Multiple Sclerosis Hub

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.

For patients with multiple sclerosis (MS), the frequency of early inflammatory attacks may not be associated with the onset of secondary progressive MS, researchers wrote in the November 19 Archives of Neurology. In addition, relapse frequency may not be a valid surrogate marker for late disability.

Approximately 65% of patients with frequent early relapses converted to secondary progressive MS in a median of five years. These patients attained a Disability Status Scale (DSS) score of 6 in a median of seven years and a DSS score of 8 in a median of 17 years. The remaining patients with frequent early relapses did not convert to secondary progressive MS.

Antonio Scalfari, MD, at the Centre for Neuroscience of Imperial College London in the United Kingdom, and colleagues studied 730 patients with relapsing-remitting MS (RRMS). The study’s main outcome measure was the long-term evolution of the 158 patients who had three or more relapses during the first two years of their disease. In patients who converted to secondary progressive MS and participants grouped by number of early relapses, the investigators evaluated the predictive effect of time to secondary progressive MS on time to require a cane (ie, achieve DSS score of 6) and time to bedridden status (ie, achieve DSS score of 8).

Nearly 82% of patients with RRMS were women, compared with 63% of patients who converted to secondary progressive MS. Mean age at disease onset was 25.5 for patients with RRMS and 28.4 for patients who converted to secondary progressive MS. 

Among patients who developed secondary progressive MS, longer latency to progression was associated with a lower probability of attaining DSS score of 6 and longer time to severe disability. The researchers observed the same association in patients matched by number of early attacks.

 
“We provide strong evidence that relapse frequency cannot be validated as a surrogate marker for late disability accumulation, questioning the current practice of using relapse rate as the primary end point in trials,” said Dr. Scalfari.

For patients with multiple sclerosis (MS), the frequency of early inflammatory attacks may not be associated with the onset of secondary progressive MS, researchers wrote in the November 19 Archives of Neurology. In addition, relapse frequency may not be a valid surrogate marker for late disability.

Approximately 65% of patients with frequent early relapses converted to secondary progressive MS in a median of five years. These patients attained a Disability Status Scale (DSS) score of 6 in a median of seven years and a DSS score of 8 in a median of 17 years. The remaining patients with frequent early relapses did not convert to secondary progressive MS.

Antonio Scalfari, MD, at the Centre for Neuroscience of Imperial College London in the United Kingdom, and colleagues studied 730 patients with relapsing-remitting MS (RRMS). The study’s main outcome measure was the long-term evolution of the 158 patients who had three or more relapses during the first two years of their disease. In patients who converted to secondary progressive MS and participants grouped by number of early relapses, the investigators evaluated the predictive effect of time to secondary progressive MS on time to require a cane (ie, achieve DSS score of 6) and time to bedridden status (ie, achieve DSS score of 8).

Nearly 82% of patients with RRMS were women, compared with 63% of patients who converted to secondary progressive MS. Mean age at disease onset was 25.5 for patients with RRMS and 28.4 for patients who converted to secondary progressive MS. 

Among patients who developed secondary progressive MS, longer latency to progression was associated with a lower probability of attaining DSS score of 6 and longer time to severe disability. The researchers observed the same association in patients matched by number of early attacks.

 
“We provide strong evidence that relapse frequency cannot be validated as a surrogate marker for late disability accumulation, questioning the current practice of using relapse rate as the primary end point in trials,” said Dr. Scalfari.

For patients with multiple sclerosis (MS), the frequency of early inflammatory attacks may not be associated with the onset of secondary progressive MS, researchers wrote in the November 19 Archives of Neurology. In addition, relapse frequency may not be a valid surrogate marker for late disability.

Approximately 65% of patients with frequent early relapses converted to secondary progressive MS in a median of five years. These patients attained a Disability Status Scale (DSS) score of 6 in a median of seven years and a DSS score of 8 in a median of 17 years. The remaining patients with frequent early relapses did not convert to secondary progressive MS.

Antonio Scalfari, MD, at the Centre for Neuroscience of Imperial College London in the United Kingdom, and colleagues studied 730 patients with relapsing-remitting MS (RRMS). The study’s main outcome measure was the long-term evolution of the 158 patients who had three or more relapses during the first two years of their disease. In patients who converted to secondary progressive MS and participants grouped by number of early relapses, the investigators evaluated the predictive effect of time to secondary progressive MS on time to require a cane (ie, achieve DSS score of 6) and time to bedridden status (ie, achieve DSS score of 8).

Nearly 82% of patients with RRMS were women, compared with 63% of patients who converted to secondary progressive MS. Mean age at disease onset was 25.5 for patients with RRMS and 28.4 for patients who converted to secondary progressive MS. 

Among patients who developed secondary progressive MS, longer latency to progression was associated with a lower probability of attaining DSS score of 6 and longer time to severe disability. The researchers observed the same association in patients matched by number of early attacks.

 
“We provide strong evidence that relapse frequency cannot be validated as a surrogate marker for late disability accumulation, questioning the current practice of using relapse rate as the primary end point in trials,” said Dr. Scalfari.

LYON, FRANCE—Among patients with multiple sclerosis (MS) who are treated with natalizumab, those of North African origin may be more likely to test positive for John Cunningham virus (JCV) than patients of European origin, according to research presented at the 28th Congress of the European Committee for Treatment and Research in MS (ECTRIMS). No previous research has linked ethnicity and risk of JCV, according to Patrick Vermersch, MD, a coauthor of the study. Increasing antibody titers have been identified as a risk factor for progressive multifocal leukoencephalopathy (PML).

Using multivariate analysis, Dr. Vermersch, Assistant Dean of Research at the University of Lille Medical School in France, and colleagues found that age at serology and length of exposure to natalizumab at serology also were significantly linked to the presence of anti-JCV antibodies. Patients older than 36.5 and those exposed to natalizumab for 24.5 months or more were more likely to have anti-JCV antibodies than were younger patients or those with shorter duration of treatment.

Using a validated enzyme-linked immunosorbent assay (ELISA), the researchers analyzed sera of 361 patients with MS who were receiving natalizumab. The mean duration of participants’ exposure to natalizumab was 27.27 months. Approximately 15% of patients had used immunosuppressants previously. More than half (51%) of participants tested positive for JCV.

New Assay May Improve Detection of JCV Antibodies
Gen-2, a new generation of the ELISA test, has improved signal resolution and appears to detect JCV antibodies with greater sensitivity than Gen-1, said Dr. Vermersch. He and his colleagues measured the seroprevalence of anti-JCV antibodies twice in the same patient cohort—once using the original assay, and again one year later with the new assay.

The Gen-1 test resulted in a seroprevalence of approximately 46%, and the Gen-2 test yielded a seroprevalence of nearly 61%. The proportion of patients converting from a negative result in the first test to a positive result in the second test was 29.1%, an “unexpectedly high rate,” said Dr. Vermersch. The false negative rates were 2.5% and 2.7%for STRATA and STRATIFY-1, respectively.

Most Patients With PML Have Anti-JCV Antibodies
The new test could soon improve neurologists’ ability to identify patients with MS who are at risk for PML. Of 91 patients with MS and PML who were treated with natalizumab, 89 (98%) tested anti-JCV positive at all time points in which samples were available for testing.

Patients who test positive for anti-JCV antibodies six months before being diagnosed with PML are considered anti-JCV antibody positive, said Dr. Vermersch. One patient was considered anti-JCV antibody negative because he or she tested anti-JCV antibody negative nine months before PML diagnosis and no additional pre-PML samples were available.

Another patient tested anti-JCV antibody negative 15 months before PML diagnosis and antibody positive two months before PML diagnosis. This patient’s time of seroconversion is unknown, so his or her anti-JCV antibody status six months before PML diagnosis cannot be known with certainty.

Early Diagnosis of PML Could Improve Patient Outcomes
The overall risk of PML is 2.71 for 1,000 patients with MS. Of 285 reported cases of natalizumab-associated PML, 62 patients died, yielding a mortality rate of 22%. The median time to death is 2.2 months. A total of 140 surviving patients with PML were followed up as of last year. A minority of these patients had mild disability, but approximately 40% were severely disabled, and approximately half had moderate disability.

JCV exposure, natalizumab treatment for more than two years, and receiving an immunosuppressant before receiving natalizumab have been documented as risk factors for developing PML, noted Dr. Vermersch. Patients with all three risk factors have an approximately 1% risk of developing PML.

Younger age at PML diagnosis, lower MS-related disability before PML diagnosis, and a shorter time from first symptoms to PML diagnosis appear to be associated with improved survival, said Dr. Vermersch. Gender, previous use of immunosuppressants, MS duration, natalizumab exposure at PML diagnosis, JCV DNA load in CSF at PML diagnosis, and gadolinium enhancement on MRI at time of diagnosis do not appear to affect survival.

“We are now able to detect PML very early—maybe even in presymptomatic cases … and we have quite good clinical outcomes in these patients,” said Dr. Vermersch. “A shorter time from first symptoms of PML to diagnosis is critical” because, in a 2011 study, the time from symptom onset to PML diagnosis was 10 days shorter for nonfatal cases of PML than for fatal cases of PML, he added. Localized PML extension on MRI at diagnosis is equally important, and neurologists should exercise good clinical vigilance with patients to improve outcomes, concluded Dr. Vermersch.    

LYON, FRANCE—Among patients with multiple sclerosis (MS) who are treated with natalizumab, those of North African origin may be more likely to test positive for John Cunningham virus (JCV) than patients of European origin, according to research presented at the 28th Congress of the European Committee for Treatment and Research in MS (ECTRIMS). No previous research has linked ethnicity and risk of JCV, according to Patrick Vermersch, MD, a coauthor of the study. Increasing antibody titers have been identified as a risk factor for progressive multifocal leukoencephalopathy (PML).

Using multivariate analysis, Dr. Vermersch, Assistant Dean of Research at the University of Lille Medical School in France, and colleagues found that age at serology and length of exposure to natalizumab at serology also were significantly linked to the presence of anti-JCV antibodies. Patients older than 36.5 and those exposed to natalizumab for 24.5 months or more were more likely to have anti-JCV antibodies than were younger patients or those with shorter duration of treatment.

Using a validated enzyme-linked immunosorbent assay (ELISA), the researchers analyzed sera of 361 patients with MS who were receiving natalizumab. The mean duration of participants’ exposure to natalizumab was 27.27 months. Approximately 15% of patients had used immunosuppressants previously. More than half (51%) of participants tested positive for JCV.

New Assay May Improve Detection of JCV Antibodies
Gen-2, a new generation of the ELISA test, has improved signal resolution and appears to detect JCV antibodies with greater sensitivity than Gen-1, said Dr. Vermersch. He and his colleagues measured the seroprevalence of anti-JCV antibodies twice in the same patient cohort—once using the original assay, and again one year later with the new assay.

The Gen-1 test resulted in a seroprevalence of approximately 46%, and the Gen-2 test yielded a seroprevalence of nearly 61%. The proportion of patients converting from a negative result in the first test to a positive result in the second test was 29.1%, an “unexpectedly high rate,” said Dr. Vermersch. The false negative rates were 2.5% and 2.7%for STRATA and STRATIFY-1, respectively.

Most Patients With PML Have Anti-JCV Antibodies
The new test could soon improve neurologists’ ability to identify patients with MS who are at risk for PML. Of 91 patients with MS and PML who were treated with natalizumab, 89 (98%) tested anti-JCV positive at all time points in which samples were available for testing.

Patients who test positive for anti-JCV antibodies six months before being diagnosed with PML are considered anti-JCV antibody positive, said Dr. Vermersch. One patient was considered anti-JCV antibody negative because he or she tested anti-JCV antibody negative nine months before PML diagnosis and no additional pre-PML samples were available.

Another patient tested anti-JCV antibody negative 15 months before PML diagnosis and antibody positive two months before PML diagnosis. This patient’s time of seroconversion is unknown, so his or her anti-JCV antibody status six months before PML diagnosis cannot be known with certainty.

Early Diagnosis of PML Could Improve Patient Outcomes
The overall risk of PML is 2.71 for 1,000 patients with MS. Of 285 reported cases of natalizumab-associated PML, 62 patients died, yielding a mortality rate of 22%. The median time to death is 2.2 months. A total of 140 surviving patients with PML were followed up as of last year. A minority of these patients had mild disability, but approximately 40% were severely disabled, and approximately half had moderate disability.

JCV exposure, natalizumab treatment for more than two years, and receiving an immunosuppressant before receiving natalizumab have been documented as risk factors for developing PML, noted Dr. Vermersch. Patients with all three risk factors have an approximately 1% risk of developing PML.

Younger age at PML diagnosis, lower MS-related disability before PML diagnosis, and a shorter time from first symptoms to PML diagnosis appear to be associated with improved survival, said Dr. Vermersch. Gender, previous use of immunosuppressants, MS duration, natalizumab exposure at PML diagnosis, JCV DNA load in CSF at PML diagnosis, and gadolinium enhancement on MRI at time of diagnosis do not appear to affect survival.

“We are now able to detect PML very early—maybe even in presymptomatic cases … and we have quite good clinical outcomes in these patients,” said Dr. Vermersch. “A shorter time from first symptoms of PML to diagnosis is critical” because, in a 2011 study, the time from symptom onset to PML diagnosis was 10 days shorter for nonfatal cases of PML than for fatal cases of PML, he added. Localized PML extension on MRI at diagnosis is equally important, and neurologists should exercise good clinical vigilance with patients to improve outcomes, concluded Dr. Vermersch.    

LYON, FRANCE—Among patients with multiple sclerosis (MS) who are treated with natalizumab, those of North African origin may be more likely to test positive for John Cunningham virus (JCV) than patients of European origin, according to research presented at the 28th Congress of the European Committee for Treatment and Research in MS (ECTRIMS). No previous research has linked ethnicity and risk of JCV, according to Patrick Vermersch, MD, a coauthor of the study. Increasing antibody titers have been identified as a risk factor for progressive multifocal leukoencephalopathy (PML).

Using multivariate analysis, Dr. Vermersch, Assistant Dean of Research at the University of Lille Medical School in France, and colleagues found that age at serology and length of exposure to natalizumab at serology also were significantly linked to the presence of anti-JCV antibodies. Patients older than 36.5 and those exposed to natalizumab for 24.5 months or more were more likely to have anti-JCV antibodies than were younger patients or those with shorter duration of treatment.

Using a validated enzyme-linked immunosorbent assay (ELISA), the researchers analyzed sera of 361 patients with MS who were receiving natalizumab. The mean duration of participants’ exposure to natalizumab was 27.27 months. Approximately 15% of patients had used immunosuppressants previously. More than half (51%) of participants tested positive for JCV.

New Assay May Improve Detection of JCV Antibodies
Gen-2, a new generation of the ELISA test, has improved signal resolution and appears to detect JCV antibodies with greater sensitivity than Gen-1, said Dr. Vermersch. He and his colleagues measured the seroprevalence of anti-JCV antibodies twice in the same patient cohort—once using the original assay, and again one year later with the new assay.

The Gen-1 test resulted in a seroprevalence of approximately 46%, and the Gen-2 test yielded a seroprevalence of nearly 61%. The proportion of patients converting from a negative result in the first test to a positive result in the second test was 29.1%, an “unexpectedly high rate,” said Dr. Vermersch. The false negative rates were 2.5% and 2.7%for STRATA and STRATIFY-1, respectively.

Most Patients With PML Have Anti-JCV Antibodies
The new test could soon improve neurologists’ ability to identify patients with MS who are at risk for PML. Of 91 patients with MS and PML who were treated with natalizumab, 89 (98%) tested anti-JCV positive at all time points in which samples were available for testing.

Patients who test positive for anti-JCV antibodies six months before being diagnosed with PML are considered anti-JCV antibody positive, said Dr. Vermersch. One patient was considered anti-JCV antibody negative because he or she tested anti-JCV antibody negative nine months before PML diagnosis and no additional pre-PML samples were available.

Another patient tested anti-JCV antibody negative 15 months before PML diagnosis and antibody positive two months before PML diagnosis. This patient’s time of seroconversion is unknown, so his or her anti-JCV antibody status six months before PML diagnosis cannot be known with certainty.

Early Diagnosis of PML Could Improve Patient Outcomes
The overall risk of PML is 2.71 for 1,000 patients with MS. Of 285 reported cases of natalizumab-associated PML, 62 patients died, yielding a mortality rate of 22%. The median time to death is 2.2 months. A total of 140 surviving patients with PML were followed up as of last year. A minority of these patients had mild disability, but approximately 40% were severely disabled, and approximately half had moderate disability.

JCV exposure, natalizumab treatment for more than two years, and receiving an immunosuppressant before receiving natalizumab have been documented as risk factors for developing PML, noted Dr. Vermersch. Patients with all three risk factors have an approximately 1% risk of developing PML.

Younger age at PML diagnosis, lower MS-related disability before PML diagnosis, and a shorter time from first symptoms to PML diagnosis appear to be associated with improved survival, said Dr. Vermersch. Gender, previous use of immunosuppressants, MS duration, natalizumab exposure at PML diagnosis, JCV DNA load in CSF at PML diagnosis, and gadolinium enhancement on MRI at time of diagnosis do not appear to affect survival.

“We are now able to detect PML very early—maybe even in presymptomatic cases … and we have quite good clinical outcomes in these patients,” said Dr. Vermersch. “A shorter time from first symptoms of PML to diagnosis is critical” because, in a 2011 study, the time from symptom onset to PML diagnosis was 10 days shorter for nonfatal cases of PML than for fatal cases of PML, he added. Localized PML extension on MRI at diagnosis is equally important, and neurologists should exercise good clinical vigilance with patients to improve outcomes, concluded Dr. Vermersch.    

LYON, FRANCE—Smoking may be associated with an increased risk of multiple sclerosis (MS) among young people, according to research presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Levels of cotinine, a nicotine metabolite recognized as a biochemical marker for tobacco use, of 10 ng/mL or higher were associated with an odds ratio of developing MS of 1.5, said Jonatan Salzer, a postgraduate student, and colleagues at Umeå University in Sverige, Sweden. After users of smokeless tobacco were excluded in accordance with questionnaire data, patients with cotinine levels of 10 ng/mL or higher had an odds ratio of developing MS of 1.6.

The effect of elevated cotinine levels on the risk of MS was only evident among individuals younger than 26.4. The investigators did not observe a dose–response effect. The study findings on cotinine were replicated in the results of a retrospective smoking questionnaire.

An Analysis of Prospectively Collected Blood Samples
To investigate the effects of laboratory-defined tobacco use on the risk of MS, Mr. Salzer and his colleagues conducted a nested case–control study. The group searched for diagnoses of MS in northern Sweden in two population-based biobank cohorts to identify blood samples taken before MS onset. Of the 2,887 patients initially identified, 192 had donated blood to the biobanks before disease onset and were eligible for inclusion in the study.

Blood samples were drawn a median of nine years before disease onset. The researchers measured levels of cotinine using an immunoassay. In addition, the investigators collected data on tobacco use retrospectively using a questionnaire in a subset of the subjects. This step enabled the exclusion of subjects who had used smokeless tobacco. The risk for MS was estimated using matched logistic regression.

Smoking Early in Life May Trigger Immunologic Events Leading to MS
Smoking increased the risk for MS by 50% among all subjects. Among patients younger than 26 with cotinine levels of 10 ng/mL or higher, the odds ratio of MS was 2.2. Excluding patients who used smokeless tobacco, individuals younger than 26 with cotinine levels of 10 ng/mL or higher had an odds ratio of MS of 2.4. Conversely, no effect on MS risk by cotinine levels was observed when analyzing only subjects above the age of 26.

"This study confirms that smoking is associated with an increased risk for MS. It has the advantage of using analyses of cotinine levels in samples collected several years before disease onset, thus excluding any risk for recall bias and minimizing the risk for reversed causation," said Mr. Salzer. The fact that the increased risk for MS was only observed in young subjects "indicates that smoking-related immunologic events contributing to the development of MS may occur early in life," he added.

—Erik Greb

LYON, FRANCE—Smoking may be associated with an increased risk of multiple sclerosis (MS) among young people, according to research presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Levels of cotinine, a nicotine metabolite recognized as a biochemical marker for tobacco use, of 10 ng/mL or higher were associated with an odds ratio of developing MS of 1.5, said Jonatan Salzer, a postgraduate student, and colleagues at Umeå University in Sverige, Sweden. After users of smokeless tobacco were excluded in accordance with questionnaire data, patients with cotinine levels of 10 ng/mL or higher had an odds ratio of developing MS of 1.6.

The effect of elevated cotinine levels on the risk of MS was only evident among individuals younger than 26.4. The investigators did not observe a dose–response effect. The study findings on cotinine were replicated in the results of a retrospective smoking questionnaire.

An Analysis of Prospectively Collected Blood Samples
To investigate the effects of laboratory-defined tobacco use on the risk of MS, Mr. Salzer and his colleagues conducted a nested case–control study. The group searched for diagnoses of MS in northern Sweden in two population-based biobank cohorts to identify blood samples taken before MS onset. Of the 2,887 patients initially identified, 192 had donated blood to the biobanks before disease onset and were eligible for inclusion in the study.

Blood samples were drawn a median of nine years before disease onset. The researchers measured levels of cotinine using an immunoassay. In addition, the investigators collected data on tobacco use retrospectively using a questionnaire in a subset of the subjects. This step enabled the exclusion of subjects who had used smokeless tobacco. The risk for MS was estimated using matched logistic regression.

Smoking Early in Life May Trigger Immunologic Events Leading to MS
Smoking increased the risk for MS by 50% among all subjects. Among patients younger than 26 with cotinine levels of 10 ng/mL or higher, the odds ratio of MS was 2.2. Excluding patients who used smokeless tobacco, individuals younger than 26 with cotinine levels of 10 ng/mL or higher had an odds ratio of MS of 2.4. Conversely, no effect on MS risk by cotinine levels was observed when analyzing only subjects above the age of 26.

"This study confirms that smoking is associated with an increased risk for MS. It has the advantage of using analyses of cotinine levels in samples collected several years before disease onset, thus excluding any risk for recall bias and minimizing the risk for reversed causation," said Mr. Salzer. The fact that the increased risk for MS was only observed in young subjects "indicates that smoking-related immunologic events contributing to the development of MS may occur early in life," he added.

—Erik Greb

LYON, FRANCE—Smoking may be associated with an increased risk of multiple sclerosis (MS) among young people, according to research presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Levels of cotinine, a nicotine metabolite recognized as a biochemical marker for tobacco use, of 10 ng/mL or higher were associated with an odds ratio of developing MS of 1.5, said Jonatan Salzer, a postgraduate student, and colleagues at Umeå University in Sverige, Sweden. After users of smokeless tobacco were excluded in accordance with questionnaire data, patients with cotinine levels of 10 ng/mL or higher had an odds ratio of developing MS of 1.6.

The effect of elevated cotinine levels on the risk of MS was only evident among individuals younger than 26.4. The investigators did not observe a dose–response effect. The study findings on cotinine were replicated in the results of a retrospective smoking questionnaire.

An Analysis of Prospectively Collected Blood Samples
To investigate the effects of laboratory-defined tobacco use on the risk of MS, Mr. Salzer and his colleagues conducted a nested case–control study. The group searched for diagnoses of MS in northern Sweden in two population-based biobank cohorts to identify blood samples taken before MS onset. Of the 2,887 patients initially identified, 192 had donated blood to the biobanks before disease onset and were eligible for inclusion in the study.

Blood samples were drawn a median of nine years before disease onset. The researchers measured levels of cotinine using an immunoassay. In addition, the investigators collected data on tobacco use retrospectively using a questionnaire in a subset of the subjects. This step enabled the exclusion of subjects who had used smokeless tobacco. The risk for MS was estimated using matched logistic regression.

Smoking Early in Life May Trigger Immunologic Events Leading to MS
Smoking increased the risk for MS by 50% among all subjects. Among patients younger than 26 with cotinine levels of 10 ng/mL or higher, the odds ratio of MS was 2.2. Excluding patients who used smokeless tobacco, individuals younger than 26 with cotinine levels of 10 ng/mL or higher had an odds ratio of MS of 2.4. Conversely, no effect on MS risk by cotinine levels was observed when analyzing only subjects above the age of 26.

"This study confirms that smoking is associated with an increased risk for MS. It has the advantage of using analyses of cotinine levels in samples collected several years before disease onset, thus excluding any risk for recall bias and minimizing the risk for reversed causation," said Mr. Salzer. The fact that the increased risk for MS was only observed in young subjects "indicates that smoking-related immunologic events contributing to the development of MS may occur early in life," he added.

—Erik Greb

LYON, FRANCE—Cognitive reserve may provide protection from disease-related cognitive decline independently of brain reserve in patients with multiple sclerosis (MS), according to a study presented at the 28th Congress of the European Committee for Treatment and Research in MS (ECTRIMS). Greater maximal lifetime brain size (ie, brain reserve) was associated with a slower rate of cognitive decline than lower maximal lifetime brain size among patients with MS. Brain reserve is established by genetics rather than through voluntary control.

Intellectual enrichment (a source of cognitive reserve) gained in early life may reduce the harmful effect of T2 lesion load on cognitive status, even after controlling for brain reserve, according to James F. Sumowski, PhD, Research Scientist at the Kessler Foundation Research Center in West Orange, New Jersey. That is, life experiences (ie, cognitive reserve) protect against cognitive decline among MS patients independently of genetic sources of reserve (brain reserve).

Estimating Patients' Brain Reserve and Cognitive Reserve
Dr. Sumowski and his colleagues studied 62 patients with MS to test the brain reserve and cognitive reserve hypotheses and to investigate whether cognitive reserve protects against cognitive decline independently of brain reserve. The researchers used total T2 lesion load to estimate the extent of patients' MS neuropathology. Intracranial volume was the basis for the group's estimates of patients' maximal lifetime brain size.

Participants completed a questionnaire surveying the cognitive leisure activities that they had pursued in their early 20s, and the questionnaires helped the investigators gauge patients' cognitive reserve. Patients rated leisure activities based on the frequency with which they had pursued them. Tests such as the Symbol Digit Modalities Test were used to assess participants' cognitive status.

Of the 62 patients, 41 had relapsing-remitting MS and 21 had secondary progressive MS. Patients had received an average of 13 years of education and had an average Expanded Disability Status Scale score of 3.2.

Independent Protection
“Greater brain reserve, estimated with intracranial volume, moderated or reduced the deleterious impact of T2 lesion load on cognitive status,” said Dr. Sumowski. The study provides “the first evidence for brain reserve in MS,” he added. Greater cognitive reserve independently moderated the harmful effects of T2 lesion load as well. “Randomized, controlled trials of cognitive leisure are needed to support a causal relationship between leisure and protection from cognitive decline,” Dr. Sumowski concluded.

LYON, FRANCE—Cognitive reserve may provide protection from disease-related cognitive decline independently of brain reserve in patients with multiple sclerosis (MS), according to a study presented at the 28th Congress of the European Committee for Treatment and Research in MS (ECTRIMS). Greater maximal lifetime brain size (ie, brain reserve) was associated with a slower rate of cognitive decline than lower maximal lifetime brain size among patients with MS. Brain reserve is established by genetics rather than through voluntary control.

Intellectual enrichment (a source of cognitive reserve) gained in early life may reduce the harmful effect of T2 lesion load on cognitive status, even after controlling for brain reserve, according to James F. Sumowski, PhD, Research Scientist at the Kessler Foundation Research Center in West Orange, New Jersey. That is, life experiences (ie, cognitive reserve) protect against cognitive decline among MS patients independently of genetic sources of reserve (brain reserve).

Estimating Patients' Brain Reserve and Cognitive Reserve
Dr. Sumowski and his colleagues studied 62 patients with MS to test the brain reserve and cognitive reserve hypotheses and to investigate whether cognitive reserve protects against cognitive decline independently of brain reserve. The researchers used total T2 lesion load to estimate the extent of patients' MS neuropathology. Intracranial volume was the basis for the group's estimates of patients' maximal lifetime brain size.

Participants completed a questionnaire surveying the cognitive leisure activities that they had pursued in their early 20s, and the questionnaires helped the investigators gauge patients' cognitive reserve. Patients rated leisure activities based on the frequency with which they had pursued them. Tests such as the Symbol Digit Modalities Test were used to assess participants' cognitive status.

Of the 62 patients, 41 had relapsing-remitting MS and 21 had secondary progressive MS. Patients had received an average of 13 years of education and had an average Expanded Disability Status Scale score of 3.2.

Independent Protection
“Greater brain reserve, estimated with intracranial volume, moderated or reduced the deleterious impact of T2 lesion load on cognitive status,” said Dr. Sumowski. The study provides “the first evidence for brain reserve in MS,” he added. Greater cognitive reserve independently moderated the harmful effects of T2 lesion load as well. “Randomized, controlled trials of cognitive leisure are needed to support a causal relationship between leisure and protection from cognitive decline,” Dr. Sumowski concluded.

LYON, FRANCE—Cognitive reserve may provide protection from disease-related cognitive decline independently of brain reserve in patients with multiple sclerosis (MS), according to a study presented at the 28th Congress of the European Committee for Treatment and Research in MS (ECTRIMS). Greater maximal lifetime brain size (ie, brain reserve) was associated with a slower rate of cognitive decline than lower maximal lifetime brain size among patients with MS. Brain reserve is established by genetics rather than through voluntary control.

Intellectual enrichment (a source of cognitive reserve) gained in early life may reduce the harmful effect of T2 lesion load on cognitive status, even after controlling for brain reserve, according to James F. Sumowski, PhD, Research Scientist at the Kessler Foundation Research Center in West Orange, New Jersey. That is, life experiences (ie, cognitive reserve) protect against cognitive decline among MS patients independently of genetic sources of reserve (brain reserve).

Estimating Patients' Brain Reserve and Cognitive Reserve
Dr. Sumowski and his colleagues studied 62 patients with MS to test the brain reserve and cognitive reserve hypotheses and to investigate whether cognitive reserve protects against cognitive decline independently of brain reserve. The researchers used total T2 lesion load to estimate the extent of patients' MS neuropathology. Intracranial volume was the basis for the group's estimates of patients' maximal lifetime brain size.

Participants completed a questionnaire surveying the cognitive leisure activities that they had pursued in their early 20s, and the questionnaires helped the investigators gauge patients' cognitive reserve. Patients rated leisure activities based on the frequency with which they had pursued them. Tests such as the Symbol Digit Modalities Test were used to assess participants' cognitive status.

Of the 62 patients, 41 had relapsing-remitting MS and 21 had secondary progressive MS. Patients had received an average of 13 years of education and had an average Expanded Disability Status Scale score of 3.2.

Independent Protection
“Greater brain reserve, estimated with intracranial volume, moderated or reduced the deleterious impact of T2 lesion load on cognitive status,” said Dr. Sumowski. The study provides “the first evidence for brain reserve in MS,” he added. Greater cognitive reserve independently moderated the harmful effects of T2 lesion load as well. “Randomized, controlled trials of cognitive leisure are needed to support a causal relationship between leisure and protection from cognitive decline,” Dr. Sumowski concluded.