ICYMI Multiple Sclerosis

Over time, neurologists who specialize in multiple sclerosis (MS) have tended to tolerate less and less disease activity before they consider changing their patients’ therapies. “The concept that’s starting to emerge in the MS field is that of striving for no detectable disease activity,” said Jeffrey A. Cohen, MD, Director of Experimental Therapeutics at the Cleveland Clinic Mellen MS Center.

Neurologists generally understand a disease activity–free state to mean an absence of MRI activity, relapses, and progression of disability. “With some of the more highly effective therapies, we’re also looking for remission of fatigue and depression complaints,” said Timothy Vollmer, MD, Professor of Neurology and Director of Clinical Research at the University of Colorado School of Medicine.

Why Is Tolerance for Disease Activity Decreasing?
One reason that the treating-to-target or “zero tolerance” approach to MS disease activity is gaining acceptance is that “we’re realizing that almost any ongoing disease activity has some potential ramifications, in terms of causing additional tissue damage,” said Dr. Cohen. The emergence of an increasing number of new and more effective disease-modifying therapies also has decreased tolerance for disease activity.

Some new therapies are more potent than the established drugs, but they also raise concerns about patient safety. For example, natalizumab increases the risk of progressive multifocal leukoencephalopathy in patients who have John Cunningham virus (JCV). The JCV antibody assay, however “increases the potential for using natalizumab,” and thus broadens neurologists’ therapeutic options, said Fred Lublin, MD, Saunders Family Professor of Neurology at the Icahn School of Medicine at Mount Sinai in New York City.

“Increasingly, we strive for a completely stable disease if we can attain it with reasonable safety and tolerability,” said Dr. Cohen. “Because none of our assessment tools is 100% sensitive, repeated re-evaluation of individual patients over time is needed. In addition, no particular treatment is going to work for all patients.”

How Should Neurologists Respond to Disease Activity?
The zero-tolerance approach would prompt a neurologist to consider changing therapies if the patient showed any signs of disease activity. But, because of a lack of data, the neurologist could not be sure that the patient would improve after switching to the new drug. Switch studies have all shown benefits, “but they’ve not been properly designed,” said Dr. Lublin.

“To answer the question in a scientific fashion, you’d have to take individuals who meet your definition of an inadequate response and randomize them to one of two other therapies. And then you could say whether switching them to therapy A is better than switching to therapy B,” he continued. “If you say to someone, ‘Well, we don’t think you’re doing so well, so we’re going to try you on this therapy or keep you on your same therapy,’ that’s not a real scientifically valid study design.

“When you take people who meet a definition of inadequate response, you’ve already got a biased population,” Dr. Lublin explained. “When you switch them to something else, just by regression to the mean, they tend to do better. And that’s why switch studies are challenged and, if not designed properly, don’t answer the question,” Dr. Lublin observed. Remission and Improvement May Be Possible for Some Patients The complete suppression of disease activity remains an elusive goal. “The problem with zero tolerance is that we don’t have any zero-activity drugs,” said Dr. Lublin. “Even with a therapy as good as natalizumab, 63% of individuals will fail that definition [ie, a disease activity–free state] over two years.

“However, we’ve seen zero activity with every drug we have out there in some people,” added Dr. Lublin. “So, for some people, it’s achievable ... for some people, it may not be achievable.”

Full disease remission is not possible in patients with high levels of disability, but it may be possible in patients with early-onset MS. A disease activity–free state appears to be achievable in at least some patients who are JCV antibody negative (ie, approximately 45% of the overall patient population) and are in the earlier relapsing-remitting phase of the disease, said Dr. Vollmer.

“On natalizumab and, we think, also on rituxumab, and probably on alemtuzumab, … in that patient population, a majority of patients … will not only have cessation of disease activity, they’ll actually get better over time,” he added. “About 30% continue to have relapses and will continue to develop ongoing disability.” Symptom stability or improvement may also be achievable in some patients with newer drugs such as fingolimod and dimethyl fumarate, “but we just haven’t treated enough patients and haven’t had them out long enough to be sure yet,” said Dr. Vollmer.

“In our clinic, we’re now trying to actually improve patient function over time,” noted Dr. Vollmer. “We expect them to get better, particularly if they exercise and take some of the more highly effective therapies. Particularly for patients with the earlier phase disease, we’re looking for full disease remission, including remission of fatigue and depression symptoms.”

Functional recovery has become possible for some patients following the introduction of disease-modifying therapies with increased efficacy. Oral formulations of fingolimod, dimethyl fumarate, and teriflunomide also could become highly effective treatment options in the coming years. As these and other new drugs emerge, they could expand the number of patients who can achieve remission or improvement—and also make the suppression of MS disease activity increasingly feasible.

Over time, neurologists who specialize in multiple sclerosis (MS) have tended to tolerate less and less disease activity before they consider changing their patients’ therapies. “The concept that’s starting to emerge in the MS field is that of striving for no detectable disease activity,” said Jeffrey A. Cohen, MD, Director of Experimental Therapeutics at the Cleveland Clinic Mellen MS Center.

Neurologists generally understand a disease activity–free state to mean an absence of MRI activity, relapses, and progression of disability. “With some of the more highly effective therapies, we’re also looking for remission of fatigue and depression complaints,” said Timothy Vollmer, MD, Professor of Neurology and Director of Clinical Research at the University of Colorado School of Medicine.

Why Is Tolerance for Disease Activity Decreasing?
One reason that the treating-to-target or “zero tolerance” approach to MS disease activity is gaining acceptance is that “we’re realizing that almost any ongoing disease activity has some potential ramifications, in terms of causing additional tissue damage,” said Dr. Cohen. The emergence of an increasing number of new and more effective disease-modifying therapies also has decreased tolerance for disease activity.

Some new therapies are more potent than the established drugs, but they also raise concerns about patient safety. For example, natalizumab increases the risk of progressive multifocal leukoencephalopathy in patients who have John Cunningham virus (JCV). The JCV antibody assay, however “increases the potential for using natalizumab,” and thus broadens neurologists’ therapeutic options, said Fred Lublin, MD, Saunders Family Professor of Neurology at the Icahn School of Medicine at Mount Sinai in New York City.

“Increasingly, we strive for a completely stable disease if we can attain it with reasonable safety and tolerability,” said Dr. Cohen. “Because none of our assessment tools is 100% sensitive, repeated re-evaluation of individual patients over time is needed. In addition, no particular treatment is going to work for all patients.”

How Should Neurologists Respond to Disease Activity?
The zero-tolerance approach would prompt a neurologist to consider changing therapies if the patient showed any signs of disease activity. But, because of a lack of data, the neurologist could not be sure that the patient would improve after switching to the new drug. Switch studies have all shown benefits, “but they’ve not been properly designed,” said Dr. Lublin.

“To answer the question in a scientific fashion, you’d have to take individuals who meet your definition of an inadequate response and randomize them to one of two other therapies. And then you could say whether switching them to therapy A is better than switching to therapy B,” he continued. “If you say to someone, ‘Well, we don’t think you’re doing so well, so we’re going to try you on this therapy or keep you on your same therapy,’ that’s not a real scientifically valid study design.

“When you take people who meet a definition of inadequate response, you’ve already got a biased population,” Dr. Lublin explained. “When you switch them to something else, just by regression to the mean, they tend to do better. And that’s why switch studies are challenged and, if not designed properly, don’t answer the question,” Dr. Lublin observed. Remission and Improvement May Be Possible for Some Patients The complete suppression of disease activity remains an elusive goal. “The problem with zero tolerance is that we don’t have any zero-activity drugs,” said Dr. Lublin. “Even with a therapy as good as natalizumab, 63% of individuals will fail that definition [ie, a disease activity–free state] over two years.

“However, we’ve seen zero activity with every drug we have out there in some people,” added Dr. Lublin. “So, for some people, it’s achievable ... for some people, it may not be achievable.”

Full disease remission is not possible in patients with high levels of disability, but it may be possible in patients with early-onset MS. A disease activity–free state appears to be achievable in at least some patients who are JCV antibody negative (ie, approximately 45% of the overall patient population) and are in the earlier relapsing-remitting phase of the disease, said Dr. Vollmer.

“On natalizumab and, we think, also on rituxumab, and probably on alemtuzumab, … in that patient population, a majority of patients … will not only have cessation of disease activity, they’ll actually get better over time,” he added. “About 30% continue to have relapses and will continue to develop ongoing disability.” Symptom stability or improvement may also be achievable in some patients with newer drugs such as fingolimod and dimethyl fumarate, “but we just haven’t treated enough patients and haven’t had them out long enough to be sure yet,” said Dr. Vollmer.

“In our clinic, we’re now trying to actually improve patient function over time,” noted Dr. Vollmer. “We expect them to get better, particularly if they exercise and take some of the more highly effective therapies. Particularly for patients with the earlier phase disease, we’re looking for full disease remission, including remission of fatigue and depression symptoms.”

Functional recovery has become possible for some patients following the introduction of disease-modifying therapies with increased efficacy. Oral formulations of fingolimod, dimethyl fumarate, and teriflunomide also could become highly effective treatment options in the coming years. As these and other new drugs emerge, they could expand the number of patients who can achieve remission or improvement—and also make the suppression of MS disease activity increasingly feasible.

Over time, neurologists who specialize in multiple sclerosis (MS) have tended to tolerate less and less disease activity before they consider changing their patients’ therapies. “The concept that’s starting to emerge in the MS field is that of striving for no detectable disease activity,” said Jeffrey A. Cohen, MD, Director of Experimental Therapeutics at the Cleveland Clinic Mellen MS Center.

Neurologists generally understand a disease activity–free state to mean an absence of MRI activity, relapses, and progression of disability. “With some of the more highly effective therapies, we’re also looking for remission of fatigue and depression complaints,” said Timothy Vollmer, MD, Professor of Neurology and Director of Clinical Research at the University of Colorado School of Medicine.

Why Is Tolerance for Disease Activity Decreasing?
One reason that the treating-to-target or “zero tolerance” approach to MS disease activity is gaining acceptance is that “we’re realizing that almost any ongoing disease activity has some potential ramifications, in terms of causing additional tissue damage,” said Dr. Cohen. The emergence of an increasing number of new and more effective disease-modifying therapies also has decreased tolerance for disease activity.

Some new therapies are more potent than the established drugs, but they also raise concerns about patient safety. For example, natalizumab increases the risk of progressive multifocal leukoencephalopathy in patients who have John Cunningham virus (JCV). The JCV antibody assay, however “increases the potential for using natalizumab,” and thus broadens neurologists’ therapeutic options, said Fred Lublin, MD, Saunders Family Professor of Neurology at the Icahn School of Medicine at Mount Sinai in New York City.

“Increasingly, we strive for a completely stable disease if we can attain it with reasonable safety and tolerability,” said Dr. Cohen. “Because none of our assessment tools is 100% sensitive, repeated re-evaluation of individual patients over time is needed. In addition, no particular treatment is going to work for all patients.”

How Should Neurologists Respond to Disease Activity?
The zero-tolerance approach would prompt a neurologist to consider changing therapies if the patient showed any signs of disease activity. But, because of a lack of data, the neurologist could not be sure that the patient would improve after switching to the new drug. Switch studies have all shown benefits, “but they’ve not been properly designed,” said Dr. Lublin.

“To answer the question in a scientific fashion, you’d have to take individuals who meet your definition of an inadequate response and randomize them to one of two other therapies. And then you could say whether switching them to therapy A is better than switching to therapy B,” he continued. “If you say to someone, ‘Well, we don’t think you’re doing so well, so we’re going to try you on this therapy or keep you on your same therapy,’ that’s not a real scientifically valid study design.

“When you take people who meet a definition of inadequate response, you’ve already got a biased population,” Dr. Lublin explained. “When you switch them to something else, just by regression to the mean, they tend to do better. And that’s why switch studies are challenged and, if not designed properly, don’t answer the question,” Dr. Lublin observed. Remission and Improvement May Be Possible for Some Patients The complete suppression of disease activity remains an elusive goal. “The problem with zero tolerance is that we don’t have any zero-activity drugs,” said Dr. Lublin. “Even with a therapy as good as natalizumab, 63% of individuals will fail that definition [ie, a disease activity–free state] over two years.

“However, we’ve seen zero activity with every drug we have out there in some people,” added Dr. Lublin. “So, for some people, it’s achievable ... for some people, it may not be achievable.”

Full disease remission is not possible in patients with high levels of disability, but it may be possible in patients with early-onset MS. A disease activity–free state appears to be achievable in at least some patients who are JCV antibody negative (ie, approximately 45% of the overall patient population) and are in the earlier relapsing-remitting phase of the disease, said Dr. Vollmer.

“On natalizumab and, we think, also on rituxumab, and probably on alemtuzumab, … in that patient population, a majority of patients … will not only have cessation of disease activity, they’ll actually get better over time,” he added. “About 30% continue to have relapses and will continue to develop ongoing disability.” Symptom stability or improvement may also be achievable in some patients with newer drugs such as fingolimod and dimethyl fumarate, “but we just haven’t treated enough patients and haven’t had them out long enough to be sure yet,” said Dr. Vollmer.

“In our clinic, we’re now trying to actually improve patient function over time,” noted Dr. Vollmer. “We expect them to get better, particularly if they exercise and take some of the more highly effective therapies. Particularly for patients with the earlier phase disease, we’re looking for full disease remission, including remission of fatigue and depression symptoms.”

Functional recovery has become possible for some patients following the introduction of disease-modifying therapies with increased efficacy. Oral formulations of fingolimod, dimethyl fumarate, and teriflunomide also could become highly effective treatment options in the coming years. As these and other new drugs emerge, they could expand the number of patients who can achieve remission or improvement—and also make the suppression of MS disease activity increasingly feasible.

Ludwig Kappos’s assessment of approved and emerging oral disease-modifying therapies (DMTs) for multiple sclerosis and his comparison of these medicines with injectable therapies nicely summarizes efficacy and safety data for fingolimod, dimethyl fumarate, teriflunomide, and laquinimod.

Although these drugs were primarily compared to placebo in pivotal trials, all were also compared with injectable DMTs. Dimethyl fumarate was compared with glatiramer acetate, fingolimod and laquinimod were compared with intramuscular interferon beta-1a, and teriflunomide was compared with a high dose of subcutaneous interferon beta-1a.

Some clinical and MRI outcomes significantly favored fingolimod over interferon beta 1-a, whereas laquinimod did not demonstrate superiority to the latter drug. Dimethyl fumarate also showed a significant reduction in relapse rate in the 240-mg tid dosage group (but not in the 240-mg bid group) and on some MRI indicators, compared with glatiramer acetate. None of these drugs, however, showed a benefit versus a comparator on disability progression. In most instances, the comparator data did not reflect the primary outcome of the trial.

The best way to compare efficacy is by well-designed, head-to-head trials. Such studies require a large number of patients and are expensive to carry out. Whether such studies will eventually be initiated remains to be seen. Although preliminary evidence from the oral drug pivotal trials suggests the comparative efficacy of each, more studies are clearly needed. It is worth remembering that not all the injectable DMTs have the same effect on MRI or clinical outcomes, which must be considered when comparison studies are carried out.

Lastly, it is still early in the assessment of the relative safety of oral drugs, safety being the other major factor in drug assessment. On the other hand, the interferons and glatiramer acetate have been shown to have excellent safety records over long periods of time.

Ludwig Kappos’s assessment of approved and emerging oral disease-modifying therapies (DMTs) for multiple sclerosis and his comparison of these medicines with injectable therapies nicely summarizes efficacy and safety data for fingolimod, dimethyl fumarate, teriflunomide, and laquinimod.

Although these drugs were primarily compared to placebo in pivotal trials, all were also compared with injectable DMTs. Dimethyl fumarate was compared with glatiramer acetate, fingolimod and laquinimod were compared with intramuscular interferon beta-1a, and teriflunomide was compared with a high dose of subcutaneous interferon beta-1a.

Some clinical and MRI outcomes significantly favored fingolimod over interferon beta 1-a, whereas laquinimod did not demonstrate superiority to the latter drug. Dimethyl fumarate also showed a significant reduction in relapse rate in the 240-mg tid dosage group (but not in the 240-mg bid group) and on some MRI indicators, compared with glatiramer acetate. None of these drugs, however, showed a benefit versus a comparator on disability progression. In most instances, the comparator data did not reflect the primary outcome of the trial.

The best way to compare efficacy is by well-designed, head-to-head trials. Such studies require a large number of patients and are expensive to carry out. Whether such studies will eventually be initiated remains to be seen. Although preliminary evidence from the oral drug pivotal trials suggests the comparative efficacy of each, more studies are clearly needed. It is worth remembering that not all the injectable DMTs have the same effect on MRI or clinical outcomes, which must be considered when comparison studies are carried out.

Lastly, it is still early in the assessment of the relative safety of oral drugs, safety being the other major factor in drug assessment. On the other hand, the interferons and glatiramer acetate have been shown to have excellent safety records over long periods of time.

Ludwig Kappos’s assessment of approved and emerging oral disease-modifying therapies (DMTs) for multiple sclerosis and his comparison of these medicines with injectable therapies nicely summarizes efficacy and safety data for fingolimod, dimethyl fumarate, teriflunomide, and laquinimod.

Although these drugs were primarily compared to placebo in pivotal trials, all were also compared with injectable DMTs. Dimethyl fumarate was compared with glatiramer acetate, fingolimod and laquinimod were compared with intramuscular interferon beta-1a, and teriflunomide was compared with a high dose of subcutaneous interferon beta-1a.

Some clinical and MRI outcomes significantly favored fingolimod over interferon beta 1-a, whereas laquinimod did not demonstrate superiority to the latter drug. Dimethyl fumarate also showed a significant reduction in relapse rate in the 240-mg tid dosage group (but not in the 240-mg bid group) and on some MRI indicators, compared with glatiramer acetate. None of these drugs, however, showed a benefit versus a comparator on disability progression. In most instances, the comparator data did not reflect the primary outcome of the trial.

The best way to compare efficacy is by well-designed, head-to-head trials. Such studies require a large number of patients and are expensive to carry out. Whether such studies will eventually be initiated remains to be seen. Although preliminary evidence from the oral drug pivotal trials suggests the comparative efficacy of each, more studies are clearly needed. It is worth remembering that not all the injectable DMTs have the same effect on MRI or clinical outcomes, which must be considered when comparison studies are carried out.

Lastly, it is still early in the assessment of the relative safety of oral drugs, safety being the other major factor in drug assessment. On the other hand, the interferons and glatiramer acetate have been shown to have excellent safety records over long periods of time.

LYON, FRANCE—Emerging oral therapies for multiple sclerosis (MS) may be more effective than established drugs such as interferon beta and glatiramer acetate, according to research presented at the 28th Congress of the European Committee for Treatment and Research in MS (ECTRIMS).

Based on various clinical trials, investigators expect the drugs—fingolimod, dimethyl fumarate, teriflunomide, and laquinimod—to suppress inflammation, reduce relapse activity, and provide neuroprotection. “If all these oral drugs appear and deliver what they are promising to do based on the controlled studies, then the future for the ABCR drugs [Avonex, Betaseron, Copaxone, and Rebif] may be a little bit darker,” said Ludwig Kappos, MD, Chair of Neurology at University Hospital in Basel, Switzerland.

Fingolimod Reduces MS-Related Brain Volume Reduction
Fingolimod, a chemical derivative of myriocin, interacts with four of the five S1P receptors that are distributed throughout the body. In three large, prospective, phase III studies (FREEDOMS 1 and 2 and TRANSFORMS), fingolimod reduced annual relapse rate by approximately 50%. The drug was associated with a longer time to relapse and a higher number of relapse-free patients than placebo. In all three studies, fingolimod improved MS Functional Composite (MSFC) score by a statistically significant 5%. The drug also had a greater effect on inflammatory outcomes than once-weekly interferon. “The most intriguing finding” was that fingolimod decreased MS-related brain volume reduction by approximately one-third, said Dr. Kappos. The finding was consistent and statistically significant, appeared after the first six months of treatment, and persisted over time, he added. Fingolimod was associated with bradycardia that developed within one to three days of the initial dose. “If the receptor is saturated with fingolimod …, then the effect cannot be elicited again, and there is no persisting bradyarrhythmic effect after the first dose,” said Dr. Kappos.

Dimethyl Fumarate Reduces Gadolinium-Enhancing Lesions
Dimethyl fumarate is an immunomodulator that induces “a cascade of cytoprotective effects that may be important for the way it acts in MS,” said Dr. Kappos. In the phase III CONFIRM study, which compared the drug with placebo and glatiramer acetate, dimethyl fumarate had an anti-inflammatory effect on gadolinium-enhancing lesions similar to that of fingolimod. The drug’s effect on disability progression, as measured by MSFC score, was statistically insignificant, however. Dimethyl fumarate’s effect on brain atrophy also failed to reach statistical significance. In contrast to fingolimod, dimethyl fumarate was not associated with bradyarrhythmia. The drug was not associated with macular edema, but it was linked to gastrointestinal side effects that “may present an obstacle for compliance,” said Dr. Kappos.

Teriflunomide Reduces Relapse Rate
Teriflunomide “seems to have a mild immunosuppressive and immunomodulating aspect” and “could be a good oral alternative to interferons and glatiramer acetate,” said Dr. Kappos. By reversibly inhibiting dihydroorotate dehydrogenase, teriflunomide inhibits pathologic immune response. In the TEMSO and TOWER studies, 7- and 14-mg doses of teriflunomide reduced relapse rate by 30%. The 14-mg dose of teriflunomide reduced disability progression by 30%, but the 7-mg dose did not have a significant effect on this outcome. In both studies, teriflunomide and placebo were associated with a similar number of adverse events. Although serious adverse events such as hair thinning occurred somewhat more frequently with teriflunomide than with placebo, “this compound will have a place in our therapeutic armamentarium,” said Dr. Kappos.

Laquinimod Has Weak Anti-Inflammatory Effects
Laquinimod, a quinoline-3-carboxamide, appears to provide neuroprotection by reducing astrocyte activation. The drug is notable for the dissociation between its neuroprotective effect and its “rather weak anti-inflammatory effect,” said Dr. Kappos. In the ALLEGRO study, laquinimod reduced relapse rate by a “disappointing” 21%, said Dr. Kappos. The drug reduced inflammatory outcomes by 30%, which is “rather modest” compared with other compounds, he added. At six months, however, laquinimod reduced disability progression by more than 34%. In two phase III studies, the drug also decreased brain volume reduction by 30%—a rate similar to that of fingolimod. Because laquinimod did not raise safety concerns, researchers may investigate whether the dose could be increased and what effect the new dose would have on relapses. But as of now, “laquinimod is perhaps the most remote from [clinical] practice” of all the emerging oral therapies, Dr. Kappos concluded.

LYON, FRANCE—Emerging oral therapies for multiple sclerosis (MS) may be more effective than established drugs such as interferon beta and glatiramer acetate, according to research presented at the 28th Congress of the European Committee for Treatment and Research in MS (ECTRIMS).

Based on various clinical trials, investigators expect the drugs—fingolimod, dimethyl fumarate, teriflunomide, and laquinimod—to suppress inflammation, reduce relapse activity, and provide neuroprotection. “If all these oral drugs appear and deliver what they are promising to do based on the controlled studies, then the future for the ABCR drugs [Avonex, Betaseron, Copaxone, and Rebif] may be a little bit darker,” said Ludwig Kappos, MD, Chair of Neurology at University Hospital in Basel, Switzerland.

Fingolimod Reduces MS-Related Brain Volume Reduction
Fingolimod, a chemical derivative of myriocin, interacts with four of the five S1P receptors that are distributed throughout the body. In three large, prospective, phase III studies (FREEDOMS 1 and 2 and TRANSFORMS), fingolimod reduced annual relapse rate by approximately 50%. The drug was associated with a longer time to relapse and a higher number of relapse-free patients than placebo. In all three studies, fingolimod improved MS Functional Composite (MSFC) score by a statistically significant 5%. The drug also had a greater effect on inflammatory outcomes than once-weekly interferon. “The most intriguing finding” was that fingolimod decreased MS-related brain volume reduction by approximately one-third, said Dr. Kappos. The finding was consistent and statistically significant, appeared after the first six months of treatment, and persisted over time, he added. Fingolimod was associated with bradycardia that developed within one to three days of the initial dose. “If the receptor is saturated with fingolimod …, then the effect cannot be elicited again, and there is no persisting bradyarrhythmic effect after the first dose,” said Dr. Kappos.

Dimethyl Fumarate Reduces Gadolinium-Enhancing Lesions
Dimethyl fumarate is an immunomodulator that induces “a cascade of cytoprotective effects that may be important for the way it acts in MS,” said Dr. Kappos. In the phase III CONFIRM study, which compared the drug with placebo and glatiramer acetate, dimethyl fumarate had an anti-inflammatory effect on gadolinium-enhancing lesions similar to that of fingolimod. The drug’s effect on disability progression, as measured by MSFC score, was statistically insignificant, however. Dimethyl fumarate’s effect on brain atrophy also failed to reach statistical significance. In contrast to fingolimod, dimethyl fumarate was not associated with bradyarrhythmia. The drug was not associated with macular edema, but it was linked to gastrointestinal side effects that “may present an obstacle for compliance,” said Dr. Kappos.

Teriflunomide Reduces Relapse Rate
Teriflunomide “seems to have a mild immunosuppressive and immunomodulating aspect” and “could be a good oral alternative to interferons and glatiramer acetate,” said Dr. Kappos. By reversibly inhibiting dihydroorotate dehydrogenase, teriflunomide inhibits pathologic immune response. In the TEMSO and TOWER studies, 7- and 14-mg doses of teriflunomide reduced relapse rate by 30%. The 14-mg dose of teriflunomide reduced disability progression by 30%, but the 7-mg dose did not have a significant effect on this outcome. In both studies, teriflunomide and placebo were associated with a similar number of adverse events. Although serious adverse events such as hair thinning occurred somewhat more frequently with teriflunomide than with placebo, “this compound will have a place in our therapeutic armamentarium,” said Dr. Kappos.

Laquinimod Has Weak Anti-Inflammatory Effects
Laquinimod, a quinoline-3-carboxamide, appears to provide neuroprotection by reducing astrocyte activation. The drug is notable for the dissociation between its neuroprotective effect and its “rather weak anti-inflammatory effect,” said Dr. Kappos. In the ALLEGRO study, laquinimod reduced relapse rate by a “disappointing” 21%, said Dr. Kappos. The drug reduced inflammatory outcomes by 30%, which is “rather modest” compared with other compounds, he added. At six months, however, laquinimod reduced disability progression by more than 34%. In two phase III studies, the drug also decreased brain volume reduction by 30%—a rate similar to that of fingolimod. Because laquinimod did not raise safety concerns, researchers may investigate whether the dose could be increased and what effect the new dose would have on relapses. But as of now, “laquinimod is perhaps the most remote from [clinical] practice” of all the emerging oral therapies, Dr. Kappos concluded.

LYON, FRANCE—Emerging oral therapies for multiple sclerosis (MS) may be more effective than established drugs such as interferon beta and glatiramer acetate, according to research presented at the 28th Congress of the European Committee for Treatment and Research in MS (ECTRIMS).

Based on various clinical trials, investigators expect the drugs—fingolimod, dimethyl fumarate, teriflunomide, and laquinimod—to suppress inflammation, reduce relapse activity, and provide neuroprotection. “If all these oral drugs appear and deliver what they are promising to do based on the controlled studies, then the future for the ABCR drugs [Avonex, Betaseron, Copaxone, and Rebif] may be a little bit darker,” said Ludwig Kappos, MD, Chair of Neurology at University Hospital in Basel, Switzerland.

Fingolimod Reduces MS-Related Brain Volume Reduction
Fingolimod, a chemical derivative of myriocin, interacts with four of the five S1P receptors that are distributed throughout the body. In three large, prospective, phase III studies (FREEDOMS 1 and 2 and TRANSFORMS), fingolimod reduced annual relapse rate by approximately 50%. The drug was associated with a longer time to relapse and a higher number of relapse-free patients than placebo. In all three studies, fingolimod improved MS Functional Composite (MSFC) score by a statistically significant 5%. The drug also had a greater effect on inflammatory outcomes than once-weekly interferon. “The most intriguing finding” was that fingolimod decreased MS-related brain volume reduction by approximately one-third, said Dr. Kappos. The finding was consistent and statistically significant, appeared after the first six months of treatment, and persisted over time, he added. Fingolimod was associated with bradycardia that developed within one to three days of the initial dose. “If the receptor is saturated with fingolimod …, then the effect cannot be elicited again, and there is no persisting bradyarrhythmic effect after the first dose,” said Dr. Kappos.

Dimethyl Fumarate Reduces Gadolinium-Enhancing Lesions
Dimethyl fumarate is an immunomodulator that induces “a cascade of cytoprotective effects that may be important for the way it acts in MS,” said Dr. Kappos. In the phase III CONFIRM study, which compared the drug with placebo and glatiramer acetate, dimethyl fumarate had an anti-inflammatory effect on gadolinium-enhancing lesions similar to that of fingolimod. The drug’s effect on disability progression, as measured by MSFC score, was statistically insignificant, however. Dimethyl fumarate’s effect on brain atrophy also failed to reach statistical significance. In contrast to fingolimod, dimethyl fumarate was not associated with bradyarrhythmia. The drug was not associated with macular edema, but it was linked to gastrointestinal side effects that “may present an obstacle for compliance,” said Dr. Kappos.

Teriflunomide Reduces Relapse Rate
Teriflunomide “seems to have a mild immunosuppressive and immunomodulating aspect” and “could be a good oral alternative to interferons and glatiramer acetate,” said Dr. Kappos. By reversibly inhibiting dihydroorotate dehydrogenase, teriflunomide inhibits pathologic immune response. In the TEMSO and TOWER studies, 7- and 14-mg doses of teriflunomide reduced relapse rate by 30%. The 14-mg dose of teriflunomide reduced disability progression by 30%, but the 7-mg dose did not have a significant effect on this outcome. In both studies, teriflunomide and placebo were associated with a similar number of adverse events. Although serious adverse events such as hair thinning occurred somewhat more frequently with teriflunomide than with placebo, “this compound will have a place in our therapeutic armamentarium,” said Dr. Kappos.

Laquinimod Has Weak Anti-Inflammatory Effects
Laquinimod, a quinoline-3-carboxamide, appears to provide neuroprotection by reducing astrocyte activation. The drug is notable for the dissociation between its neuroprotective effect and its “rather weak anti-inflammatory effect,” said Dr. Kappos. In the ALLEGRO study, laquinimod reduced relapse rate by a “disappointing” 21%, said Dr. Kappos. The drug reduced inflammatory outcomes by 30%, which is “rather modest” compared with other compounds, he added. At six months, however, laquinimod reduced disability progression by more than 34%. In two phase III studies, the drug also decreased brain volume reduction by 30%—a rate similar to that of fingolimod. Because laquinimod did not raise safety concerns, researchers may investigate whether the dose could be increased and what effect the new dose would have on relapses. But as of now, “laquinimod is perhaps the most remote from [clinical] practice” of all the emerging oral therapies, Dr. Kappos concluded.

LYON, FRANCE—Teriflunomide does not interfere significantly with the serologic responses to recall antigens, allowing patients with multiple sclerosis (MS) treated with teriflunomide to mount effective immune responses to the seasonal flu vaccine. At the 28th Congress of the European Committee for Treatment and Research in MS (ECTRIMS), researchers presented the results of the phase II TERIVA study, which investigated the ability of patients with relapsing forms of MS receiving teriflunomide to respond to influenza vaccine and determine whether antigen responses were preserved under teriflunomide treatment.

Amit Bar-Or, MDCM, MSc, and colleagues conducted a multicenter, multinational, parallel-group study involving 128 patients in three treatment groups. Groups one and two included patients with relapsing forms of MS treated for at least six months with either teriflunomide 7 mg or 14 mg, respectively. Median treatment duration was 5.7 years for the 7-mg dose group and 5.8 years for the 14-mg dose group. Group three comprised patients with relapsing forms of MS treated for at least six months with a stable dose of interferon beta. Median treatment duration in this group was 5.7 years. Group three represented a reference population of patients who have been reported to mount normal immune responses to influenza vaccination.

A screening period of up to 21 days was followed by influenza vaccination with the 2011/12 seasonal influenza vaccine per country standard on day 1 with antibody assessments at day 28 postimmunization.

The primary efficacy end point was the proportion of patients who achieved seroprotection to influenza vaccine strains, as defined as an influenza antibody titre of 40 or more for each strain (H1N1, H3N2, B) 28 days postvaccination. Evaluation of vaccine effectiveness was based on European criteria for influenza vaccine efficacy. The study enrolled 122 patients: 40 in group one, 39 in group two, and 43 in group three.

Dr. Bar-Or, who is an Associate Professor and Director of the Experimental Therapeutics Program and Scientific Director of the Clinical Research Unit at Montreal Neurological Institute, and colleagues reported that more than 90% of patients achieved postvaccination antibody titres of 40 or above for H1N1 and B strains in all treatment groups. For H3N2, titres of 40 or above were achieved in 90% or more of patients in the teriflunomide 7-mg and interferon beta groups and in 77% of the patients in the teriflunomide 14-mg group.

The study revealed no new safety concerns with teriflunomide administration, and influenza vaccination was generally well tolerated by the study population. The overall incidence of treatment-emergent adverse events was higher in the interferon beta group (45.7%) than in the two teriflunomide groups (26.8% in the 7-mg group and 36.6% in the 14-mg group).

The researchers found that patients with relapsing forms of MS treated with teriflunomide mounted effective immune responses to seasonal flu vaccination. These responses, they note, were in accordance with the European criteria for efficacy of influenza vaccination in a population of 18- to 60-year-olds. Further, following influenza vaccination, no new safety concerns arose in patients receiving teriflunomide.

“These results, combined with data from the TEMSO study, support the view that teriflunomide appears to limit abnormal pathogenic T-cell responses effectively, and it does not interfere significantly with the serologic responses to recall antigens,” the researchers concluded.

LYON, FRANCE—Teriflunomide does not interfere significantly with the serologic responses to recall antigens, allowing patients with multiple sclerosis (MS) treated with teriflunomide to mount effective immune responses to the seasonal flu vaccine. At the 28th Congress of the European Committee for Treatment and Research in MS (ECTRIMS), researchers presented the results of the phase II TERIVA study, which investigated the ability of patients with relapsing forms of MS receiving teriflunomide to respond to influenza vaccine and determine whether antigen responses were preserved under teriflunomide treatment.

Amit Bar-Or, MDCM, MSc, and colleagues conducted a multicenter, multinational, parallel-group study involving 128 patients in three treatment groups. Groups one and two included patients with relapsing forms of MS treated for at least six months with either teriflunomide 7 mg or 14 mg, respectively. Median treatment duration was 5.7 years for the 7-mg dose group and 5.8 years for the 14-mg dose group. Group three comprised patients with relapsing forms of MS treated for at least six months with a stable dose of interferon beta. Median treatment duration in this group was 5.7 years. Group three represented a reference population of patients who have been reported to mount normal immune responses to influenza vaccination.

A screening period of up to 21 days was followed by influenza vaccination with the 2011/12 seasonal influenza vaccine per country standard on day 1 with antibody assessments at day 28 postimmunization.

The primary efficacy end point was the proportion of patients who achieved seroprotection to influenza vaccine strains, as defined as an influenza antibody titre of 40 or more for each strain (H1N1, H3N2, B) 28 days postvaccination. Evaluation of vaccine effectiveness was based on European criteria for influenza vaccine efficacy. The study enrolled 122 patients: 40 in group one, 39 in group two, and 43 in group three.

Dr. Bar-Or, who is an Associate Professor and Director of the Experimental Therapeutics Program and Scientific Director of the Clinical Research Unit at Montreal Neurological Institute, and colleagues reported that more than 90% of patients achieved postvaccination antibody titres of 40 or above for H1N1 and B strains in all treatment groups. For H3N2, titres of 40 or above were achieved in 90% or more of patients in the teriflunomide 7-mg and interferon beta groups and in 77% of the patients in the teriflunomide 14-mg group.

The study revealed no new safety concerns with teriflunomide administration, and influenza vaccination was generally well tolerated by the study population. The overall incidence of treatment-emergent adverse events was higher in the interferon beta group (45.7%) than in the two teriflunomide groups (26.8% in the 7-mg group and 36.6% in the 14-mg group).

The researchers found that patients with relapsing forms of MS treated with teriflunomide mounted effective immune responses to seasonal flu vaccination. These responses, they note, were in accordance with the European criteria for efficacy of influenza vaccination in a population of 18- to 60-year-olds. Further, following influenza vaccination, no new safety concerns arose in patients receiving teriflunomide.

“These results, combined with data from the TEMSO study, support the view that teriflunomide appears to limit abnormal pathogenic T-cell responses effectively, and it does not interfere significantly with the serologic responses to recall antigens,” the researchers concluded.

LYON, FRANCE—Teriflunomide does not interfere significantly with the serologic responses to recall antigens, allowing patients with multiple sclerosis (MS) treated with teriflunomide to mount effective immune responses to the seasonal flu vaccine. At the 28th Congress of the European Committee for Treatment and Research in MS (ECTRIMS), researchers presented the results of the phase II TERIVA study, which investigated the ability of patients with relapsing forms of MS receiving teriflunomide to respond to influenza vaccine and determine whether antigen responses were preserved under teriflunomide treatment.

Amit Bar-Or, MDCM, MSc, and colleagues conducted a multicenter, multinational, parallel-group study involving 128 patients in three treatment groups. Groups one and two included patients with relapsing forms of MS treated for at least six months with either teriflunomide 7 mg or 14 mg, respectively. Median treatment duration was 5.7 years for the 7-mg dose group and 5.8 years for the 14-mg dose group. Group three comprised patients with relapsing forms of MS treated for at least six months with a stable dose of interferon beta. Median treatment duration in this group was 5.7 years. Group three represented a reference population of patients who have been reported to mount normal immune responses to influenza vaccination.

A screening period of up to 21 days was followed by influenza vaccination with the 2011/12 seasonal influenza vaccine per country standard on day 1 with antibody assessments at day 28 postimmunization.

The primary efficacy end point was the proportion of patients who achieved seroprotection to influenza vaccine strains, as defined as an influenza antibody titre of 40 or more for each strain (H1N1, H3N2, B) 28 days postvaccination. Evaluation of vaccine effectiveness was based on European criteria for influenza vaccine efficacy. The study enrolled 122 patients: 40 in group one, 39 in group two, and 43 in group three.

Dr. Bar-Or, who is an Associate Professor and Director of the Experimental Therapeutics Program and Scientific Director of the Clinical Research Unit at Montreal Neurological Institute, and colleagues reported that more than 90% of patients achieved postvaccination antibody titres of 40 or above for H1N1 and B strains in all treatment groups. For H3N2, titres of 40 or above were achieved in 90% or more of patients in the teriflunomide 7-mg and interferon beta groups and in 77% of the patients in the teriflunomide 14-mg group.

The study revealed no new safety concerns with teriflunomide administration, and influenza vaccination was generally well tolerated by the study population. The overall incidence of treatment-emergent adverse events was higher in the interferon beta group (45.7%) than in the two teriflunomide groups (26.8% in the 7-mg group and 36.6% in the 14-mg group).

The researchers found that patients with relapsing forms of MS treated with teriflunomide mounted effective immune responses to seasonal flu vaccination. These responses, they note, were in accordance with the European criteria for efficacy of influenza vaccination in a population of 18- to 60-year-olds. Further, following influenza vaccination, no new safety concerns arose in patients receiving teriflunomide.

“These results, combined with data from the TEMSO study, support the view that teriflunomide appears to limit abnormal pathogenic T-cell responses effectively, and it does not interfere significantly with the serologic responses to recall antigens,” the researchers concluded.

Neurologists try to prescribe the appropriate drugs for patients with relapsing-remitting multiple sclerosis (MS) to prevent ongoing disease activity. "Most of us feel that if a patient has incomplete control of his or her disease by their current therapy, we should consider switching therapy," said Jeffrey A. Cohen, MD, Director of Experimental Therapeutics at the Cleveland Clinic Mellen MS Center.

"In practice, it ends up being quite difficult," he added. "There's probably not unanimity among clinicians as to what constitutes excessive disease activity and which outcome to put more weight on. Exactly what to monitor and what criteria to use to change therapy probably differ from person to person."

“There are no standard guidelines for determining an inadequate response to therapy for any of the agents,” agreed Fred Lublin, MD, Saunders Family Professor of Neurology at Mount Sinai School of Medicine in New York City. It is difficult to know whether new lesions, for example, occur because the patient’s drug is not working or because his or her disease is getting worse.

Neutralizing antibodies to interferon or natalizumab are “one of the few indicators we have” that the therapy is not working, added Dr. Lublin. “If someone’s not doing well and they have neutralizing antibodies, then that would suggest it’s time for a switch.”

Undesirable side effects and adverse reactions are other fairly straightforward signs that a patient’s therapy should be changed. “If someone transitions into progressive disease, that’s a reasonably good indicator that he or she is probably not doing well enough on their current therapy,” said Dr. Lublin. Other criteria are less clear, however.

How Many Relapses Are Acceptable?
Many neurologists agree about the need to monitor the number and severity of a patient’s relapses, as well as the extent to which the patient recovers from them. If relapses continue, the clinician should consider changing the patient’s medication. But the number of relapses that should prompt a change is uncertain.

In addition, a lack of relapses may not mean that a patient’s disease is stable. “If you look at other markers of disease activity, primarily MRI, you can see that the patients’ brains are continuing to shrink—they’re developing cerebral atrophy—[and] they have multiple new gadolinium-enhancing lesions and T2 lesions forming,” said Timothy Vollmer, MD, Professor of Neurology and Director of Clinical Research at the University of Colorado School of Medicine in Denver. A patient may have between 10 and 20 MRI lesions before having a relapse, he added. If subclinical disease activity remains untreated, a patient risks developing progressive MS, which can’t be reversed.

MRI May Not Provide a Clear Image of a Patient’s Status
Neurologists also agree about the value of MRI as a measure of a patient’s condition, but have not arrived at a consensus about how many new MRI lesions should prompt a change in therapy. The scans’ relative importance may not be clear, either. “Sometimes MRI activity can happen in the absence of clinical activity, so there’s not always agreement [about] which should take precedence,” said Dr. Cohen.

In addition, MRIs obtained in clinical practice are highly variable. MRIs may be taken on different machines, at different field strengths, and with different acquisition parameters. The orientation of the patient in the machine also may change from one MRI to another. “It can sometimes be hard because of technical considerations to compare one scan to another,” observed Dr. Cohen. “You can see an obvious difference, but it’s very difficult sometimes to quantify the total amount of lesions and to say whether [the patient is] better or worse than last time.”

Clinical trials usually include a detailed protocol for obtaining MRIs, which typically are registered for consistency. Computers often quantify abnormalities such as lesion burden or brain volume. “Most of us don’t have access to those sorts of things in practice,” notes Dr. Cohen. “There may be subtle differences that may be significant, but not so obvious, that we sometimes miss.”

In addition, if a neurologist performs MRI scans once per year, he or she may not notice disease activity if the scans are taken during quiet phases when lesions have shrunk, said Dr. Vollmer. “If you do an MRI on a monthly basis, you can see a remarkable amount of disease activity,” he added, “but we can’t do that in a clinical setting.”

Revisiting the Neurologic Exam
The accumulation of neurologic impairment or disability, as measured by the neurologic exam, also could suggest that a patient’s current therapy is not working. But the neurologic exam “is highly subjective and not readily quantifiable,” said Dr. Cohen. For example, “it’s very hard to tell whether someone’s eye movements are worse today than when you saw them six months ago,” he added.

The Expanded Disability Status Scale (EDSS) helps quantify the results of a standard neurologic exam, but “it’s fairly insensitive to change, and there’s a 25% examiner variability issue,” said Mark Gudesblatt, MD, Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, New York. “The EDSS was invented by John Kurtzke 50 years ago,” he added. “What other technology has been unchanged for 50 years and remains the mainstay for clinical trials and patient care?”

Another concern is that, particularly in the early course of MS, “a fair amount of damage can accumulate, as evidenced by MRI, and not be apparent clinically, either to the patient or to the physician,” said Dr. Cohen.

In addition, the neurologic exam often does not measure cognition, which greatly influences a patient’s quality of life. But neurologists can incorporate a cognitive exam into an office visit by testing patients’ memory, reaction speed, and general awareness, said Anthony Reder, MD, Professor of Neurology at the University of Chicago Medical Center. Neurologists also can administer the Symbol Digit Modalities test, which is “the most sensitive single test for measuring cognitive decline in MS,” he added.

Is Help on the Way?
Because of the difficulty of conducting placebo-controlled trials, future drug studies are likely to include active comparators, said Dr. Lublin. The resulting comparative efficacy data will greatly help neurologists make treatment decisions. Studies comparing one highly active agent with another are unlikely to be performed, but comparisons of new products with older therapies probably will be published. “Alemtuzumab’s whole development program, practically, was against interferon,” and it has provided useful information, said Dr. Lublin.

The current emphasis on personalized medicine has raised questions about whether an individual patient may respond better to one agent than to another agent. “We hope to be able to get this kind of information in the not-too-distant future by using biomarkers of responsiveness,” said Dr. Lublin. Trials of daclizumab provided evidence that patients likely to respond to the drug had an immunologic biomarker. “It’s an interesting and exciting area for the future—and hopefully not-too-distant future,” said Dr. Lublin.

For the moment, individual clinical judgment remains the basis for decisions about patients’ drug regimens. “It’s a matter of trying to figure out the threshold of [disease] activity that would justify switching,” said Dr. Lublin. “None of these therapies is perfect. People have had attacks and changes on their MRI with every one of the therapies that we have. And so it becomes rather individualized as to what you think is best for the patient.”

When considering whether to change a patient’s drug regimen, neurologists should first consider the number and severity of the patient’s relapses and how well he or she has recovered from them. The neurologist also should look for the accumulation of neurologic impairment, which could indicate incomplete recovery from relapses or a transition to progressive disease. The physician should ask the patient how his or her life is going and watch for symptoms of depression, fatigue, and cognitive problems. Clinicians should also get input from the family about whether the patient is stable or worsening.

In addition, neurologists should consider how well the patient is tolerating the current drug, how long he or she has been using it, and how satisfied he or she is with it. The clinician also should consider the patient’s comorbidities and the stage of the patient’s illness. It may be better to treat aggressively in early stages, but aggressive therapy is not necessarily the most effective therapy for a given patient. Finally, if switching therapies is being considered, the neurologist should review the other available drugs, with an eye toward effective and safe drugs that the patient would tolerate and with which the neurologist is comfortable.

Neurologists try to prescribe the appropriate drugs for patients with relapsing-remitting multiple sclerosis (MS) to prevent ongoing disease activity. "Most of us feel that if a patient has incomplete control of his or her disease by their current therapy, we should consider switching therapy," said Jeffrey A. Cohen, MD, Director of Experimental Therapeutics at the Cleveland Clinic Mellen MS Center.

"In practice, it ends up being quite difficult," he added. "There's probably not unanimity among clinicians as to what constitutes excessive disease activity and which outcome to put more weight on. Exactly what to monitor and what criteria to use to change therapy probably differ from person to person."

“There are no standard guidelines for determining an inadequate response to therapy for any of the agents,” agreed Fred Lublin, MD, Saunders Family Professor of Neurology at Mount Sinai School of Medicine in New York City. It is difficult to know whether new lesions, for example, occur because the patient’s drug is not working or because his or her disease is getting worse.

Neutralizing antibodies to interferon or natalizumab are “one of the few indicators we have” that the therapy is not working, added Dr. Lublin. “If someone’s not doing well and they have neutralizing antibodies, then that would suggest it’s time for a switch.”

Undesirable side effects and adverse reactions are other fairly straightforward signs that a patient’s therapy should be changed. “If someone transitions into progressive disease, that’s a reasonably good indicator that he or she is probably not doing well enough on their current therapy,” said Dr. Lublin. Other criteria are less clear, however.

How Many Relapses Are Acceptable?
Many neurologists agree about the need to monitor the number and severity of a patient’s relapses, as well as the extent to which the patient recovers from them. If relapses continue, the clinician should consider changing the patient’s medication. But the number of relapses that should prompt a change is uncertain.

In addition, a lack of relapses may not mean that a patient’s disease is stable. “If you look at other markers of disease activity, primarily MRI, you can see that the patients’ brains are continuing to shrink—they’re developing cerebral atrophy—[and] they have multiple new gadolinium-enhancing lesions and T2 lesions forming,” said Timothy Vollmer, MD, Professor of Neurology and Director of Clinical Research at the University of Colorado School of Medicine in Denver. A patient may have between 10 and 20 MRI lesions before having a relapse, he added. If subclinical disease activity remains untreated, a patient risks developing progressive MS, which can’t be reversed.

MRI May Not Provide a Clear Image of a Patient’s Status
Neurologists also agree about the value of MRI as a measure of a patient’s condition, but have not arrived at a consensus about how many new MRI lesions should prompt a change in therapy. The scans’ relative importance may not be clear, either. “Sometimes MRI activity can happen in the absence of clinical activity, so there’s not always agreement [about] which should take precedence,” said Dr. Cohen.

In addition, MRIs obtained in clinical practice are highly variable. MRIs may be taken on different machines, at different field strengths, and with different acquisition parameters. The orientation of the patient in the machine also may change from one MRI to another. “It can sometimes be hard because of technical considerations to compare one scan to another,” observed Dr. Cohen. “You can see an obvious difference, but it’s very difficult sometimes to quantify the total amount of lesions and to say whether [the patient is] better or worse than last time.”

Clinical trials usually include a detailed protocol for obtaining MRIs, which typically are registered for consistency. Computers often quantify abnormalities such as lesion burden or brain volume. “Most of us don’t have access to those sorts of things in practice,” notes Dr. Cohen. “There may be subtle differences that may be significant, but not so obvious, that we sometimes miss.”

In addition, if a neurologist performs MRI scans once per year, he or she may not notice disease activity if the scans are taken during quiet phases when lesions have shrunk, said Dr. Vollmer. “If you do an MRI on a monthly basis, you can see a remarkable amount of disease activity,” he added, “but we can’t do that in a clinical setting.”

Revisiting the Neurologic Exam
The accumulation of neurologic impairment or disability, as measured by the neurologic exam, also could suggest that a patient’s current therapy is not working. But the neurologic exam “is highly subjective and not readily quantifiable,” said Dr. Cohen. For example, “it’s very hard to tell whether someone’s eye movements are worse today than when you saw them six months ago,” he added.

The Expanded Disability Status Scale (EDSS) helps quantify the results of a standard neurologic exam, but “it’s fairly insensitive to change, and there’s a 25% examiner variability issue,” said Mark Gudesblatt, MD, Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, New York. “The EDSS was invented by John Kurtzke 50 years ago,” he added. “What other technology has been unchanged for 50 years and remains the mainstay for clinical trials and patient care?”

Another concern is that, particularly in the early course of MS, “a fair amount of damage can accumulate, as evidenced by MRI, and not be apparent clinically, either to the patient or to the physician,” said Dr. Cohen.

In addition, the neurologic exam often does not measure cognition, which greatly influences a patient’s quality of life. But neurologists can incorporate a cognitive exam into an office visit by testing patients’ memory, reaction speed, and general awareness, said Anthony Reder, MD, Professor of Neurology at the University of Chicago Medical Center. Neurologists also can administer the Symbol Digit Modalities test, which is “the most sensitive single test for measuring cognitive decline in MS,” he added.

Is Help on the Way?
Because of the difficulty of conducting placebo-controlled trials, future drug studies are likely to include active comparators, said Dr. Lublin. The resulting comparative efficacy data will greatly help neurologists make treatment decisions. Studies comparing one highly active agent with another are unlikely to be performed, but comparisons of new products with older therapies probably will be published. “Alemtuzumab’s whole development program, practically, was against interferon,” and it has provided useful information, said Dr. Lublin.

The current emphasis on personalized medicine has raised questions about whether an individual patient may respond better to one agent than to another agent. “We hope to be able to get this kind of information in the not-too-distant future by using biomarkers of responsiveness,” said Dr. Lublin. Trials of daclizumab provided evidence that patients likely to respond to the drug had an immunologic biomarker. “It’s an interesting and exciting area for the future—and hopefully not-too-distant future,” said Dr. Lublin.

For the moment, individual clinical judgment remains the basis for decisions about patients’ drug regimens. “It’s a matter of trying to figure out the threshold of [disease] activity that would justify switching,” said Dr. Lublin. “None of these therapies is perfect. People have had attacks and changes on their MRI with every one of the therapies that we have. And so it becomes rather individualized as to what you think is best for the patient.”

When considering whether to change a patient’s drug regimen, neurologists should first consider the number and severity of the patient’s relapses and how well he or she has recovered from them. The neurologist also should look for the accumulation of neurologic impairment, which could indicate incomplete recovery from relapses or a transition to progressive disease. The physician should ask the patient how his or her life is going and watch for symptoms of depression, fatigue, and cognitive problems. Clinicians should also get input from the family about whether the patient is stable or worsening.

In addition, neurologists should consider how well the patient is tolerating the current drug, how long he or she has been using it, and how satisfied he or she is with it. The clinician also should consider the patient’s comorbidities and the stage of the patient’s illness. It may be better to treat aggressively in early stages, but aggressive therapy is not necessarily the most effective therapy for a given patient. Finally, if switching therapies is being considered, the neurologist should review the other available drugs, with an eye toward effective and safe drugs that the patient would tolerate and with which the neurologist is comfortable.

Neurologists try to prescribe the appropriate drugs for patients with relapsing-remitting multiple sclerosis (MS) to prevent ongoing disease activity. "Most of us feel that if a patient has incomplete control of his or her disease by their current therapy, we should consider switching therapy," said Jeffrey A. Cohen, MD, Director of Experimental Therapeutics at the Cleveland Clinic Mellen MS Center.

"In practice, it ends up being quite difficult," he added. "There's probably not unanimity among clinicians as to what constitutes excessive disease activity and which outcome to put more weight on. Exactly what to monitor and what criteria to use to change therapy probably differ from person to person."

“There are no standard guidelines for determining an inadequate response to therapy for any of the agents,” agreed Fred Lublin, MD, Saunders Family Professor of Neurology at Mount Sinai School of Medicine in New York City. It is difficult to know whether new lesions, for example, occur because the patient’s drug is not working or because his or her disease is getting worse.

Neutralizing antibodies to interferon or natalizumab are “one of the few indicators we have” that the therapy is not working, added Dr. Lublin. “If someone’s not doing well and they have neutralizing antibodies, then that would suggest it’s time for a switch.”

Undesirable side effects and adverse reactions are other fairly straightforward signs that a patient’s therapy should be changed. “If someone transitions into progressive disease, that’s a reasonably good indicator that he or she is probably not doing well enough on their current therapy,” said Dr. Lublin. Other criteria are less clear, however.

How Many Relapses Are Acceptable?
Many neurologists agree about the need to monitor the number and severity of a patient’s relapses, as well as the extent to which the patient recovers from them. If relapses continue, the clinician should consider changing the patient’s medication. But the number of relapses that should prompt a change is uncertain.

In addition, a lack of relapses may not mean that a patient’s disease is stable. “If you look at other markers of disease activity, primarily MRI, you can see that the patients’ brains are continuing to shrink—they’re developing cerebral atrophy—[and] they have multiple new gadolinium-enhancing lesions and T2 lesions forming,” said Timothy Vollmer, MD, Professor of Neurology and Director of Clinical Research at the University of Colorado School of Medicine in Denver. A patient may have between 10 and 20 MRI lesions before having a relapse, he added. If subclinical disease activity remains untreated, a patient risks developing progressive MS, which can’t be reversed.

MRI May Not Provide a Clear Image of a Patient’s Status
Neurologists also agree about the value of MRI as a measure of a patient’s condition, but have not arrived at a consensus about how many new MRI lesions should prompt a change in therapy. The scans’ relative importance may not be clear, either. “Sometimes MRI activity can happen in the absence of clinical activity, so there’s not always agreement [about] which should take precedence,” said Dr. Cohen.

In addition, MRIs obtained in clinical practice are highly variable. MRIs may be taken on different machines, at different field strengths, and with different acquisition parameters. The orientation of the patient in the machine also may change from one MRI to another. “It can sometimes be hard because of technical considerations to compare one scan to another,” observed Dr. Cohen. “You can see an obvious difference, but it’s very difficult sometimes to quantify the total amount of lesions and to say whether [the patient is] better or worse than last time.”

Clinical trials usually include a detailed protocol for obtaining MRIs, which typically are registered for consistency. Computers often quantify abnormalities such as lesion burden or brain volume. “Most of us don’t have access to those sorts of things in practice,” notes Dr. Cohen. “There may be subtle differences that may be significant, but not so obvious, that we sometimes miss.”

In addition, if a neurologist performs MRI scans once per year, he or she may not notice disease activity if the scans are taken during quiet phases when lesions have shrunk, said Dr. Vollmer. “If you do an MRI on a monthly basis, you can see a remarkable amount of disease activity,” he added, “but we can’t do that in a clinical setting.”

Revisiting the Neurologic Exam
The accumulation of neurologic impairment or disability, as measured by the neurologic exam, also could suggest that a patient’s current therapy is not working. But the neurologic exam “is highly subjective and not readily quantifiable,” said Dr. Cohen. For example, “it’s very hard to tell whether someone’s eye movements are worse today than when you saw them six months ago,” he added.

The Expanded Disability Status Scale (EDSS) helps quantify the results of a standard neurologic exam, but “it’s fairly insensitive to change, and there’s a 25% examiner variability issue,” said Mark Gudesblatt, MD, Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, New York. “The EDSS was invented by John Kurtzke 50 years ago,” he added. “What other technology has been unchanged for 50 years and remains the mainstay for clinical trials and patient care?”

Another concern is that, particularly in the early course of MS, “a fair amount of damage can accumulate, as evidenced by MRI, and not be apparent clinically, either to the patient or to the physician,” said Dr. Cohen.

In addition, the neurologic exam often does not measure cognition, which greatly influences a patient’s quality of life. But neurologists can incorporate a cognitive exam into an office visit by testing patients’ memory, reaction speed, and general awareness, said Anthony Reder, MD, Professor of Neurology at the University of Chicago Medical Center. Neurologists also can administer the Symbol Digit Modalities test, which is “the most sensitive single test for measuring cognitive decline in MS,” he added.

Is Help on the Way?
Because of the difficulty of conducting placebo-controlled trials, future drug studies are likely to include active comparators, said Dr. Lublin. The resulting comparative efficacy data will greatly help neurologists make treatment decisions. Studies comparing one highly active agent with another are unlikely to be performed, but comparisons of new products with older therapies probably will be published. “Alemtuzumab’s whole development program, practically, was against interferon,” and it has provided useful information, said Dr. Lublin.

The current emphasis on personalized medicine has raised questions about whether an individual patient may respond better to one agent than to another agent. “We hope to be able to get this kind of information in the not-too-distant future by using biomarkers of responsiveness,” said Dr. Lublin. Trials of daclizumab provided evidence that patients likely to respond to the drug had an immunologic biomarker. “It’s an interesting and exciting area for the future—and hopefully not-too-distant future,” said Dr. Lublin.

For the moment, individual clinical judgment remains the basis for decisions about patients’ drug regimens. “It’s a matter of trying to figure out the threshold of [disease] activity that would justify switching,” said Dr. Lublin. “None of these therapies is perfect. People have had attacks and changes on their MRI with every one of the therapies that we have. And so it becomes rather individualized as to what you think is best for the patient.”

When considering whether to change a patient’s drug regimen, neurologists should first consider the number and severity of the patient’s relapses and how well he or she has recovered from them. The neurologist also should look for the accumulation of neurologic impairment, which could indicate incomplete recovery from relapses or a transition to progressive disease. The physician should ask the patient how his or her life is going and watch for symptoms of depression, fatigue, and cognitive problems. Clinicians should also get input from the family about whether the patient is stable or worsening.

In addition, neurologists should consider how well the patient is tolerating the current drug, how long he or she has been using it, and how satisfied he or she is with it. The clinician also should consider the patient’s comorbidities and the stage of the patient’s illness. It may be better to treat aggressively in early stages, but aggressive therapy is not necessarily the most effective therapy for a given patient. Finally, if switching therapies is being considered, the neurologist should review the other available drugs, with an eye toward effective and safe drugs that the patient would tolerate and with which the neurologist is comfortable.

LYON, FRANCE—Chronic cerebrospinal venous insufficiency (CCSVI) appears to occur at a similarly low rate among patients with multiple sclerosis (MS), patients with other neurologic disorders, and healthy controls, researchers reported at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). CCSVI also appears to occur at similar rates among patients with various types of MS.

The study results cast doubt on the hypothesis, first proposed by Paolo Zamboni, MD, Associate Professor of Morphology, Surgery, and Experimental Medicine at the University of Ferrara, Italy, that CCSVI is an important factor in MS. The findings also call into question Dr. Zamboni’s proposal that a type of angioplasty known as “liberation therapy” could be an effective treatment for patients with CCSVI and MS.

Testing the Zamboni Hypothesis
To determine whether there was a relationship between CCSVI and MS, under the sponsorship of the Italian Multiple Sclerosis Society, Giancarlo Comi, MD, Head of the Neurorehabilitation Unit at Fondazione San Raffaele del Monte Tabor in Milan, and colleagues enrolled subjects in a case–control observational study conducted at 35 Italian clinical centers. Of the study population, 1,165 patients had MS, 226 patients had other neurologic disorders, and 376 subjects were healthy controls. Subjects between ages 18 and 55 were eligible to participate.

All patients were evaluated by a neurologist. Local neurosonologists, who previously had been certified as having learned standardized criteria for diagnosing CCSVI, then performed blinded Echo Color Doppler (ECD) evaluations according to a predefined protocol to determine whether the subjects had CCSVI. Each exam was recorded and sent in a random manner to one of three expert central neurosonologists, who also had blind access to the ECDs.

The study’s primary end point, the presence of CCSVI, was determined by the agreement of the local and central neurosonologists. When the local and central neurosonologists disagreed, the exam was sent to the other two central neurosonologists, and the final diagnosis was made by a consensus of two of the three central neurosonologists.

The researchers excluded patients for technical reasons and 55 other subjects because of protocol violations. A total of 1,767 patients were included in the final analysis.

Most Subjects Did Not Have CCSVI
CCSVI was diagnosed in 3.26% of patients with MS, 3.10% of patients with other neurologic disorders, and 2.13% of healthy controls. The investigators found no statistical difference in CCSVI prevalence among the three groups. After comparing patients with various types of MS, the researchers found no statistical difference in CCSVI prevalence.

The central neurosonologists diagnosed CCSVI in 3.3% of patients with MS, 2.7% of patients with other neurologic disorders, and 3.2% of healthy controls. The investigators found no statistical difference between the three groups. The local neurosonologists diagnosed CCSVI in 15.9% of patients with MS, 15% of patients with other neurologic disorders, and 12% of controls. The investigators found no statistical difference between these groups.

Local clinical centers varied widely in their diagnoses of CCSVI. Some centers found CCSVI in 60% of all evaluated cases, and others found no cases, said Gianluigi Mancardi, MD, Head of the Department of Neuroscience at the University of Genoa and a coauthor of the study.

Local and central neurosonologists agreed on the absence of CCSVI 92% of the time, but disagreement on positive diagnoses was common. Central neurosonologists evaluated as positive 28 cases that had been evaluated as negative by local neurosonologists. Of 236 cases that had been evaluated as positive by local neurosonologists, 28 were evaluated as positive by central neurosonologists.

The three central neurosonologists agreed 99% of the time on negative diagnoses, but they had an “extremely low” rate of agreement for positive diagnoses, reported Dr. Comi and his coinvestigators. This result suggests that CCSVI diagnoses are highly subjective. “Even for experts, it was extremely difficult to say, ‘Oh yes, this is CCSVI,’” Dr. Comi noted.

Liberation Therapy May Have No Medical Basis
“This is the first multicenter study done in a blinded manner with a tremendous amount of patients,” said Dr. Mancardi. “The conclusion is that CCSVI is not associated with MS or with other neurologic disorders. There is no statistical difference [in CCSVI prevalence] between [patients with] MS, healthy controls, and [patients with] other neurologic disorders. Therefore, there is no evident role for CCSVI in MS.”

More than 1,000 patients worldwide have undergone angioplasty to treat CCSVI, according to Dr. Comi. Although it is understandable that patients with MS would seek alternative therapies, angioplasty “is an interventional type of treatment,” he said. “Interventional means that you expose the patient to potential risks. And this is one of the main reasons why we need to use a very objective approach, because we are taking care of our patients.”

To perform a clinical trial of angioplasty for CCSVI in patients with MS, researchers must first demonstrate that patients with MS have an increased risk of CCSVI, compared with normal controls or patients with other neurologic diseases. Dr. Comi’s study, however, found no difference among the three patient groups. “If we … decide to operate for this condition, then we should theoretically operate also on the normal controls,” said Dr. Comi.

“There is no rationale for a trial exploring the efficacy of the liberation therapy,” and a randomized trial of an endovascular procedure in patients with MS would be unethical, Dr. Comi commented. “The risk to treat patients is that the adverse effect of the intervention would overcome all the potential advantages,” he concluded.

LYON, FRANCE—Chronic cerebrospinal venous insufficiency (CCSVI) appears to occur at a similarly low rate among patients with multiple sclerosis (MS), patients with other neurologic disorders, and healthy controls, researchers reported at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). CCSVI also appears to occur at similar rates among patients with various types of MS.

The study results cast doubt on the hypothesis, first proposed by Paolo Zamboni, MD, Associate Professor of Morphology, Surgery, and Experimental Medicine at the University of Ferrara, Italy, that CCSVI is an important factor in MS. The findings also call into question Dr. Zamboni’s proposal that a type of angioplasty known as “liberation therapy” could be an effective treatment for patients with CCSVI and MS.

Testing the Zamboni Hypothesis
To determine whether there was a relationship between CCSVI and MS, under the sponsorship of the Italian Multiple Sclerosis Society, Giancarlo Comi, MD, Head of the Neurorehabilitation Unit at Fondazione San Raffaele del Monte Tabor in Milan, and colleagues enrolled subjects in a case–control observational study conducted at 35 Italian clinical centers. Of the study population, 1,165 patients had MS, 226 patients had other neurologic disorders, and 376 subjects were healthy controls. Subjects between ages 18 and 55 were eligible to participate.

All patients were evaluated by a neurologist. Local neurosonologists, who previously had been certified as having learned standardized criteria for diagnosing CCSVI, then performed blinded Echo Color Doppler (ECD) evaluations according to a predefined protocol to determine whether the subjects had CCSVI. Each exam was recorded and sent in a random manner to one of three expert central neurosonologists, who also had blind access to the ECDs.

The study’s primary end point, the presence of CCSVI, was determined by the agreement of the local and central neurosonologists. When the local and central neurosonologists disagreed, the exam was sent to the other two central neurosonologists, and the final diagnosis was made by a consensus of two of the three central neurosonologists.

The researchers excluded patients for technical reasons and 55 other subjects because of protocol violations. A total of 1,767 patients were included in the final analysis.

Most Subjects Did Not Have CCSVI
CCSVI was diagnosed in 3.26% of patients with MS, 3.10% of patients with other neurologic disorders, and 2.13% of healthy controls. The investigators found no statistical difference in CCSVI prevalence among the three groups. After comparing patients with various types of MS, the researchers found no statistical difference in CCSVI prevalence.

The central neurosonologists diagnosed CCSVI in 3.3% of patients with MS, 2.7% of patients with other neurologic disorders, and 3.2% of healthy controls. The investigators found no statistical difference between the three groups. The local neurosonologists diagnosed CCSVI in 15.9% of patients with MS, 15% of patients with other neurologic disorders, and 12% of controls. The investigators found no statistical difference between these groups.

Local clinical centers varied widely in their diagnoses of CCSVI. Some centers found CCSVI in 60% of all evaluated cases, and others found no cases, said Gianluigi Mancardi, MD, Head of the Department of Neuroscience at the University of Genoa and a coauthor of the study.

Local and central neurosonologists agreed on the absence of CCSVI 92% of the time, but disagreement on positive diagnoses was common. Central neurosonologists evaluated as positive 28 cases that had been evaluated as negative by local neurosonologists. Of 236 cases that had been evaluated as positive by local neurosonologists, 28 were evaluated as positive by central neurosonologists.

The three central neurosonologists agreed 99% of the time on negative diagnoses, but they had an “extremely low” rate of agreement for positive diagnoses, reported Dr. Comi and his coinvestigators. This result suggests that CCSVI diagnoses are highly subjective. “Even for experts, it was extremely difficult to say, ‘Oh yes, this is CCSVI,’” Dr. Comi noted.

Liberation Therapy May Have No Medical Basis
“This is the first multicenter study done in a blinded manner with a tremendous amount of patients,” said Dr. Mancardi. “The conclusion is that CCSVI is not associated with MS or with other neurologic disorders. There is no statistical difference [in CCSVI prevalence] between [patients with] MS, healthy controls, and [patients with] other neurologic disorders. Therefore, there is no evident role for CCSVI in MS.”

More than 1,000 patients worldwide have undergone angioplasty to treat CCSVI, according to Dr. Comi. Although it is understandable that patients with MS would seek alternative therapies, angioplasty “is an interventional type of treatment,” he said. “Interventional means that you expose the patient to potential risks. And this is one of the main reasons why we need to use a very objective approach, because we are taking care of our patients.”

To perform a clinical trial of angioplasty for CCSVI in patients with MS, researchers must first demonstrate that patients with MS have an increased risk of CCSVI, compared with normal controls or patients with other neurologic diseases. Dr. Comi’s study, however, found no difference among the three patient groups. “If we … decide to operate for this condition, then we should theoretically operate also on the normal controls,” said Dr. Comi.

“There is no rationale for a trial exploring the efficacy of the liberation therapy,” and a randomized trial of an endovascular procedure in patients with MS would be unethical, Dr. Comi commented. “The risk to treat patients is that the adverse effect of the intervention would overcome all the potential advantages,” he concluded.

LYON, FRANCE—Chronic cerebrospinal venous insufficiency (CCSVI) appears to occur at a similarly low rate among patients with multiple sclerosis (MS), patients with other neurologic disorders, and healthy controls, researchers reported at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). CCSVI also appears to occur at similar rates among patients with various types of MS.

The study results cast doubt on the hypothesis, first proposed by Paolo Zamboni, MD, Associate Professor of Morphology, Surgery, and Experimental Medicine at the University of Ferrara, Italy, that CCSVI is an important factor in MS. The findings also call into question Dr. Zamboni’s proposal that a type of angioplasty known as “liberation therapy” could be an effective treatment for patients with CCSVI and MS.

Testing the Zamboni Hypothesis
To determine whether there was a relationship between CCSVI and MS, under the sponsorship of the Italian Multiple Sclerosis Society, Giancarlo Comi, MD, Head of the Neurorehabilitation Unit at Fondazione San Raffaele del Monte Tabor in Milan, and colleagues enrolled subjects in a case–control observational study conducted at 35 Italian clinical centers. Of the study population, 1,165 patients had MS, 226 patients had other neurologic disorders, and 376 subjects were healthy controls. Subjects between ages 18 and 55 were eligible to participate.

All patients were evaluated by a neurologist. Local neurosonologists, who previously had been certified as having learned standardized criteria for diagnosing CCSVI, then performed blinded Echo Color Doppler (ECD) evaluations according to a predefined protocol to determine whether the subjects had CCSVI. Each exam was recorded and sent in a random manner to one of three expert central neurosonologists, who also had blind access to the ECDs.

The study’s primary end point, the presence of CCSVI, was determined by the agreement of the local and central neurosonologists. When the local and central neurosonologists disagreed, the exam was sent to the other two central neurosonologists, and the final diagnosis was made by a consensus of two of the three central neurosonologists.

The researchers excluded patients for technical reasons and 55 other subjects because of protocol violations. A total of 1,767 patients were included in the final analysis.

Most Subjects Did Not Have CCSVI
CCSVI was diagnosed in 3.26% of patients with MS, 3.10% of patients with other neurologic disorders, and 2.13% of healthy controls. The investigators found no statistical difference in CCSVI prevalence among the three groups. After comparing patients with various types of MS, the researchers found no statistical difference in CCSVI prevalence.

The central neurosonologists diagnosed CCSVI in 3.3% of patients with MS, 2.7% of patients with other neurologic disorders, and 3.2% of healthy controls. The investigators found no statistical difference between the three groups. The local neurosonologists diagnosed CCSVI in 15.9% of patients with MS, 15% of patients with other neurologic disorders, and 12% of controls. The investigators found no statistical difference between these groups.

Local clinical centers varied widely in their diagnoses of CCSVI. Some centers found CCSVI in 60% of all evaluated cases, and others found no cases, said Gianluigi Mancardi, MD, Head of the Department of Neuroscience at the University of Genoa and a coauthor of the study.

Local and central neurosonologists agreed on the absence of CCSVI 92% of the time, but disagreement on positive diagnoses was common. Central neurosonologists evaluated as positive 28 cases that had been evaluated as negative by local neurosonologists. Of 236 cases that had been evaluated as positive by local neurosonologists, 28 were evaluated as positive by central neurosonologists.

The three central neurosonologists agreed 99% of the time on negative diagnoses, but they had an “extremely low” rate of agreement for positive diagnoses, reported Dr. Comi and his coinvestigators. This result suggests that CCSVI diagnoses are highly subjective. “Even for experts, it was extremely difficult to say, ‘Oh yes, this is CCSVI,’” Dr. Comi noted.

Liberation Therapy May Have No Medical Basis
“This is the first multicenter study done in a blinded manner with a tremendous amount of patients,” said Dr. Mancardi. “The conclusion is that CCSVI is not associated with MS or with other neurologic disorders. There is no statistical difference [in CCSVI prevalence] between [patients with] MS, healthy controls, and [patients with] other neurologic disorders. Therefore, there is no evident role for CCSVI in MS.”

More than 1,000 patients worldwide have undergone angioplasty to treat CCSVI, according to Dr. Comi. Although it is understandable that patients with MS would seek alternative therapies, angioplasty “is an interventional type of treatment,” he said. “Interventional means that you expose the patient to potential risks. And this is one of the main reasons why we need to use a very objective approach, because we are taking care of our patients.”

To perform a clinical trial of angioplasty for CCSVI in patients with MS, researchers must first demonstrate that patients with MS have an increased risk of CCSVI, compared with normal controls or patients with other neurologic diseases. Dr. Comi’s study, however, found no difference among the three patient groups. “If we … decide to operate for this condition, then we should theoretically operate also on the normal controls,” said Dr. Comi.

“There is no rationale for a trial exploring the efficacy of the liberation therapy,” and a randomized trial of an endovascular procedure in patients with MS would be unethical, Dr. Comi commented. “The risk to treat patients is that the adverse effect of the intervention would overcome all the potential advantages,” he concluded.

Arecent study by Outteryck et al. confirmed the seroprevalence of John Cunningham virus (JCV) observed in other cohorts of patients with multiple sclerosis (MS) exposed to natalizumab (51%). The study also identified three independent risk factors for JCV seropositivity—higher age at the time of serology, longer natalizumab exposure duration, and North African origin. Although age is a well-established factor for JCV seropositivity, no previous studies had linked ethnicity and duration of natalizumab therapy to JCV seroprevalence. 

Progressive multifocal leukoencephalopathy (PML) has recently emerged as a life-threatening complication among individuals on natalizumab therapy (Tyler et al.; Ryschkewitsch  et al.). Stratifying patients on natalizumab therapy based on their risk of developing PML may help investigators develop strategies to prevent natalizumab-associated PML. Prior research, including a study by Bozic et al., has identified anti-JCV antibody status, duration of natalizumab therapy of 24 months or more, and prior exposure to immunosuppressive drugs as risk factors for developing PML.

It would indeed be important if we could confirm that ethnicity and duration of natalizumab therapy were independent risk factors for JCV infection. Without comparable pre- and post-natalizumab exposure serum showing a clear increase in the prevalence of JCV seropositivity during a given period (using the same test) after the initiation of natalizumab, it is not possible to reach any conclusion. Moreover, the authors themselves concluded that the prevalence of anti-JCV antibodies was not influenced by prior immunomodulatory or immunosuppressive use, and it is unlikely that natalizumab exposure duration causes high JCV seropositivity. Furthermore, the conclusion was based on two different tests with different sensitivities and may merely reflect the differences between these two tests. However, the study warrants a well-planned longitudinal study to determine conclusively whether natalizumab exposure duration has any effect on JCV infection or seroprevalence.

Another interesting and novel, but barely significant, finding of this study is the higher prevalence of JCV seropositivity among patients of North African origin, compared with patients of European descent. However, as the authors have rightly stated, most of these patients of North African origin were born in Africa and might have been exposed to JCV before migrating to France. The higher prevalence of JCV-seropositivity among them may represent environmental or regional factors, rather than ethnic or genetic factors.

References
Bozic C, Richman S, Plavina T, et al. Anti-John Cunnigham virus antibody prevalence in multiple sclerosis patients: baseline results of STRATIFY-1. Ann Neurol. 2011;70(5):742-750.
Outteryck O, Ongagna JC, Duhamel A, et al. Anti-JCV antibody prevalence in a French cohort of MS patients under natalizumab therapy. J Neurol. 2012;259(11):2293-2298.
Ryschkewitsch CF, Jensen PN, Monaco MC, Major EO. JC virus persistence following progressive multifocal leukoencephalopathy in multiple sclerosis patients treated with natalizumab. Ann Neurol. 2010;68(3):384-391.
Tyler KL. Emerging viral infections of the central nervous system: part 2. Arch Neurol. 2008;66(9):1065-1074.

Arecent study by Outteryck et al. confirmed the seroprevalence of John Cunningham virus (JCV) observed in other cohorts of patients with multiple sclerosis (MS) exposed to natalizumab (51%). The study also identified three independent risk factors for JCV seropositivity—higher age at the time of serology, longer natalizumab exposure duration, and North African origin. Although age is a well-established factor for JCV seropositivity, no previous studies had linked ethnicity and duration of natalizumab therapy to JCV seroprevalence. 

Progressive multifocal leukoencephalopathy (PML) has recently emerged as a life-threatening complication among individuals on natalizumab therapy (Tyler et al.; Ryschkewitsch  et al.). Stratifying patients on natalizumab therapy based on their risk of developing PML may help investigators develop strategies to prevent natalizumab-associated PML. Prior research, including a study by Bozic et al., has identified anti-JCV antibody status, duration of natalizumab therapy of 24 months or more, and prior exposure to immunosuppressive drugs as risk factors for developing PML.

It would indeed be important if we could confirm that ethnicity and duration of natalizumab therapy were independent risk factors for JCV infection. Without comparable pre- and post-natalizumab exposure serum showing a clear increase in the prevalence of JCV seropositivity during a given period (using the same test) after the initiation of natalizumab, it is not possible to reach any conclusion. Moreover, the authors themselves concluded that the prevalence of anti-JCV antibodies was not influenced by prior immunomodulatory or immunosuppressive use, and it is unlikely that natalizumab exposure duration causes high JCV seropositivity. Furthermore, the conclusion was based on two different tests with different sensitivities and may merely reflect the differences between these two tests. However, the study warrants a well-planned longitudinal study to determine conclusively whether natalizumab exposure duration has any effect on JCV infection or seroprevalence.

Another interesting and novel, but barely significant, finding of this study is the higher prevalence of JCV seropositivity among patients of North African origin, compared with patients of European descent. However, as the authors have rightly stated, most of these patients of North African origin were born in Africa and might have been exposed to JCV before migrating to France. The higher prevalence of JCV-seropositivity among them may represent environmental or regional factors, rather than ethnic or genetic factors.

References
Bozic C, Richman S, Plavina T, et al. Anti-John Cunnigham virus antibody prevalence in multiple sclerosis patients: baseline results of STRATIFY-1. Ann Neurol. 2011;70(5):742-750.
Outteryck O, Ongagna JC, Duhamel A, et al. Anti-JCV antibody prevalence in a French cohort of MS patients under natalizumab therapy. J Neurol. 2012;259(11):2293-2298.
Ryschkewitsch CF, Jensen PN, Monaco MC, Major EO. JC virus persistence following progressive multifocal leukoencephalopathy in multiple sclerosis patients treated with natalizumab. Ann Neurol. 2010;68(3):384-391.
Tyler KL. Emerging viral infections of the central nervous system: part 2. Arch Neurol. 2008;66(9):1065-1074.

Arecent study by Outteryck et al. confirmed the seroprevalence of John Cunningham virus (JCV) observed in other cohorts of patients with multiple sclerosis (MS) exposed to natalizumab (51%). The study also identified three independent risk factors for JCV seropositivity—higher age at the time of serology, longer natalizumab exposure duration, and North African origin. Although age is a well-established factor for JCV seropositivity, no previous studies had linked ethnicity and duration of natalizumab therapy to JCV seroprevalence. 

Progressive multifocal leukoencephalopathy (PML) has recently emerged as a life-threatening complication among individuals on natalizumab therapy (Tyler et al.; Ryschkewitsch  et al.). Stratifying patients on natalizumab therapy based on their risk of developing PML may help investigators develop strategies to prevent natalizumab-associated PML. Prior research, including a study by Bozic et al., has identified anti-JCV antibody status, duration of natalizumab therapy of 24 months or more, and prior exposure to immunosuppressive drugs as risk factors for developing PML.

It would indeed be important if we could confirm that ethnicity and duration of natalizumab therapy were independent risk factors for JCV infection. Without comparable pre- and post-natalizumab exposure serum showing a clear increase in the prevalence of JCV seropositivity during a given period (using the same test) after the initiation of natalizumab, it is not possible to reach any conclusion. Moreover, the authors themselves concluded that the prevalence of anti-JCV antibodies was not influenced by prior immunomodulatory or immunosuppressive use, and it is unlikely that natalizumab exposure duration causes high JCV seropositivity. Furthermore, the conclusion was based on two different tests with different sensitivities and may merely reflect the differences between these two tests. However, the study warrants a well-planned longitudinal study to determine conclusively whether natalizumab exposure duration has any effect on JCV infection or seroprevalence.

Another interesting and novel, but barely significant, finding of this study is the higher prevalence of JCV seropositivity among patients of North African origin, compared with patients of European descent. However, as the authors have rightly stated, most of these patients of North African origin were born in Africa and might have been exposed to JCV before migrating to France. The higher prevalence of JCV-seropositivity among them may represent environmental or regional factors, rather than ethnic or genetic factors.

References
Bozic C, Richman S, Plavina T, et al. Anti-John Cunnigham virus antibody prevalence in multiple sclerosis patients: baseline results of STRATIFY-1. Ann Neurol. 2011;70(5):742-750.
Outteryck O, Ongagna JC, Duhamel A, et al. Anti-JCV antibody prevalence in a French cohort of MS patients under natalizumab therapy. J Neurol. 2012;259(11):2293-2298.
Ryschkewitsch CF, Jensen PN, Monaco MC, Major EO. JC virus persistence following progressive multifocal leukoencephalopathy in multiple sclerosis patients treated with natalizumab. Ann Neurol. 2010;68(3):384-391.
Tyler KL. Emerging viral infections of the central nervous system: part 2. Arch Neurol. 2008;66(9):1065-1074.