Multiple Sclerosis

PHILADELPHIA—Daily treatment with estriol and glatiramer acetate may reduce multiple sclerosis (MS) relapses significantly, compared with placebo and glatiramer acetate, according to research presented at the 66th Annual Meeting of the American Academy of Neurology. The difference may become evident within 12 months of treatment. Cognitive scores also may improve within 12 months of treatment with estriol and glatiramer acetate, compared with placebo plus glatiramer acetate.

A previous study of women with MS who were not pregnant indicated that the pregnancy hormone estriol was associated with a significant decrease in the number and volume of gadolinium-enhancing lesions on MRI. To examine the hormone’s effect on relapse rate, Rhonda Voskuhl, MD, Jack H. Skirball Chair of MS Research at the University of California, Los Angeles (UCLA), and colleagues conducted a randomized controlled trial of women with relapsing-remitting MS.

Comparing Estriol With Placebo in Patients With Active MS
Eligible patients were between ages 18 and 50, had active disease, and had an Expanded Disability Status Scale (EDSS) score between 0 and 4.5. Women who were pregnant, breastfeeding, taking hormone replacement therapy, or taking oral contraceptives were excluded from the trial.

Patients were randomized to glatiramer acetate injections (20 mg/day) and oral estriol (8 mg/day) or to glatiramer acetate injections and placebo. Gynecologists examined the patients before, during, and after the study. Each patient was examined at three- to six-month intervals during the trial. Patients also underwent mammograms before and after the study. In addition, at baseline, three months, six months, 12 months, 18 months, and 24 months, the investigators measured participants’ estriol levels, administered the EDSS, and administered the MS Functional Composite.

A total of 82 patients received glatiramer acetate plus estriol, and 76 patients received glatiramer acetate plus placebo. The trial’s dropout rate was 29%. Baseline characteristics were similar in both patient groups. Participants’ mean age was approximately 38, and their mean EDSS score was 2.2.

Estriol Was Associated With Reduced Relapse Rate
At 12 months, the annualized relapse rate was 47% lower among patients receiving estriol and glatiramer acetate, compared with patients receiving placebo and glatiramer acetate. After month 12, the group receiving estriol and glatiramer acetate had few relapses and few gadolinium-enhancing lesions on MRI, and the group’s annualized relapse rate remained stable and low at 24 months. Participants receiving placebo and glatiramer acetate had fewer relapses at month 24 than at baseline, and the difference in annualized relapse rate between the two groups decreased to 32%.

After 12 months of treatment, scores on the Paced Auditory Serial Addition Test (PASAT) at 3 and 2 seconds improved by approximately 6% (ie, 3 points), compared with scores at baseline, among patients receiving estriol and glatiramer acetate. The change largely resulted from a 12% improvement (ie, six to seven points) among participants scoring less than 55 at baseline, which reflected cognitive disability. The investigators observed no change in patients who scored higher than 55 (ie, those with little cognitive disability) at baseline. After 24 months of treatment, patients receiving estriol plus glatiramer acetate continued to have high PASAT scores, and participants receiving placebo plus glatiramer acetate began to improve.

Dr. Voskuhl is conducting an ongoing study at UCLA, the University of New Mexico, the University of Pennsylvania, and the University of Colorado that involves treatment with estriol in combination with most of the currently approved treatments for MS, including injectables and newer oral treatments. The goal of the study is to examine the effect of estriol on cognition.

—Erik Greb

PHILADELPHIA—Daily treatment with estriol and glatiramer acetate may reduce multiple sclerosis (MS) relapses significantly, compared with placebo and glatiramer acetate, according to research presented at the 66th Annual Meeting of the American Academy of Neurology. The difference may become evident within 12 months of treatment. Cognitive scores also may improve within 12 months of treatment with estriol and glatiramer acetate, compared with placebo plus glatiramer acetate.

A previous study of women with MS who were not pregnant indicated that the pregnancy hormone estriol was associated with a significant decrease in the number and volume of gadolinium-enhancing lesions on MRI. To examine the hormone’s effect on relapse rate, Rhonda Voskuhl, MD, Jack H. Skirball Chair of MS Research at the University of California, Los Angeles (UCLA), and colleagues conducted a randomized controlled trial of women with relapsing-remitting MS.

Comparing Estriol With Placebo in Patients With Active MS
Eligible patients were between ages 18 and 50, had active disease, and had an Expanded Disability Status Scale (EDSS) score between 0 and 4.5. Women who were pregnant, breastfeeding, taking hormone replacement therapy, or taking oral contraceptives were excluded from the trial.

Patients were randomized to glatiramer acetate injections (20 mg/day) and oral estriol (8 mg/day) or to glatiramer acetate injections and placebo. Gynecologists examined the patients before, during, and after the study. Each patient was examined at three- to six-month intervals during the trial. Patients also underwent mammograms before and after the study. In addition, at baseline, three months, six months, 12 months, 18 months, and 24 months, the investigators measured participants’ estriol levels, administered the EDSS, and administered the MS Functional Composite.

A total of 82 patients received glatiramer acetate plus estriol, and 76 patients received glatiramer acetate plus placebo. The trial’s dropout rate was 29%. Baseline characteristics were similar in both patient groups. Participants’ mean age was approximately 38, and their mean EDSS score was 2.2.

Estriol Was Associated With Reduced Relapse Rate
At 12 months, the annualized relapse rate was 47% lower among patients receiving estriol and glatiramer acetate, compared with patients receiving placebo and glatiramer acetate. After month 12, the group receiving estriol and glatiramer acetate had few relapses and few gadolinium-enhancing lesions on MRI, and the group’s annualized relapse rate remained stable and low at 24 months. Participants receiving placebo and glatiramer acetate had fewer relapses at month 24 than at baseline, and the difference in annualized relapse rate between the two groups decreased to 32%.

After 12 months of treatment, scores on the Paced Auditory Serial Addition Test (PASAT) at 3 and 2 seconds improved by approximately 6% (ie, 3 points), compared with scores at baseline, among patients receiving estriol and glatiramer acetate. The change largely resulted from a 12% improvement (ie, six to seven points) among participants scoring less than 55 at baseline, which reflected cognitive disability. The investigators observed no change in patients who scored higher than 55 (ie, those with little cognitive disability) at baseline. After 24 months of treatment, patients receiving estriol plus glatiramer acetate continued to have high PASAT scores, and participants receiving placebo plus glatiramer acetate began to improve.

Dr. Voskuhl is conducting an ongoing study at UCLA, the University of New Mexico, the University of Pennsylvania, and the University of Colorado that involves treatment with estriol in combination with most of the currently approved treatments for MS, including injectables and newer oral treatments. The goal of the study is to examine the effect of estriol on cognition.

—Erik Greb

PHILADELPHIA—Daily treatment with estriol and glatiramer acetate may reduce multiple sclerosis (MS) relapses significantly, compared with placebo and glatiramer acetate, according to research presented at the 66th Annual Meeting of the American Academy of Neurology. The difference may become evident within 12 months of treatment. Cognitive scores also may improve within 12 months of treatment with estriol and glatiramer acetate, compared with placebo plus glatiramer acetate.

A previous study of women with MS who were not pregnant indicated that the pregnancy hormone estriol was associated with a significant decrease in the number and volume of gadolinium-enhancing lesions on MRI. To examine the hormone’s effect on relapse rate, Rhonda Voskuhl, MD, Jack H. Skirball Chair of MS Research at the University of California, Los Angeles (UCLA), and colleagues conducted a randomized controlled trial of women with relapsing-remitting MS.

Comparing Estriol With Placebo in Patients With Active MS
Eligible patients were between ages 18 and 50, had active disease, and had an Expanded Disability Status Scale (EDSS) score between 0 and 4.5. Women who were pregnant, breastfeeding, taking hormone replacement therapy, or taking oral contraceptives were excluded from the trial.

Patients were randomized to glatiramer acetate injections (20 mg/day) and oral estriol (8 mg/day) or to glatiramer acetate injections and placebo. Gynecologists examined the patients before, during, and after the study. Each patient was examined at three- to six-month intervals during the trial. Patients also underwent mammograms before and after the study. In addition, at baseline, three months, six months, 12 months, 18 months, and 24 months, the investigators measured participants’ estriol levels, administered the EDSS, and administered the MS Functional Composite.

A total of 82 patients received glatiramer acetate plus estriol, and 76 patients received glatiramer acetate plus placebo. The trial’s dropout rate was 29%. Baseline characteristics were similar in both patient groups. Participants’ mean age was approximately 38, and their mean EDSS score was 2.2.

Estriol Was Associated With Reduced Relapse Rate
At 12 months, the annualized relapse rate was 47% lower among patients receiving estriol and glatiramer acetate, compared with patients receiving placebo and glatiramer acetate. After month 12, the group receiving estriol and glatiramer acetate had few relapses and few gadolinium-enhancing lesions on MRI, and the group’s annualized relapse rate remained stable and low at 24 months. Participants receiving placebo and glatiramer acetate had fewer relapses at month 24 than at baseline, and the difference in annualized relapse rate between the two groups decreased to 32%.

After 12 months of treatment, scores on the Paced Auditory Serial Addition Test (PASAT) at 3 and 2 seconds improved by approximately 6% (ie, 3 points), compared with scores at baseline, among patients receiving estriol and glatiramer acetate. The change largely resulted from a 12% improvement (ie, six to seven points) among participants scoring less than 55 at baseline, which reflected cognitive disability. The investigators observed no change in patients who scored higher than 55 (ie, those with little cognitive disability) at baseline. After 24 months of treatment, patients receiving estriol plus glatiramer acetate continued to have high PASAT scores, and participants receiving placebo plus glatiramer acetate began to improve.

Dr. Voskuhl is conducting an ongoing study at UCLA, the University of New Mexico, the University of Pennsylvania, and the University of Colorado that involves treatment with estriol in combination with most of the currently approved treatments for MS, including injectables and newer oral treatments. The goal of the study is to examine the effect of estriol on cognition.

—Erik Greb

PHILADELPHIA—Among patients with relapsing-remitting multiple sclerosis (MS), a thrice-weekly 40-mg subcutaneous dose of glatiramer acetate, which the FDA approved in January 2014, reduces the rate of injection-related adverse events by approximately 50%, compared with the standard dose of 20 mg/day, according to research presented at the 66th Annual Meeting of the American Academy of Neurology. The 40-mg dose is associated with a similar reduction in the rate of direct injection-site reactions.

In a separate study, early treatment with 40 mg of glatiramer acetate was associated with a 31% reduction in the number of confirmed relapses, compared with delayed treatment. Early treatment also was associated with a 67.5% likelihood of relapse freedom, compared with delayed treatment. Early treatment did not affect the rate of disease progression significantly, compared with delayed treatment, but the open-label extension study was not designed to assess disease progression.

The 40-mg dose of glatiramer acetate could affect patient compliance in several ways. For example, patients may prefer receiving injections three times per week to receiving daily injections, but the latter schedule may be easier for patients to remember than the former. “I counsel my patients who want less-frequent injections to set their calendars up [and] to be careful about what they’re doing, because it will take a little bit more behavior change or adaptation on their part to do this correctly,” said Jerry Wolinsky, MD, Interim Chair of the Department of Neurology at the University of Texas in Houston.

One problem with the long-term injection of glatiramer acetate is that patients may develop lipoatrophy. “We expect, but don’t know, that with fewer injections, what has been a major compliance problem for some patients in the long run may be put off for years by this kind of a preparation,” added Dr. Wolinsky.

Safety Study Compared 20-mg and 40-mg Doses
Dr. Wolinsky and colleagues performed an open-label, multicenter study to compare the acceptability and tolerability of two formulations of glatiramer acetate. For the study, the researchers enrolled 209 patients with relapsing-remitting MS who had been receiving daily 20-mg injections of glatiramer acetate for at least six months. Eligible participants were 18 or older, were fully ambulatory, had an Expanded Disability Status Scale (EDSS) score between 0 and 5.5, and were relapse-free in the 60 days before randomization.

The investigators randomized 101 participants to continue daily 20-mg injections of glatiramer acetate. The remaining 108 patients were randomized to 40-mg injections of glatiramer acetate three times per week. At the end of a four-month study period, patients were given the option of continuing on 40-mg injections until the trial was completed. Dr. Wolinsky and colleagues conducted various assessments, including subject-reported outcome questionnaires and standard examinations and testing.

The study population differed from that of the typical clinical trial in MS, said Dr. Wolinsky. Average age for patients in this trial was more than 50, and the population included a larger proportion of women than is common in similar studies. In addition, patients’ average disease duration was approximately 16 years, and average time to diagnosis ranged from 10 to 12 years. Participants had a low reported exacerbation rate and a low EDSS score at study entry.

Patients Found the 40-mg Dose Convenient
The trial’s primary end point was the rate of injection-related adverse events, and 40-mg injections of glatiramer acetate were associated with a significant reduction in these events. Secondary end points included the treatment’s effect on questionnaires of physical and psychological well-being (as measured by the MS Impact Scale 29) and subjects’ perceptions of convenience and satisfaction. The researchers found no significant differences between treatment arms in the physical or psychological scores of the MS Impact Scale 29. Convenience scores on the Treatment Satisfaction Questionnaire for Medication-9 appeared to favor the high dose of glatiramer acetate.

Most adverse events in the trial were related to the direct injection, and no new safety signals were reported for glatiramer acetate. “The 40-mg three-times-a-week dosing regime appears to be a favorable treatment option for patients who want glatiramer acetate treatment but prefer fewer subcutaneous injections,” concluded Dr. Wolinsky.

Researchers Examined Efficacy of 40-mg Injections
Omar Khan, MD, Chair and Professor of Neurology at Wayne State University School of Medicine in Detroit, and colleagues conducted an open-label extension study to assess the ongoing safety and efficacy of thrice-weekly subcutaneous 40-mg injections of glatiramer acetate. Of the approximately 1,400 participants in a previous placebo-controlled study, 1,253 patients with relapsing-remitting MS agreed to participate in the open-label extension. The investigators grouped patients into two distinct arms. Participants in the early-start arm had received 40-mg injections of glatiramer acetate thrice weekly for 12 months in the placebo-controlled trial, and they continued to receive this treatment in the extension. Patients in the delayed-start arm had received placebo for 12 months in the placebo-controlled study and received thrice-weekly 40-mg injections of glatiramer acetate in the extension. The clinical end point was the total number of confirmed relapses.

The participants’ average EDSS was approximately 2.8, and disease onset had occurred approximately seven and a half years previously, on average. The volume of T2 lesion load ranged from 17 cm³ to 20 cm³, which was “remarkably high” for patients with relapsing-remitting MS, said Dr. Khan. In most relapsing-remitting trials, T2 lesion load ranges between 7 cm³ and 9 cm³, he added.

Early Treatment Was Associated With Improved Outcomes
At the end of the placebo-controlled study, the new formulation of glatiramer acetate was associated with a 34% reduction in confirmed relapses, compared with placebo. At 12 months of the open-label extension, participants who had never been exposed to placebo had 31% fewer confirmed relapses, compared with patients in the delayed-start arm. The results emphasize “that starting treatment early makes a difference,” said Dr. Khan.

Many of the adverse events recorded during the extension were related to the local injection site. They included injection-site erythema, pain, pruritus, and swelling. Approximately 1% of patients had injection-site atrophy, which tends to appear in the second and third year of treatment with glatiramer acetate. Eight participants became pregnant during the study. Four had elective abortions, and four discontinued the study and gave birth to normal newborns.

The new formulation of glatiramer acetate appears to have a favorable safety profile that is similar to that of the conventional 20-mg formulation. The study is ongoing, and patients will have been followed up for 36 months, including the 12-month placebo-controlled phase, by the time of completion.

—Erik Greb

PHILADELPHIA—Among patients with relapsing-remitting multiple sclerosis (MS), a thrice-weekly 40-mg subcutaneous dose of glatiramer acetate, which the FDA approved in January 2014, reduces the rate of injection-related adverse events by approximately 50%, compared with the standard dose of 20 mg/day, according to research presented at the 66th Annual Meeting of the American Academy of Neurology. The 40-mg dose is associated with a similar reduction in the rate of direct injection-site reactions.

In a separate study, early treatment with 40 mg of glatiramer acetate was associated with a 31% reduction in the number of confirmed relapses, compared with delayed treatment. Early treatment also was associated with a 67.5% likelihood of relapse freedom, compared with delayed treatment. Early treatment did not affect the rate of disease progression significantly, compared with delayed treatment, but the open-label extension study was not designed to assess disease progression.

The 40-mg dose of glatiramer acetate could affect patient compliance in several ways. For example, patients may prefer receiving injections three times per week to receiving daily injections, but the latter schedule may be easier for patients to remember than the former. “I counsel my patients who want less-frequent injections to set their calendars up [and] to be careful about what they’re doing, because it will take a little bit more behavior change or adaptation on their part to do this correctly,” said Jerry Wolinsky, MD, Interim Chair of the Department of Neurology at the University of Texas in Houston.

One problem with the long-term injection of glatiramer acetate is that patients may develop lipoatrophy. “We expect, but don’t know, that with fewer injections, what has been a major compliance problem for some patients in the long run may be put off for years by this kind of a preparation,” added Dr. Wolinsky.

Safety Study Compared 20-mg and 40-mg Doses
Dr. Wolinsky and colleagues performed an open-label, multicenter study to compare the acceptability and tolerability of two formulations of glatiramer acetate. For the study, the researchers enrolled 209 patients with relapsing-remitting MS who had been receiving daily 20-mg injections of glatiramer acetate for at least six months. Eligible participants were 18 or older, were fully ambulatory, had an Expanded Disability Status Scale (EDSS) score between 0 and 5.5, and were relapse-free in the 60 days before randomization.

The investigators randomized 101 participants to continue daily 20-mg injections of glatiramer acetate. The remaining 108 patients were randomized to 40-mg injections of glatiramer acetate three times per week. At the end of a four-month study period, patients were given the option of continuing on 40-mg injections until the trial was completed. Dr. Wolinsky and colleagues conducted various assessments, including subject-reported outcome questionnaires and standard examinations and testing.

The study population differed from that of the typical clinical trial in MS, said Dr. Wolinsky. Average age for patients in this trial was more than 50, and the population included a larger proportion of women than is common in similar studies. In addition, patients’ average disease duration was approximately 16 years, and average time to diagnosis ranged from 10 to 12 years. Participants had a low reported exacerbation rate and a low EDSS score at study entry.

Patients Found the 40-mg Dose Convenient
The trial’s primary end point was the rate of injection-related adverse events, and 40-mg injections of glatiramer acetate were associated with a significant reduction in these events. Secondary end points included the treatment’s effect on questionnaires of physical and psychological well-being (as measured by the MS Impact Scale 29) and subjects’ perceptions of convenience and satisfaction. The researchers found no significant differences between treatment arms in the physical or psychological scores of the MS Impact Scale 29. Convenience scores on the Treatment Satisfaction Questionnaire for Medication-9 appeared to favor the high dose of glatiramer acetate.

Most adverse events in the trial were related to the direct injection, and no new safety signals were reported for glatiramer acetate. “The 40-mg three-times-a-week dosing regime appears to be a favorable treatment option for patients who want glatiramer acetate treatment but prefer fewer subcutaneous injections,” concluded Dr. Wolinsky.

Researchers Examined Efficacy of 40-mg Injections
Omar Khan, MD, Chair and Professor of Neurology at Wayne State University School of Medicine in Detroit, and colleagues conducted an open-label extension study to assess the ongoing safety and efficacy of thrice-weekly subcutaneous 40-mg injections of glatiramer acetate. Of the approximately 1,400 participants in a previous placebo-controlled study, 1,253 patients with relapsing-remitting MS agreed to participate in the open-label extension. The investigators grouped patients into two distinct arms. Participants in the early-start arm had received 40-mg injections of glatiramer acetate thrice weekly for 12 months in the placebo-controlled trial, and they continued to receive this treatment in the extension. Patients in the delayed-start arm had received placebo for 12 months in the placebo-controlled study and received thrice-weekly 40-mg injections of glatiramer acetate in the extension. The clinical end point was the total number of confirmed relapses.

The participants’ average EDSS was approximately 2.8, and disease onset had occurred approximately seven and a half years previously, on average. The volume of T2 lesion load ranged from 17 cm³ to 20 cm³, which was “remarkably high” for patients with relapsing-remitting MS, said Dr. Khan. In most relapsing-remitting trials, T2 lesion load ranges between 7 cm³ and 9 cm³, he added.

Early Treatment Was Associated With Improved Outcomes
At the end of the placebo-controlled study, the new formulation of glatiramer acetate was associated with a 34% reduction in confirmed relapses, compared with placebo. At 12 months of the open-label extension, participants who had never been exposed to placebo had 31% fewer confirmed relapses, compared with patients in the delayed-start arm. The results emphasize “that starting treatment early makes a difference,” said Dr. Khan.

Many of the adverse events recorded during the extension were related to the local injection site. They included injection-site erythema, pain, pruritus, and swelling. Approximately 1% of patients had injection-site atrophy, which tends to appear in the second and third year of treatment with glatiramer acetate. Eight participants became pregnant during the study. Four had elective abortions, and four discontinued the study and gave birth to normal newborns.

The new formulation of glatiramer acetate appears to have a favorable safety profile that is similar to that of the conventional 20-mg formulation. The study is ongoing, and patients will have been followed up for 36 months, including the 12-month placebo-controlled phase, by the time of completion.

—Erik Greb

PHILADELPHIA—Among patients with relapsing-remitting multiple sclerosis (MS), a thrice-weekly 40-mg subcutaneous dose of glatiramer acetate, which the FDA approved in January 2014, reduces the rate of injection-related adverse events by approximately 50%, compared with the standard dose of 20 mg/day, according to research presented at the 66th Annual Meeting of the American Academy of Neurology. The 40-mg dose is associated with a similar reduction in the rate of direct injection-site reactions.

In a separate study, early treatment with 40 mg of glatiramer acetate was associated with a 31% reduction in the number of confirmed relapses, compared with delayed treatment. Early treatment also was associated with a 67.5% likelihood of relapse freedom, compared with delayed treatment. Early treatment did not affect the rate of disease progression significantly, compared with delayed treatment, but the open-label extension study was not designed to assess disease progression.

The 40-mg dose of glatiramer acetate could affect patient compliance in several ways. For example, patients may prefer receiving injections three times per week to receiving daily injections, but the latter schedule may be easier for patients to remember than the former. “I counsel my patients who want less-frequent injections to set their calendars up [and] to be careful about what they’re doing, because it will take a little bit more behavior change or adaptation on their part to do this correctly,” said Jerry Wolinsky, MD, Interim Chair of the Department of Neurology at the University of Texas in Houston.

One problem with the long-term injection of glatiramer acetate is that patients may develop lipoatrophy. “We expect, but don’t know, that with fewer injections, what has been a major compliance problem for some patients in the long run may be put off for years by this kind of a preparation,” added Dr. Wolinsky.

Safety Study Compared 20-mg and 40-mg Doses
Dr. Wolinsky and colleagues performed an open-label, multicenter study to compare the acceptability and tolerability of two formulations of glatiramer acetate. For the study, the researchers enrolled 209 patients with relapsing-remitting MS who had been receiving daily 20-mg injections of glatiramer acetate for at least six months. Eligible participants were 18 or older, were fully ambulatory, had an Expanded Disability Status Scale (EDSS) score between 0 and 5.5, and were relapse-free in the 60 days before randomization.

The investigators randomized 101 participants to continue daily 20-mg injections of glatiramer acetate. The remaining 108 patients were randomized to 40-mg injections of glatiramer acetate three times per week. At the end of a four-month study period, patients were given the option of continuing on 40-mg injections until the trial was completed. Dr. Wolinsky and colleagues conducted various assessments, including subject-reported outcome questionnaires and standard examinations and testing.

The study population differed from that of the typical clinical trial in MS, said Dr. Wolinsky. Average age for patients in this trial was more than 50, and the population included a larger proportion of women than is common in similar studies. In addition, patients’ average disease duration was approximately 16 years, and average time to diagnosis ranged from 10 to 12 years. Participants had a low reported exacerbation rate and a low EDSS score at study entry.

Patients Found the 40-mg Dose Convenient
The trial’s primary end point was the rate of injection-related adverse events, and 40-mg injections of glatiramer acetate were associated with a significant reduction in these events. Secondary end points included the treatment’s effect on questionnaires of physical and psychological well-being (as measured by the MS Impact Scale 29) and subjects’ perceptions of convenience and satisfaction. The researchers found no significant differences between treatment arms in the physical or psychological scores of the MS Impact Scale 29. Convenience scores on the Treatment Satisfaction Questionnaire for Medication-9 appeared to favor the high dose of glatiramer acetate.

Most adverse events in the trial were related to the direct injection, and no new safety signals were reported for glatiramer acetate. “The 40-mg three-times-a-week dosing regime appears to be a favorable treatment option for patients who want glatiramer acetate treatment but prefer fewer subcutaneous injections,” concluded Dr. Wolinsky.

Researchers Examined Efficacy of 40-mg Injections
Omar Khan, MD, Chair and Professor of Neurology at Wayne State University School of Medicine in Detroit, and colleagues conducted an open-label extension study to assess the ongoing safety and efficacy of thrice-weekly subcutaneous 40-mg injections of glatiramer acetate. Of the approximately 1,400 participants in a previous placebo-controlled study, 1,253 patients with relapsing-remitting MS agreed to participate in the open-label extension. The investigators grouped patients into two distinct arms. Participants in the early-start arm had received 40-mg injections of glatiramer acetate thrice weekly for 12 months in the placebo-controlled trial, and they continued to receive this treatment in the extension. Patients in the delayed-start arm had received placebo for 12 months in the placebo-controlled study and received thrice-weekly 40-mg injections of glatiramer acetate in the extension. The clinical end point was the total number of confirmed relapses.

The participants’ average EDSS was approximately 2.8, and disease onset had occurred approximately seven and a half years previously, on average. The volume of T2 lesion load ranged from 17 cm³ to 20 cm³, which was “remarkably high” for patients with relapsing-remitting MS, said Dr. Khan. In most relapsing-remitting trials, T2 lesion load ranges between 7 cm³ and 9 cm³, he added.

Early Treatment Was Associated With Improved Outcomes
At the end of the placebo-controlled study, the new formulation of glatiramer acetate was associated with a 34% reduction in confirmed relapses, compared with placebo. At 12 months of the open-label extension, participants who had never been exposed to placebo had 31% fewer confirmed relapses, compared with patients in the delayed-start arm. The results emphasize “that starting treatment early makes a difference,” said Dr. Khan.

Many of the adverse events recorded during the extension were related to the local injection site. They included injection-site erythema, pain, pruritus, and swelling. Approximately 1% of patients had injection-site atrophy, which tends to appear in the second and third year of treatment with glatiramer acetate. Eight participants became pregnant during the study. Four had elective abortions, and four discontinued the study and gave birth to normal newborns.

The new formulation of glatiramer acetate appears to have a favorable safety profile that is similar to that of the conventional 20-mg formulation. The study is ongoing, and patients will have been followed up for 36 months, including the 12-month placebo-controlled phase, by the time of completion.

—Erik Greb

PHILADELPHIA – A proposed revision of the neuromyelitis optica diagnostic criteria takes into account newly appreciated variations in how the disease can present clinically.

If adopted, the new criteria would offer diagnostic pathways for patients who have symptoms, but who might or might not have the serum antibodies usually associated with the disorder, Dr. Dean Wingerchuk said at the annual meeting of the American Academy of Neurology.

They reflect the current understanding of neuromyelitis optica as a spectrum of clinical symptoms, said Dr. Wingerchuk, professor of neurology at the Mayo Clinic, Scottsdale, Ariz. Neuromyelitis optica spectrum disorder (NMOSD) was identified in 2007 – 1 year after the existing diagnostic criteria were published.

In the new guidelines, "we wanted to encompass all patients who would have previously been diagnosed as having neuromyelitis optica or NMOSD," he said. A new stratification of antibody positive or antibody negative reflects the fact that not all patients are seropositive at presentation, particularly early in the disease course; that antibody testing is not available or reliable everywhere; and that as-yet-unidentified antibodies might be implicated in the disorder.

The workgroup that authored the document consisted of 18 members from nine countries. It began its work in 2011. The proposed criteria still need to be prospectively validated before they could be widely adopted, noted Dr. Wingerchuk, who was a primary author of the 2006 criteria.

The existing criteria require the presence of transverse myelitis, optic neuritis, and at least two of the following:

• Brain MRI imaging findings that are nondiagnostic for multiple sclerosis.

• A spinal cord lesion extending over three or more vertebral segments.

• Seropositivity for NMO-IgG.

The newly proposed criteria have been expanded to include six different core characteristics: optic neuritis; acute myelitis; area postrema syndrome (nausea, vomiting, and hiccups); other brain stem syndromes; symptomatic narcolepsy or acute diencephalic syndrome with MRI findings; and symptomatic cerebral syndrome with MRI findings.

Antibody-positive patients need to show at least one of these core characteristics, with no other better explanation for their symptoms.

The bar is a little higher for antibody-negative patients. They need to show at least two of the core characteristics, meeting the following requirements:

• At least one of the core symptoms must be optic neuritis, myelitis, or area postrema syndrome.

• The core characteristics must be disseminated in space.

• MRI findings must distinguish NMOSD from multiple sclerosis or other demyelinating disorders.

Prospective validation will require follow-up of patients who are seropositive at diagnosis but present with less common syndromes, and detailed descriptions of seronegative groups to determine whether they eventually convert to a clinical NMOSD, Dr. Wingerchuk said.

The project is being funded by the Guthy-Jackson Charitable Foundation. Dr. Wingerchuk disclosed that he has received financial compensation on an adjudication committee for an NMO trial that was sponsored by MedImmune.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

PHILADELPHIA – A proposed revision of the neuromyelitis optica diagnostic criteria takes into account newly appreciated variations in how the disease can present clinically.

If adopted, the new criteria would offer diagnostic pathways for patients who have symptoms, but who might or might not have the serum antibodies usually associated with the disorder, Dr. Dean Wingerchuk said at the annual meeting of the American Academy of Neurology.

They reflect the current understanding of neuromyelitis optica as a spectrum of clinical symptoms, said Dr. Wingerchuk, professor of neurology at the Mayo Clinic, Scottsdale, Ariz. Neuromyelitis optica spectrum disorder (NMOSD) was identified in 2007 – 1 year after the existing diagnostic criteria were published.

In the new guidelines, "we wanted to encompass all patients who would have previously been diagnosed as having neuromyelitis optica or NMOSD," he said. A new stratification of antibody positive or antibody negative reflects the fact that not all patients are seropositive at presentation, particularly early in the disease course; that antibody testing is not available or reliable everywhere; and that as-yet-unidentified antibodies might be implicated in the disorder.

The workgroup that authored the document consisted of 18 members from nine countries. It began its work in 2011. The proposed criteria still need to be prospectively validated before they could be widely adopted, noted Dr. Wingerchuk, who was a primary author of the 2006 criteria.

The existing criteria require the presence of transverse myelitis, optic neuritis, and at least two of the following:

• Brain MRI imaging findings that are nondiagnostic for multiple sclerosis.

• A spinal cord lesion extending over three or more vertebral segments.

• Seropositivity for NMO-IgG.

The newly proposed criteria have been expanded to include six different core characteristics: optic neuritis; acute myelitis; area postrema syndrome (nausea, vomiting, and hiccups); other brain stem syndromes; symptomatic narcolepsy or acute diencephalic syndrome with MRI findings; and symptomatic cerebral syndrome with MRI findings.

Antibody-positive patients need to show at least one of these core characteristics, with no other better explanation for their symptoms.

The bar is a little higher for antibody-negative patients. They need to show at least two of the core characteristics, meeting the following requirements:

• At least one of the core symptoms must be optic neuritis, myelitis, or area postrema syndrome.

• The core characteristics must be disseminated in space.

• MRI findings must distinguish NMOSD from multiple sclerosis or other demyelinating disorders.

Prospective validation will require follow-up of patients who are seropositive at diagnosis but present with less common syndromes, and detailed descriptions of seronegative groups to determine whether they eventually convert to a clinical NMOSD, Dr. Wingerchuk said.

The project is being funded by the Guthy-Jackson Charitable Foundation. Dr. Wingerchuk disclosed that he has received financial compensation on an adjudication committee for an NMO trial that was sponsored by MedImmune.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

PHILADELPHIA – A proposed revision of the neuromyelitis optica diagnostic criteria takes into account newly appreciated variations in how the disease can present clinically.

If adopted, the new criteria would offer diagnostic pathways for patients who have symptoms, but who might or might not have the serum antibodies usually associated with the disorder, Dr. Dean Wingerchuk said at the annual meeting of the American Academy of Neurology.

They reflect the current understanding of neuromyelitis optica as a spectrum of clinical symptoms, said Dr. Wingerchuk, professor of neurology at the Mayo Clinic, Scottsdale, Ariz. Neuromyelitis optica spectrum disorder (NMOSD) was identified in 2007 – 1 year after the existing diagnostic criteria were published.

In the new guidelines, "we wanted to encompass all patients who would have previously been diagnosed as having neuromyelitis optica or NMOSD," he said. A new stratification of antibody positive or antibody negative reflects the fact that not all patients are seropositive at presentation, particularly early in the disease course; that antibody testing is not available or reliable everywhere; and that as-yet-unidentified antibodies might be implicated in the disorder.

The workgroup that authored the document consisted of 18 members from nine countries. It began its work in 2011. The proposed criteria still need to be prospectively validated before they could be widely adopted, noted Dr. Wingerchuk, who was a primary author of the 2006 criteria.

The existing criteria require the presence of transverse myelitis, optic neuritis, and at least two of the following:

• Brain MRI imaging findings that are nondiagnostic for multiple sclerosis.

• A spinal cord lesion extending over three or more vertebral segments.

• Seropositivity for NMO-IgG.

The newly proposed criteria have been expanded to include six different core characteristics: optic neuritis; acute myelitis; area postrema syndrome (nausea, vomiting, and hiccups); other brain stem syndromes; symptomatic narcolepsy or acute diencephalic syndrome with MRI findings; and symptomatic cerebral syndrome with MRI findings.

Antibody-positive patients need to show at least one of these core characteristics, with no other better explanation for their symptoms.

The bar is a little higher for antibody-negative patients. They need to show at least two of the core characteristics, meeting the following requirements:

• At least one of the core symptoms must be optic neuritis, myelitis, or area postrema syndrome.

• The core characteristics must be disseminated in space.

• MRI findings must distinguish NMOSD from multiple sclerosis or other demyelinating disorders.

Prospective validation will require follow-up of patients who are seropositive at diagnosis but present with less common syndromes, and detailed descriptions of seronegative groups to determine whether they eventually convert to a clinical NMOSD, Dr. Wingerchuk said.

The project is being funded by the Guthy-Jackson Charitable Foundation. Dr. Wingerchuk disclosed that he has received financial compensation on an adjudication committee for an NMO trial that was sponsored by MedImmune.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

PHILADELPHIA – Correctly identifying the onset of multiple sclerosis in childhood and adolescence can pose a difficult diagnostic challenge, but predictive factors including older age, female gender, and the presence of persistent lesions on MRI are more likely to point to a first attack of MS.

In an interview at the annual meeting of the American Academy of Neurology, Dr. Brenda Banwell of the University of Pennsylvania, Philadelphia, talked with Dr. Timothy Vartanian of New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, about the diagnostic keys to differentiating monophasic illnesses such as acute disseminated encephalomyelitis from the onset of multiple sclerosis.

PHILADELPHIA – Correctly identifying the onset of multiple sclerosis in childhood and adolescence can pose a difficult diagnostic challenge, but predictive factors including older age, female gender, and the presence of persistent lesions on MRI are more likely to point to a first attack of MS.

In an interview at the annual meeting of the American Academy of Neurology, Dr. Brenda Banwell of the University of Pennsylvania, Philadelphia, talked with Dr. Timothy Vartanian of New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, about the diagnostic keys to differentiating monophasic illnesses such as acute disseminated encephalomyelitis from the onset of multiple sclerosis.

PHILADELPHIA – Correctly identifying the onset of multiple sclerosis in childhood and adolescence can pose a difficult diagnostic challenge, but predictive factors including older age, female gender, and the presence of persistent lesions on MRI are more likely to point to a first attack of MS.

In an interview at the annual meeting of the American Academy of Neurology, Dr. Brenda Banwell of the University of Pennsylvania, Philadelphia, talked with Dr. Timothy Vartanian of New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, about the diagnostic keys to differentiating monophasic illnesses such as acute disseminated encephalomyelitis from the onset of multiple sclerosis.

PHILADELPHIA – From biomarkers for better diagnosis to new biologic agents for more effective treatment, multiple sclerosis patients may soon enjoy a wave of promising advances.

In an interview at the annual meeting of the American Academy of Neurology, Dr. Emmanuelle Waubant, professor of neurology at the University of California, San Francisco, talked about progress being made with remyelination therapies and discussed three investigational drugs that could reach the market soon.

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

PHILADELPHIA – From biomarkers for better diagnosis to new biologic agents for more effective treatment, multiple sclerosis patients may soon enjoy a wave of promising advances.

In an interview at the annual meeting of the American Academy of Neurology, Dr. Emmanuelle Waubant, professor of neurology at the University of California, San Francisco, talked about progress being made with remyelination therapies and discussed three investigational drugs that could reach the market soon.

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

PHILADELPHIA – From biomarkers for better diagnosis to new biologic agents for more effective treatment, multiple sclerosis patients may soon enjoy a wave of promising advances.

In an interview at the annual meeting of the American Academy of Neurology, Dr. Emmanuelle Waubant, professor of neurology at the University of California, San Francisco, talked about progress being made with remyelination therapies and discussed three investigational drugs that could reach the market soon.

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

PHILADELPHIA—Certain forms of medical marijuana can help treat symptoms of multiple sclerosis (MS), but may not be helpful in treating levodopa-induced movements in Parkinson’s disease, researchers reported at the 66th Annual Meeting of the American Academy of Neurology (AAN). The researchers did not find enough evidence to show whether medical marijuana is helpful in treating motor problems in Huntington’s disease, tics in Tourette syndrome, cervical dystonia, and seizures in epilepsy. These conclusions are part of AAN’s review of scientific research on the use of medical marijuana in brain diseases. The findings were published in the April 29, 2014, print issue of Neurology.

“This review by the world’s largest association for neurologists is intended to help neurologists and their patients understand the current research on medical marijuana for the treatment of certain brain diseases,” said review author Barbara S. Koppel, MD, of New York Medical College in Valhalla, and Fellow of the AAN. “The AAN review also highlights the need for more high-quality studies of the long-term efficacy and safety of medical marijuana in the treatment of neurologic diseases.”

The AAN review concluded that only the pill or oral spray forms of medical marijuana can help treat symptoms of MS, including spasticity, certain types of pain (ie, pain related to spasticity, including painful spasms, and painful burning and numbness), and overactive bladder. Most of the MS studies examined pill or oral spray forms of medical marijuana. Two studies examined smoked medical marijuana for treating MS symptoms, but these studies did not provide enough information to show whether smoked medical marijuana is effective. “It’s important to note that medical marijuana can worsen thinking and memory problems, and this is a concern, since many people with MS suffer from these problems already due to the disease itself,” said Dr. Koppel.

In addition, the AAN review concluded that medical marijuana, in the form of synthetic tetrahydrocannabinol (THC) pills, likely does not help relieve abnormal movements that can develop in the late stages of Parkinson’s disease as a result of levodopa.

Medical marijuana use does entail safety concerns. In at least two studies, participants reported side effects such as nausea, increased weakness, behavioral or mood changes, suicidal thoughts or hallucinations, dizziness or fainting symptoms, fatigue, and feelings of intoxication. There were reports of two seizures. Mood changes and suicidal thoughts are of special concern for people with neurologic illness, who are at an increased risk for depression and suicide. The risk of serious psychologic effects is approximately 1%, according to the studies.

The only two medical marijuana pills with FDA approval contain THC. “The psychoactive side effects, like feeling intoxicated, seemed to come from the THC,” said Dr. Koppel. “They’re trying to create pills that are leaning more toward the cannabinoid, which has the therapeutic effects with fewer psychoactive side effects.”

Clinicians who practice in states where medical marijuana is legal may recommend the drug for the MS symptoms that respond to it, Dr. Koppel added. “The problem is that the studies are done very rigorously with a certain amount of THC versus cannabinoid. The type of marijuana you can buy so far is not so rigorously defined.” Clinicians also should warn their patients about marijuana’s potential side effects.

In general, medical marijuana is prescribed as a treatment only when standard treatment has not helped. In most of the studies reviewed, patients were allowed to continue their standard treatments. The AAN review is endorsed by the American Autonomic Society, the American Epilepsy Society, and the International Rett Syndrome Foundation.

—Erik Greb

PHILADELPHIA—Certain forms of medical marijuana can help treat symptoms of multiple sclerosis (MS), but may not be helpful in treating levodopa-induced movements in Parkinson’s disease, researchers reported at the 66th Annual Meeting of the American Academy of Neurology (AAN). The researchers did not find enough evidence to show whether medical marijuana is helpful in treating motor problems in Huntington’s disease, tics in Tourette syndrome, cervical dystonia, and seizures in epilepsy. These conclusions are part of AAN’s review of scientific research on the use of medical marijuana in brain diseases. The findings were published in the April 29, 2014, print issue of Neurology.

“This review by the world’s largest association for neurologists is intended to help neurologists and their patients understand the current research on medical marijuana for the treatment of certain brain diseases,” said review author Barbara S. Koppel, MD, of New York Medical College in Valhalla, and Fellow of the AAN. “The AAN review also highlights the need for more high-quality studies of the long-term efficacy and safety of medical marijuana in the treatment of neurologic diseases.”

The AAN review concluded that only the pill or oral spray forms of medical marijuana can help treat symptoms of MS, including spasticity, certain types of pain (ie, pain related to spasticity, including painful spasms, and painful burning and numbness), and overactive bladder. Most of the MS studies examined pill or oral spray forms of medical marijuana. Two studies examined smoked medical marijuana for treating MS symptoms, but these studies did not provide enough information to show whether smoked medical marijuana is effective. “It’s important to note that medical marijuana can worsen thinking and memory problems, and this is a concern, since many people with MS suffer from these problems already due to the disease itself,” said Dr. Koppel.

In addition, the AAN review concluded that medical marijuana, in the form of synthetic tetrahydrocannabinol (THC) pills, likely does not help relieve abnormal movements that can develop in the late stages of Parkinson’s disease as a result of levodopa.

Medical marijuana use does entail safety concerns. In at least two studies, participants reported side effects such as nausea, increased weakness, behavioral or mood changes, suicidal thoughts or hallucinations, dizziness or fainting symptoms, fatigue, and feelings of intoxication. There were reports of two seizures. Mood changes and suicidal thoughts are of special concern for people with neurologic illness, who are at an increased risk for depression and suicide. The risk of serious psychologic effects is approximately 1%, according to the studies.

The only two medical marijuana pills with FDA approval contain THC. “The psychoactive side effects, like feeling intoxicated, seemed to come from the THC,” said Dr. Koppel. “They’re trying to create pills that are leaning more toward the cannabinoid, which has the therapeutic effects with fewer psychoactive side effects.”

Clinicians who practice in states where medical marijuana is legal may recommend the drug for the MS symptoms that respond to it, Dr. Koppel added. “The problem is that the studies are done very rigorously with a certain amount of THC versus cannabinoid. The type of marijuana you can buy so far is not so rigorously defined.” Clinicians also should warn their patients about marijuana’s potential side effects.

In general, medical marijuana is prescribed as a treatment only when standard treatment has not helped. In most of the studies reviewed, patients were allowed to continue their standard treatments. The AAN review is endorsed by the American Autonomic Society, the American Epilepsy Society, and the International Rett Syndrome Foundation.

—Erik Greb

PHILADELPHIA—Certain forms of medical marijuana can help treat symptoms of multiple sclerosis (MS), but may not be helpful in treating levodopa-induced movements in Parkinson’s disease, researchers reported at the 66th Annual Meeting of the American Academy of Neurology (AAN). The researchers did not find enough evidence to show whether medical marijuana is helpful in treating motor problems in Huntington’s disease, tics in Tourette syndrome, cervical dystonia, and seizures in epilepsy. These conclusions are part of AAN’s review of scientific research on the use of medical marijuana in brain diseases. The findings were published in the April 29, 2014, print issue of Neurology.

“This review by the world’s largest association for neurologists is intended to help neurologists and their patients understand the current research on medical marijuana for the treatment of certain brain diseases,” said review author Barbara S. Koppel, MD, of New York Medical College in Valhalla, and Fellow of the AAN. “The AAN review also highlights the need for more high-quality studies of the long-term efficacy and safety of medical marijuana in the treatment of neurologic diseases.”

The AAN review concluded that only the pill or oral spray forms of medical marijuana can help treat symptoms of MS, including spasticity, certain types of pain (ie, pain related to spasticity, including painful spasms, and painful burning and numbness), and overactive bladder. Most of the MS studies examined pill or oral spray forms of medical marijuana. Two studies examined smoked medical marijuana for treating MS symptoms, but these studies did not provide enough information to show whether smoked medical marijuana is effective. “It’s important to note that medical marijuana can worsen thinking and memory problems, and this is a concern, since many people with MS suffer from these problems already due to the disease itself,” said Dr. Koppel.

In addition, the AAN review concluded that medical marijuana, in the form of synthetic tetrahydrocannabinol (THC) pills, likely does not help relieve abnormal movements that can develop in the late stages of Parkinson’s disease as a result of levodopa.

Medical marijuana use does entail safety concerns. In at least two studies, participants reported side effects such as nausea, increased weakness, behavioral or mood changes, suicidal thoughts or hallucinations, dizziness or fainting symptoms, fatigue, and feelings of intoxication. There were reports of two seizures. Mood changes and suicidal thoughts are of special concern for people with neurologic illness, who are at an increased risk for depression and suicide. The risk of serious psychologic effects is approximately 1%, according to the studies.

The only two medical marijuana pills with FDA approval contain THC. “The psychoactive side effects, like feeling intoxicated, seemed to come from the THC,” said Dr. Koppel. “They’re trying to create pills that are leaning more toward the cannabinoid, which has the therapeutic effects with fewer psychoactive side effects.”

Clinicians who practice in states where medical marijuana is legal may recommend the drug for the MS symptoms that respond to it, Dr. Koppel added. “The problem is that the studies are done very rigorously with a certain amount of THC versus cannabinoid. The type of marijuana you can buy so far is not so rigorously defined.” Clinicians also should warn their patients about marijuana’s potential side effects.

In general, medical marijuana is prescribed as a treatment only when standard treatment has not helped. In most of the studies reviewed, patients were allowed to continue their standard treatments. The AAN review is endorsed by the American Autonomic Society, the American Epilepsy Society, and the International Rett Syndrome Foundation.

—Erik Greb

A drug that inhibits early-stage B-lymphocyte activation reduced disease activity in patients with relapsing-remitting multiple sclerosis, and showed potential to significantly decrease the annual number of new brain lesions.

The "intriguing" early results of a phase II randomized study suggest that ofatumumab’s targeting of peripheral B cells may be beneficial in treating the disease, according to Daren Austin, Ph.D., head of biopharm clinical pharmacology and biometrics at GlaxoSmithKline, Uxbridge, U.K. He will present these data Wednesday, April 30, at the annual meeting of the American Academy of Neurology.

"These results need to be validated, of course, but the findings are interesting," Dr. Austin said in a press statement. "They provide new insight into the mechanism of B cells in MS [multiple sclerosis] and present a possible new target threshold for exploring the potential benefit of anti-B-cell therapy."

Ofatumumab (Arzerra) is a fully humanized monoclonal antibody against B-lymphocyte antigen CD20, which optimizes B-cell antibody response. On April 17, the U.S. Food and Drug Administration approved the agent for use in combination with chlorambucil in previously untreated patients with chronic lymphocytic leukemia, for whom fludarabine-based therapy is considered inappropriate.

The drug also has shown potential in treating follicular non-Hodgkin’s lymphoma, diffuse large B-cell lymphoma, and rheumatoid arthritis.

The data Dr. Austin will report are part of an ongoing dose-ranging evaluation of 3 to 180 mg of ofatumumab for relapsing-remitting MS. The drug is administered by subcutaneous injection.

The current study included 231 patients who were randomized to placebo or ofatumumab for 24 weeks. The primary endpoint was the correlation of CD19 B-cell count to new gadolinium-enhancing brain lesions (a proxy measure for disease activity). Brain imaging was conducted every 4 weeks throughout the trial.

All of the groups – including placebo – showed lesion activity in the first 4 weeks. However, patients in the active groups showed some lesion suppression after that time. The beneficial effect seemed to appear when patients’ CD19 count fell below 64 cells/mcL, Dr. Austin said.

Researchers correlated B-cell levels to the total number of new brain lesions that appeared on magnetic resonance imaging. If CD19 levels were maintained in the range of 32-64 cells/mcL, patients taking the drug would develop fewer than 1 new lesion per year, compared with 16 new lesions per year in untreated patients, Dr. Austin said in the statement.

The most common side effects, which occurred twice as often in the active group as in the placebo group, were injection-site reaction, dizziness, anxiety, fever, respiratory tract infection, and neuropathy.

Ofatumumab is not approved anywhere in the world for use in the treatment of MS, Dr. Austin added.

GlaxoSmithKline sponsored the study. Dr. Austin is an employee of the company.

msullivan@frontlinemedcom.com

A drug that inhibits early-stage B-lymphocyte activation reduced disease activity in patients with relapsing-remitting multiple sclerosis, and showed potential to significantly decrease the annual number of new brain lesions.

The "intriguing" early results of a phase II randomized study suggest that ofatumumab’s targeting of peripheral B cells may be beneficial in treating the disease, according to Daren Austin, Ph.D., head of biopharm clinical pharmacology and biometrics at GlaxoSmithKline, Uxbridge, U.K. He will present these data Wednesday, April 30, at the annual meeting of the American Academy of Neurology.

"These results need to be validated, of course, but the findings are interesting," Dr. Austin said in a press statement. "They provide new insight into the mechanism of B cells in MS [multiple sclerosis] and present a possible new target threshold for exploring the potential benefit of anti-B-cell therapy."

Ofatumumab (Arzerra) is a fully humanized monoclonal antibody against B-lymphocyte antigen CD20, which optimizes B-cell antibody response. On April 17, the U.S. Food and Drug Administration approved the agent for use in combination with chlorambucil in previously untreated patients with chronic lymphocytic leukemia, for whom fludarabine-based therapy is considered inappropriate.

The drug also has shown potential in treating follicular non-Hodgkin’s lymphoma, diffuse large B-cell lymphoma, and rheumatoid arthritis.

The data Dr. Austin will report are part of an ongoing dose-ranging evaluation of 3 to 180 mg of ofatumumab for relapsing-remitting MS. The drug is administered by subcutaneous injection.

The current study included 231 patients who were randomized to placebo or ofatumumab for 24 weeks. The primary endpoint was the correlation of CD19 B-cell count to new gadolinium-enhancing brain lesions (a proxy measure for disease activity). Brain imaging was conducted every 4 weeks throughout the trial.

All of the groups – including placebo – showed lesion activity in the first 4 weeks. However, patients in the active groups showed some lesion suppression after that time. The beneficial effect seemed to appear when patients’ CD19 count fell below 64 cells/mcL, Dr. Austin said.

Researchers correlated B-cell levels to the total number of new brain lesions that appeared on magnetic resonance imaging. If CD19 levels were maintained in the range of 32-64 cells/mcL, patients taking the drug would develop fewer than 1 new lesion per year, compared with 16 new lesions per year in untreated patients, Dr. Austin said in the statement.

The most common side effects, which occurred twice as often in the active group as in the placebo group, were injection-site reaction, dizziness, anxiety, fever, respiratory tract infection, and neuropathy.

Ofatumumab is not approved anywhere in the world for use in the treatment of MS, Dr. Austin added.

GlaxoSmithKline sponsored the study. Dr. Austin is an employee of the company.

msullivan@frontlinemedcom.com

A drug that inhibits early-stage B-lymphocyte activation reduced disease activity in patients with relapsing-remitting multiple sclerosis, and showed potential to significantly decrease the annual number of new brain lesions.

The "intriguing" early results of a phase II randomized study suggest that ofatumumab’s targeting of peripheral B cells may be beneficial in treating the disease, according to Daren Austin, Ph.D., head of biopharm clinical pharmacology and biometrics at GlaxoSmithKline, Uxbridge, U.K. He will present these data Wednesday, April 30, at the annual meeting of the American Academy of Neurology.

"These results need to be validated, of course, but the findings are interesting," Dr. Austin said in a press statement. "They provide new insight into the mechanism of B cells in MS [multiple sclerosis] and present a possible new target threshold for exploring the potential benefit of anti-B-cell therapy."

Ofatumumab (Arzerra) is a fully humanized monoclonal antibody against B-lymphocyte antigen CD20, which optimizes B-cell antibody response. On April 17, the U.S. Food and Drug Administration approved the agent for use in combination with chlorambucil in previously untreated patients with chronic lymphocytic leukemia, for whom fludarabine-based therapy is considered inappropriate.

The drug also has shown potential in treating follicular non-Hodgkin’s lymphoma, diffuse large B-cell lymphoma, and rheumatoid arthritis.

The data Dr. Austin will report are part of an ongoing dose-ranging evaluation of 3 to 180 mg of ofatumumab for relapsing-remitting MS. The drug is administered by subcutaneous injection.

The current study included 231 patients who were randomized to placebo or ofatumumab for 24 weeks. The primary endpoint was the correlation of CD19 B-cell count to new gadolinium-enhancing brain lesions (a proxy measure for disease activity). Brain imaging was conducted every 4 weeks throughout the trial.

All of the groups – including placebo – showed lesion activity in the first 4 weeks. However, patients in the active groups showed some lesion suppression after that time. The beneficial effect seemed to appear when patients’ CD19 count fell below 64 cells/mcL, Dr. Austin said.

Researchers correlated B-cell levels to the total number of new brain lesions that appeared on magnetic resonance imaging. If CD19 levels were maintained in the range of 32-64 cells/mcL, patients taking the drug would develop fewer than 1 new lesion per year, compared with 16 new lesions per year in untreated patients, Dr. Austin said in the statement.

The most common side effects, which occurred twice as often in the active group as in the placebo group, were injection-site reaction, dizziness, anxiety, fever, respiratory tract infection, and neuropathy.

Ofatumumab is not approved anywhere in the world for use in the treatment of MS, Dr. Austin added.

GlaxoSmithKline sponsored the study. Dr. Austin is an employee of the company.

msullivan@frontlinemedcom.com

Measuring anti–JC virus antibody levels in cerebrospinal fluid may complement testing for viral DNA in cerebrospinal fluid and provide earlier detection of progressive multifocal leukoencephalopathy cases, according to the results of a retrospective case-control study of natalizumab-treated multiple sclerosis patients.

Cerebrospinal fluid (CSF) measurements of anti–JC virus (JCV) antibodies could help to identify patients with natalizumab (Tysabri)-associated progressive multifocal leukoencephalopathy (PML) who have repetitively undetectable levels of JC virus DNA in cerebrospinal fluid and often have levels less than 100 copies/mL at the time of PML diagnosis. Such measurements could help to avoid a delayed diagnosis or the need for brain biopsy to confirm the clinical suspicion of PML, said Dr. Clemens Warnke of the department of neurology at Heinrich-Heine-University, Düsseldorf, Germany, and his colleagues (Ann. Neurol. 2014 April 11 [doi:10.1002/ana.24153]).

The investigators compared serums and CSF samples taken from 37 multiple sclerosis patients with natalizumab-associated PML and 89 multiple sclerosis patients treated with natalizumab who did not have PML and calculated their cerebrospinal fluid JCV antibody index (AI_JCV) as a measure of intrathecal synthesis of anti–JC virus antibodies. An AI_JCV greater than 1.5 was observed in 26 (70%) of the 37 patients with natalizumab-associated PML, but not in any of the 89 control patients. In 20 patients with samples available from the time of diagnosis of natalizumab-associated PML, 11 (55%) had an AI_JCV greater than 1.5. A total of 14 of the 20 patients had JC virus DNA levels less than 100 copies/mL, including 8 with an AI_JCV greater than 1.5.

The calculation of an AI_JCV greater than 1.5 – which provides clear evidence of intrathecal synthesis of anti-JCV antibodies – allowed the investigators to "exclude pure diffusion and disturbance of blood-CSF barrier function as a putative explanation of increased levels of anti-JCV antibodies in CSF in cases of PML."

The necessity of a lumbar puncture to determine the AI_JCV – just as with screening CSF for JC virus DNA – makes the technique "unsuitable for PML risk prediction," but because other promising methods for risk prediction have not been prospectively validated, the investigators "propose the determination of the CSF AI_JCV in addition to the JCV-DNA PCR [polymerase chain reaction] in CSF in cases of possible or probable PML (based on clinical, MRI-, and/or JCV-DNA PCR findings) in patients at risk."

The investigators’ work was supported by various sources, including grants from Heinrich-Heine University, the German Ministry for Education and Research, and the Innovative Medicines Initiative Joint Undertaking within the European Union’s Seventh Framework Program, as well as a fellowship stipend from the European Committee for Treatment and Research in MS.

jevans@frontlinemedcom.com

Measuring anti–JC virus antibody levels in cerebrospinal fluid may complement testing for viral DNA in cerebrospinal fluid and provide earlier detection of progressive multifocal leukoencephalopathy cases, according to the results of a retrospective case-control study of natalizumab-treated multiple sclerosis patients.

Cerebrospinal fluid (CSF) measurements of anti–JC virus (JCV) antibodies could help to identify patients with natalizumab (Tysabri)-associated progressive multifocal leukoencephalopathy (PML) who have repetitively undetectable levels of JC virus DNA in cerebrospinal fluid and often have levels less than 100 copies/mL at the time of PML diagnosis. Such measurements could help to avoid a delayed diagnosis or the need for brain biopsy to confirm the clinical suspicion of PML, said Dr. Clemens Warnke of the department of neurology at Heinrich-Heine-University, Düsseldorf, Germany, and his colleagues (Ann. Neurol. 2014 April 11 [doi:10.1002/ana.24153]).

The investigators compared serums and CSF samples taken from 37 multiple sclerosis patients with natalizumab-associated PML and 89 multiple sclerosis patients treated with natalizumab who did not have PML and calculated their cerebrospinal fluid JCV antibody index (AI_JCV) as a measure of intrathecal synthesis of anti–JC virus antibodies. An AI_JCV greater than 1.5 was observed in 26 (70%) of the 37 patients with natalizumab-associated PML, but not in any of the 89 control patients. In 20 patients with samples available from the time of diagnosis of natalizumab-associated PML, 11 (55%) had an AI_JCV greater than 1.5. A total of 14 of the 20 patients had JC virus DNA levels less than 100 copies/mL, including 8 with an AI_JCV greater than 1.5.

The calculation of an AI_JCV greater than 1.5 – which provides clear evidence of intrathecal synthesis of anti-JCV antibodies – allowed the investigators to "exclude pure diffusion and disturbance of blood-CSF barrier function as a putative explanation of increased levels of anti-JCV antibodies in CSF in cases of PML."

The necessity of a lumbar puncture to determine the AI_JCV – just as with screening CSF for JC virus DNA – makes the technique "unsuitable for PML risk prediction," but because other promising methods for risk prediction have not been prospectively validated, the investigators "propose the determination of the CSF AI_JCV in addition to the JCV-DNA PCR [polymerase chain reaction] in CSF in cases of possible or probable PML (based on clinical, MRI-, and/or JCV-DNA PCR findings) in patients at risk."

The investigators’ work was supported by various sources, including grants from Heinrich-Heine University, the German Ministry for Education and Research, and the Innovative Medicines Initiative Joint Undertaking within the European Union’s Seventh Framework Program, as well as a fellowship stipend from the European Committee for Treatment and Research in MS.

jevans@frontlinemedcom.com

Measuring anti–JC virus antibody levels in cerebrospinal fluid may complement testing for viral DNA in cerebrospinal fluid and provide earlier detection of progressive multifocal leukoencephalopathy cases, according to the results of a retrospective case-control study of natalizumab-treated multiple sclerosis patients.

Cerebrospinal fluid (CSF) measurements of anti–JC virus (JCV) antibodies could help to identify patients with natalizumab (Tysabri)-associated progressive multifocal leukoencephalopathy (PML) who have repetitively undetectable levels of JC virus DNA in cerebrospinal fluid and often have levels less than 100 copies/mL at the time of PML diagnosis. Such measurements could help to avoid a delayed diagnosis or the need for brain biopsy to confirm the clinical suspicion of PML, said Dr. Clemens Warnke of the department of neurology at Heinrich-Heine-University, Düsseldorf, Germany, and his colleagues (Ann. Neurol. 2014 April 11 [doi:10.1002/ana.24153]).

The investigators compared serums and CSF samples taken from 37 multiple sclerosis patients with natalizumab-associated PML and 89 multiple sclerosis patients treated with natalizumab who did not have PML and calculated their cerebrospinal fluid JCV antibody index (AI_JCV) as a measure of intrathecal synthesis of anti–JC virus antibodies. An AI_JCV greater than 1.5 was observed in 26 (70%) of the 37 patients with natalizumab-associated PML, but not in any of the 89 control patients. In 20 patients with samples available from the time of diagnosis of natalizumab-associated PML, 11 (55%) had an AI_JCV greater than 1.5. A total of 14 of the 20 patients had JC virus DNA levels less than 100 copies/mL, including 8 with an AI_JCV greater than 1.5.

The calculation of an AI_JCV greater than 1.5 – which provides clear evidence of intrathecal synthesis of anti-JCV antibodies – allowed the investigators to "exclude pure diffusion and disturbance of blood-CSF barrier function as a putative explanation of increased levels of anti-JCV antibodies in CSF in cases of PML."

The necessity of a lumbar puncture to determine the AI_JCV – just as with screening CSF for JC virus DNA – makes the technique "unsuitable for PML risk prediction," but because other promising methods for risk prediction have not been prospectively validated, the investigators "propose the determination of the CSF AI_JCV in addition to the JCV-DNA PCR [polymerase chain reaction] in CSF in cases of possible or probable PML (based on clinical, MRI-, and/or JCV-DNA PCR findings) in patients at risk."

The investigators’ work was supported by various sources, including grants from Heinrich-Heine University, the German Ministry for Education and Research, and the Innovative Medicines Initiative Joint Undertaking within the European Union’s Seventh Framework Program, as well as a fellowship stipend from the European Committee for Treatment and Research in MS.

jevans@frontlinemedcom.com

The monoclonal antibody natalizumab significantly reduced cerebrospinal fluid markers of intrathecal inflammation in patients with progressive multiple sclerosis, according to data from an open-label, single-arm, phase IIa study.

Dr. Jeppe Romme Christensen and his colleagues from Copenhagen University Hospital, Denmark, found that 60 weeks of treatment with natalizumab (Tysabri) was associated with significant reductions from baseline in cerebrospinal fluid (CSF) osteopontin, as well as other CSF biomarkers of inflammation, axonal damage, demyelination, and CSF mononuclear cells. The study also may have helped to establish the feasibility of using CSF biomarkers in proof-of-concept trials.

The study, which included 12 patients with primary progressive multiple sclerosis and 12 with secondary progressive multiple sclerosis, showed similar treatment outcomes for both disease courses (Neurology 2014 March 28 [doi: 10.1212/WNL.0000000000000361]).

The authors said this was, to their knowledge, the first study to use a CSF biomarker as the primary endpoint. They noted that CSF osteopontin was a sensitive and dynamic marker of intrathecal inflammation, and its use enabled a smaller sample size and duration of study. "Osteopontin is a pleiotropic proinflammatory cytokine that is abundantly expressed in MS ... lesions, and is associated with the development of a progressive disease course," they wrote.

The study was supported by Biogen Idec, the Danish MS Society, the Danish Council for Strategic Research, and Brdr. Rønje Holding. Most authors declared honoraria and support from various pharmaceutical companies.

The monoclonal antibody natalizumab significantly reduced cerebrospinal fluid markers of intrathecal inflammation in patients with progressive multiple sclerosis, according to data from an open-label, single-arm, phase IIa study.

Dr. Jeppe Romme Christensen and his colleagues from Copenhagen University Hospital, Denmark, found that 60 weeks of treatment with natalizumab (Tysabri) was associated with significant reductions from baseline in cerebrospinal fluid (CSF) osteopontin, as well as other CSF biomarkers of inflammation, axonal damage, demyelination, and CSF mononuclear cells. The study also may have helped to establish the feasibility of using CSF biomarkers in proof-of-concept trials.

The study, which included 12 patients with primary progressive multiple sclerosis and 12 with secondary progressive multiple sclerosis, showed similar treatment outcomes for both disease courses (Neurology 2014 March 28 [doi: 10.1212/WNL.0000000000000361]).

The authors said this was, to their knowledge, the first study to use a CSF biomarker as the primary endpoint. They noted that CSF osteopontin was a sensitive and dynamic marker of intrathecal inflammation, and its use enabled a smaller sample size and duration of study. "Osteopontin is a pleiotropic proinflammatory cytokine that is abundantly expressed in MS ... lesions, and is associated with the development of a progressive disease course," they wrote.

The study was supported by Biogen Idec, the Danish MS Society, the Danish Council for Strategic Research, and Brdr. Rønje Holding. Most authors declared honoraria and support from various pharmaceutical companies.

The monoclonal antibody natalizumab significantly reduced cerebrospinal fluid markers of intrathecal inflammation in patients with progressive multiple sclerosis, according to data from an open-label, single-arm, phase IIa study.

Dr. Jeppe Romme Christensen and his colleagues from Copenhagen University Hospital, Denmark, found that 60 weeks of treatment with natalizumab (Tysabri) was associated with significant reductions from baseline in cerebrospinal fluid (CSF) osteopontin, as well as other CSF biomarkers of inflammation, axonal damage, demyelination, and CSF mononuclear cells. The study also may have helped to establish the feasibility of using CSF biomarkers in proof-of-concept trials.

The study, which included 12 patients with primary progressive multiple sclerosis and 12 with secondary progressive multiple sclerosis, showed similar treatment outcomes for both disease courses (Neurology 2014 March 28 [doi: 10.1212/WNL.0000000000000361]).

The authors said this was, to their knowledge, the first study to use a CSF biomarker as the primary endpoint. They noted that CSF osteopontin was a sensitive and dynamic marker of intrathecal inflammation, and its use enabled a smaller sample size and duration of study. "Osteopontin is a pleiotropic proinflammatory cytokine that is abundantly expressed in MS ... lesions, and is associated with the development of a progressive disease course," they wrote.

The study was supported by Biogen Idec, the Danish MS Society, the Danish Council for Strategic Research, and Brdr. Rønje Holding. Most authors declared honoraria and support from various pharmaceutical companies.

Researchers have detected John Cunningham virus DNA in the mononuclear cells of patients with multiple sclerosis who have been treated with natalizumab, suggesting a possible mechanism to explain the association of natalizumab with the development of progressive multifocal leukoencephalopathy.

The results from the study, published online March 24 in JAMA Neurology, also suggest that some patients who test seronegative for antibodies against John Cunningham virus (JCV) and undergo treatment with natalizumab have cell-associated viremia that goes undetected by current assays.

More than 440 cases of progressive multifocal leukoencephalopathy (PML) have been reported since the monoclonal antibody natalizumab was reintroduced in 2006 for the treatment of relapsing-remitting forms of multiple sclerosis (MS), and approximately 11 new cases are reported each month.

"Natalizumab is known to promote mobilization of hematopoietic stem cells from the bone marrow, a putative site for JCV latency, into the peripheral circulation, resulting in higher-than-normal physiological levels of CD34-positive cells for months to years after treatment," wrote Dr. Elliot M. Frohman from the University of Texas Southwestern Medical Center, Dallas, and his colleagues.

"The observation of JCV latency within these characterized mononuclear cells makes a direct mechanistic link between natalizumab and the occurrence of PML."

Researchers collected peripheral blood samples from 26 MS patients at baseline before initiation of natalizumab, and at approximately 3-month intervals over the next 10 monthly infusions. They also collected blood samples at a single time point from 23 MS patients who had received 24 or more natalizumab infusions and 19 healthy age- and sex-matched controls (JAMA Neurol. 2014 March 24 [doi: 10.1001/jamaneurol.2014.63]).

They found JCV DNA in half of the 26 MS patients with baseline and follow-up blood samples at one or more points, and significantly more MS patients had detectable JCV DNA in either the CD19-positive or CD34-positive cell compartments, compared with the healthy volunteers.

However, the investigators observed a low viral copy number, as compared with what would usually be seen in virus excreted in urine, regardless of which cell compartment the viral DNA was detected in. The viral copy numbers were generally higher in patients treated for longer periods.

"The low viral copy number in our study is consistent with a latent or a persistent infection," the investigators wrote. "In previous work, a cell culture model had shown that even a low level of persistence of JCV has significance because JCV can be transferred to other cells."

Of 23 MS patients overall who had cell-associated viremia, 14 were seronegative for antibodies against JC virus. One healthy control patient who had cell-associated viremia also tested seronegative. The investigators cautioned that serology alone may not be enough to identify all patients with prior exposure to JCV.

"Other measures of JCV infection may be of equal importance and should be considered, including T-cell responses, a rise in antibody titer indicating active infection, and the presence of JCV DNA variants in peripheral circulation, particularly in cell compartments."

The study was supported by intramural research funds within the National Institute of Neurological Disorders and Stroke and the National Institute of Allergy and Infectious Disease and a grant from the National Multiple Sclerosis Society. Four researchers declared that they received speaking and consultancy fees, honoraria, and grant support from a range of pharmaceutical companies that market drugs for MS, including Biogen Idec, manufacturer of natalizumab.

Researchers have detected John Cunningham virus DNA in the mononuclear cells of patients with multiple sclerosis who have been treated with natalizumab, suggesting a possible mechanism to explain the association of natalizumab with the development of progressive multifocal leukoencephalopathy.

The results from the study, published online March 24 in JAMA Neurology, also suggest that some patients who test seronegative for antibodies against John Cunningham virus (JCV) and undergo treatment with natalizumab have cell-associated viremia that goes undetected by current assays.

More than 440 cases of progressive multifocal leukoencephalopathy (PML) have been reported since the monoclonal antibody natalizumab was reintroduced in 2006 for the treatment of relapsing-remitting forms of multiple sclerosis (MS), and approximately 11 new cases are reported each month.

"Natalizumab is known to promote mobilization of hematopoietic stem cells from the bone marrow, a putative site for JCV latency, into the peripheral circulation, resulting in higher-than-normal physiological levels of CD34-positive cells for months to years after treatment," wrote Dr. Elliot M. Frohman from the University of Texas Southwestern Medical Center, Dallas, and his colleagues.

"The observation of JCV latency within these characterized mononuclear cells makes a direct mechanistic link between natalizumab and the occurrence of PML."

Researchers collected peripheral blood samples from 26 MS patients at baseline before initiation of natalizumab, and at approximately 3-month intervals over the next 10 monthly infusions. They also collected blood samples at a single time point from 23 MS patients who had received 24 or more natalizumab infusions and 19 healthy age- and sex-matched controls (JAMA Neurol. 2014 March 24 [doi: 10.1001/jamaneurol.2014.63]).

They found JCV DNA in half of the 26 MS patients with baseline and follow-up blood samples at one or more points, and significantly more MS patients had detectable JCV DNA in either the CD19-positive or CD34-positive cell compartments, compared with the healthy volunteers.

However, the investigators observed a low viral copy number, as compared with what would usually be seen in virus excreted in urine, regardless of which cell compartment the viral DNA was detected in. The viral copy numbers were generally higher in patients treated for longer periods.

"The low viral copy number in our study is consistent with a latent or a persistent infection," the investigators wrote. "In previous work, a cell culture model had shown that even a low level of persistence of JCV has significance because JCV can be transferred to other cells."

Of 23 MS patients overall who had cell-associated viremia, 14 were seronegative for antibodies against JC virus. One healthy control patient who had cell-associated viremia also tested seronegative. The investigators cautioned that serology alone may not be enough to identify all patients with prior exposure to JCV.

"Other measures of JCV infection may be of equal importance and should be considered, including T-cell responses, a rise in antibody titer indicating active infection, and the presence of JCV DNA variants in peripheral circulation, particularly in cell compartments."

The study was supported by intramural research funds within the National Institute of Neurological Disorders and Stroke and the National Institute of Allergy and Infectious Disease and a grant from the National Multiple Sclerosis Society. Four researchers declared that they received speaking and consultancy fees, honoraria, and grant support from a range of pharmaceutical companies that market drugs for MS, including Biogen Idec, manufacturer of natalizumab.

Researchers have detected John Cunningham virus DNA in the mononuclear cells of patients with multiple sclerosis who have been treated with natalizumab, suggesting a possible mechanism to explain the association of natalizumab with the development of progressive multifocal leukoencephalopathy.

The results from the study, published online March 24 in JAMA Neurology, also suggest that some patients who test seronegative for antibodies against John Cunningham virus (JCV) and undergo treatment with natalizumab have cell-associated viremia that goes undetected by current assays.

More than 440 cases of progressive multifocal leukoencephalopathy (PML) have been reported since the monoclonal antibody natalizumab was reintroduced in 2006 for the treatment of relapsing-remitting forms of multiple sclerosis (MS), and approximately 11 new cases are reported each month.

"Natalizumab is known to promote mobilization of hematopoietic stem cells from the bone marrow, a putative site for JCV latency, into the peripheral circulation, resulting in higher-than-normal physiological levels of CD34-positive cells for months to years after treatment," wrote Dr. Elliot M. Frohman from the University of Texas Southwestern Medical Center, Dallas, and his colleagues.

"The observation of JCV latency within these characterized mononuclear cells makes a direct mechanistic link between natalizumab and the occurrence of PML."

Researchers collected peripheral blood samples from 26 MS patients at baseline before initiation of natalizumab, and at approximately 3-month intervals over the next 10 monthly infusions. They also collected blood samples at a single time point from 23 MS patients who had received 24 or more natalizumab infusions and 19 healthy age- and sex-matched controls (JAMA Neurol. 2014 March 24 [doi: 10.1001/jamaneurol.2014.63]).

They found JCV DNA in half of the 26 MS patients with baseline and follow-up blood samples at one or more points, and significantly more MS patients had detectable JCV DNA in either the CD19-positive or CD34-positive cell compartments, compared with the healthy volunteers.

However, the investigators observed a low viral copy number, as compared with what would usually be seen in virus excreted in urine, regardless of which cell compartment the viral DNA was detected in. The viral copy numbers were generally higher in patients treated for longer periods.

"The low viral copy number in our study is consistent with a latent or a persistent infection," the investigators wrote. "In previous work, a cell culture model had shown that even a low level of persistence of JCV has significance because JCV can be transferred to other cells."

Of 23 MS patients overall who had cell-associated viremia, 14 were seronegative for antibodies against JC virus. One healthy control patient who had cell-associated viremia also tested seronegative. The investigators cautioned that serology alone may not be enough to identify all patients with prior exposure to JCV.

"Other measures of JCV infection may be of equal importance and should be considered, including T-cell responses, a rise in antibody titer indicating active infection, and the presence of JCV DNA variants in peripheral circulation, particularly in cell compartments."

The study was supported by intramural research funds within the National Institute of Neurological Disorders and Stroke and the National Institute of Allergy and Infectious Disease and a grant from the National Multiple Sclerosis Society. Four researchers declared that they received speaking and consultancy fees, honoraria, and grant support from a range of pharmaceutical companies that market drugs for MS, including Biogen Idec, manufacturer of natalizumab.