Multiple Sclerosis

Conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) can be predicted from oglioclonal bands (OCBs), MRI lesion load, and age at CIS, according to a multicenter study of 1,047 CIS cases.

Investigators followed subjects for an average of 4.3 years, during which time 623 CIS cases converted to CDMS. Predictors associated with conversion included:

• OCB (HR, 2.18)

• 2 to 9 T2 lesions compared to 1 or less lesions (HR, 1.97)

• more than 9 lesions (HR, 2.74)

• age at CIS (HR per year inversely increase, 0.98)

Lower serum vitamin D levels were associated with CDMS in univariable analysis, but not in the multivariable model.

Citation: Ciccarelli O, Toosy AT. Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study. Mult Scler. 2015;21(8):967-968. doi: 10.1177/1352458515588583.

Conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) can be predicted from oglioclonal bands (OCBs), MRI lesion load, and age at CIS, according to a multicenter study of 1,047 CIS cases.

Investigators followed subjects for an average of 4.3 years, during which time 623 CIS cases converted to CDMS. Predictors associated with conversion included:

• OCB (HR, 2.18)

• 2 to 9 T2 lesions compared to 1 or less lesions (HR, 1.97)

• more than 9 lesions (HR, 2.74)

• age at CIS (HR per year inversely increase, 0.98)

Lower serum vitamin D levels were associated with CDMS in univariable analysis, but not in the multivariable model.

Citation: Ciccarelli O, Toosy AT. Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study. Mult Scler. 2015;21(8):967-968. doi: 10.1177/1352458515588583.

Conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) can be predicted from oglioclonal bands (OCBs), MRI lesion load, and age at CIS, according to a multicenter study of 1,047 CIS cases.

Investigators followed subjects for an average of 4.3 years, during which time 623 CIS cases converted to CDMS. Predictors associated with conversion included:

• OCB (HR, 2.18)

• 2 to 9 T2 lesions compared to 1 or less lesions (HR, 1.97)

• more than 9 lesions (HR, 2.74)

• age at CIS (HR per year inversely increase, 0.98)

Lower serum vitamin D levels were associated with CDMS in univariable analysis, but not in the multivariable model.

Citation: Ciccarelli O, Toosy AT. Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study. Mult Scler. 2015;21(8):967-968. doi: 10.1177/1352458515588583.

Patients with multiple sclerosis (MS) have a moderate decrease in life expectancy with disease duration and disability strongly correlated to risk of dying, according to a multicenter observational study of 27,603 MS patients who were followed for an average of 15 years.

Researchers reviewed clinical longitudinal data from patients linked to the national deaths register and determined the death rates were significantly higher in men, patients with later clinical onset, and in progressive MS. 

Overall excess mortality compared with the general population was moderate, with a standardized mortality ratio of 1.48, but increased considerably after 20 years of disease (2.20).

Citation: Leray E, Vukusic S, Debouverie M, et al. Excess mortality in patients with multiple sclerosis starts at 20 years from clinical onset: data from a large-scale French observational study. PLoS One. 2015;10(7):e0132033. doi: 10.1371/journal.pone.0132033.

Patients with multiple sclerosis (MS) have a moderate decrease in life expectancy with disease duration and disability strongly correlated to risk of dying, according to a multicenter observational study of 27,603 MS patients who were followed for an average of 15 years.

Researchers reviewed clinical longitudinal data from patients linked to the national deaths register and determined the death rates were significantly higher in men, patients with later clinical onset, and in progressive MS. 

Overall excess mortality compared with the general population was moderate, with a standardized mortality ratio of 1.48, but increased considerably after 20 years of disease (2.20).

Citation: Leray E, Vukusic S, Debouverie M, et al. Excess mortality in patients with multiple sclerosis starts at 20 years from clinical onset: data from a large-scale French observational study. PLoS One. 2015;10(7):e0132033. doi: 10.1371/journal.pone.0132033.

Patients with multiple sclerosis (MS) have a moderate decrease in life expectancy with disease duration and disability strongly correlated to risk of dying, according to a multicenter observational study of 27,603 MS patients who were followed for an average of 15 years.

Researchers reviewed clinical longitudinal data from patients linked to the national deaths register and determined the death rates were significantly higher in men, patients with later clinical onset, and in progressive MS. 

Overall excess mortality compared with the general population was moderate, with a standardized mortality ratio of 1.48, but increased considerably after 20 years of disease (2.20).

Citation: Leray E, Vukusic S, Debouverie M, et al. Excess mortality in patients with multiple sclerosis starts at 20 years from clinical onset: data from a large-scale French observational study. PLoS One. 2015;10(7):e0132033. doi: 10.1371/journal.pone.0132033.

An intronic variant in SLC9A9 (rs9828519) is associated with nonresponse to interferon-β (INFβ) in patients with multiple sclerosis (MS), according to a genome-wide association study.

Researchers confirmed the association in a meta-analysis across 3 replication data sets and found the SLC9A9 mRNA expression is diminished in MS subjects who are more likely to have relapses. 

In addition, SLC9A9 knockdown in T cells in vitro leads to an increase in expression of proinflammatory molecule IFNϒ.

Citation: Esposito F, Sorosina M, Ottoboni L, et al. A pharmacogenetic study implicates SLC9a9 in multiple sclerosis disease activity. Ann Neurol. 2015;78(1):115-127. doi: 10.1002/ana.24429.

An intronic variant in SLC9A9 (rs9828519) is associated with nonresponse to interferon-β (INFβ) in patients with multiple sclerosis (MS), according to a genome-wide association study.

Researchers confirmed the association in a meta-analysis across 3 replication data sets and found the SLC9A9 mRNA expression is diminished in MS subjects who are more likely to have relapses. 

In addition, SLC9A9 knockdown in T cells in vitro leads to an increase in expression of proinflammatory molecule IFNϒ.

Citation: Esposito F, Sorosina M, Ottoboni L, et al. A pharmacogenetic study implicates SLC9a9 in multiple sclerosis disease activity. Ann Neurol. 2015;78(1):115-127. doi: 10.1002/ana.24429.

An intronic variant in SLC9A9 (rs9828519) is associated with nonresponse to interferon-β (INFβ) in patients with multiple sclerosis (MS), according to a genome-wide association study.

Researchers confirmed the association in a meta-analysis across 3 replication data sets and found the SLC9A9 mRNA expression is diminished in MS subjects who are more likely to have relapses. 

In addition, SLC9A9 knockdown in T cells in vitro leads to an increase in expression of proinflammatory molecule IFNϒ.

Citation: Esposito F, Sorosina M, Ottoboni L, et al. A pharmacogenetic study implicates SLC9a9 in multiple sclerosis disease activity. Ann Neurol. 2015;78(1):115-127. doi: 10.1002/ana.24429.

WASHINGTON, DC—Although treatment algorithms for multiple sclerosis (MS) cannot be adopted formally yet, FDA approval of nearly a dozen new therapies in recent years has yielded enough data to support several useful treatment strategies. At the center of current approaches for using these newer disease-modifying therapies (DMT), including the induction and escalation treatment paradigms, is the concept of no evidence of disease activity (NEDA), according to a presentation at the 67th Annual Meeting of the American Academy of Neurology.

“NEDA may be a viable goal and may be attainable with many [treatment] options,” said Timothy West, MD, a neurologist at the Sansum Clinic in Santa Barbara, California. It is unclear which patients will achieve NEDA, however. “We cannot yet predict response to therapy, so therapeutic risk probably should be a factor [in treatment decisions]. If I can give you a much lower-risk medicine and you get a really good clinical response … that would make us think that [clinicians] might want to do that first, which would support the escalation model.”

Recent data have helped establish several clinical and radiologic markers of poor prognosis that may help neurologists choose among available therapies. “If you see an African American male with 30 lesions, and 10 of them are enhancing, and he’s got an [Expanded Disability Status Scale (EDSS) score] of 4 … that person’s not going to do well,” he said. “You may [now] think about that person differently, and that’s a good thing.”

When a treatment fails, data can suggest which therapy clinicians should try next. These data, which are somewhat limited, derive largely from studies involving the modified Rio Score and the Bermel approach to DMT failure—both of which are based on interferon data alone—as well as the consensus-based Canadian Treatment Optimization Model. “That’s where we are right now as far as an algorithm and data,” said Dr. West. “We’re really basing this off of a small portion of our DMT arsenal…. You might get a little bit more of a bang for your buck if you switched to something in the same efficacy class. You might get a lot more bang for your buck if you jump to that next level of efficacy.”

How Can Patients Achieve NEDA?
Eleven DMTs have received FDA approval since 1993. “The current therapies … have varying mechanisms of action. They have varying efficacies. They have varying safety profiles, and it’s hard to know where to use which medicine and what is the right patient for each medicine.”

The concept of NEDA is based on the idea that clinicians can define and attain a target in patients. The concept was first identified in the AFFIRM study, which sought to analyze the effect of natalizumab, in an effort to define composite measures for use in clinical practice. The study goal of clinical disease-free status, which was defined as no activity on clinical measures (ie, no relapses and no sustained disability progression), was combined with radiologic disease-free status (ie, no gadolinium-enhancing lesions and no new enlarging T2-hyperintense lesions on cranial MRI) into the larger goal of combined disease-free status, which came to be known as NEDA.

NEDA has proven to be achievable. In the AFFIRM study, 37% of patients on natalizumab achieved this goal, versus 7% on placebo, and Dr. West cited more than a half dozen other trials involving various treatments in which a sizable percentage of patients achieved NEDA. Maintaining NEDA, however, is another matter. In a seven-year longitudinal cohort of 215 patients with MS, Rotstein et al found that 46% of patients on DMT reached NEDA at one year, but 8% of the patients maintained NEDA for seven years.

“There wasn’t any difference between early or established MS in this metric, which argues a little bit against [the concept of a] window of opportunity,” said Dr. West. “It’s also worth noting that NEDA can predict itself, which is helpful [in the] long term. NEDA, two years later, had a positive predictive value of 78% for no progression in seven years—and this speaks to possibly that window of opportunity.” A patient with active MS who achieves NEDA for two years has a chance of maintaining NEDA for seven years, added Dr. West.

Induction Versus Escalation
Given that roughly one-third of patients on any approved MS medication are likely to achieve this goal, the questions for clinicians are how to enable a patient to attain NEDA and how to assess it. The induction and escalation treatment paradigms are relevant to these questions. The induction paradigm involves maximizing therapeutic benefit while tolerating increased therapeutic risk, based on the assumption that the risk of MS outweighs the risk of the treatment. The escalation paradigm involves minimizing therapeutic risk while maximizing therapeutic benefit, based on the assumption that one can decrease the risk of MS sufficiently while exposing the patient to less therapeutic risk.

The goal of the induction model is to stop MS activity as soon as possible. This goal is based on the assumption that a window of opportunity early in the disease warrants the increased therapeutic risk despite an unclear prognosis. “If there’s no window of opportunity, we can wait to induce [patients] a few years down the road,” said Dr. West. “But if there is really a narrow window at the beginning … then the induction model makes a lot of sense.”

The idea of the window of therapeutic opportunity arose from studies of alemtuzumab in the late 1990s and early 2000s in patients with severe MS. In a 2006 article that examined EDSS change following alemtuzumab therapy, Coles et al found that while most patients with secondary progressive MS got worse, those in the relapsing-remitting arm achieved significant and striking improvement. “Not only did they stabilize … they actually gained multiple points on their EDSS score,” said Dr. West.

One caveat with the induction paradigm is that because one gets a variable response from available DMTs, clinicians can achieve NEDA with any of these medicines, but often at a high cost: they all raise significant safety and tolerability concerns. These concerns provided the rationale for the escalation paradigm.

Data indicate that a Caucasian patient with features such as monofocal onset, a low relapse rate in the first two to five years, or good recovery after the first relapse likely has a better prognosis than an African American or other nonwhite patient with features such as multifocal onset, a high relapse rate in the first two to five years, or poor recovery after the first relapse. A patient with a good prognosis may limit a clinician’s tolerance of risk and incline him or her toward the escalation model, said Dr. West.

“The idea here is: can we basically work through medicines in a quick way to get [patients] to a NEDA status while also limiting the risk? The assumption here is that sometimes the risk of treatment is greater than that of the MS.... We can define and identify what constitutes treatment failure … and then the next DMT might be more effective.

“We have a lot of tools with which to fight this disease,” Dr. West continued. “Our goal should be to stop the illness as soon as we can…. Both the escalation model and the induction model are trying to get to that goal—they’re just doing it a little bit differently.”

—Fred Balzac

WASHINGTON, DC—Although treatment algorithms for multiple sclerosis (MS) cannot be adopted formally yet, FDA approval of nearly a dozen new therapies in recent years has yielded enough data to support several useful treatment strategies. At the center of current approaches for using these newer disease-modifying therapies (DMT), including the induction and escalation treatment paradigms, is the concept of no evidence of disease activity (NEDA), according to a presentation at the 67th Annual Meeting of the American Academy of Neurology.

“NEDA may be a viable goal and may be attainable with many [treatment] options,” said Timothy West, MD, a neurologist at the Sansum Clinic in Santa Barbara, California. It is unclear which patients will achieve NEDA, however. “We cannot yet predict response to therapy, so therapeutic risk probably should be a factor [in treatment decisions]. If I can give you a much lower-risk medicine and you get a really good clinical response … that would make us think that [clinicians] might want to do that first, which would support the escalation model.”

Recent data have helped establish several clinical and radiologic markers of poor prognosis that may help neurologists choose among available therapies. “If you see an African American male with 30 lesions, and 10 of them are enhancing, and he’s got an [Expanded Disability Status Scale (EDSS) score] of 4 … that person’s not going to do well,” he said. “You may [now] think about that person differently, and that’s a good thing.”

When a treatment fails, data can suggest which therapy clinicians should try next. These data, which are somewhat limited, derive largely from studies involving the modified Rio Score and the Bermel approach to DMT failure—both of which are based on interferon data alone—as well as the consensus-based Canadian Treatment Optimization Model. “That’s where we are right now as far as an algorithm and data,” said Dr. West. “We’re really basing this off of a small portion of our DMT arsenal…. You might get a little bit more of a bang for your buck if you switched to something in the same efficacy class. You might get a lot more bang for your buck if you jump to that next level of efficacy.”

How Can Patients Achieve NEDA?
Eleven DMTs have received FDA approval since 1993. “The current therapies … have varying mechanisms of action. They have varying efficacies. They have varying safety profiles, and it’s hard to know where to use which medicine and what is the right patient for each medicine.”

The concept of NEDA is based on the idea that clinicians can define and attain a target in patients. The concept was first identified in the AFFIRM study, which sought to analyze the effect of natalizumab, in an effort to define composite measures for use in clinical practice. The study goal of clinical disease-free status, which was defined as no activity on clinical measures (ie, no relapses and no sustained disability progression), was combined with radiologic disease-free status (ie, no gadolinium-enhancing lesions and no new enlarging T2-hyperintense lesions on cranial MRI) into the larger goal of combined disease-free status, which came to be known as NEDA.

NEDA has proven to be achievable. In the AFFIRM study, 37% of patients on natalizumab achieved this goal, versus 7% on placebo, and Dr. West cited more than a half dozen other trials involving various treatments in which a sizable percentage of patients achieved NEDA. Maintaining NEDA, however, is another matter. In a seven-year longitudinal cohort of 215 patients with MS, Rotstein et al found that 46% of patients on DMT reached NEDA at one year, but 8% of the patients maintained NEDA for seven years.

“There wasn’t any difference between early or established MS in this metric, which argues a little bit against [the concept of a] window of opportunity,” said Dr. West. “It’s also worth noting that NEDA can predict itself, which is helpful [in the] long term. NEDA, two years later, had a positive predictive value of 78% for no progression in seven years—and this speaks to possibly that window of opportunity.” A patient with active MS who achieves NEDA for two years has a chance of maintaining NEDA for seven years, added Dr. West.

Induction Versus Escalation
Given that roughly one-third of patients on any approved MS medication are likely to achieve this goal, the questions for clinicians are how to enable a patient to attain NEDA and how to assess it. The induction and escalation treatment paradigms are relevant to these questions. The induction paradigm involves maximizing therapeutic benefit while tolerating increased therapeutic risk, based on the assumption that the risk of MS outweighs the risk of the treatment. The escalation paradigm involves minimizing therapeutic risk while maximizing therapeutic benefit, based on the assumption that one can decrease the risk of MS sufficiently while exposing the patient to less therapeutic risk.

The goal of the induction model is to stop MS activity as soon as possible. This goal is based on the assumption that a window of opportunity early in the disease warrants the increased therapeutic risk despite an unclear prognosis. “If there’s no window of opportunity, we can wait to induce [patients] a few years down the road,” said Dr. West. “But if there is really a narrow window at the beginning … then the induction model makes a lot of sense.”

The idea of the window of therapeutic opportunity arose from studies of alemtuzumab in the late 1990s and early 2000s in patients with severe MS. In a 2006 article that examined EDSS change following alemtuzumab therapy, Coles et al found that while most patients with secondary progressive MS got worse, those in the relapsing-remitting arm achieved significant and striking improvement. “Not only did they stabilize … they actually gained multiple points on their EDSS score,” said Dr. West.

One caveat with the induction paradigm is that because one gets a variable response from available DMTs, clinicians can achieve NEDA with any of these medicines, but often at a high cost: they all raise significant safety and tolerability concerns. These concerns provided the rationale for the escalation paradigm.

Data indicate that a Caucasian patient with features such as monofocal onset, a low relapse rate in the first two to five years, or good recovery after the first relapse likely has a better prognosis than an African American or other nonwhite patient with features such as multifocal onset, a high relapse rate in the first two to five years, or poor recovery after the first relapse. A patient with a good prognosis may limit a clinician’s tolerance of risk and incline him or her toward the escalation model, said Dr. West.

“The idea here is: can we basically work through medicines in a quick way to get [patients] to a NEDA status while also limiting the risk? The assumption here is that sometimes the risk of treatment is greater than that of the MS.... We can define and identify what constitutes treatment failure … and then the next DMT might be more effective.

“We have a lot of tools with which to fight this disease,” Dr. West continued. “Our goal should be to stop the illness as soon as we can…. Both the escalation model and the induction model are trying to get to that goal—they’re just doing it a little bit differently.”

—Fred Balzac

WASHINGTON, DC—Although treatment algorithms for multiple sclerosis (MS) cannot be adopted formally yet, FDA approval of nearly a dozen new therapies in recent years has yielded enough data to support several useful treatment strategies. At the center of current approaches for using these newer disease-modifying therapies (DMT), including the induction and escalation treatment paradigms, is the concept of no evidence of disease activity (NEDA), according to a presentation at the 67th Annual Meeting of the American Academy of Neurology.

“NEDA may be a viable goal and may be attainable with many [treatment] options,” said Timothy West, MD, a neurologist at the Sansum Clinic in Santa Barbara, California. It is unclear which patients will achieve NEDA, however. “We cannot yet predict response to therapy, so therapeutic risk probably should be a factor [in treatment decisions]. If I can give you a much lower-risk medicine and you get a really good clinical response … that would make us think that [clinicians] might want to do that first, which would support the escalation model.”

Recent data have helped establish several clinical and radiologic markers of poor prognosis that may help neurologists choose among available therapies. “If you see an African American male with 30 lesions, and 10 of them are enhancing, and he’s got an [Expanded Disability Status Scale (EDSS) score] of 4 … that person’s not going to do well,” he said. “You may [now] think about that person differently, and that’s a good thing.”

When a treatment fails, data can suggest which therapy clinicians should try next. These data, which are somewhat limited, derive largely from studies involving the modified Rio Score and the Bermel approach to DMT failure—both of which are based on interferon data alone—as well as the consensus-based Canadian Treatment Optimization Model. “That’s where we are right now as far as an algorithm and data,” said Dr. West. “We’re really basing this off of a small portion of our DMT arsenal…. You might get a little bit more of a bang for your buck if you switched to something in the same efficacy class. You might get a lot more bang for your buck if you jump to that next level of efficacy.”

How Can Patients Achieve NEDA?
Eleven DMTs have received FDA approval since 1993. “The current therapies … have varying mechanisms of action. They have varying efficacies. They have varying safety profiles, and it’s hard to know where to use which medicine and what is the right patient for each medicine.”

The concept of NEDA is based on the idea that clinicians can define and attain a target in patients. The concept was first identified in the AFFIRM study, which sought to analyze the effect of natalizumab, in an effort to define composite measures for use in clinical practice. The study goal of clinical disease-free status, which was defined as no activity on clinical measures (ie, no relapses and no sustained disability progression), was combined with radiologic disease-free status (ie, no gadolinium-enhancing lesions and no new enlarging T2-hyperintense lesions on cranial MRI) into the larger goal of combined disease-free status, which came to be known as NEDA.

NEDA has proven to be achievable. In the AFFIRM study, 37% of patients on natalizumab achieved this goal, versus 7% on placebo, and Dr. West cited more than a half dozen other trials involving various treatments in which a sizable percentage of patients achieved NEDA. Maintaining NEDA, however, is another matter. In a seven-year longitudinal cohort of 215 patients with MS, Rotstein et al found that 46% of patients on DMT reached NEDA at one year, but 8% of the patients maintained NEDA for seven years.

“There wasn’t any difference between early or established MS in this metric, which argues a little bit against [the concept of a] window of opportunity,” said Dr. West. “It’s also worth noting that NEDA can predict itself, which is helpful [in the] long term. NEDA, two years later, had a positive predictive value of 78% for no progression in seven years—and this speaks to possibly that window of opportunity.” A patient with active MS who achieves NEDA for two years has a chance of maintaining NEDA for seven years, added Dr. West.

Induction Versus Escalation
Given that roughly one-third of patients on any approved MS medication are likely to achieve this goal, the questions for clinicians are how to enable a patient to attain NEDA and how to assess it. The induction and escalation treatment paradigms are relevant to these questions. The induction paradigm involves maximizing therapeutic benefit while tolerating increased therapeutic risk, based on the assumption that the risk of MS outweighs the risk of the treatment. The escalation paradigm involves minimizing therapeutic risk while maximizing therapeutic benefit, based on the assumption that one can decrease the risk of MS sufficiently while exposing the patient to less therapeutic risk.

The goal of the induction model is to stop MS activity as soon as possible. This goal is based on the assumption that a window of opportunity early in the disease warrants the increased therapeutic risk despite an unclear prognosis. “If there’s no window of opportunity, we can wait to induce [patients] a few years down the road,” said Dr. West. “But if there is really a narrow window at the beginning … then the induction model makes a lot of sense.”

The idea of the window of therapeutic opportunity arose from studies of alemtuzumab in the late 1990s and early 2000s in patients with severe MS. In a 2006 article that examined EDSS change following alemtuzumab therapy, Coles et al found that while most patients with secondary progressive MS got worse, those in the relapsing-remitting arm achieved significant and striking improvement. “Not only did they stabilize … they actually gained multiple points on their EDSS score,” said Dr. West.

One caveat with the induction paradigm is that because one gets a variable response from available DMTs, clinicians can achieve NEDA with any of these medicines, but often at a high cost: they all raise significant safety and tolerability concerns. These concerns provided the rationale for the escalation paradigm.

Data indicate that a Caucasian patient with features such as monofocal onset, a low relapse rate in the first two to five years, or good recovery after the first relapse likely has a better prognosis than an African American or other nonwhite patient with features such as multifocal onset, a high relapse rate in the first two to five years, or poor recovery after the first relapse. A patient with a good prognosis may limit a clinician’s tolerance of risk and incline him or her toward the escalation model, said Dr. West.

“The idea here is: can we basically work through medicines in a quick way to get [patients] to a NEDA status while also limiting the risk? The assumption here is that sometimes the risk of treatment is greater than that of the MS.... We can define and identify what constitutes treatment failure … and then the next DMT might be more effective.

“We have a lot of tools with which to fight this disease,” Dr. West continued. “Our goal should be to stop the illness as soon as we can…. Both the escalation model and the induction model are trying to get to that goal—they’re just doing it a little bit differently.”

—Fred Balzac

Intermittent walking, rather than continuous walking, can help patients with multiple sclerosis (MS) walk farther and with less fatigue, and may help patients tolerate a greater dose of walking training, according to a randomized crossover study of 27 patients.

Researchers measured subjects’ walking distance under both intermittent (INT) walking conditions of three 2-minute bouts and continuous (CONT) walking conditions for 6 minutes straight. They found: 

• INT resulted in greater walking distances than CONT.

• Scores on the visual analog scale of fatigue were lower in the INT condition than CONT.

The study authors recommend further study to determine if exercise programs using intermittent walking would be beneficial.

Citation: Karpatkin H, Cohen ET, Rzetelny A, et al. Effects of intermittent versus continuous walking on distance walked and fatigue in persons with multiple sclerosis: a randomized crossover trial. J Neurol Phys Ther. 2015;39(3):172-178. doi:10.1097/NPT.0000000000000091.

Commentary: This is an important analysis identifying a missing piece of information that could provide additional effective avenues for evaluating the impact of MS in real life and improving therapeutic outcomes. The ability to evaluate the impact of MS in real life is limited by information obtained from Extended Disability Status Scale (EDSS) and MRI. Real everyday impact of the disease on daily life and activities extends beyond the 25-foot walk and is typically measured as prolonged impact over the course of a day or longer and involves extended activities and intermittent activities. This analysis provides insight into people with MS who perform activities intermittently or in stages and not perhaps ongoing. This is real life, and this approach could provide a remedy of intermittent exercise or therapy to achieve effective improvement without the impact of exercise induced heating up causing greater impact from MS and negative effective exercise and therapy. – Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, NY

Intermittent walking, rather than continuous walking, can help patients with multiple sclerosis (MS) walk farther and with less fatigue, and may help patients tolerate a greater dose of walking training, according to a randomized crossover study of 27 patients.

Researchers measured subjects’ walking distance under both intermittent (INT) walking conditions of three 2-minute bouts and continuous (CONT) walking conditions for 6 minutes straight. They found: 

• INT resulted in greater walking distances than CONT.

• Scores on the visual analog scale of fatigue were lower in the INT condition than CONT.

The study authors recommend further study to determine if exercise programs using intermittent walking would be beneficial.

Citation: Karpatkin H, Cohen ET, Rzetelny A, et al. Effects of intermittent versus continuous walking on distance walked and fatigue in persons with multiple sclerosis: a randomized crossover trial. J Neurol Phys Ther. 2015;39(3):172-178. doi:10.1097/NPT.0000000000000091.

Commentary: This is an important analysis identifying a missing piece of information that could provide additional effective avenues for evaluating the impact of MS in real life and improving therapeutic outcomes. The ability to evaluate the impact of MS in real life is limited by information obtained from Extended Disability Status Scale (EDSS) and MRI. Real everyday impact of the disease on daily life and activities extends beyond the 25-foot walk and is typically measured as prolonged impact over the course of a day or longer and involves extended activities and intermittent activities. This analysis provides insight into people with MS who perform activities intermittently or in stages and not perhaps ongoing. This is real life, and this approach could provide a remedy of intermittent exercise or therapy to achieve effective improvement without the impact of exercise induced heating up causing greater impact from MS and negative effective exercise and therapy. – Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, NY

Intermittent walking, rather than continuous walking, can help patients with multiple sclerosis (MS) walk farther and with less fatigue, and may help patients tolerate a greater dose of walking training, according to a randomized crossover study of 27 patients.

Researchers measured subjects’ walking distance under both intermittent (INT) walking conditions of three 2-minute bouts and continuous (CONT) walking conditions for 6 minutes straight. They found: 

• INT resulted in greater walking distances than CONT.

• Scores on the visual analog scale of fatigue were lower in the INT condition than CONT.

The study authors recommend further study to determine if exercise programs using intermittent walking would be beneficial.

Citation: Karpatkin H, Cohen ET, Rzetelny A, et al. Effects of intermittent versus continuous walking on distance walked and fatigue in persons with multiple sclerosis: a randomized crossover trial. J Neurol Phys Ther. 2015;39(3):172-178. doi:10.1097/NPT.0000000000000091.

Commentary: This is an important analysis identifying a missing piece of information that could provide additional effective avenues for evaluating the impact of MS in real life and improving therapeutic outcomes. The ability to evaluate the impact of MS in real life is limited by information obtained from Extended Disability Status Scale (EDSS) and MRI. Real everyday impact of the disease on daily life and activities extends beyond the 25-foot walk and is typically measured as prolonged impact over the course of a day or longer and involves extended activities and intermittent activities. This analysis provides insight into people with MS who perform activities intermittently or in stages and not perhaps ongoing. This is real life, and this approach could provide a remedy of intermittent exercise or therapy to achieve effective improvement without the impact of exercise induced heating up causing greater impact from MS and negative effective exercise and therapy. – Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, NY

In patients with multiple sclerosis (MS), remarkable cord gray matter (GM) atrophy is present at multiple cervical and lower thoracic levels, and may reflect widespread cord GM degeneration, according to an imaging study of 142 patients with MS and 20 healthy controls.

Investigators used phase-sensitive inversion recovery magnetic resonance imaging at 3T to measure total cord areas (TCAs), GM areas, and white matter (WM) areas at discs C2/3, C3/4, T8/9 and T9/10. They found: 

• Patients with relapsing MS had smaller thoracic cord GM areas than controls.

• Patients with progressive MS showed smaller GM areas and TCAs compared with patients with RMS.

• All measurements were inversely correlated with Expanded Disability Status Scale scores.

• Thoracic cord GM areas correlated with lower limb function.

• In multivariable models, cervical cord GM areas had the strongest correlation with Expanded Disability Status Scale scores, followed by thoracic cord GM area and brain GM volume.

Citation: Schlaeger R, Papinutto N, Zhu AH, et al. Association between thoracic spinal cord gray matter atrophy and disability in multiple sclerosis. JAMA Neurol. 2015. doi: 10.1001/jamaneurol.2015.0993.

In patients with multiple sclerosis (MS), remarkable cord gray matter (GM) atrophy is present at multiple cervical and lower thoracic levels, and may reflect widespread cord GM degeneration, according to an imaging study of 142 patients with MS and 20 healthy controls.

Investigators used phase-sensitive inversion recovery magnetic resonance imaging at 3T to measure total cord areas (TCAs), GM areas, and white matter (WM) areas at discs C2/3, C3/4, T8/9 and T9/10. They found: 

• Patients with relapsing MS had smaller thoracic cord GM areas than controls.

• Patients with progressive MS showed smaller GM areas and TCAs compared with patients with RMS.

• All measurements were inversely correlated with Expanded Disability Status Scale scores.

• Thoracic cord GM areas correlated with lower limb function.

• In multivariable models, cervical cord GM areas had the strongest correlation with Expanded Disability Status Scale scores, followed by thoracic cord GM area and brain GM volume.

Citation: Schlaeger R, Papinutto N, Zhu AH, et al. Association between thoracic spinal cord gray matter atrophy and disability in multiple sclerosis. JAMA Neurol. 2015. doi: 10.1001/jamaneurol.2015.0993.

In patients with multiple sclerosis (MS), remarkable cord gray matter (GM) atrophy is present at multiple cervical and lower thoracic levels, and may reflect widespread cord GM degeneration, according to an imaging study of 142 patients with MS and 20 healthy controls.

Investigators used phase-sensitive inversion recovery magnetic resonance imaging at 3T to measure total cord areas (TCAs), GM areas, and white matter (WM) areas at discs C2/3, C3/4, T8/9 and T9/10. They found: 

• Patients with relapsing MS had smaller thoracic cord GM areas than controls.

• Patients with progressive MS showed smaller GM areas and TCAs compared with patients with RMS.

• All measurements were inversely correlated with Expanded Disability Status Scale scores.

• Thoracic cord GM areas correlated with lower limb function.

• In multivariable models, cervical cord GM areas had the strongest correlation with Expanded Disability Status Scale scores, followed by thoracic cord GM area and brain GM volume.

Citation: Schlaeger R, Papinutto N, Zhu AH, et al. Association between thoracic spinal cord gray matter atrophy and disability in multiple sclerosis. JAMA Neurol. 2015. doi: 10.1001/jamaneurol.2015.0993.

Percutaneous balloon compression is an effective treatment for trigeminal neuralgia in patients with multiple sclerosis (MS), but compared to non-MS patients, symptom recurrence is higher and requires multiple procedures, according to a retrospective study of 80 consecutive patients who underwent a total of 144 procedures.

Investigators analyzed the results of 17 MS and 63 non-MS patients and found:     

• The first operation was performed in younger patients with MS, than non-MS patients, at an average of 59 years verses 72 years.

• Symptom recurrence rates were higher in patients with MS than those without (86% versus 47%).

• More MS patients than non-MS patients required multiple procedures (70% versus 44%).

Citation: Martin S, Teo M, Suttner N. The effectiveness of percutaneous balloon compression in the treatment of trigeminal neuralgia in patients with multiple sclerosis. J Neurosurg. 2015:1-5. [Epub ahead of print]

Percutaneous balloon compression is an effective treatment for trigeminal neuralgia in patients with multiple sclerosis (MS), but compared to non-MS patients, symptom recurrence is higher and requires multiple procedures, according to a retrospective study of 80 consecutive patients who underwent a total of 144 procedures.

Investigators analyzed the results of 17 MS and 63 non-MS patients and found:     

• The first operation was performed in younger patients with MS, than non-MS patients, at an average of 59 years verses 72 years.

• Symptom recurrence rates were higher in patients with MS than those without (86% versus 47%).

• More MS patients than non-MS patients required multiple procedures (70% versus 44%).

Citation: Martin S, Teo M, Suttner N. The effectiveness of percutaneous balloon compression in the treatment of trigeminal neuralgia in patients with multiple sclerosis. J Neurosurg. 2015:1-5. [Epub ahead of print]

Percutaneous balloon compression is an effective treatment for trigeminal neuralgia in patients with multiple sclerosis (MS), but compared to non-MS patients, symptom recurrence is higher and requires multiple procedures, according to a retrospective study of 80 consecutive patients who underwent a total of 144 procedures.

Investigators analyzed the results of 17 MS and 63 non-MS patients and found:     

• The first operation was performed in younger patients with MS, than non-MS patients, at an average of 59 years verses 72 years.

• Symptom recurrence rates were higher in patients with MS than those without (86% versus 47%).

• More MS patients than non-MS patients required multiple procedures (70% versus 44%).

Citation: Martin S, Teo M, Suttner N. The effectiveness of percutaneous balloon compression in the treatment of trigeminal neuralgia in patients with multiple sclerosis. J Neurosurg. 2015:1-5. [Epub ahead of print]

Combining quantitative susceptibility mapping (QSM) with R2* mapping is useful for characterizing heterogeneity in multiple sclerosis (MS) lesions, according to a study of 306 MS lesions from 24 MS patients who underwent 7T MRI.

Investigators calculated maps of R₂*, frequency, and qualitative susceptibility using acquired multiecho gradient echo (GRE) phase data and found:

• 93% of lesions showed hypointensity on R₂*.

• Susceptibility contrast in lesions varied with 40% being isointense and 58% hyperintense in the lesion core.

• Correlations between R₂* and susceptibility were found in hyperintense lesions but not in isointense ones.

• 74% of periventricular, 53% of subcortical, and 38% of juxtacortical lesions were found to be susceptibility hyperintense.

Citation: Li X, Harrison DM, Liu H, et al. Magnetic susceptibility contrast variations in multiple sclerosis lesions. J Magn Reson Imaging. 2015. doi: 10.1002/jmri.24976. [Epub ahead of print]

Combining quantitative susceptibility mapping (QSM) with R2* mapping is useful for characterizing heterogeneity in multiple sclerosis (MS) lesions, according to a study of 306 MS lesions from 24 MS patients who underwent 7T MRI.

Investigators calculated maps of R₂*, frequency, and qualitative susceptibility using acquired multiecho gradient echo (GRE) phase data and found:

• 93% of lesions showed hypointensity on R₂*.

• Susceptibility contrast in lesions varied with 40% being isointense and 58% hyperintense in the lesion core.

• Correlations between R₂* and susceptibility were found in hyperintense lesions but not in isointense ones.

• 74% of periventricular, 53% of subcortical, and 38% of juxtacortical lesions were found to be susceptibility hyperintense.

Citation: Li X, Harrison DM, Liu H, et al. Magnetic susceptibility contrast variations in multiple sclerosis lesions. J Magn Reson Imaging. 2015. doi: 10.1002/jmri.24976. [Epub ahead of print]

Combining quantitative susceptibility mapping (QSM) with R2* mapping is useful for characterizing heterogeneity in multiple sclerosis (MS) lesions, according to a study of 306 MS lesions from 24 MS patients who underwent 7T MRI.

Investigators calculated maps of R₂*, frequency, and qualitative susceptibility using acquired multiecho gradient echo (GRE) phase data and found:

• 93% of lesions showed hypointensity on R₂*.

• Susceptibility contrast in lesions varied with 40% being isointense and 58% hyperintense in the lesion core.

• Correlations between R₂* and susceptibility were found in hyperintense lesions but not in isointense ones.

• 74% of periventricular, 53% of subcortical, and 38% of juxtacortical lesions were found to be susceptibility hyperintense.

Citation: Li X, Harrison DM, Liu H, et al. Magnetic susceptibility contrast variations in multiple sclerosis lesions. J Magn Reson Imaging. 2015. doi: 10.1002/jmri.24976. [Epub ahead of print]

Multiple sclerosis (MS) survival is influenced not only by the underlying autoimmune process, but also by patient comorbidities and lifestyle factors, according to a retrospective analysis of 1,713 MS patients in the UK Clinical Practice Research Datalink.

Investigators followed patients to identify deaths and causes and found infections and depression are common comorbidities at 80% and 46%, respectively. In addition, the adjusted hazard ratios for all-cause mortality were:

•current smoking: 2.0

•alcohol abuse: 7.6

•pneumonia and influenza: 2.7

•urinary tract infections: 4.1

•heart disease, 2.2

•cancer: 4.9

Citation: Jick SS, Li L, Falcone GJ, Vassilev ZP, Wallander MA. Epidemiology of multiple sclerosis: results from a large observational study in the UK. J Neurol. 2015. [Epub ahead of print]

Multiple sclerosis (MS) survival is influenced not only by the underlying autoimmune process, but also by patient comorbidities and lifestyle factors, according to a retrospective analysis of 1,713 MS patients in the UK Clinical Practice Research Datalink.

Investigators followed patients to identify deaths and causes and found infections and depression are common comorbidities at 80% and 46%, respectively. In addition, the adjusted hazard ratios for all-cause mortality were:

•current smoking: 2.0

•alcohol abuse: 7.6

•pneumonia and influenza: 2.7

•urinary tract infections: 4.1

•heart disease, 2.2

•cancer: 4.9

Citation: Jick SS, Li L, Falcone GJ, Vassilev ZP, Wallander MA. Epidemiology of multiple sclerosis: results from a large observational study in the UK. J Neurol. 2015. [Epub ahead of print]

Multiple sclerosis (MS) survival is influenced not only by the underlying autoimmune process, but also by patient comorbidities and lifestyle factors, according to a retrospective analysis of 1,713 MS patients in the UK Clinical Practice Research Datalink.

Investigators followed patients to identify deaths and causes and found infections and depression are common comorbidities at 80% and 46%, respectively. In addition, the adjusted hazard ratios for all-cause mortality were:

•current smoking: 2.0

•alcohol abuse: 7.6

•pneumonia and influenza: 2.7

•urinary tract infections: 4.1

•heart disease, 2.2

•cancer: 4.9

Citation: Jick SS, Li L, Falcone GJ, Vassilev ZP, Wallander MA. Epidemiology of multiple sclerosis: results from a large observational study in the UK. J Neurol. 2015. [Epub ahead of print]

INDIANAPOLIS – With the emergence of 11 Food and Drug Administration–approved treatments for clinically isolated syndrome and/or relapsing forms of multiple sclerosis since 1993, patients have more choices for disease-modifying therapy than ever before. Dr. Mitzi Joi Williams describes choosing the right disease-modifying therapy as a balancing act that considers efficacy, safety, and tolerability.

“As we have more medications for MS, especially with different mechanisms of action, there may be some side effects that we may not be familiar with,” Dr. Williams, a neurologist at the Multiple Sclerosis Center of Atlanta, said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “You want a drug that you and the patient feel comfortable with and find tolerable. In the past when we only had injections, we’d say, ‘you have to tough it out; we don’t have anything else.’ ”

Other considerations, she said, include non–neurologic side effects, sequencing of therapies, and compliance with monitoring. “Some medications require blood work every month for 6 months, others require blood work every month for 4 or 5 years,” Dr. Williams said. “That’s a lot for patients to keep up with.”

The two most recent drugs approved for MS are alemtuzumab and pegylated interferon beta-1a. Alemtuzumab, which is indicated for the treatment of relapsing-remitting MS, is a monoclonal antibody to CD52 and has been previously used in patients with chronic lymphocytic leukemia. Dosing is 12 mg/day delivered intravenously for 3-5 days once a year. Possible adverse effects include profound lymphopenia, autoimmune thyroid disease, immune thrombocytopenic purpura, infusion reaction, and increased susceptibility to infections.

The other newcomer, pegylated interferon beta-1a is a recombinant interferon beta-1a protein attached to a polyethylene glycol molecule that reduces proinflammatory cytokines and inhibits T-cell migration and is indicated for relapsing MS. Dosing is 125 mcg subcutaneously every 2 or 4 weeks. Common adverse events include flulike symptoms, infection-site reactions, fever, and headache.

Another drug that has been submitted to the FDA for approval is daclizumab, a humanized monoclonal antibody that binds to CD25, decreasing activated T cells. It is intended for the treatment of relapsing MS. The dosing schedule would be 150 mg delivered subcutaneously every other week at home. Data from the SELECT trial, a year-long, phase II study of the agent, showed a 50%-54% decrease in annualized relapse rate (ARR), a 43%-57% decrease in confirmed disability, a 79%-86% reduction in new gadolinium (Gd)-enhancing lesions, and a 70%-79% reduction in new or enlarging T2 lesions. A phase II extension trial called SELECTION showed a 59% decrease in ARR, a 54% decrease in confirmed disability, a 86% reduction in new Gd-enhancing lesions, and a 74% reduction in new or enlarging T2 lesions. Potential adverse side effects include increased risk for infection, abnormal liver function tests, diarrhea, constipation, and swelling of the extremities. It has previously been used in rheumatoid arthritis and in kidney transplant patients.

Another promising agent in phase III studies is ocrelizumab, which is being studied in doses of 600 mg or 2,000 mg in patients with relapsing-remitting MS and primary-progressive MS. “It’s an anti-CD20 molecule that is similar to rituximab, which has been used in MS for some time, but it’s a more humanized antibody,” Dr. Williams said. She noted that a multicenter phase II study showed that ARR decreased by 73% with the 2,000-mg dose and by 80% with the 600-mg dose (Lancet 2011;378:1779-87). It also showed that Gd-enhancing lesions decreased by 96% with the 2,000-mg dose and by 89% with the 600-mg dose. “Potential adverse events reported in the trial include infusion-site reactions and increased risk of infection,” she said. “One study participant died from systemic inflammatory response of unknown cause.”

Other drugs for relapsing MS in earlier phases of research included ofatumumab, S1P receptor modulators, Tcelna, statins, antibiotics, and vitamin D3. Agents being investigated for progressive MS include S1P receptor modulators, masitinib, and ibudilast. “The more options we have for our patients, the better, because there’s no one drug that’s right for everyone,” Dr. Williams said.

Potential therapies could eventually come via more studies of drugs and mechanisms for myelin repair, including anti-LINGO-1 and stem cell therapies, as well as hormone therapy in the form of estrogen and testosterone. Other avenues of research include gene and DNA studies, personalized medicine and biomarkers, and monitoring progression of disease.

Dr. Williams disclosed that she is a consultant and speaker for Biogen Idec, Teva Neuroscience, EMD Serono, Mallinckrodt Pharmaceuticals, Novartis, Genzyme, and Acorda Therapeutics.

dbrunk@frontlinemedcom.com

INDIANAPOLIS – With the emergence of 11 Food and Drug Administration–approved treatments for clinically isolated syndrome and/or relapsing forms of multiple sclerosis since 1993, patients have more choices for disease-modifying therapy than ever before. Dr. Mitzi Joi Williams describes choosing the right disease-modifying therapy as a balancing act that considers efficacy, safety, and tolerability.

“As we have more medications for MS, especially with different mechanisms of action, there may be some side effects that we may not be familiar with,” Dr. Williams, a neurologist at the Multiple Sclerosis Center of Atlanta, said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “You want a drug that you and the patient feel comfortable with and find tolerable. In the past when we only had injections, we’d say, ‘you have to tough it out; we don’t have anything else.’ ”

Other considerations, she said, include non–neurologic side effects, sequencing of therapies, and compliance with monitoring. “Some medications require blood work every month for 6 months, others require blood work every month for 4 or 5 years,” Dr. Williams said. “That’s a lot for patients to keep up with.”

The two most recent drugs approved for MS are alemtuzumab and pegylated interferon beta-1a. Alemtuzumab, which is indicated for the treatment of relapsing-remitting MS, is a monoclonal antibody to CD52 and has been previously used in patients with chronic lymphocytic leukemia. Dosing is 12 mg/day delivered intravenously for 3-5 days once a year. Possible adverse effects include profound lymphopenia, autoimmune thyroid disease, immune thrombocytopenic purpura, infusion reaction, and increased susceptibility to infections.

The other newcomer, pegylated interferon beta-1a is a recombinant interferon beta-1a protein attached to a polyethylene glycol molecule that reduces proinflammatory cytokines and inhibits T-cell migration and is indicated for relapsing MS. Dosing is 125 mcg subcutaneously every 2 or 4 weeks. Common adverse events include flulike symptoms, infection-site reactions, fever, and headache.

Another drug that has been submitted to the FDA for approval is daclizumab, a humanized monoclonal antibody that binds to CD25, decreasing activated T cells. It is intended for the treatment of relapsing MS. The dosing schedule would be 150 mg delivered subcutaneously every other week at home. Data from the SELECT trial, a year-long, phase II study of the agent, showed a 50%-54% decrease in annualized relapse rate (ARR), a 43%-57% decrease in confirmed disability, a 79%-86% reduction in new gadolinium (Gd)-enhancing lesions, and a 70%-79% reduction in new or enlarging T2 lesions. A phase II extension trial called SELECTION showed a 59% decrease in ARR, a 54% decrease in confirmed disability, a 86% reduction in new Gd-enhancing lesions, and a 74% reduction in new or enlarging T2 lesions. Potential adverse side effects include increased risk for infection, abnormal liver function tests, diarrhea, constipation, and swelling of the extremities. It has previously been used in rheumatoid arthritis and in kidney transplant patients.

Another promising agent in phase III studies is ocrelizumab, which is being studied in doses of 600 mg or 2,000 mg in patients with relapsing-remitting MS and primary-progressive MS. “It’s an anti-CD20 molecule that is similar to rituximab, which has been used in MS for some time, but it’s a more humanized antibody,” Dr. Williams said. She noted that a multicenter phase II study showed that ARR decreased by 73% with the 2,000-mg dose and by 80% with the 600-mg dose (Lancet 2011;378:1779-87). It also showed that Gd-enhancing lesions decreased by 96% with the 2,000-mg dose and by 89% with the 600-mg dose. “Potential adverse events reported in the trial include infusion-site reactions and increased risk of infection,” she said. “One study participant died from systemic inflammatory response of unknown cause.”

Other drugs for relapsing MS in earlier phases of research included ofatumumab, S1P receptor modulators, Tcelna, statins, antibiotics, and vitamin D3. Agents being investigated for progressive MS include S1P receptor modulators, masitinib, and ibudilast. “The more options we have for our patients, the better, because there’s no one drug that’s right for everyone,” Dr. Williams said.

Potential therapies could eventually come via more studies of drugs and mechanisms for myelin repair, including anti-LINGO-1 and stem cell therapies, as well as hormone therapy in the form of estrogen and testosterone. Other avenues of research include gene and DNA studies, personalized medicine and biomarkers, and monitoring progression of disease.

Dr. Williams disclosed that she is a consultant and speaker for Biogen Idec, Teva Neuroscience, EMD Serono, Mallinckrodt Pharmaceuticals, Novartis, Genzyme, and Acorda Therapeutics.

dbrunk@frontlinemedcom.com

INDIANAPOLIS – With the emergence of 11 Food and Drug Administration–approved treatments for clinically isolated syndrome and/or relapsing forms of multiple sclerosis since 1993, patients have more choices for disease-modifying therapy than ever before. Dr. Mitzi Joi Williams describes choosing the right disease-modifying therapy as a balancing act that considers efficacy, safety, and tolerability.

“As we have more medications for MS, especially with different mechanisms of action, there may be some side effects that we may not be familiar with,” Dr. Williams, a neurologist at the Multiple Sclerosis Center of Atlanta, said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “You want a drug that you and the patient feel comfortable with and find tolerable. In the past when we only had injections, we’d say, ‘you have to tough it out; we don’t have anything else.’ ”

Other considerations, she said, include non–neurologic side effects, sequencing of therapies, and compliance with monitoring. “Some medications require blood work every month for 6 months, others require blood work every month for 4 or 5 years,” Dr. Williams said. “That’s a lot for patients to keep up with.”

The two most recent drugs approved for MS are alemtuzumab and pegylated interferon beta-1a. Alemtuzumab, which is indicated for the treatment of relapsing-remitting MS, is a monoclonal antibody to CD52 and has been previously used in patients with chronic lymphocytic leukemia. Dosing is 12 mg/day delivered intravenously for 3-5 days once a year. Possible adverse effects include profound lymphopenia, autoimmune thyroid disease, immune thrombocytopenic purpura, infusion reaction, and increased susceptibility to infections.

The other newcomer, pegylated interferon beta-1a is a recombinant interferon beta-1a protein attached to a polyethylene glycol molecule that reduces proinflammatory cytokines and inhibits T-cell migration and is indicated for relapsing MS. Dosing is 125 mcg subcutaneously every 2 or 4 weeks. Common adverse events include flulike symptoms, infection-site reactions, fever, and headache.

Another drug that has been submitted to the FDA for approval is daclizumab, a humanized monoclonal antibody that binds to CD25, decreasing activated T cells. It is intended for the treatment of relapsing MS. The dosing schedule would be 150 mg delivered subcutaneously every other week at home. Data from the SELECT trial, a year-long, phase II study of the agent, showed a 50%-54% decrease in annualized relapse rate (ARR), a 43%-57% decrease in confirmed disability, a 79%-86% reduction in new gadolinium (Gd)-enhancing lesions, and a 70%-79% reduction in new or enlarging T2 lesions. A phase II extension trial called SELECTION showed a 59% decrease in ARR, a 54% decrease in confirmed disability, a 86% reduction in new Gd-enhancing lesions, and a 74% reduction in new or enlarging T2 lesions. Potential adverse side effects include increased risk for infection, abnormal liver function tests, diarrhea, constipation, and swelling of the extremities. It has previously been used in rheumatoid arthritis and in kidney transplant patients.

Another promising agent in phase III studies is ocrelizumab, which is being studied in doses of 600 mg or 2,000 mg in patients with relapsing-remitting MS and primary-progressive MS. “It’s an anti-CD20 molecule that is similar to rituximab, which has been used in MS for some time, but it’s a more humanized antibody,” Dr. Williams said. She noted that a multicenter phase II study showed that ARR decreased by 73% with the 2,000-mg dose and by 80% with the 600-mg dose (Lancet 2011;378:1779-87). It also showed that Gd-enhancing lesions decreased by 96% with the 2,000-mg dose and by 89% with the 600-mg dose. “Potential adverse events reported in the trial include infusion-site reactions and increased risk of infection,” she said. “One study participant died from systemic inflammatory response of unknown cause.”

Other drugs for relapsing MS in earlier phases of research included ofatumumab, S1P receptor modulators, Tcelna, statins, antibiotics, and vitamin D3. Agents being investigated for progressive MS include S1P receptor modulators, masitinib, and ibudilast. “The more options we have for our patients, the better, because there’s no one drug that’s right for everyone,” Dr. Williams said.

Potential therapies could eventually come via more studies of drugs and mechanisms for myelin repair, including anti-LINGO-1 and stem cell therapies, as well as hormone therapy in the form of estrogen and testosterone. Other avenues of research include gene and DNA studies, personalized medicine and biomarkers, and monitoring progression of disease.

Dr. Williams disclosed that she is a consultant and speaker for Biogen Idec, Teva Neuroscience, EMD Serono, Mallinckrodt Pharmaceuticals, Novartis, Genzyme, and Acorda Therapeutics.

dbrunk@frontlinemedcom.com