervin SM, et al. Therapeutic testosterone administration preserves excitatory synaptic transmission in the hippocampus during autoimmune demyelinating disease. J Neurosci. 2012; 32(36):12312-12324.

In patients presenting with a first clinical demyelinating event, early treatment with subcutaneous interferon beta-1a three times per week over five years prolonged the time to clinically definite multiple sclerosis (MS), compared with delayed treatment, according to research published online ahead of print December 30, 2016 in the Journal of Neurology, Neurosurgery and Psychiatry. Compared with delayed treatment, early treatment also prolonged the time to McDonald MS conversion.

Giancarlo Comi, MD, Professor of Neurology at the Scientific Institute H.S. Raffaele in Milan, and colleagues conducted REFLEXION, a preplanned extension of the REFLEX study, to compare the effect of more frequent and early dosing with that of delayed treatment. Eligible patients were between ages 18 and 50, had an Expanded Disability Status Scale (EDSS) score of 5.0 or lower, and a single clinical event suggestive of MS within 60 days of enrollment. In REFLEX, patients had been randomized to interferon beta-1a (44 μg) thrice weekly or once weekly, or placebo. Treatment lasted for 24 months or until a patient developed clinically definite MS.

In REFLEXION, patients first randomized to interferon beta-1a who had not converted to clinically definite MS continued their original dosing regimen. Patients originally receiving placebo who had not converted to clinically definite MS were switched to interferon beta-1a (44 μg thrice weekly). These patients became the delayed-treatment group. Patients who converted to clinically definite MS during REFLEX or REFLEXION received open-label interferon beta-1a 44 μg thrice weekly from then on.

EDSS scores and clinically definite MS assessments were recorded at extension baseline (ie, month 24) and every six months thereafter. The primary end point was time to conversion to clinically definite MS from first randomization to month 36. Time to clinically definite MS to month 60 was a secondary end point.

The extension study included 127 participants originally randomized to interferon beta-1a thrice weekly, 142 participants originally randomized to interferon beta-1a once weekly, and 133 patients originally randomized to placebo. At month 36, the proportion of patients who had converted to clinically definite MS was lower among patients receiving interferon thrice weekly or weekly, compared with the delayed-treatment group (25.1%, 25.7%, and 38.6%, respectively). The risk of conversion to clinically definite MS was significantly reduced for patients receiving early treatment, compared with delayed treatment. The researchers found no significant difference between the early-treatment groups.

The analysis for month 60 also found that both early-treatment groups had longer times to clinically definite MS, compared with delayed treatment. The proportion of patients who converted to clinically definite MS increased at month 60, but was still lower among participants receiving thrice-weekly or weekly interferon than among patients on delayed treatment (32.2%, 36.0%, and 40.4%, respectively). Cumulative probability of conversion was lower with thrice-weekly and weekly early treatment than with delayed treatment (39.2%, 40.7%, and 44.6%, respectively).

—Erik Greb

Suggested Reading

Comi G, De Stefano N, Freedman MS, et al. Subcutaneous interferon β-1a in the treatment of clinically isolated syndromes: 3-year and 5-year results of the phase III dosing frequency-blind multicentre REFLEXION study. J Neurol Neurosurg Psychiatry. 2016 Dec 30 [Epub ahead of print].

In patients presenting with a first clinical demyelinating event, early treatment with subcutaneous interferon beta-1a three times per week over five years prolonged the time to clinically definite multiple sclerosis (MS), compared with delayed treatment, according to research published online ahead of print December 30, 2016 in the Journal of Neurology, Neurosurgery and Psychiatry. Compared with delayed treatment, early treatment also prolonged the time to McDonald MS conversion.

Giancarlo Comi, MD, Professor of Neurology at the Scientific Institute H.S. Raffaele in Milan, and colleagues conducted REFLEXION, a preplanned extension of the REFLEX study, to compare the effect of more frequent and early dosing with that of delayed treatment. Eligible patients were between ages 18 and 50, had an Expanded Disability Status Scale (EDSS) score of 5.0 or lower, and a single clinical event suggestive of MS within 60 days of enrollment. In REFLEX, patients had been randomized to interferon beta-1a (44 μg) thrice weekly or once weekly, or placebo. Treatment lasted for 24 months or until a patient developed clinically definite MS.

In REFLEXION, patients first randomized to interferon beta-1a who had not converted to clinically definite MS continued their original dosing regimen. Patients originally receiving placebo who had not converted to clinically definite MS were switched to interferon beta-1a (44 μg thrice weekly). These patients became the delayed-treatment group. Patients who converted to clinically definite MS during REFLEX or REFLEXION received open-label interferon beta-1a 44 μg thrice weekly from then on.

EDSS scores and clinically definite MS assessments were recorded at extension baseline (ie, month 24) and every six months thereafter. The primary end point was time to conversion to clinically definite MS from first randomization to month 36. Time to clinically definite MS to month 60 was a secondary end point.

The extension study included 127 participants originally randomized to interferon beta-1a thrice weekly, 142 participants originally randomized to interferon beta-1a once weekly, and 133 patients originally randomized to placebo. At month 36, the proportion of patients who had converted to clinically definite MS was lower among patients receiving interferon thrice weekly or weekly, compared with the delayed-treatment group (25.1%, 25.7%, and 38.6%, respectively). The risk of conversion to clinically definite MS was significantly reduced for patients receiving early treatment, compared with delayed treatment. The researchers found no significant difference between the early-treatment groups.

The analysis for month 60 also found that both early-treatment groups had longer times to clinically definite MS, compared with delayed treatment. The proportion of patients who converted to clinically definite MS increased at month 60, but was still lower among participants receiving thrice-weekly or weekly interferon than among patients on delayed treatment (32.2%, 36.0%, and 40.4%, respectively). Cumulative probability of conversion was lower with thrice-weekly and weekly early treatment than with delayed treatment (39.2%, 40.7%, and 44.6%, respectively).

—Erik Greb

Suggested Reading

Comi G, De Stefano N, Freedman MS, et al. Subcutaneous interferon β-1a in the treatment of clinically isolated syndromes: 3-year and 5-year results of the phase III dosing frequency-blind multicentre REFLEXION study. J Neurol Neurosurg Psychiatry. 2016 Dec 30 [Epub ahead of print].

In patients presenting with a first clinical demyelinating event, early treatment with subcutaneous interferon beta-1a three times per week over five years prolonged the time to clinically definite multiple sclerosis (MS), compared with delayed treatment, according to research published online ahead of print December 30, 2016 in the Journal of Neurology, Neurosurgery and Psychiatry. Compared with delayed treatment, early treatment also prolonged the time to McDonald MS conversion.

Giancarlo Comi, MD, Professor of Neurology at the Scientific Institute H.S. Raffaele in Milan, and colleagues conducted REFLEXION, a preplanned extension of the REFLEX study, to compare the effect of more frequent and early dosing with that of delayed treatment. Eligible patients were between ages 18 and 50, had an Expanded Disability Status Scale (EDSS) score of 5.0 or lower, and a single clinical event suggestive of MS within 60 days of enrollment. In REFLEX, patients had been randomized to interferon beta-1a (44 μg) thrice weekly or once weekly, or placebo. Treatment lasted for 24 months or until a patient developed clinically definite MS.

In REFLEXION, patients first randomized to interferon beta-1a who had not converted to clinically definite MS continued their original dosing regimen. Patients originally receiving placebo who had not converted to clinically definite MS were switched to interferon beta-1a (44 μg thrice weekly). These patients became the delayed-treatment group. Patients who converted to clinically definite MS during REFLEX or REFLEXION received open-label interferon beta-1a 44 μg thrice weekly from then on.

EDSS scores and clinically definite MS assessments were recorded at extension baseline (ie, month 24) and every six months thereafter. The primary end point was time to conversion to clinically definite MS from first randomization to month 36. Time to clinically definite MS to month 60 was a secondary end point.

The extension study included 127 participants originally randomized to interferon beta-1a thrice weekly, 142 participants originally randomized to interferon beta-1a once weekly, and 133 patients originally randomized to placebo. At month 36, the proportion of patients who had converted to clinically definite MS was lower among patients receiving interferon thrice weekly or weekly, compared with the delayed-treatment group (25.1%, 25.7%, and 38.6%, respectively). The risk of conversion to clinically definite MS was significantly reduced for patients receiving early treatment, compared with delayed treatment. The researchers found no significant difference between the early-treatment groups.

The analysis for month 60 also found that both early-treatment groups had longer times to clinically definite MS, compared with delayed treatment. The proportion of patients who converted to clinically definite MS increased at month 60, but was still lower among participants receiving thrice-weekly or weekly interferon than among patients on delayed treatment (32.2%, 36.0%, and 40.4%, respectively). Cumulative probability of conversion was lower with thrice-weekly and weekly early treatment than with delayed treatment (39.2%, 40.7%, and 44.6%, respectively).

—Erik Greb

Suggested Reading

Comi G, De Stefano N, Freedman MS, et al. Subcutaneous interferon β-1a in the treatment of clinically isolated syndromes: 3-year and 5-year results of the phase III dosing frequency-blind multicentre REFLEXION study. J Neurol Neurosurg Psychiatry. 2016 Dec 30 [Epub ahead of print].

VANCOUVER—Pediatric multiple sclerosis (MS) presents unique concerns, making appropriate treatment especially important, according to an overview presented at the 45th Annual Meeting of the Child Neurology Society. Currently, disease-modifying therapies with FDA approval in adult MS have not been approved for the treatment of pediatric MS. In addition, brain growth and cognition are adversely affected in pediatric MS. Furthermore, children with MS tend to become disabled at a younger age, compared with adults.

Diagnosis and Initiation of Therapy

Neurologists should be prepared to engage with children and their families to ensure the most efficacious treatment. “Whenever you are having that conversation or you are considering starting the disease-modifying therapy, you need to balance the need to treat the disease with the idea that you are going to be starting a therapy for a lifetime,” said Dr. Lotze.

Disease-modifying therapies target the inflammatory aspects of pediatric-onset MS and should be initiated in children with a confirmed diagnosis, said Dr. Lotze. Children with clinically isolated syndrome who appear to be at high risk for MS and children with positive oligoclonal bands or elevated IgG index may also need to begin a disease-modifying therapy. Distinguishing between MS, acute disseminated encephalomyelitis (ADEM), and neuromyelitis optica (NMO) poses challenges, especially in children under age 10. Certain interferons can exacerbate NMO and may be harmful in children with ADEM or multiphasic ADEM.

Setting Goals

Neurologists are encouraged to counsel patients about the purpose and side effects of treatment, as well as to establish reasonable expectations for treatment. Additionally, children and families should be aware that another attack may occur during treatment and should be informed about what to do if it does.

No therapy is 100% efficacious in pediatric or adult MS, said Dr. Lotze. Research suggests that 50% of adults have no evidence of disease activity (NEDA) at two years of the disease. After seven years, however, 7% of these adults meet NEDA criteria. As a result, minimal disease progression (defined as less than one attack per year, fewer than three new lesions on a yearly MRI, and no progression in disability) may be a more attainable goal. “We would like to see a drug in a single individual or patient that is effective in achieving NEDA. If that is not possible … you might find that ultimately what you can go for is minimal disease progression,” said Dr. Lotze. He added that there appears to be no clear difference in terms of long-term outcome between children with MS who achieve NEDA and those who achieve minimal disease progression.

First-Line Therapies and Follow-Up Appointments

First-line agents for pediatric MS are the injectable drugs known as platform therapies. The International Pediatric MS Society Group (IPMSSG) recommends that all patients start first-line therapy (ie, interferon β or glatiramer acetate) soon after diagnosis.

Positive results from phase IV observational studies suggest that interferon β and glatiramer acetate are safe and efficacious treatments in pediatric MS. When studied in populations ranging in age from 12 to 17, these therapies decreased relapse rate, stabilized disability, and reduced accrual of new lesions. However, injectable treatments are associated with flu-like symptoms and injection-site reactions. Neurologists should start pediatric patients on interferon β with 25% to 50% of full dosing and titrate to a full adult dosing over four to six weeks. When initiating glatiramer acetate, neurologists should start children with a full adult dosing, 20 mg subcutaneous daily or 40 mg subcutaneous three times per week.

Follow-up appointments should occur every three to six months to assess adherence and determine efficacy of treatment. Neurologists are advised to ask patients whether they are comfortable with taking shots. Patients with needle anxiety, a common problem in pediatric MS, may need assistance from a child psychologist or child life specialist. Asking patients how often the patient or family forgets to take the disease-modifying therapy is also necessary, said Dr. Lotze. In addition, the transition from pediatric to adult care should be addressed in follow-up discussions. Teens must understand that certain disease-modifying therapies are contraindicated for pregnant patients. They also should be aware of how alcohol and other drugs interact with treatment.

Treatment Failure

Research indicates that approximately 30% of patients with pediatric-onset MS will not respond to the first-line therapies, and numerous variables may explain why. Age and disease duration can influence treatment efficacy, as can the number of relapses and the level of disease activity before treatment initiation. Patients who are nonadherent because of side effects and who continue to struggle with needle anxiety may experience treatment failure. The IPMSSG defines treatment failure as adherence to treatment for at least six months with no reduction in relapse rate or in new MRI T2 or contrast-enhancing lesions, or with two or more relapses within a 12-month period.

Second-Line Therapies

Trials of several oral agents are currently under way. The IPMSSG, however, urges neurologists to use extreme caution when considering nonplatform therapies for pediatric patients.

Fingolimod is a second-line drug for pediatric MS that blocks the egress of lymphocytes from the lymph nodes. A small percentage of patients taking this oral agent may develop bradycardia. Monitoring is required for the first six hours of treatment to ensure that the patient has no side effects. Some adverse effects associated with the drug include: first dose bradycardia, macular edema, and herpetic infections.

Dimethyl fumarate is an Nrf2 antioxidant pathway modulator that is associated with adverse effects such as flushing and gastrointestinal upset, said Dr. Lotze. Low-dose aspirin may help with flushing, and a proton pump inhibitor can help to manage the gastrointestinal upset. This treatment requires patients to undergo monitoring for blood count and liver function, as does fingolimod.

Teriflunomide, a pyrimidine synthesis inhibitor, is a Pregnancy Category X drug because it increases the risk of birth defects. Rituximab, an anti-CD20 chimeric monoclonal antibody, is gaining popularity for treating MS. Studies suggest that ocrelizumab may be well tolerated in pediatric MS. Natlizumamb, cladribine, and alemtuzumab are typically used to treat more aggressive forms of MS.

Neurologists rarely prescribe cyclophosphamide or mitoxantrone in pediatric MS. Cyclophosphamide has no formal FDA approval for adult MS or pediatric-onset MS and is associated with increased risks of bladder cancer, secondary leukemia, and infertility. Mitoxantrone is FDA-approved for adults with aggressive relapsing-remitting MS and secondary progressive MS. It is associated with increased cancer risk, however, and is highly cardiotoxic.

“After you have initiated a second-line agent, you need to continue to monitor aspects of disease control, including relapse rate, disability, MRI changes, and other adverse events. If you continue to see breakthrough disease, then you may need to consider … changing to another agent or moving to a more aggressive therapy such as rituximab or natalizumab,” said Dr. Lotze.

—Erica Tricarico

Suggested Reading

Chitnis T, Ghezzi A, Bajer-Korneck B, et al. Pediatric multiple sclerosis: Escalation and emerging treatments. Neurology. 2016;87(9 Suppl 2):S10 3-S109.

Jancic J, Nikolic B, Ivancevic N, et al. Multiple sclerosis in pediatrics: Current concepts and treatment options. Neurol Ther. 2016:5(2):131-143.

VANCOUVER—Pediatric multiple sclerosis (MS) presents unique concerns, making appropriate treatment especially important, according to an overview presented at the 45th Annual Meeting of the Child Neurology Society. Currently, disease-modifying therapies with FDA approval in adult MS have not been approved for the treatment of pediatric MS. In addition, brain growth and cognition are adversely affected in pediatric MS. Furthermore, children with MS tend to become disabled at a younger age, compared with adults.

Diagnosis and Initiation of Therapy

Neurologists should be prepared to engage with children and their families to ensure the most efficacious treatment. “Whenever you are having that conversation or you are considering starting the disease-modifying therapy, you need to balance the need to treat the disease with the idea that you are going to be starting a therapy for a lifetime,” said Dr. Lotze.

Disease-modifying therapies target the inflammatory aspects of pediatric-onset MS and should be initiated in children with a confirmed diagnosis, said Dr. Lotze. Children with clinically isolated syndrome who appear to be at high risk for MS and children with positive oligoclonal bands or elevated IgG index may also need to begin a disease-modifying therapy. Distinguishing between MS, acute disseminated encephalomyelitis (ADEM), and neuromyelitis optica (NMO) poses challenges, especially in children under age 10. Certain interferons can exacerbate NMO and may be harmful in children with ADEM or multiphasic ADEM.

Setting Goals

Neurologists are encouraged to counsel patients about the purpose and side effects of treatment, as well as to establish reasonable expectations for treatment. Additionally, children and families should be aware that another attack may occur during treatment and should be informed about what to do if it does.

No therapy is 100% efficacious in pediatric or adult MS, said Dr. Lotze. Research suggests that 50% of adults have no evidence of disease activity (NEDA) at two years of the disease. After seven years, however, 7% of these adults meet NEDA criteria. As a result, minimal disease progression (defined as less than one attack per year, fewer than three new lesions on a yearly MRI, and no progression in disability) may be a more attainable goal. “We would like to see a drug in a single individual or patient that is effective in achieving NEDA. If that is not possible … you might find that ultimately what you can go for is minimal disease progression,” said Dr. Lotze. He added that there appears to be no clear difference in terms of long-term outcome between children with MS who achieve NEDA and those who achieve minimal disease progression.

First-Line Therapies and Follow-Up Appointments

First-line agents for pediatric MS are the injectable drugs known as platform therapies. The International Pediatric MS Society Group (IPMSSG) recommends that all patients start first-line therapy (ie, interferon β or glatiramer acetate) soon after diagnosis.

Positive results from phase IV observational studies suggest that interferon β and glatiramer acetate are safe and efficacious treatments in pediatric MS. When studied in populations ranging in age from 12 to 17, these therapies decreased relapse rate, stabilized disability, and reduced accrual of new lesions. However, injectable treatments are associated with flu-like symptoms and injection-site reactions. Neurologists should start pediatric patients on interferon β with 25% to 50% of full dosing and titrate to a full adult dosing over four to six weeks. When initiating glatiramer acetate, neurologists should start children with a full adult dosing, 20 mg subcutaneous daily or 40 mg subcutaneous three times per week.

Follow-up appointments should occur every three to six months to assess adherence and determine efficacy of treatment. Neurologists are advised to ask patients whether they are comfortable with taking shots. Patients with needle anxiety, a common problem in pediatric MS, may need assistance from a child psychologist or child life specialist. Asking patients how often the patient or family forgets to take the disease-modifying therapy is also necessary, said Dr. Lotze. In addition, the transition from pediatric to adult care should be addressed in follow-up discussions. Teens must understand that certain disease-modifying therapies are contraindicated for pregnant patients. They also should be aware of how alcohol and other drugs interact with treatment.

Treatment Failure

Research indicates that approximately 30% of patients with pediatric-onset MS will not respond to the first-line therapies, and numerous variables may explain why. Age and disease duration can influence treatment efficacy, as can the number of relapses and the level of disease activity before treatment initiation. Patients who are nonadherent because of side effects and who continue to struggle with needle anxiety may experience treatment failure. The IPMSSG defines treatment failure as adherence to treatment for at least six months with no reduction in relapse rate or in new MRI T2 or contrast-enhancing lesions, or with two or more relapses within a 12-month period.

Second-Line Therapies

Trials of several oral agents are currently under way. The IPMSSG, however, urges neurologists to use extreme caution when considering nonplatform therapies for pediatric patients.

Fingolimod is a second-line drug for pediatric MS that blocks the egress of lymphocytes from the lymph nodes. A small percentage of patients taking this oral agent may develop bradycardia. Monitoring is required for the first six hours of treatment to ensure that the patient has no side effects. Some adverse effects associated with the drug include: first dose bradycardia, macular edema, and herpetic infections.

Dimethyl fumarate is an Nrf2 antioxidant pathway modulator that is associated with adverse effects such as flushing and gastrointestinal upset, said Dr. Lotze. Low-dose aspirin may help with flushing, and a proton pump inhibitor can help to manage the gastrointestinal upset. This treatment requires patients to undergo monitoring for blood count and liver function, as does fingolimod.

Teriflunomide, a pyrimidine synthesis inhibitor, is a Pregnancy Category X drug because it increases the risk of birth defects. Rituximab, an anti-CD20 chimeric monoclonal antibody, is gaining popularity for treating MS. Studies suggest that ocrelizumab may be well tolerated in pediatric MS. Natlizumamb, cladribine, and alemtuzumab are typically used to treat more aggressive forms of MS.

Neurologists rarely prescribe cyclophosphamide or mitoxantrone in pediatric MS. Cyclophosphamide has no formal FDA approval for adult MS or pediatric-onset MS and is associated with increased risks of bladder cancer, secondary leukemia, and infertility. Mitoxantrone is FDA-approved for adults with aggressive relapsing-remitting MS and secondary progressive MS. It is associated with increased cancer risk, however, and is highly cardiotoxic.

“After you have initiated a second-line agent, you need to continue to monitor aspects of disease control, including relapse rate, disability, MRI changes, and other adverse events. If you continue to see breakthrough disease, then you may need to consider … changing to another agent or moving to a more aggressive therapy such as rituximab or natalizumab,” said Dr. Lotze.

—Erica Tricarico

Suggested Reading

Chitnis T, Ghezzi A, Bajer-Korneck B, et al. Pediatric multiple sclerosis: Escalation and emerging treatments. Neurology. 2016;87(9 Suppl 2):S10 3-S109.

Jancic J, Nikolic B, Ivancevic N, et al. Multiple sclerosis in pediatrics: Current concepts and treatment options. Neurol Ther. 2016:5(2):131-143.

VANCOUVER—Pediatric multiple sclerosis (MS) presents unique concerns, making appropriate treatment especially important, according to an overview presented at the 45th Annual Meeting of the Child Neurology Society. Currently, disease-modifying therapies with FDA approval in adult MS have not been approved for the treatment of pediatric MS. In addition, brain growth and cognition are adversely affected in pediatric MS. Furthermore, children with MS tend to become disabled at a younger age, compared with adults.

Diagnosis and Initiation of Therapy

Neurologists should be prepared to engage with children and their families to ensure the most efficacious treatment. “Whenever you are having that conversation or you are considering starting the disease-modifying therapy, you need to balance the need to treat the disease with the idea that you are going to be starting a therapy for a lifetime,” said Dr. Lotze.

Disease-modifying therapies target the inflammatory aspects of pediatric-onset MS and should be initiated in children with a confirmed diagnosis, said Dr. Lotze. Children with clinically isolated syndrome who appear to be at high risk for MS and children with positive oligoclonal bands or elevated IgG index may also need to begin a disease-modifying therapy. Distinguishing between MS, acute disseminated encephalomyelitis (ADEM), and neuromyelitis optica (NMO) poses challenges, especially in children under age 10. Certain interferons can exacerbate NMO and may be harmful in children with ADEM or multiphasic ADEM.

Setting Goals

Neurologists are encouraged to counsel patients about the purpose and side effects of treatment, as well as to establish reasonable expectations for treatment. Additionally, children and families should be aware that another attack may occur during treatment and should be informed about what to do if it does.

No therapy is 100% efficacious in pediatric or adult MS, said Dr. Lotze. Research suggests that 50% of adults have no evidence of disease activity (NEDA) at two years of the disease. After seven years, however, 7% of these adults meet NEDA criteria. As a result, minimal disease progression (defined as less than one attack per year, fewer than three new lesions on a yearly MRI, and no progression in disability) may be a more attainable goal. “We would like to see a drug in a single individual or patient that is effective in achieving NEDA. If that is not possible … you might find that ultimately what you can go for is minimal disease progression,” said Dr. Lotze. He added that there appears to be no clear difference in terms of long-term outcome between children with MS who achieve NEDA and those who achieve minimal disease progression.

First-Line Therapies and Follow-Up Appointments

First-line agents for pediatric MS are the injectable drugs known as platform therapies. The International Pediatric MS Society Group (IPMSSG) recommends that all patients start first-line therapy (ie, interferon β or glatiramer acetate) soon after diagnosis.

Positive results from phase IV observational studies suggest that interferon β and glatiramer acetate are safe and efficacious treatments in pediatric MS. When studied in populations ranging in age from 12 to 17, these therapies decreased relapse rate, stabilized disability, and reduced accrual of new lesions. However, injectable treatments are associated with flu-like symptoms and injection-site reactions. Neurologists should start pediatric patients on interferon β with 25% to 50% of full dosing and titrate to a full adult dosing over four to six weeks. When initiating glatiramer acetate, neurologists should start children with a full adult dosing, 20 mg subcutaneous daily or 40 mg subcutaneous three times per week.

Follow-up appointments should occur every three to six months to assess adherence and determine efficacy of treatment. Neurologists are advised to ask patients whether they are comfortable with taking shots. Patients with needle anxiety, a common problem in pediatric MS, may need assistance from a child psychologist or child life specialist. Asking patients how often the patient or family forgets to take the disease-modifying therapy is also necessary, said Dr. Lotze. In addition, the transition from pediatric to adult care should be addressed in follow-up discussions. Teens must understand that certain disease-modifying therapies are contraindicated for pregnant patients. They also should be aware of how alcohol and other drugs interact with treatment.

Treatment Failure

Research indicates that approximately 30% of patients with pediatric-onset MS will not respond to the first-line therapies, and numerous variables may explain why. Age and disease duration can influence treatment efficacy, as can the number of relapses and the level of disease activity before treatment initiation. Patients who are nonadherent because of side effects and who continue to struggle with needle anxiety may experience treatment failure. The IPMSSG defines treatment failure as adherence to treatment for at least six months with no reduction in relapse rate or in new MRI T2 or contrast-enhancing lesions, or with two or more relapses within a 12-month period.

Second-Line Therapies

Trials of several oral agents are currently under way. The IPMSSG, however, urges neurologists to use extreme caution when considering nonplatform therapies for pediatric patients.

Fingolimod is a second-line drug for pediatric MS that blocks the egress of lymphocytes from the lymph nodes. A small percentage of patients taking this oral agent may develop bradycardia. Monitoring is required for the first six hours of treatment to ensure that the patient has no side effects. Some adverse effects associated with the drug include: first dose bradycardia, macular edema, and herpetic infections.

Dimethyl fumarate is an Nrf2 antioxidant pathway modulator that is associated with adverse effects such as flushing and gastrointestinal upset, said Dr. Lotze. Low-dose aspirin may help with flushing, and a proton pump inhibitor can help to manage the gastrointestinal upset. This treatment requires patients to undergo monitoring for blood count and liver function, as does fingolimod.

Teriflunomide, a pyrimidine synthesis inhibitor, is a Pregnancy Category X drug because it increases the risk of birth defects. Rituximab, an anti-CD20 chimeric monoclonal antibody, is gaining popularity for treating MS. Studies suggest that ocrelizumab may be well tolerated in pediatric MS. Natlizumamb, cladribine, and alemtuzumab are typically used to treat more aggressive forms of MS.

Neurologists rarely prescribe cyclophosphamide or mitoxantrone in pediatric MS. Cyclophosphamide has no formal FDA approval for adult MS or pediatric-onset MS and is associated with increased risks of bladder cancer, secondary leukemia, and infertility. Mitoxantrone is FDA-approved for adults with aggressive relapsing-remitting MS and secondary progressive MS. It is associated with increased cancer risk, however, and is highly cardiotoxic.

“After you have initiated a second-line agent, you need to continue to monitor aspects of disease control, including relapse rate, disability, MRI changes, and other adverse events. If you continue to see breakthrough disease, then you may need to consider … changing to another agent or moving to a more aggressive therapy such as rituximab or natalizumab,” said Dr. Lotze.

—Erica Tricarico

Suggested Reading

Chitnis T, Ghezzi A, Bajer-Korneck B, et al. Pediatric multiple sclerosis: Escalation and emerging treatments. Neurology. 2016;87(9 Suppl 2):S10 3-S109.

Jancic J, Nikolic B, Ivancevic N, et al. Multiple sclerosis in pediatrics: Current concepts and treatment options. Neurol Ther. 2016:5(2):131-143.

Nine patients with relapsing multiple sclerosis had significant and unexpected disease activity within 12 months of switching from fingolimod to alemtuzumab, according to a report from six European neuroscience centers. The report was published January 10 in Neurology: Neuroimmunology & Neuroinflammation.

The centers treated 174 patients with alemtuzumab (Lemtrada); 36 had been on fingolimod (Gilenya) beforehand. “Therefore, these nine patients ... represent 25% of the fingolimod-alemtuzumab cohort,” said Mark Willis, MBBCh, Clinical Research Fellow at Cardiff University, Wales, and colleagues.

The researchers speculated that prolonged sequestration of autoreactive lymphocytes following fingolimod withdrawal allowed “these cells to be concealed from the usual biological effect of alemtuzumab. Subsequent lymphocyte egress then provoke[d] disease reactivation ... This may have important implications for sequential drug selection and washout periods in a subset of patients who switch from fingolimod or drugs with similar biological mechanisms,” they said.

The nine patients were on fingolimod for between five and 33 months, but it was not effective. As a result, they were started on alemtuzumab following a median fingolimod washout period of six weeks. Eight patients had at least one clinical relapse within 12 months of the first alemtuzumab infusion cycle; the median time to relapse following alemtuzumab induction was 4.5 months. All nine patients had radiologic evidence of new disease activity.

Five patients had lymphocyte counts below normal when started on alemtuzumab. It has “been suggested that patients continue on an alternative [disease-modifying treatment] after fingolimod discontinuation, preferably until peripheral lymphocyte counts have normalized.” However, “there is currently no consensus as to which subsequent therapeutic agent is optimal,” the investigators said.

All nine patients went on to the second planned infusion of alemtuzumab; eight were relapse free during a mean follow-up of six months after the second treatment cycle. Of seven patients who had further imaging, four were radiologically stable, three had new T2 lesions, and one had a new gadolinium-enhancing lesion.

—M. Alexander Otto

Suggested Reading

Willis M, Pearson O, Illes Z, et al. An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2017;4(2):e320.

Nine patients with relapsing multiple sclerosis had significant and unexpected disease activity within 12 months of switching from fingolimod to alemtuzumab, according to a report from six European neuroscience centers. The report was published January 10 in Neurology: Neuroimmunology & Neuroinflammation.

The centers treated 174 patients with alemtuzumab (Lemtrada); 36 had been on fingolimod (Gilenya) beforehand. “Therefore, these nine patients ... represent 25% of the fingolimod-alemtuzumab cohort,” said Mark Willis, MBBCh, Clinical Research Fellow at Cardiff University, Wales, and colleagues.

The researchers speculated that prolonged sequestration of autoreactive lymphocytes following fingolimod withdrawal allowed “these cells to be concealed from the usual biological effect of alemtuzumab. Subsequent lymphocyte egress then provoke[d] disease reactivation ... This may have important implications for sequential drug selection and washout periods in a subset of patients who switch from fingolimod or drugs with similar biological mechanisms,” they said.

The nine patients were on fingolimod for between five and 33 months, but it was not effective. As a result, they were started on alemtuzumab following a median fingolimod washout period of six weeks. Eight patients had at least one clinical relapse within 12 months of the first alemtuzumab infusion cycle; the median time to relapse following alemtuzumab induction was 4.5 months. All nine patients had radiologic evidence of new disease activity.

Five patients had lymphocyte counts below normal when started on alemtuzumab. It has “been suggested that patients continue on an alternative [disease-modifying treatment] after fingolimod discontinuation, preferably until peripheral lymphocyte counts have normalized.” However, “there is currently no consensus as to which subsequent therapeutic agent is optimal,” the investigators said.

All nine patients went on to the second planned infusion of alemtuzumab; eight were relapse free during a mean follow-up of six months after the second treatment cycle. Of seven patients who had further imaging, four were radiologically stable, three had new T2 lesions, and one had a new gadolinium-enhancing lesion.

—M. Alexander Otto

Suggested Reading

Willis M, Pearson O, Illes Z, et al. An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2017;4(2):e320.

Nine patients with relapsing multiple sclerosis had significant and unexpected disease activity within 12 months of switching from fingolimod to alemtuzumab, according to a report from six European neuroscience centers. The report was published January 10 in Neurology: Neuroimmunology & Neuroinflammation.

The centers treated 174 patients with alemtuzumab (Lemtrada); 36 had been on fingolimod (Gilenya) beforehand. “Therefore, these nine patients ... represent 25% of the fingolimod-alemtuzumab cohort,” said Mark Willis, MBBCh, Clinical Research Fellow at Cardiff University, Wales, and colleagues.

The researchers speculated that prolonged sequestration of autoreactive lymphocytes following fingolimod withdrawal allowed “these cells to be concealed from the usual biological effect of alemtuzumab. Subsequent lymphocyte egress then provoke[d] disease reactivation ... This may have important implications for sequential drug selection and washout periods in a subset of patients who switch from fingolimod or drugs with similar biological mechanisms,” they said.

The nine patients were on fingolimod for between five and 33 months, but it was not effective. As a result, they were started on alemtuzumab following a median fingolimod washout period of six weeks. Eight patients had at least one clinical relapse within 12 months of the first alemtuzumab infusion cycle; the median time to relapse following alemtuzumab induction was 4.5 months. All nine patients had radiologic evidence of new disease activity.

Five patients had lymphocyte counts below normal when started on alemtuzumab. It has “been suggested that patients continue on an alternative [disease-modifying treatment] after fingolimod discontinuation, preferably until peripheral lymphocyte counts have normalized.” However, “there is currently no consensus as to which subsequent therapeutic agent is optimal,” the investigators said.

All nine patients went on to the second planned infusion of alemtuzumab; eight were relapse free during a mean follow-up of six months after the second treatment cycle. Of seven patients who had further imaging, four were radiologically stable, three had new T2 lesions, and one had a new gadolinium-enhancing lesion.

—M. Alexander Otto

Suggested Reading

Willis M, Pearson O, Illes Z, et al. An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2017;4(2):e320.

“Our results further point to a possible sequence of events leading to MS, in which changes in vibration sensitivity may precede the appearance of demyelinating lesions in the brain,” said the researchers.

Evaluating First-Degree Relatives

Dr. Xia and colleagues conducted the Genes and Environment in MS (GEMS) project, the first prospective study of populations at risk for MS and the first detailed cross-sectional examination of higher-risk and lower-risk family members of patients with MS. The study involved 100 neurologically asymptomatic adults (ages 18 to 50) who were first-degree relatives of patients with MS and participated in the GEMS project from August 2012 to July 2015.

Forty-one of the participants were high-risk patients who scored in the top 10% of a Genetic and Environmental Risk Score (GERS), and 59 participants were low-risk and scored in the bottom 10% of the GERS. The GERS included genetic risk factors (ie, HLA alleles and several MS-associated non-HLA genetic variants) and environmental factors, such as smoking status, BMI, history of infectious mononucleosis and migraine, and vitamin D levels.

Since 40 of the 41 high-risk individuals were female, and 25 of the 59 low-risk individuals were female, the investigators limited the study to the 65 female participants to avoid “attributing any potential difference primarily to the role of sex,” the researchers said.

Testing Neurologic Function

To help identify early signs of MS, the investigators used brain MRI, optical coherence tomography, and other measures of neurologic function, including the Expanded Disability Status Scale, Timed 25-Foot Walk, Nine-Hole Peg Test, Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Timed Up and Go, and high-contrast and low-contrast visual acuity.

Overall, women at high risk showed more subclinical signs of MS than women at low risk, based on an omnibus test that globally assessed the burden of neurologic dysfunction by comparing the overall differences between the two groups. Impaired vibration perception yielded a stronger result; of 47 women (27 at high risk and 20 at low risk) tested in this manner, women at high risk showed significantly reduced vibration perception in the distal lower extremities.

One patient in the high-risk group converted to clinically definite MS during the study. Four of the women at high risk had T2-weighted hyperintense lesions that met the 2010 McDonald MRI criteria for dissemination in space, compared with one woman at low risk. Two women at high risk and one at low risk met the 2016 proposed consensus MRI criteria for MS diagnosis. In addition, radiologic isolated syndrome occurred in one woman from each group. Also, there was a single focus of leptomeningeal enhancement in three women at high risk and one woman at low risk.

Some limitations of this study include the small size, the lack of male participants, the cross-sectional design, and the fact that the vibration sensitivity thresholds were in the normal range for individuals at high risk and low risk. Researchers “plan to confirm the finding of change in vibration sensitivity with a follow-up study.” They added that the “study highlights the importantneed to develop and test more sensitive measures, particularly with biometric devices, to detect subtle subclinical changes early in the disease process.”

Identifying High-Risk Individuals

“The GEMS study represents the most ambitious effort yet to identify presymptomatic individuals who are at increased risk for MS, and it is a valuable first step toward targeted screening,” said Fredrik Piehl, MD, PhD, Professor of Neuroimmunology at Karolinska Institutet and Karolinska University Hospital in Stockholm, in an accompanying editorial. “Even if we cannot yet intervene therapeutically using currently available disease-modifying treatments in presymptomatic stages of MS, the ability to better define high-risk individuals is likely to make active surveillance programs more cost effective. It also provides important information to counsel individuals about lifestyle changes, such as quitting smoking. The GERS also can likely be further refined with more up-to-date data on the interaction between specific genetic and environmental factors,” he added. Dr. Piehl disclosed research support, travel grants, and other relationships with Biogen, Genzyme, Novartis, Merck, Roche, Serono, and Teva.

—Heidi Splete

Suggested Reading

Xia Z, Steele SU, Bakshi A, et al. Assessment of early evidence of multiple sclerosis in a prospective study of asymptomatic high-risk family members. JAMA Neurol. 2017 Jan 17 [Epub ahead of print].

Piehl F. Multiple sclerosis-a tuning fork still required. JAMA Neurol. 2017 Jan 17 [Epub ahead of print].

“Our results further point to a possible sequence of events leading to MS, in which changes in vibration sensitivity may precede the appearance of demyelinating lesions in the brain,” said the researchers.

Evaluating First-Degree Relatives

Dr. Xia and colleagues conducted the Genes and Environment in MS (GEMS) project, the first prospective study of populations at risk for MS and the first detailed cross-sectional examination of higher-risk and lower-risk family members of patients with MS. The study involved 100 neurologically asymptomatic adults (ages 18 to 50) who were first-degree relatives of patients with MS and participated in the GEMS project from August 2012 to July 2015.

Forty-one of the participants were high-risk patients who scored in the top 10% of a Genetic and Environmental Risk Score (GERS), and 59 participants were low-risk and scored in the bottom 10% of the GERS. The GERS included genetic risk factors (ie, HLA alleles and several MS-associated non-HLA genetic variants) and environmental factors, such as smoking status, BMI, history of infectious mononucleosis and migraine, and vitamin D levels.

Since 40 of the 41 high-risk individuals were female, and 25 of the 59 low-risk individuals were female, the investigators limited the study to the 65 female participants to avoid “attributing any potential difference primarily to the role of sex,” the researchers said.

Testing Neurologic Function

To help identify early signs of MS, the investigators used brain MRI, optical coherence tomography, and other measures of neurologic function, including the Expanded Disability Status Scale, Timed 25-Foot Walk, Nine-Hole Peg Test, Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Timed Up and Go, and high-contrast and low-contrast visual acuity.

Overall, women at high risk showed more subclinical signs of MS than women at low risk, based on an omnibus test that globally assessed the burden of neurologic dysfunction by comparing the overall differences between the two groups. Impaired vibration perception yielded a stronger result; of 47 women (27 at high risk and 20 at low risk) tested in this manner, women at high risk showed significantly reduced vibration perception in the distal lower extremities.

One patient in the high-risk group converted to clinically definite MS during the study. Four of the women at high risk had T2-weighted hyperintense lesions that met the 2010 McDonald MRI criteria for dissemination in space, compared with one woman at low risk. Two women at high risk and one at low risk met the 2016 proposed consensus MRI criteria for MS diagnosis. In addition, radiologic isolated syndrome occurred in one woman from each group. Also, there was a single focus of leptomeningeal enhancement in three women at high risk and one woman at low risk.

Some limitations of this study include the small size, the lack of male participants, the cross-sectional design, and the fact that the vibration sensitivity thresholds were in the normal range for individuals at high risk and low risk. Researchers “plan to confirm the finding of change in vibration sensitivity with a follow-up study.” They added that the “study highlights the importantneed to develop and test more sensitive measures, particularly with biometric devices, to detect subtle subclinical changes early in the disease process.”

Identifying High-Risk Individuals

“The GEMS study represents the most ambitious effort yet to identify presymptomatic individuals who are at increased risk for MS, and it is a valuable first step toward targeted screening,” said Fredrik Piehl, MD, PhD, Professor of Neuroimmunology at Karolinska Institutet and Karolinska University Hospital in Stockholm, in an accompanying editorial. “Even if we cannot yet intervene therapeutically using currently available disease-modifying treatments in presymptomatic stages of MS, the ability to better define high-risk individuals is likely to make active surveillance programs more cost effective. It also provides important information to counsel individuals about lifestyle changes, such as quitting smoking. The GERS also can likely be further refined with more up-to-date data on the interaction between specific genetic and environmental factors,” he added. Dr. Piehl disclosed research support, travel grants, and other relationships with Biogen, Genzyme, Novartis, Merck, Roche, Serono, and Teva.

—Heidi Splete

Suggested Reading

Xia Z, Steele SU, Bakshi A, et al. Assessment of early evidence of multiple sclerosis in a prospective study of asymptomatic high-risk family members. JAMA Neurol. 2017 Jan 17 [Epub ahead of print].

Piehl F. Multiple sclerosis-a tuning fork still required. JAMA Neurol. 2017 Jan 17 [Epub ahead of print].

“Our results further point to a possible sequence of events leading to MS, in which changes in vibration sensitivity may precede the appearance of demyelinating lesions in the brain,” said the researchers.

Evaluating First-Degree Relatives

Dr. Xia and colleagues conducted the Genes and Environment in MS (GEMS) project, the first prospective study of populations at risk for MS and the first detailed cross-sectional examination of higher-risk and lower-risk family members of patients with MS. The study involved 100 neurologically asymptomatic adults (ages 18 to 50) who were first-degree relatives of patients with MS and participated in the GEMS project from August 2012 to July 2015.

Forty-one of the participants were high-risk patients who scored in the top 10% of a Genetic and Environmental Risk Score (GERS), and 59 participants were low-risk and scored in the bottom 10% of the GERS. The GERS included genetic risk factors (ie, HLA alleles and several MS-associated non-HLA genetic variants) and environmental factors, such as smoking status, BMI, history of infectious mononucleosis and migraine, and vitamin D levels.

Since 40 of the 41 high-risk individuals were female, and 25 of the 59 low-risk individuals were female, the investigators limited the study to the 65 female participants to avoid “attributing any potential difference primarily to the role of sex,” the researchers said.

Testing Neurologic Function

To help identify early signs of MS, the investigators used brain MRI, optical coherence tomography, and other measures of neurologic function, including the Expanded Disability Status Scale, Timed 25-Foot Walk, Nine-Hole Peg Test, Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Timed Up and Go, and high-contrast and low-contrast visual acuity.

Overall, women at high risk showed more subclinical signs of MS than women at low risk, based on an omnibus test that globally assessed the burden of neurologic dysfunction by comparing the overall differences between the two groups. Impaired vibration perception yielded a stronger result; of 47 women (27 at high risk and 20 at low risk) tested in this manner, women at high risk showed significantly reduced vibration perception in the distal lower extremities.

One patient in the high-risk group converted to clinically definite MS during the study. Four of the women at high risk had T2-weighted hyperintense lesions that met the 2010 McDonald MRI criteria for dissemination in space, compared with one woman at low risk. Two women at high risk and one at low risk met the 2016 proposed consensus MRI criteria for MS diagnosis. In addition, radiologic isolated syndrome occurred in one woman from each group. Also, there was a single focus of leptomeningeal enhancement in three women at high risk and one woman at low risk.

Some limitations of this study include the small size, the lack of male participants, the cross-sectional design, and the fact that the vibration sensitivity thresholds were in the normal range for individuals at high risk and low risk. Researchers “plan to confirm the finding of change in vibration sensitivity with a follow-up study.” They added that the “study highlights the importantneed to develop and test more sensitive measures, particularly with biometric devices, to detect subtle subclinical changes early in the disease process.”

Identifying High-Risk Individuals

“The GEMS study represents the most ambitious effort yet to identify presymptomatic individuals who are at increased risk for MS, and it is a valuable first step toward targeted screening,” said Fredrik Piehl, MD, PhD, Professor of Neuroimmunology at Karolinska Institutet and Karolinska University Hospital in Stockholm, in an accompanying editorial. “Even if we cannot yet intervene therapeutically using currently available disease-modifying treatments in presymptomatic stages of MS, the ability to better define high-risk individuals is likely to make active surveillance programs more cost effective. It also provides important information to counsel individuals about lifestyle changes, such as quitting smoking. The GERS also can likely be further refined with more up-to-date data on the interaction between specific genetic and environmental factors,” he added. Dr. Piehl disclosed research support, travel grants, and other relationships with Biogen, Genzyme, Novartis, Merck, Roche, Serono, and Teva.

—Heidi Splete

Suggested Reading

Xia Z, Steele SU, Bakshi A, et al. Assessment of early evidence of multiple sclerosis in a prospective study of asymptomatic high-risk family members. JAMA Neurol. 2017 Jan 17 [Epub ahead of print].

Piehl F. Multiple sclerosis-a tuning fork still required. JAMA Neurol. 2017 Jan 17 [Epub ahead of print].

Compared with the natural history of the disease, disease-modifying treatments for multiple sclerosis (MS) significantly reduce the risks of long-term disability worsening and evolution to secondary progressive MS (SPMS), according to research published in the October issue of Annals of Neurology. The data also suggest that patients who have no evidence of disease activity (NEDA) for two years are no more likely to have long-term stability than patients who do not reach this end point.

“These observations challenge the concept that NEDA represents remission. Although NEDA may be a useful measure for assessing relative therapeutic efficacy, many patients who meet NEDA criteria over two years go on to develop clinically significant disability,” said Bruce A. C. Cree, MD, PhD, Associate Professor of Neurology at the University of California, San Francisco School of Medicine. “Worsening in patients who meet the two-year NEDA end point could result from active spinal cord disease not captured with brain MRI, progressive axonal or neuronal degeneration, or an escape from a true but transient remission state.

Researchers had anticipated that between 36% and 50% of patients with relapsing MS (RMS) would develop SPMS, but 11.3% of the cohort transitioned to SPMS during the course of the study. Evolution of sustained disability was also slower than expected, said Dr. Cree.

Examining Long-Term Effects of Treatment

Natural history studies from the pretreatment era suggest that between one-third and one-half of patients with MS experience substantial worsening of neurologic disability approximately 15 years after disease onset. Disease-modifying therapies in MS have been studied during the past two decades and are associated with improvement in the short term. Their effect on long-term outcomes is unknown, however. Furthermore, little is known about the relationship between short-term MRI measurements and long-term disability in MS.

As a result, Dr. Cree and colleagues conducted a prospective study to characterize the accrual of long-term disability in a cohort of actively treated patients with MS. Additionally, they sought to assess whether clinical and MRI data used in clinical trials have long-term prognostic value.

Eligible participants had all clinical subtypes of MS and were first evaluated at the MS Center at the University of California, San Francisco between July 2004 and September 2005. Patients were excluded if they were unable to tolerate MRI scans, had poor venous access, or if they had other significant medical illnesses that might interfere with goals of the study. Investigators followed participants annually for five years. In addition, patients underwent re-evaluation at extended time points for as long as 10 years after baseline.

Researchers defined disability progression as a clinically significant worsening in the Expanded Disability Status Scale (EDSS), the timed 25-foot walk, the nine-hole peg test, and the paced serial auditory addition test.

Two Tiers of Therapy

Participants were treated with FDA-approved therapies or off-label therapies. Researchers defined two treatment tiers and categorized therapies based on their relative perceived effectiveness using data from clinical trials.

The first tier of treatment, platform therapy, included interferon (IFN) beta, glatiramer acetate, and off-label therapies such as glucocorticoids, azathioprine, and mycophenolate mofetil. The second tier of treatment, high-potency therapy, included natalizumab, rituximab, mitoxantrone, and cyclophosphamide.

NEDA and Long-Term Disability

Of 517 actively managed patients with MS enrolled in the study, 366 had RMS, 48 had SPMS, 21 had primary progressive MS (PPMS), and 82 had clinically isolated syndrome (CIS). After 10 years of follow-up, neurologic disability was stable or improved, compared with baseline, in 41% of patients. Serum vitamin D levels were inversely associated with short-term MS disease activity, but were not associated with long-term disability. At a median time of 16.8 years after disease onset, 10.7% of patients reached an EDSS score of greater than or equal to 6, and 18.1% of patients evolved from RMS to SPMS.

The investigators concluded that evolution to SPMS in this study was significantly lower than expected, based on natural history studies. They also noted that short-term increases in EDSS did not necessarily predict future accumulation of long-term disability in patients with RMS. In addition, subjects with NEDA by clinical and MRI criteria during the first two years had long-term outcomes that were no different from those of the cohort as a whole.

“Treating to target with two-year NEDA as the goal may not result in protection against long-term disability,” said Dr. Cree. “Long-term studies are urgently needed to determine if high-intensity therapy, initiated at the time of diagnosis or used in patients with seemingly inactive disease, is superior to the escalation approach employed in this cohort.”

—Erica Tricarico

Suggested Reading

University of California, San Francisco MS-EPIC Team, Cree BA, Gourraud PA, et al. Long-term evolution of multiple sclerosis disability in the treatment era. Ann Neurol. 2016;80(4):499-510.

Compared with the natural history of the disease, disease-modifying treatments for multiple sclerosis (MS) significantly reduce the risks of long-term disability worsening and evolution to secondary progressive MS (SPMS), according to research published in the October issue of Annals of Neurology. The data also suggest that patients who have no evidence of disease activity (NEDA) for two years are no more likely to have long-term stability than patients who do not reach this end point.

“These observations challenge the concept that NEDA represents remission. Although NEDA may be a useful measure for assessing relative therapeutic efficacy, many patients who meet NEDA criteria over two years go on to develop clinically significant disability,” said Bruce A. C. Cree, MD, PhD, Associate Professor of Neurology at the University of California, San Francisco School of Medicine. “Worsening in patients who meet the two-year NEDA end point could result from active spinal cord disease not captured with brain MRI, progressive axonal or neuronal degeneration, or an escape from a true but transient remission state.

Researchers had anticipated that between 36% and 50% of patients with relapsing MS (RMS) would develop SPMS, but 11.3% of the cohort transitioned to SPMS during the course of the study. Evolution of sustained disability was also slower than expected, said Dr. Cree.

Examining Long-Term Effects of Treatment

Natural history studies from the pretreatment era suggest that between one-third and one-half of patients with MS experience substantial worsening of neurologic disability approximately 15 years after disease onset. Disease-modifying therapies in MS have been studied during the past two decades and are associated with improvement in the short term. Their effect on long-term outcomes is unknown, however. Furthermore, little is known about the relationship between short-term MRI measurements and long-term disability in MS.

As a result, Dr. Cree and colleagues conducted a prospective study to characterize the accrual of long-term disability in a cohort of actively treated patients with MS. Additionally, they sought to assess whether clinical and MRI data used in clinical trials have long-term prognostic value.

Eligible participants had all clinical subtypes of MS and were first evaluated at the MS Center at the University of California, San Francisco between July 2004 and September 2005. Patients were excluded if they were unable to tolerate MRI scans, had poor venous access, or if they had other significant medical illnesses that might interfere with goals of the study. Investigators followed participants annually for five years. In addition, patients underwent re-evaluation at extended time points for as long as 10 years after baseline.

Researchers defined disability progression as a clinically significant worsening in the Expanded Disability Status Scale (EDSS), the timed 25-foot walk, the nine-hole peg test, and the paced serial auditory addition test.

Two Tiers of Therapy

Participants were treated with FDA-approved therapies or off-label therapies. Researchers defined two treatment tiers and categorized therapies based on their relative perceived effectiveness using data from clinical trials.

The first tier of treatment, platform therapy, included interferon (IFN) beta, glatiramer acetate, and off-label therapies such as glucocorticoids, azathioprine, and mycophenolate mofetil. The second tier of treatment, high-potency therapy, included natalizumab, rituximab, mitoxantrone, and cyclophosphamide.

NEDA and Long-Term Disability

Of 517 actively managed patients with MS enrolled in the study, 366 had RMS, 48 had SPMS, 21 had primary progressive MS (PPMS), and 82 had clinically isolated syndrome (CIS). After 10 years of follow-up, neurologic disability was stable or improved, compared with baseline, in 41% of patients. Serum vitamin D levels were inversely associated with short-term MS disease activity, but were not associated with long-term disability. At a median time of 16.8 years after disease onset, 10.7% of patients reached an EDSS score of greater than or equal to 6, and 18.1% of patients evolved from RMS to SPMS.

The investigators concluded that evolution to SPMS in this study was significantly lower than expected, based on natural history studies. They also noted that short-term increases in EDSS did not necessarily predict future accumulation of long-term disability in patients with RMS. In addition, subjects with NEDA by clinical and MRI criteria during the first two years had long-term outcomes that were no different from those of the cohort as a whole.

“Treating to target with two-year NEDA as the goal may not result in protection against long-term disability,” said Dr. Cree. “Long-term studies are urgently needed to determine if high-intensity therapy, initiated at the time of diagnosis or used in patients with seemingly inactive disease, is superior to the escalation approach employed in this cohort.”

—Erica Tricarico

Suggested Reading

University of California, San Francisco MS-EPIC Team, Cree BA, Gourraud PA, et al. Long-term evolution of multiple sclerosis disability in the treatment era. Ann Neurol. 2016;80(4):499-510.

Compared with the natural history of the disease, disease-modifying treatments for multiple sclerosis (MS) significantly reduce the risks of long-term disability worsening and evolution to secondary progressive MS (SPMS), according to research published in the October issue of Annals of Neurology. The data also suggest that patients who have no evidence of disease activity (NEDA) for two years are no more likely to have long-term stability than patients who do not reach this end point.

“These observations challenge the concept that NEDA represents remission. Although NEDA may be a useful measure for assessing relative therapeutic efficacy, many patients who meet NEDA criteria over two years go on to develop clinically significant disability,” said Bruce A. C. Cree, MD, PhD, Associate Professor of Neurology at the University of California, San Francisco School of Medicine. “Worsening in patients who meet the two-year NEDA end point could result from active spinal cord disease not captured with brain MRI, progressive axonal or neuronal degeneration, or an escape from a true but transient remission state.

Researchers had anticipated that between 36% and 50% of patients with relapsing MS (RMS) would develop SPMS, but 11.3% of the cohort transitioned to SPMS during the course of the study. Evolution of sustained disability was also slower than expected, said Dr. Cree.

Examining Long-Term Effects of Treatment

Natural history studies from the pretreatment era suggest that between one-third and one-half of patients with MS experience substantial worsening of neurologic disability approximately 15 years after disease onset. Disease-modifying therapies in MS have been studied during the past two decades and are associated with improvement in the short term. Their effect on long-term outcomes is unknown, however. Furthermore, little is known about the relationship between short-term MRI measurements and long-term disability in MS.

As a result, Dr. Cree and colleagues conducted a prospective study to characterize the accrual of long-term disability in a cohort of actively treated patients with MS. Additionally, they sought to assess whether clinical and MRI data used in clinical trials have long-term prognostic value.

Eligible participants had all clinical subtypes of MS and were first evaluated at the MS Center at the University of California, San Francisco between July 2004 and September 2005. Patients were excluded if they were unable to tolerate MRI scans, had poor venous access, or if they had other significant medical illnesses that might interfere with goals of the study. Investigators followed participants annually for five years. In addition, patients underwent re-evaluation at extended time points for as long as 10 years after baseline.

Researchers defined disability progression as a clinically significant worsening in the Expanded Disability Status Scale (EDSS), the timed 25-foot walk, the nine-hole peg test, and the paced serial auditory addition test.

Two Tiers of Therapy

Participants were treated with FDA-approved therapies or off-label therapies. Researchers defined two treatment tiers and categorized therapies based on their relative perceived effectiveness using data from clinical trials.

The first tier of treatment, platform therapy, included interferon (IFN) beta, glatiramer acetate, and off-label therapies such as glucocorticoids, azathioprine, and mycophenolate mofetil. The second tier of treatment, high-potency therapy, included natalizumab, rituximab, mitoxantrone, and cyclophosphamide.

NEDA and Long-Term Disability

Of 517 actively managed patients with MS enrolled in the study, 366 had RMS, 48 had SPMS, 21 had primary progressive MS (PPMS), and 82 had clinically isolated syndrome (CIS). After 10 years of follow-up, neurologic disability was stable or improved, compared with baseline, in 41% of patients. Serum vitamin D levels were inversely associated with short-term MS disease activity, but were not associated with long-term disability. At a median time of 16.8 years after disease onset, 10.7% of patients reached an EDSS score of greater than or equal to 6, and 18.1% of patients evolved from RMS to SPMS.

The investigators concluded that evolution to SPMS in this study was significantly lower than expected, based on natural history studies. They also noted that short-term increases in EDSS did not necessarily predict future accumulation of long-term disability in patients with RMS. In addition, subjects with NEDA by clinical and MRI criteria during the first two years had long-term outcomes that were no different from those of the cohort as a whole.

“Treating to target with two-year NEDA as the goal may not result in protection against long-term disability,” said Dr. Cree. “Long-term studies are urgently needed to determine if high-intensity therapy, initiated at the time of diagnosis or used in patients with seemingly inactive disease, is superior to the escalation approach employed in this cohort.”

—Erica Tricarico

Suggested Reading

University of California, San Francisco MS-EPIC Team, Cree BA, Gourraud PA, et al. Long-term evolution of multiple sclerosis disability in the treatment era. Ann Neurol. 2016;80(4):499-510.