ICYMI Multiple Sclerosis

BOSTON—Bright spotty lesions on MRI can help neurologists distinguish neuromyelitis optica spectrum disorder (NMOSD) from other neurologic disorders, according to data presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. These lesions may be an additional MRI indicator of NMOSD, combined with aquaporin 4 antibody, which has modest sensitivity, and longitudinally extensive transverse myelitis, which is characteristic of but not a pathognomonic feature of NMOSD.

A Series of 127 MRIs
To examine the potential relationship between bright spotty lesions and NMOSD, Jae-Won Hyun, MD, a neurologist at Research Institute and Hospital of National Cancer Center in Goyang, South Korea, and colleagues analyzed 127 spinal MRIs of patients who were having an acute myelitis attack. The study was led by Ho Jin Kim, MD, PhD, Head of the MS Clinic at Research Institute and Hospital of National Cancer Center. Of the participants, 62 had NMOSD, 32 had multiple sclerosis (MS), and 33 had idiopathic transverse myelitis. One neuroradiologist and two neurologists without knowledge of the patients’ diagnoses reviewed the spinal MRIs independently. The investigators defined bright spotty lesions as hyperintense spotty lesions with signal intensities at least as high as, but not higher than, that of the surrounding CSF on a T2-weighted image without flow void effects, and not as low as that of the surrounding CSF on a T1-weighted image.

The male-to-female ratio, the mean age at attack onset, and the mean age at time of MRI were higher among people with idiopathic transverse myelitis than in participants with NMOSD and those with MS. All patients with NMOSD tested positive for aquaporin 4 antibodies. Participants with MS and those with idiopathic transverse myelitis were negative for aquaporin 4 antibodies following repeated assays using three different methods. All subjects with idiopathic transverse myelitis were negative for anti-myelin oligodendrocyte glycoprotein antibody as well.

The Lesions’ Clinical Relevance Is Uncertain
The researchers found bright spotty lesions exclusively in patients with NMOSD. Of the 62 patients with NMOSD, 17 had bright spotty lesions. Dr. Hyun and colleagues identified longitudinally extensive transverse myelitis in all study participants. MRI features, including bright spotty lesions, were completely different between patients with NMOSD and those with MS. Bright spotty lesions, however, were the only MRI feature that distinguished NMOSD from idiopathic transverse myelitis.

Among patients with NMOSD, demographic data were not significantly different between individuals with and without bright spotty lesions. The investigators thus could not draw conclusions about the bright spotty lesions’ clinical relevance. To determine whether the lesions indicated attack severity, the researchers estimated the Expanded Disability Status Scale score of 36 patients with first myelitis attacks, as well as disease duration and attack numbers for all patients with NMOSD. Again, the researchers found no significant differences between patients with NMOSD with and without lesions. The investigators concluded that bright spotty lesions could not represent attack severity. In addition, other MRI findings were not significantly different between the two groups.

Dr. Hyun and colleagues followed up the patients with bright spotty lesions longitudinally. They performed 14 follow-up MRIs at two to 20 months after baseline.

No bright spotty lesions were detectable on follow-up MRI, but high signal intensities on T2 images remained for some patients. The results suggest that bright spotty lesions exist in a transient state during the acute phase of myelitis and ultimately undergo a fundamental change in properties, like contrast-enhanced lesions do, said Dr. Hyun.

—Erik Greb

BOSTON—Bright spotty lesions on MRI can help neurologists distinguish neuromyelitis optica spectrum disorder (NMOSD) from other neurologic disorders, according to data presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. These lesions may be an additional MRI indicator of NMOSD, combined with aquaporin 4 antibody, which has modest sensitivity, and longitudinally extensive transverse myelitis, which is characteristic of but not a pathognomonic feature of NMOSD.

A Series of 127 MRIs
To examine the potential relationship between bright spotty lesions and NMOSD, Jae-Won Hyun, MD, a neurologist at Research Institute and Hospital of National Cancer Center in Goyang, South Korea, and colleagues analyzed 127 spinal MRIs of patients who were having an acute myelitis attack. The study was led by Ho Jin Kim, MD, PhD, Head of the MS Clinic at Research Institute and Hospital of National Cancer Center. Of the participants, 62 had NMOSD, 32 had multiple sclerosis (MS), and 33 had idiopathic transverse myelitis. One neuroradiologist and two neurologists without knowledge of the patients’ diagnoses reviewed the spinal MRIs independently. The investigators defined bright spotty lesions as hyperintense spotty lesions with signal intensities at least as high as, but not higher than, that of the surrounding CSF on a T2-weighted image without flow void effects, and not as low as that of the surrounding CSF on a T1-weighted image.

The male-to-female ratio, the mean age at attack onset, and the mean age at time of MRI were higher among people with idiopathic transverse myelitis than in participants with NMOSD and those with MS. All patients with NMOSD tested positive for aquaporin 4 antibodies. Participants with MS and those with idiopathic transverse myelitis were negative for aquaporin 4 antibodies following repeated assays using three different methods. All subjects with idiopathic transverse myelitis were negative for anti-myelin oligodendrocyte glycoprotein antibody as well.

The Lesions’ Clinical Relevance Is Uncertain
The researchers found bright spotty lesions exclusively in patients with NMOSD. Of the 62 patients with NMOSD, 17 had bright spotty lesions. Dr. Hyun and colleagues identified longitudinally extensive transverse myelitis in all study participants. MRI features, including bright spotty lesions, were completely different between patients with NMOSD and those with MS. Bright spotty lesions, however, were the only MRI feature that distinguished NMOSD from idiopathic transverse myelitis.

Among patients with NMOSD, demographic data were not significantly different between individuals with and without bright spotty lesions. The investigators thus could not draw conclusions about the bright spotty lesions’ clinical relevance. To determine whether the lesions indicated attack severity, the researchers estimated the Expanded Disability Status Scale score of 36 patients with first myelitis attacks, as well as disease duration and attack numbers for all patients with NMOSD. Again, the researchers found no significant differences between patients with NMOSD with and without lesions. The investigators concluded that bright spotty lesions could not represent attack severity. In addition, other MRI findings were not significantly different between the two groups.

Dr. Hyun and colleagues followed up the patients with bright spotty lesions longitudinally. They performed 14 follow-up MRIs at two to 20 months after baseline.

No bright spotty lesions were detectable on follow-up MRI, but high signal intensities on T2 images remained for some patients. The results suggest that bright spotty lesions exist in a transient state during the acute phase of myelitis and ultimately undergo a fundamental change in properties, like contrast-enhanced lesions do, said Dr. Hyun.

—Erik Greb

BOSTON—Bright spotty lesions on MRI can help neurologists distinguish neuromyelitis optica spectrum disorder (NMOSD) from other neurologic disorders, according to data presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. These lesions may be an additional MRI indicator of NMOSD, combined with aquaporin 4 antibody, which has modest sensitivity, and longitudinally extensive transverse myelitis, which is characteristic of but not a pathognomonic feature of NMOSD.

A Series of 127 MRIs
To examine the potential relationship between bright spotty lesions and NMOSD, Jae-Won Hyun, MD, a neurologist at Research Institute and Hospital of National Cancer Center in Goyang, South Korea, and colleagues analyzed 127 spinal MRIs of patients who were having an acute myelitis attack. The study was led by Ho Jin Kim, MD, PhD, Head of the MS Clinic at Research Institute and Hospital of National Cancer Center. Of the participants, 62 had NMOSD, 32 had multiple sclerosis (MS), and 33 had idiopathic transverse myelitis. One neuroradiologist and two neurologists without knowledge of the patients’ diagnoses reviewed the spinal MRIs independently. The investigators defined bright spotty lesions as hyperintense spotty lesions with signal intensities at least as high as, but not higher than, that of the surrounding CSF on a T2-weighted image without flow void effects, and not as low as that of the surrounding CSF on a T1-weighted image.

The male-to-female ratio, the mean age at attack onset, and the mean age at time of MRI were higher among people with idiopathic transverse myelitis than in participants with NMOSD and those with MS. All patients with NMOSD tested positive for aquaporin 4 antibodies. Participants with MS and those with idiopathic transverse myelitis were negative for aquaporin 4 antibodies following repeated assays using three different methods. All subjects with idiopathic transverse myelitis were negative for anti-myelin oligodendrocyte glycoprotein antibody as well.

The Lesions’ Clinical Relevance Is Uncertain
The researchers found bright spotty lesions exclusively in patients with NMOSD. Of the 62 patients with NMOSD, 17 had bright spotty lesions. Dr. Hyun and colleagues identified longitudinally extensive transverse myelitis in all study participants. MRI features, including bright spotty lesions, were completely different between patients with NMOSD and those with MS. Bright spotty lesions, however, were the only MRI feature that distinguished NMOSD from idiopathic transverse myelitis.

Among patients with NMOSD, demographic data were not significantly different between individuals with and without bright spotty lesions. The investigators thus could not draw conclusions about the bright spotty lesions’ clinical relevance. To determine whether the lesions indicated attack severity, the researchers estimated the Expanded Disability Status Scale score of 36 patients with first myelitis attacks, as well as disease duration and attack numbers for all patients with NMOSD. Again, the researchers found no significant differences between patients with NMOSD with and without lesions. The investigators concluded that bright spotty lesions could not represent attack severity. In addition, other MRI findings were not significantly different between the two groups.

Dr. Hyun and colleagues followed up the patients with bright spotty lesions longitudinally. They performed 14 follow-up MRIs at two to 20 months after baseline.

No bright spotty lesions were detectable on follow-up MRI, but high signal intensities on T2 images remained for some patients. The results suggest that bright spotty lesions exist in a transient state during the acute phase of myelitis and ultimately undergo a fundamental change in properties, like contrast-enhanced lesions do, said Dr. Hyun.

—Erik Greb

BOSTON—Neurologists may consider changing the medication for a patient with relapsing-remitting multiple sclerosis (MS) who has ongoing disease activity despite treatment, according to a presentation at the 2014 Joint ACTRIMS–ECTRIMS Meeting. Patients with a poor response to their initial treatment often benefit from a change to a new drug.

“The rationale for escalating treatment strategies in MS is based on a combination of clinical experience, expected benefit, and calculated risk,” said Xavier Montalban, MD, Chair of Neurology and Neuroimmunology at University Hospital and Research Institute, Vall d’Hebron in Barcelona. Yet neurologists must remember that “we do not have good class I evidence for switching patients from a platform therapy to a second-line treatment strategy,” he added.

Assessing Treatment Response
Treatment response is a major element of a treatment algorithm and can be defined in various ways. A common definition includes two clinical parameters (ie, relapses and disability progression) and MRI activity.

In an article published in Multiple Sclerosis in 2009, Río et al proposed a multicomponent score to assess treatment failure. The Río score incorporates the following three criteria: one or more relapse during the first 12 months, an increase in Expanded Disability Status Scale (EDSS) score of one point that is confirmed at six months, and three or more active new T2 or gadolinium-enhancing lesions on MRI. The authors found that patients who met two of these criteria had an odds ratio (OR) of 5.9 for clinical activity within three years. Fulfilling all three criteria was associated with an OR of 13.2 for this outcome.

Río and colleagues recently completed a study examining potential predictors of long-term outcomes. The investigators monitored clinical activity among 234 patients with MS during the first two years of treatment with interferon beta. They followed patients for 12 years and tracked three outcomes: the development of progressive MS, confinement to a wheelchair, and an increase in EDSS score of 5 or more points. The researchers found that clinical activity during the first two years of treatment increased the likelihood of the three end points at 12 years. These results are consistent with those of a 2013 study by Bermel et al, said Dr. Montalban.

The Results of Switching Treatments
If a neurologist decides that a change in therapy is advisable, one option is to switch from one first-line treatment to another. In a 2012 study, Río and colleagues found that patients who switched from an interferon to another interferon, from an interferon to glatiramer acetate, or from glatiramer acetate to an interferon had a decreased annualized relapse rate at 12 months.

A 2009 trial by Gajofatto and colleagues resulted in similar findings. Patients who switched from interferon beta or glatiramer acetate to natalizumab had greater reductions in annualized relapse rate at 24 months than participants who switched from one first-line therapy to another. In a similar study conducted in 2012, Prosperini and colleagues found no significant differences in disease activity at 12 months between patients switching from one first-line treatment to another and patients switching from a first-line to a second-line treatment. At 24 months freedom from disease activity was more common among patients who had escalated therapies than among patients who had switched between first-line treatments.

Few studies have examined the results of escalating to fingolimod, but their results generally have been positive. In a retrospective study, Bergvall and colleagues found a 59% reduction in the probability of having a relapse in patients who switched to fingolimod, compared with patients who switched to glatiramer acetate. In a 2011 extension of the TRANSFORMS trial, patients who had been treated with interferon beta-1a for one year were switched to fingolimod. These patients had a 50% reduction in annualized relapse rate after the switch, and the benefits were sustained for 4.5 years.

Considering Factors Beyond Clinical Efficacy
When neurologists consider switching a patient’s therapy because of clinical inefficacy, they must take other factors such as side effects, convenience, patient preferences, and cost into account, said Dr. Montalban. Disease severity, in terms of the numbers and volumes of gadolinium-enhancing and T2 lesions and the presence of oligoclonal bands, also should be considered. Apart from clinical activity, gender, age, the desire to become pregnant, comorbidities, and concomitant drugs may influence treatment decisions.

If a patient taking a first-line therapy has mild disease activity, it would be reasonable to consider switching him or her to another first-line therapy, to teriflunomide, or to dimethyl fumarate, said Dr. Montalban. But for a patient who has moderately severe disease activity despite treatment with a first- or second-line medicine, the neurologist might consider switching to a more potent drug such as natalizumab, fingolimod, or alemtuzumab.

Finally, the neurologist must remember that a change in treatment may require a washout period. If a patient will switch from natalizumab to fingolimod, teriflunomide, or dimethyl fumarate, a two- to three-month washout period is recommended. Switching from teriflunomide to other MS therapies may require a 3.5-month washout, but an accelerated elimination procedure may be used, said Dr. Montalban. To change from fingolimod to teriflunomide or natalizumab requires one to two months to allow lymphocytes to return to the normal range. For similar reasons, a neurologist may recommend a two- or three-month washout when a patient switches from fingolimod or natalizumab to alemtuzumab.

Switching a patient to or from interferon beta or glatiramer acetate, however, does not require a washout period, said Dr. Montalban. Likewise, no washout period is needed when moving a patient from dimethyl fumarate to alemtuzumab, natalizumab, or fingolimod.

—Erik Greb

BOSTON—Neurologists may consider changing the medication for a patient with relapsing-remitting multiple sclerosis (MS) who has ongoing disease activity despite treatment, according to a presentation at the 2014 Joint ACTRIMS–ECTRIMS Meeting. Patients with a poor response to their initial treatment often benefit from a change to a new drug.

“The rationale for escalating treatment strategies in MS is based on a combination of clinical experience, expected benefit, and calculated risk,” said Xavier Montalban, MD, Chair of Neurology and Neuroimmunology at University Hospital and Research Institute, Vall d’Hebron in Barcelona. Yet neurologists must remember that “we do not have good class I evidence for switching patients from a platform therapy to a second-line treatment strategy,” he added.

Assessing Treatment Response
Treatment response is a major element of a treatment algorithm and can be defined in various ways. A common definition includes two clinical parameters (ie, relapses and disability progression) and MRI activity.

In an article published in Multiple Sclerosis in 2009, Río et al proposed a multicomponent score to assess treatment failure. The Río score incorporates the following three criteria: one or more relapse during the first 12 months, an increase in Expanded Disability Status Scale (EDSS) score of one point that is confirmed at six months, and three or more active new T2 or gadolinium-enhancing lesions on MRI. The authors found that patients who met two of these criteria had an odds ratio (OR) of 5.9 for clinical activity within three years. Fulfilling all three criteria was associated with an OR of 13.2 for this outcome.

Río and colleagues recently completed a study examining potential predictors of long-term outcomes. The investigators monitored clinical activity among 234 patients with MS during the first two years of treatment with interferon beta. They followed patients for 12 years and tracked three outcomes: the development of progressive MS, confinement to a wheelchair, and an increase in EDSS score of 5 or more points. The researchers found that clinical activity during the first two years of treatment increased the likelihood of the three end points at 12 years. These results are consistent with those of a 2013 study by Bermel et al, said Dr. Montalban.

The Results of Switching Treatments
If a neurologist decides that a change in therapy is advisable, one option is to switch from one first-line treatment to another. In a 2012 study, Río and colleagues found that patients who switched from an interferon to another interferon, from an interferon to glatiramer acetate, or from glatiramer acetate to an interferon had a decreased annualized relapse rate at 12 months.

A 2009 trial by Gajofatto and colleagues resulted in similar findings. Patients who switched from interferon beta or glatiramer acetate to natalizumab had greater reductions in annualized relapse rate at 24 months than participants who switched from one first-line therapy to another. In a similar study conducted in 2012, Prosperini and colleagues found no significant differences in disease activity at 12 months between patients switching from one first-line treatment to another and patients switching from a first-line to a second-line treatment. At 24 months freedom from disease activity was more common among patients who had escalated therapies than among patients who had switched between first-line treatments.

Few studies have examined the results of escalating to fingolimod, but their results generally have been positive. In a retrospective study, Bergvall and colleagues found a 59% reduction in the probability of having a relapse in patients who switched to fingolimod, compared with patients who switched to glatiramer acetate. In a 2011 extension of the TRANSFORMS trial, patients who had been treated with interferon beta-1a for one year were switched to fingolimod. These patients had a 50% reduction in annualized relapse rate after the switch, and the benefits were sustained for 4.5 years.

Considering Factors Beyond Clinical Efficacy
When neurologists consider switching a patient’s therapy because of clinical inefficacy, they must take other factors such as side effects, convenience, patient preferences, and cost into account, said Dr. Montalban. Disease severity, in terms of the numbers and volumes of gadolinium-enhancing and T2 lesions and the presence of oligoclonal bands, also should be considered. Apart from clinical activity, gender, age, the desire to become pregnant, comorbidities, and concomitant drugs may influence treatment decisions.

If a patient taking a first-line therapy has mild disease activity, it would be reasonable to consider switching him or her to another first-line therapy, to teriflunomide, or to dimethyl fumarate, said Dr. Montalban. But for a patient who has moderately severe disease activity despite treatment with a first- or second-line medicine, the neurologist might consider switching to a more potent drug such as natalizumab, fingolimod, or alemtuzumab.

Finally, the neurologist must remember that a change in treatment may require a washout period. If a patient will switch from natalizumab to fingolimod, teriflunomide, or dimethyl fumarate, a two- to three-month washout period is recommended. Switching from teriflunomide to other MS therapies may require a 3.5-month washout, but an accelerated elimination procedure may be used, said Dr. Montalban. To change from fingolimod to teriflunomide or natalizumab requires one to two months to allow lymphocytes to return to the normal range. For similar reasons, a neurologist may recommend a two- or three-month washout when a patient switches from fingolimod or natalizumab to alemtuzumab.

Switching a patient to or from interferon beta or glatiramer acetate, however, does not require a washout period, said Dr. Montalban. Likewise, no washout period is needed when moving a patient from dimethyl fumarate to alemtuzumab, natalizumab, or fingolimod.

—Erik Greb

BOSTON—Neurologists may consider changing the medication for a patient with relapsing-remitting multiple sclerosis (MS) who has ongoing disease activity despite treatment, according to a presentation at the 2014 Joint ACTRIMS–ECTRIMS Meeting. Patients with a poor response to their initial treatment often benefit from a change to a new drug.

“The rationale for escalating treatment strategies in MS is based on a combination of clinical experience, expected benefit, and calculated risk,” said Xavier Montalban, MD, Chair of Neurology and Neuroimmunology at University Hospital and Research Institute, Vall d’Hebron in Barcelona. Yet neurologists must remember that “we do not have good class I evidence for switching patients from a platform therapy to a second-line treatment strategy,” he added.

Assessing Treatment Response
Treatment response is a major element of a treatment algorithm and can be defined in various ways. A common definition includes two clinical parameters (ie, relapses and disability progression) and MRI activity.

In an article published in Multiple Sclerosis in 2009, Río et al proposed a multicomponent score to assess treatment failure. The Río score incorporates the following three criteria: one or more relapse during the first 12 months, an increase in Expanded Disability Status Scale (EDSS) score of one point that is confirmed at six months, and three or more active new T2 or gadolinium-enhancing lesions on MRI. The authors found that patients who met two of these criteria had an odds ratio (OR) of 5.9 for clinical activity within three years. Fulfilling all three criteria was associated with an OR of 13.2 for this outcome.

Río and colleagues recently completed a study examining potential predictors of long-term outcomes. The investigators monitored clinical activity among 234 patients with MS during the first two years of treatment with interferon beta. They followed patients for 12 years and tracked three outcomes: the development of progressive MS, confinement to a wheelchair, and an increase in EDSS score of 5 or more points. The researchers found that clinical activity during the first two years of treatment increased the likelihood of the three end points at 12 years. These results are consistent with those of a 2013 study by Bermel et al, said Dr. Montalban.

The Results of Switching Treatments
If a neurologist decides that a change in therapy is advisable, one option is to switch from one first-line treatment to another. In a 2012 study, Río and colleagues found that patients who switched from an interferon to another interferon, from an interferon to glatiramer acetate, or from glatiramer acetate to an interferon had a decreased annualized relapse rate at 12 months.

A 2009 trial by Gajofatto and colleagues resulted in similar findings. Patients who switched from interferon beta or glatiramer acetate to natalizumab had greater reductions in annualized relapse rate at 24 months than participants who switched from one first-line therapy to another. In a similar study conducted in 2012, Prosperini and colleagues found no significant differences in disease activity at 12 months between patients switching from one first-line treatment to another and patients switching from a first-line to a second-line treatment. At 24 months freedom from disease activity was more common among patients who had escalated therapies than among patients who had switched between first-line treatments.

Few studies have examined the results of escalating to fingolimod, but their results generally have been positive. In a retrospective study, Bergvall and colleagues found a 59% reduction in the probability of having a relapse in patients who switched to fingolimod, compared with patients who switched to glatiramer acetate. In a 2011 extension of the TRANSFORMS trial, patients who had been treated with interferon beta-1a for one year were switched to fingolimod. These patients had a 50% reduction in annualized relapse rate after the switch, and the benefits were sustained for 4.5 years.

Considering Factors Beyond Clinical Efficacy
When neurologists consider switching a patient’s therapy because of clinical inefficacy, they must take other factors such as side effects, convenience, patient preferences, and cost into account, said Dr. Montalban. Disease severity, in terms of the numbers and volumes of gadolinium-enhancing and T2 lesions and the presence of oligoclonal bands, also should be considered. Apart from clinical activity, gender, age, the desire to become pregnant, comorbidities, and concomitant drugs may influence treatment decisions.

If a patient taking a first-line therapy has mild disease activity, it would be reasonable to consider switching him or her to another first-line therapy, to teriflunomide, or to dimethyl fumarate, said Dr. Montalban. But for a patient who has moderately severe disease activity despite treatment with a first- or second-line medicine, the neurologist might consider switching to a more potent drug such as natalizumab, fingolimod, or alemtuzumab.

Finally, the neurologist must remember that a change in treatment may require a washout period. If a patient will switch from natalizumab to fingolimod, teriflunomide, or dimethyl fumarate, a two- to three-month washout period is recommended. Switching from teriflunomide to other MS therapies may require a 3.5-month washout, but an accelerated elimination procedure may be used, said Dr. Montalban. To change from fingolimod to teriflunomide or natalizumab requires one to two months to allow lymphocytes to return to the normal range. For similar reasons, a neurologist may recommend a two- or three-month washout when a patient switches from fingolimod or natalizumab to alemtuzumab.

Switching a patient to or from interferon beta or glatiramer acetate, however, does not require a washout period, said Dr. Montalban. Likewise, no washout period is needed when moving a patient from dimethyl fumarate to alemtuzumab, natalizumab, or fingolimod.

—Erik Greb

BOSTON—Along with baseline characteristics, clinical and MRI changes during the first year after diagnosis of clinically isolated syndrome (CIS) can improve neurologists’ estimation of a patient’s prognosis, according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The presence of MRI lesions at baseline and the emergence of new T2 lesions during the first year after CIS diagnosis predict the occurrence of a second attack, said Mar Tintoré, MD. Treatment after the first attack, however, may protect against further attacks.

The presence of oligoclonal bands, the emergence of new T2 lesions during the first year after CIS diagnosis, and incomplete recovery from the first attack are independent predictors of the accumulation of disability, said Dr. Tintoré, Professor of Neurology and Neuroimmunology at Vall d’Hebron University Hospital in Barcelona.

A Prospective Study of Patients With CIS
In a previous prospective study of patients with CIS, Dr. Tintoré and colleagues concluded that baseline MRI was of great value in predicting future attacks and accumulation of disability. The presence of oligoclonal bands at baseline is a medium-impact prognostic factor for these outcomes, and demographic characteristics and topography of CIS are low-impact prognostic factors, the investigators concluded.

The researchers next decided to investigate the added value of clinical and brain MRI changes during the first year after a diagnosis of CIS for predicting conversion to multiple sclerosis (MS) or disability accumulation. For this investigation, Dr. Tintoré’s group began prospectively following patients with CIS in 1995. Eligible patients were younger than 50. During regular clinical follow-up, neurologists monitored patients for a second attack and disability accumulation. Participants also underwent regular MRI monitoring.

Age, gender, topography of CIS, date of disease-modifying therapy initiation (if applicable), number of T2 lesions, presence of gadolinium-enhancing lesions, and presence of oligoclonal bands were the baseline variables that the investigators examined. First-year variables included the presence of a second attack and recovery from the first attack, which was measured as Expanded Disability Status Scale (EDSS) score at year one. Incomplete recovery was defined as an EDSS score of 2 or higher. The investigators also looked at the number of new T2 lesions and the presence of gadolinium-enhancing lesions at 12 months.

The total cohort included 1,058 participants, but the investigators excluded 43 people who were ineligible. The researchers have more than 12 months of follow-up data for 887 patients. Approximately 68% of participants were female, and the cohort’s mean age was 31. Oligoclonal bands were performed for about 82% of patients, and the mean follow-up duration was 7.7 years.

New T2 Lesions at One Year Were Common
At baseline, approximately one-third of patients had a normal MRI, and 41.4% had 10 or more T2 lesions. In addition, 23% of participants had gadolinium-enhancing lesions at baseline.

During the first year after CIS diagnosis, 17% of patients had a relapse, and 24% of participants had incomplete recovery from the first attack. Approximately 43% of patients had new T2 lesions at 12 months, and approximately 20% had gadolinium-enhancing lesions at 12 months.

Multivariate analysis indicated that gender and topography did not affect the risk of having a second attack. Younger age, however, was associated with a higher risk of having a second attack. The presence of T2 lesions on baseline MRI was a strong predictor of new relapses, as was the presence of new T2 lesions at 12 months.

A separate multivariate analysis suggested that gender and age did not predict the accumulation of disability, which was defined as a confirmed EDSS score of 3. Oligoclonal bands, however, increased the risk of disability accumulation. Incomplete recovery from the first attack also was “a clear predictor of disability in the long term,” said Dr. Tintoré.

—Erik Greb

BOSTON—Along with baseline characteristics, clinical and MRI changes during the first year after diagnosis of clinically isolated syndrome (CIS) can improve neurologists’ estimation of a patient’s prognosis, according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The presence of MRI lesions at baseline and the emergence of new T2 lesions during the first year after CIS diagnosis predict the occurrence of a second attack, said Mar Tintoré, MD. Treatment after the first attack, however, may protect against further attacks.

The presence of oligoclonal bands, the emergence of new T2 lesions during the first year after CIS diagnosis, and incomplete recovery from the first attack are independent predictors of the accumulation of disability, said Dr. Tintoré, Professor of Neurology and Neuroimmunology at Vall d’Hebron University Hospital in Barcelona.

A Prospective Study of Patients With CIS
In a previous prospective study of patients with CIS, Dr. Tintoré and colleagues concluded that baseline MRI was of great value in predicting future attacks and accumulation of disability. The presence of oligoclonal bands at baseline is a medium-impact prognostic factor for these outcomes, and demographic characteristics and topography of CIS are low-impact prognostic factors, the investigators concluded.

The researchers next decided to investigate the added value of clinical and brain MRI changes during the first year after a diagnosis of CIS for predicting conversion to multiple sclerosis (MS) or disability accumulation. For this investigation, Dr. Tintoré’s group began prospectively following patients with CIS in 1995. Eligible patients were younger than 50. During regular clinical follow-up, neurologists monitored patients for a second attack and disability accumulation. Participants also underwent regular MRI monitoring.

Age, gender, topography of CIS, date of disease-modifying therapy initiation (if applicable), number of T2 lesions, presence of gadolinium-enhancing lesions, and presence of oligoclonal bands were the baseline variables that the investigators examined. First-year variables included the presence of a second attack and recovery from the first attack, which was measured as Expanded Disability Status Scale (EDSS) score at year one. Incomplete recovery was defined as an EDSS score of 2 or higher. The investigators also looked at the number of new T2 lesions and the presence of gadolinium-enhancing lesions at 12 months.

The total cohort included 1,058 participants, but the investigators excluded 43 people who were ineligible. The researchers have more than 12 months of follow-up data for 887 patients. Approximately 68% of participants were female, and the cohort’s mean age was 31. Oligoclonal bands were performed for about 82% of patients, and the mean follow-up duration was 7.7 years.

New T2 Lesions at One Year Were Common
At baseline, approximately one-third of patients had a normal MRI, and 41.4% had 10 or more T2 lesions. In addition, 23% of participants had gadolinium-enhancing lesions at baseline.

During the first year after CIS diagnosis, 17% of patients had a relapse, and 24% of participants had incomplete recovery from the first attack. Approximately 43% of patients had new T2 lesions at 12 months, and approximately 20% had gadolinium-enhancing lesions at 12 months.

Multivariate analysis indicated that gender and topography did not affect the risk of having a second attack. Younger age, however, was associated with a higher risk of having a second attack. The presence of T2 lesions on baseline MRI was a strong predictor of new relapses, as was the presence of new T2 lesions at 12 months.

A separate multivariate analysis suggested that gender and age did not predict the accumulation of disability, which was defined as a confirmed EDSS score of 3. Oligoclonal bands, however, increased the risk of disability accumulation. Incomplete recovery from the first attack also was “a clear predictor of disability in the long term,” said Dr. Tintoré.

—Erik Greb

BOSTON—Along with baseline characteristics, clinical and MRI changes during the first year after diagnosis of clinically isolated syndrome (CIS) can improve neurologists’ estimation of a patient’s prognosis, according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The presence of MRI lesions at baseline and the emergence of new T2 lesions during the first year after CIS diagnosis predict the occurrence of a second attack, said Mar Tintoré, MD. Treatment after the first attack, however, may protect against further attacks.

The presence of oligoclonal bands, the emergence of new T2 lesions during the first year after CIS diagnosis, and incomplete recovery from the first attack are independent predictors of the accumulation of disability, said Dr. Tintoré, Professor of Neurology and Neuroimmunology at Vall d’Hebron University Hospital in Barcelona.

A Prospective Study of Patients With CIS
In a previous prospective study of patients with CIS, Dr. Tintoré and colleagues concluded that baseline MRI was of great value in predicting future attacks and accumulation of disability. The presence of oligoclonal bands at baseline is a medium-impact prognostic factor for these outcomes, and demographic characteristics and topography of CIS are low-impact prognostic factors, the investigators concluded.

The researchers next decided to investigate the added value of clinical and brain MRI changes during the first year after a diagnosis of CIS for predicting conversion to multiple sclerosis (MS) or disability accumulation. For this investigation, Dr. Tintoré’s group began prospectively following patients with CIS in 1995. Eligible patients were younger than 50. During regular clinical follow-up, neurologists monitored patients for a second attack and disability accumulation. Participants also underwent regular MRI monitoring.

Age, gender, topography of CIS, date of disease-modifying therapy initiation (if applicable), number of T2 lesions, presence of gadolinium-enhancing lesions, and presence of oligoclonal bands were the baseline variables that the investigators examined. First-year variables included the presence of a second attack and recovery from the first attack, which was measured as Expanded Disability Status Scale (EDSS) score at year one. Incomplete recovery was defined as an EDSS score of 2 or higher. The investigators also looked at the number of new T2 lesions and the presence of gadolinium-enhancing lesions at 12 months.

The total cohort included 1,058 participants, but the investigators excluded 43 people who were ineligible. The researchers have more than 12 months of follow-up data for 887 patients. Approximately 68% of participants were female, and the cohort’s mean age was 31. Oligoclonal bands were performed for about 82% of patients, and the mean follow-up duration was 7.7 years.

New T2 Lesions at One Year Were Common
At baseline, approximately one-third of patients had a normal MRI, and 41.4% had 10 or more T2 lesions. In addition, 23% of participants had gadolinium-enhancing lesions at baseline.

During the first year after CIS diagnosis, 17% of patients had a relapse, and 24% of participants had incomplete recovery from the first attack. Approximately 43% of patients had new T2 lesions at 12 months, and approximately 20% had gadolinium-enhancing lesions at 12 months.

Multivariate analysis indicated that gender and topography did not affect the risk of having a second attack. Younger age, however, was associated with a higher risk of having a second attack. The presence of T2 lesions on baseline MRI was a strong predictor of new relapses, as was the presence of new T2 lesions at 12 months.

A separate multivariate analysis suggested that gender and age did not predict the accumulation of disability, which was defined as a confirmed EDSS score of 3. Oligoclonal bands, however, increased the risk of disability accumulation. Incomplete recovery from the first attack also was “a clear predictor of disability in the long term,” said Dr. Tintoré.

—Erik Greb

BOSTON—Delivering subcutaneous glatiramer acetate as a 40-mg/mL dose three times weekly, rather than 20 mg/mL daily, may reduce the annualized rate of injection-related adverse events by half, according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The results are from a randomized, open-label, phase III b trial of patients with relapsing-remitting multiple sclerosis (MS).

The reduction in the annualized rate of moderate and severe injection-related adverse events in patients who received lower-frequency dosing was about 60%, said Jerry S. Wolinsky, MD, Director of the MS Research Group at the University of Texas Health Science Center at Houston. The trial was called Glatiramer Acetate Low Frequency Safety and Patient Experience (GLACIER).

“As we all know, long-term, frequent injections are required for the first-line therapies for relapsing forms of MS, and this form of drug delivery presents a challenge for patients. Modification of the treatment regimen, such as using alternative dosages and lower-frequency administration schedules for these drugs with long-term proven efficacy, has the potential to improve the patient experience by reducing, perhaps, the number of adverse experiences that he or she has, improving tolerability, and, in particular, potentially increasing adherence to treatments, especially in the longer-term,” said Dr. Wolinsky. The GLACIER trial was designed, in part, to test the regimen’s potential to yield these improvements.

Patients May Prefer Fewer Injections
Glatiramer acetate 20 mg/mL administered by daily subcutaneous injection is a well-characterized treatment with a good long-term safety profile. The drug has been used for more than 20 years, has accumulated more than two million patient-years of overall exposures, and has established efficacy for the treatment of relapsing-remitting MS. In January 2014, the FDA approved a supplemental New Drug Application for the 40-mg/mL three times weekly regimen after it was shown to have an efficacy and safety profile similar to that of the daily 20-mg/mL regimen.

The GLACIER findings suggest that the 40-mg/mL dosing regimen of glatiramer acetate is a favorable treatment option for some patients, particularly people who want to be on glatiramer acetate, but who prefer to take fewer injections and have more convenient dosing, concluded Dr. Wolinsky.

The annualized rate of injection-related adverse events in 108 adult patients with relapsing-remitting MS who were randomized to receive the thrice-weekly injections was 35.3, compared with 70.4 in 101 patients who received daily injections (relative risk, 0.50). The annualized rate of moderate and severe injection-related adverse events was 0.88 vs 2.2 in the groups, respectively (relative risk, 0.40), said Dr. Wolinsky.

The most common injection-site reactions were pain, erythema, mass, swelling, and pruritus, and all of these reactions were substantially reduced with lower-frequency dosing, compared with daily dosing. For example, the annualized rate of pain events was 24.8 with lower-frequency dosing vs 55.3 with higher-frequency dosing, and the annualized rate of erythema events was 21.4 vs 43.5.

Patients Had Experience With Glatiramer Acetate
Patients in the GLACIER trial were age 18 or older (mean age, 51) with a diagnosis of relapsing-remitting MS and an Expanded Disability Status Scale score between 0 and 5.5. Most participants (82%) were women, and 94% of patients were Caucasian.

All participants had been treated continuously with the 20-mg/mL daily dosing regimen for at least six months and were stable on that regimen for at least two months prior to screening for the GLACIER trial.

At least 75% treatment compliance was achieved by 99% of the GLACIER trial patients, and only 10 people withdrew before completing the four-month treatment phase, including three participants in the daily dosing group and seven patients in the lower-frequency dosing group. One patient withdrew because of an adverse event, said Dr. Wolinsky.

—Sharon Worcester

BOSTON—Delivering subcutaneous glatiramer acetate as a 40-mg/mL dose three times weekly, rather than 20 mg/mL daily, may reduce the annualized rate of injection-related adverse events by half, according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The results are from a randomized, open-label, phase III b trial of patients with relapsing-remitting multiple sclerosis (MS).

The reduction in the annualized rate of moderate and severe injection-related adverse events in patients who received lower-frequency dosing was about 60%, said Jerry S. Wolinsky, MD, Director of the MS Research Group at the University of Texas Health Science Center at Houston. The trial was called Glatiramer Acetate Low Frequency Safety and Patient Experience (GLACIER).

“As we all know, long-term, frequent injections are required for the first-line therapies for relapsing forms of MS, and this form of drug delivery presents a challenge for patients. Modification of the treatment regimen, such as using alternative dosages and lower-frequency administration schedules for these drugs with long-term proven efficacy, has the potential to improve the patient experience by reducing, perhaps, the number of adverse experiences that he or she has, improving tolerability, and, in particular, potentially increasing adherence to treatments, especially in the longer-term,” said Dr. Wolinsky. The GLACIER trial was designed, in part, to test the regimen’s potential to yield these improvements.

Patients May Prefer Fewer Injections
Glatiramer acetate 20 mg/mL administered by daily subcutaneous injection is a well-characterized treatment with a good long-term safety profile. The drug has been used for more than 20 years, has accumulated more than two million patient-years of overall exposures, and has established efficacy for the treatment of relapsing-remitting MS. In January 2014, the FDA approved a supplemental New Drug Application for the 40-mg/mL three times weekly regimen after it was shown to have an efficacy and safety profile similar to that of the daily 20-mg/mL regimen.

The GLACIER findings suggest that the 40-mg/mL dosing regimen of glatiramer acetate is a favorable treatment option for some patients, particularly people who want to be on glatiramer acetate, but who prefer to take fewer injections and have more convenient dosing, concluded Dr. Wolinsky.

The annualized rate of injection-related adverse events in 108 adult patients with relapsing-remitting MS who were randomized to receive the thrice-weekly injections was 35.3, compared with 70.4 in 101 patients who received daily injections (relative risk, 0.50). The annualized rate of moderate and severe injection-related adverse events was 0.88 vs 2.2 in the groups, respectively (relative risk, 0.40), said Dr. Wolinsky.

The most common injection-site reactions were pain, erythema, mass, swelling, and pruritus, and all of these reactions were substantially reduced with lower-frequency dosing, compared with daily dosing. For example, the annualized rate of pain events was 24.8 with lower-frequency dosing vs 55.3 with higher-frequency dosing, and the annualized rate of erythema events was 21.4 vs 43.5.

Patients Had Experience With Glatiramer Acetate
Patients in the GLACIER trial were age 18 or older (mean age, 51) with a diagnosis of relapsing-remitting MS and an Expanded Disability Status Scale score between 0 and 5.5. Most participants (82%) were women, and 94% of patients were Caucasian.

All participants had been treated continuously with the 20-mg/mL daily dosing regimen for at least six months and were stable on that regimen for at least two months prior to screening for the GLACIER trial.

At least 75% treatment compliance was achieved by 99% of the GLACIER trial patients, and only 10 people withdrew before completing the four-month treatment phase, including three participants in the daily dosing group and seven patients in the lower-frequency dosing group. One patient withdrew because of an adverse event, said Dr. Wolinsky.

—Sharon Worcester

BOSTON—Delivering subcutaneous glatiramer acetate as a 40-mg/mL dose three times weekly, rather than 20 mg/mL daily, may reduce the annualized rate of injection-related adverse events by half, according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The results are from a randomized, open-label, phase III b trial of patients with relapsing-remitting multiple sclerosis (MS).

The reduction in the annualized rate of moderate and severe injection-related adverse events in patients who received lower-frequency dosing was about 60%, said Jerry S. Wolinsky, MD, Director of the MS Research Group at the University of Texas Health Science Center at Houston. The trial was called Glatiramer Acetate Low Frequency Safety and Patient Experience (GLACIER).

“As we all know, long-term, frequent injections are required for the first-line therapies for relapsing forms of MS, and this form of drug delivery presents a challenge for patients. Modification of the treatment regimen, such as using alternative dosages and lower-frequency administration schedules for these drugs with long-term proven efficacy, has the potential to improve the patient experience by reducing, perhaps, the number of adverse experiences that he or she has, improving tolerability, and, in particular, potentially increasing adherence to treatments, especially in the longer-term,” said Dr. Wolinsky. The GLACIER trial was designed, in part, to test the regimen’s potential to yield these improvements.

Patients May Prefer Fewer Injections
Glatiramer acetate 20 mg/mL administered by daily subcutaneous injection is a well-characterized treatment with a good long-term safety profile. The drug has been used for more than 20 years, has accumulated more than two million patient-years of overall exposures, and has established efficacy for the treatment of relapsing-remitting MS. In January 2014, the FDA approved a supplemental New Drug Application for the 40-mg/mL three times weekly regimen after it was shown to have an efficacy and safety profile similar to that of the daily 20-mg/mL regimen.

The GLACIER findings suggest that the 40-mg/mL dosing regimen of glatiramer acetate is a favorable treatment option for some patients, particularly people who want to be on glatiramer acetate, but who prefer to take fewer injections and have more convenient dosing, concluded Dr. Wolinsky.

The annualized rate of injection-related adverse events in 108 adult patients with relapsing-remitting MS who were randomized to receive the thrice-weekly injections was 35.3, compared with 70.4 in 101 patients who received daily injections (relative risk, 0.50). The annualized rate of moderate and severe injection-related adverse events was 0.88 vs 2.2 in the groups, respectively (relative risk, 0.40), said Dr. Wolinsky.

The most common injection-site reactions were pain, erythema, mass, swelling, and pruritus, and all of these reactions were substantially reduced with lower-frequency dosing, compared with daily dosing. For example, the annualized rate of pain events was 24.8 with lower-frequency dosing vs 55.3 with higher-frequency dosing, and the annualized rate of erythema events was 21.4 vs 43.5.

Patients Had Experience With Glatiramer Acetate
Patients in the GLACIER trial were age 18 or older (mean age, 51) with a diagnosis of relapsing-remitting MS and an Expanded Disability Status Scale score between 0 and 5.5. Most participants (82%) were women, and 94% of patients were Caucasian.

All participants had been treated continuously with the 20-mg/mL daily dosing regimen for at least six months and were stable on that regimen for at least two months prior to screening for the GLACIER trial.

At least 75% treatment compliance was achieved by 99% of the GLACIER trial patients, and only 10 people withdrew before completing the four-month treatment phase, including three participants in the daily dosing group and seven patients in the lower-frequency dosing group. One patient withdrew because of an adverse event, said Dr. Wolinsky.

—Sharon Worcester

BOSTON—Two-year data from the phase III ADVANCE clinical trial support the maintained benefits of pegylated interferon beta-1a (125 µg) beyond one year in patients with relapsing-remitting multiple sclerosis (MS), with significantly greater efficacy over several key end points seen in patients receiving the drug every two weeks, as opposed to a four-week dosing regimen. These extension trial results were reported by Peter A. Calabresi, MD, at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

“Overall, pegylated interferon beta-1a seems to be a well-tolerated and safe approach to treating patients with relapsing-remitting MS,” said Dr. Calabresi, who is the Director of the Division of Immunology, Director of the Multiple Sclerosis Center, and Professor of Neurology at Johns Hopkins University in Baltimore.

Year one results of the ADVANCE study were published in the July issue of Lancet Neurology. The three-arm study compared placebo with subcutaneous pegylated interferon beta-1a (125 mg) given either every two weeks or every four weeks. Compared with placebo, both treatment arms had significant reductions in annualized relapse rates, which was the primary end point. Significant reductions were also seen in secondary end points—risk of relapse, disability progression, and number of new or newly enlarging T2 lesions. Two-week dosing showed greater benefits over four-week dosing. The safety profile in year one was largely consistent with the known safety of interferon and the side effects of the interferons.

Sustained Benefit
The purpose of the extension study was to examine maintenance of efficacy. “We want the drug to continue to work over a lifetime, so we compared patients in year one to patients in year two who were consistently on pegylated interferon,” Dr. Calabresi said. The researchers also compared patients continuously on pegylated interferon with those who were switched from placebo to active treatment to determine if treatment delay had any significant changes, compared with continuous treatment. The investigators also compared the efficacy of two-week dosing with four-week dosing.

Patient retention in year two was excellent—between 88% and 94% per arm, according to Dr. Calabresi. Compared with the delayed treatment group (those switched from placebo to active treatment), the researchers found a 37% reduction in annualized relapse rates in the two-week dosing arm and a 17% reduction in the four-week dosing arm. “So we saw a significant reduction in the two-week group with a trend in the four-week dosing arm,” Dr. Calabresi said.

Over two years, there was a 39% reduction in time to first relapse in the two-week dosing arm and a 19% reduction in the four-week dosing arm, compared with delayed treatment. Regarding 12-week confirmed disability progression, a 33% reduction was observed in the two-week dosing arm and a 25% reduction was found in the four-week dosing arm, again compared with delayed treatment. With regard to 24-week confirmed disability, there was a 41% reduction in the two-week dosing arm and a 9% reduction in the four-week dosing group. Proportions of patients with relapses meeting 24-week confirmed disability progression were also significantly reduced in the two-week dosing arm, compared with the four-week dosing arms or delayed treatment.

Significant reductions occurred in the two-week dosing group, as compared with the four-week group in all three MRI outcome measures. The mean number of new or newly enlarging T2-weighted hyperintense lesions was 14.8 in the delayed treatment group, 12.5 in the four-week dosing group, and five in the two-week dosing group. The mean number of gadolinium-enhancing lesions was 0.5 in the delayed treatment group, 0.7 in the four-week dosing group, and 0.2 in the two-week dosing group. The mean number of T1 hypointense lesions was 5.6 in the delayed treatment group, 4.9 in the four-week dosing group, and 2.3 in the two-week dosing group.

The same patterns were seen when looking at no MS disease activity overall. The two-week dosing group had significant decreases in the percentage of patients with no disease activity, as compared with delayed treatment, with the four-week doing group somewhere in between.

Regarding maintenance of efficacy between years one and two, the delayed treatment group that was switched from placebo to active treatment showed a reduction in the primary and secondary outcome measures. The greatest reductions were again seen in the two-week dosing group.

The two-year data revealed no surprises or new concerns with regard to safety or tolerability. Side effects were most commonly injection-site reactions in 68% and flu-like symptoms in 53%, but these events led to discontinuation in only 6% of patients. Although nine deaths occurred during the two years, an independent safety monitoring committee concluded that none of the deaths was related to the study drug.

The Outlook at Two Years
“The results over the two years are that pegylated interferon beta-1a has a positive effect on relapse rate and disease progression beyond the one-year placebo-controlled study period,” Dr. Calabresi said. “Over the two years, we saw a benefit of being on continuous pegylated interferon beta-1a, compared to the delayed treatment group. There were continued significant differences in many of the outcome measures in the two-week dosing group, as compared to the four-week dosing group.”

—Glenn S. Williams

BOSTON—Two-year data from the phase III ADVANCE clinical trial support the maintained benefits of pegylated interferon beta-1a (125 µg) beyond one year in patients with relapsing-remitting multiple sclerosis (MS), with significantly greater efficacy over several key end points seen in patients receiving the drug every two weeks, as opposed to a four-week dosing regimen. These extension trial results were reported by Peter A. Calabresi, MD, at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

“Overall, pegylated interferon beta-1a seems to be a well-tolerated and safe approach to treating patients with relapsing-remitting MS,” said Dr. Calabresi, who is the Director of the Division of Immunology, Director of the Multiple Sclerosis Center, and Professor of Neurology at Johns Hopkins University in Baltimore.

Year one results of the ADVANCE study were published in the July issue of Lancet Neurology. The three-arm study compared placebo with subcutaneous pegylated interferon beta-1a (125 mg) given either every two weeks or every four weeks. Compared with placebo, both treatment arms had significant reductions in annualized relapse rates, which was the primary end point. Significant reductions were also seen in secondary end points—risk of relapse, disability progression, and number of new or newly enlarging T2 lesions. Two-week dosing showed greater benefits over four-week dosing. The safety profile in year one was largely consistent with the known safety of interferon and the side effects of the interferons.

Sustained Benefit
The purpose of the extension study was to examine maintenance of efficacy. “We want the drug to continue to work over a lifetime, so we compared patients in year one to patients in year two who were consistently on pegylated interferon,” Dr. Calabresi said. The researchers also compared patients continuously on pegylated interferon with those who were switched from placebo to active treatment to determine if treatment delay had any significant changes, compared with continuous treatment. The investigators also compared the efficacy of two-week dosing with four-week dosing.

Patient retention in year two was excellent—between 88% and 94% per arm, according to Dr. Calabresi. Compared with the delayed treatment group (those switched from placebo to active treatment), the researchers found a 37% reduction in annualized relapse rates in the two-week dosing arm and a 17% reduction in the four-week dosing arm. “So we saw a significant reduction in the two-week group with a trend in the four-week dosing arm,” Dr. Calabresi said.

Over two years, there was a 39% reduction in time to first relapse in the two-week dosing arm and a 19% reduction in the four-week dosing arm, compared with delayed treatment. Regarding 12-week confirmed disability progression, a 33% reduction was observed in the two-week dosing arm and a 25% reduction was found in the four-week dosing arm, again compared with delayed treatment. With regard to 24-week confirmed disability, there was a 41% reduction in the two-week dosing arm and a 9% reduction in the four-week dosing group. Proportions of patients with relapses meeting 24-week confirmed disability progression were also significantly reduced in the two-week dosing arm, compared with the four-week dosing arms or delayed treatment.

Significant reductions occurred in the two-week dosing group, as compared with the four-week group in all three MRI outcome measures. The mean number of new or newly enlarging T2-weighted hyperintense lesions was 14.8 in the delayed treatment group, 12.5 in the four-week dosing group, and five in the two-week dosing group. The mean number of gadolinium-enhancing lesions was 0.5 in the delayed treatment group, 0.7 in the four-week dosing group, and 0.2 in the two-week dosing group. The mean number of T1 hypointense lesions was 5.6 in the delayed treatment group, 4.9 in the four-week dosing group, and 2.3 in the two-week dosing group.

The same patterns were seen when looking at no MS disease activity overall. The two-week dosing group had significant decreases in the percentage of patients with no disease activity, as compared with delayed treatment, with the four-week doing group somewhere in between.

Regarding maintenance of efficacy between years one and two, the delayed treatment group that was switched from placebo to active treatment showed a reduction in the primary and secondary outcome measures. The greatest reductions were again seen in the two-week dosing group.

The two-year data revealed no surprises or new concerns with regard to safety or tolerability. Side effects were most commonly injection-site reactions in 68% and flu-like symptoms in 53%, but these events led to discontinuation in only 6% of patients. Although nine deaths occurred during the two years, an independent safety monitoring committee concluded that none of the deaths was related to the study drug.

The Outlook at Two Years
“The results over the two years are that pegylated interferon beta-1a has a positive effect on relapse rate and disease progression beyond the one-year placebo-controlled study period,” Dr. Calabresi said. “Over the two years, we saw a benefit of being on continuous pegylated interferon beta-1a, compared to the delayed treatment group. There were continued significant differences in many of the outcome measures in the two-week dosing group, as compared to the four-week dosing group.”

—Glenn S. Williams

BOSTON—Two-year data from the phase III ADVANCE clinical trial support the maintained benefits of pegylated interferon beta-1a (125 µg) beyond one year in patients with relapsing-remitting multiple sclerosis (MS), with significantly greater efficacy over several key end points seen in patients receiving the drug every two weeks, as opposed to a four-week dosing regimen. These extension trial results were reported by Peter A. Calabresi, MD, at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

“Overall, pegylated interferon beta-1a seems to be a well-tolerated and safe approach to treating patients with relapsing-remitting MS,” said Dr. Calabresi, who is the Director of the Division of Immunology, Director of the Multiple Sclerosis Center, and Professor of Neurology at Johns Hopkins University in Baltimore.

Year one results of the ADVANCE study were published in the July issue of Lancet Neurology. The three-arm study compared placebo with subcutaneous pegylated interferon beta-1a (125 mg) given either every two weeks or every four weeks. Compared with placebo, both treatment arms had significant reductions in annualized relapse rates, which was the primary end point. Significant reductions were also seen in secondary end points—risk of relapse, disability progression, and number of new or newly enlarging T2 lesions. Two-week dosing showed greater benefits over four-week dosing. The safety profile in year one was largely consistent with the known safety of interferon and the side effects of the interferons.

Sustained Benefit
The purpose of the extension study was to examine maintenance of efficacy. “We want the drug to continue to work over a lifetime, so we compared patients in year one to patients in year two who were consistently on pegylated interferon,” Dr. Calabresi said. The researchers also compared patients continuously on pegylated interferon with those who were switched from placebo to active treatment to determine if treatment delay had any significant changes, compared with continuous treatment. The investigators also compared the efficacy of two-week dosing with four-week dosing.

Patient retention in year two was excellent—between 88% and 94% per arm, according to Dr. Calabresi. Compared with the delayed treatment group (those switched from placebo to active treatment), the researchers found a 37% reduction in annualized relapse rates in the two-week dosing arm and a 17% reduction in the four-week dosing arm. “So we saw a significant reduction in the two-week group with a trend in the four-week dosing arm,” Dr. Calabresi said.

Over two years, there was a 39% reduction in time to first relapse in the two-week dosing arm and a 19% reduction in the four-week dosing arm, compared with delayed treatment. Regarding 12-week confirmed disability progression, a 33% reduction was observed in the two-week dosing arm and a 25% reduction was found in the four-week dosing arm, again compared with delayed treatment. With regard to 24-week confirmed disability, there was a 41% reduction in the two-week dosing arm and a 9% reduction in the four-week dosing group. Proportions of patients with relapses meeting 24-week confirmed disability progression were also significantly reduced in the two-week dosing arm, compared with the four-week dosing arms or delayed treatment.

Significant reductions occurred in the two-week dosing group, as compared with the four-week group in all three MRI outcome measures. The mean number of new or newly enlarging T2-weighted hyperintense lesions was 14.8 in the delayed treatment group, 12.5 in the four-week dosing group, and five in the two-week dosing group. The mean number of gadolinium-enhancing lesions was 0.5 in the delayed treatment group, 0.7 in the four-week dosing group, and 0.2 in the two-week dosing group. The mean number of T1 hypointense lesions was 5.6 in the delayed treatment group, 4.9 in the four-week dosing group, and 2.3 in the two-week dosing group.

The same patterns were seen when looking at no MS disease activity overall. The two-week dosing group had significant decreases in the percentage of patients with no disease activity, as compared with delayed treatment, with the four-week doing group somewhere in between.

Regarding maintenance of efficacy between years one and two, the delayed treatment group that was switched from placebo to active treatment showed a reduction in the primary and secondary outcome measures. The greatest reductions were again seen in the two-week dosing group.

The two-year data revealed no surprises or new concerns with regard to safety or tolerability. Side effects were most commonly injection-site reactions in 68% and flu-like symptoms in 53%, but these events led to discontinuation in only 6% of patients. Although nine deaths occurred during the two years, an independent safety monitoring committee concluded that none of the deaths was related to the study drug.

The Outlook at Two Years
“The results over the two years are that pegylated interferon beta-1a has a positive effect on relapse rate and disease progression beyond the one-year placebo-controlled study period,” Dr. Calabresi said. “Over the two years, we saw a benefit of being on continuous pegylated interferon beta-1a, compared to the delayed treatment group. There were continued significant differences in many of the outcome measures in the two-week dosing group, as compared to the four-week dosing group.”

—Glenn S. Williams

BOSTON—Patients with multiple sclerosis (MS) have an increased risk of schizophrenia and bipolar disorder, researchers reported. In addition, the results of a retrospective analysis suggest that these disorders have shared etiologies.

“To our knowledge, this is the first large-scale study to test this association,” said Sreeram Ramagopalan, PhD, a research fellow at Evidera in London. “Caregivers should appropriately diagnose and manage these conditions in patients with MS.”

Recent studies have found similar risk factors for patients with schizophrenia, bipolar disorder, and MS, including immunogenetic associations, vitamin D deficiency, and infections. Dr. Ramagopalan and colleagues sought to test whether MS patients are at an increased risk of schizophrenia and bipolar disorder using the Hospital Episode Statistics database of hospital admissions in England.

The investigators analyzed a database of linked statistical records of hospital admissions and death certificates for all of England. The analysis included the years from 1999 to 2011 and examined data for 52 million people. The researchers determined rate ratios for psychiatric disease, comparing rates of schizophrenia and bipolar disorder in a cohort of all people in England admitted with MS (n = 82,176) with rates in a comparison cohort of patients admitted for various other, mainly minor, medical and surgical conditions (n = 9,818,240). Rates were based on person-days and were standardized by age (in five-year age groups), sex, calendar year of first recorded admission, region of residence, and quintile of patients’ Index of Multiple Deprivation score (as a measure of socioeconomic status), using the indirect method of standardization.

Patients with MS had significantly elevated risks for schizophrenia (rate ratio [RR] = 1.42); schizophrenia, schizotypal, and delusional disorders (RR = 2.08); and bipolar disorder (RR = 1.73). The researchers found these associations in males and females. The associations also were evident when the investigators identified a first schizophrenia or bipolar diagnosis at least a year after the first MS admission. The latter result suggests that the association is not a reflection of surveillance bias.

—Erik Greb

Does Overactive Bladder Correlate With MS Relapses or Progression?
Overactive bladder (OAB) with leakage is associated with a higher number of relapses and increased disease progression among patients with multiple sclerosis (MS), according to researchers.

Patients with OAB and leakage “should be closely monitored for indications of overall worsening function,” said Stacey S. Cofield, PhD, Associate Professor of Biostatistics at the University of Alabama at Birmingham, and colleagues.

Dr. Cofield and colleagues investigated the relationship between self-reported bladder dysfunction and relapses and severity of disability during five years of follow-up. The researchers examined data from the North American Research Committee on MS (NARCOMS) database, a voluntary registry for people with MS that involves an enrollment survey and semiannual updates. They included participants who responded to questions about bladder function in fall 2005. Eligible participants were US residents with no surgical alterations to the bladder who completed one or more update survey annually from 2005 through 2010.

The investigators classified respondents in 2005 as having wet OAB (ie, urgency with urgency-related leakage), dry OAB (ie, urgency without urgency-related leakage), or no OAB. They defined progression as a one-point increase in Patient-Determined Disease Steps (PDDS) from 2005 to 2010 and at 2010.

A total of 4,870 respondents were included in the analysis. Approximately 74% of respondents were female. About 94% of participants were Caucasian, and the population’s mean age was approximately 51. Respondents’ mean disease duration in 2005 was 12 years.

Of all respondents, 60.2% were classified as having wet OAB, 15.2% were classified as having dry OAB, and 24.6% were classified as having no OAB. Among participants with wet OAB, 50.8% reported slight incontinence, 30.6% reported moderate incontinence, and 18.7% reported great incontinence. In 2005, patients with wet OAB were older and had a longer disease duration than the other respondents.

The proportion of respondents reporting any relapse from 2005 to 2010 did not differ across groups, but patients with wet OAB were more likely to report more than three relapses and PDDS progression. From 2005 to 2010, 55% of patients with wet OAB reported three or more relapses, compared with 51% of patients with dry OAB and 52% of patients with no OAB. In the same period, 37% of respondents with wet OAB reported progression, compared with 33% of respondents with dry OAB and 28% of respondents with no OAB. In addition, older age and longer disease duration were associated significantly with PDDS progression.

A higher proportion of patients with wet OAB in 2005 reported being severely bothered by urinary or bladder, bowel, and sexual dysfunction in 2010. Approximately 21% of respondents with wet OAB were severely bothered by urinary or bladder dysfunction in 2010, compared with 6% of patients with dry OAB and 5% of patients with no OAB. Eleven percent of patients with wet OAB were severely bothered by bowel dysfunction in 2010, compared with 5% of patients with dry OAB and 5% of patients with no OAB. In addition, 25% of participants with wet OAB were severely bothered by sexual dysfunction in 2010, compared with 5% of participants with dry OAB and 13% of participants with no OAB.

—Erik Greb

BOSTON—Patients with multiple sclerosis (MS) have an increased risk of schizophrenia and bipolar disorder, researchers reported. In addition, the results of a retrospective analysis suggest that these disorders have shared etiologies.

“To our knowledge, this is the first large-scale study to test this association,” said Sreeram Ramagopalan, PhD, a research fellow at Evidera in London. “Caregivers should appropriately diagnose and manage these conditions in patients with MS.”

Recent studies have found similar risk factors for patients with schizophrenia, bipolar disorder, and MS, including immunogenetic associations, vitamin D deficiency, and infections. Dr. Ramagopalan and colleagues sought to test whether MS patients are at an increased risk of schizophrenia and bipolar disorder using the Hospital Episode Statistics database of hospital admissions in England.

The investigators analyzed a database of linked statistical records of hospital admissions and death certificates for all of England. The analysis included the years from 1999 to 2011 and examined data for 52 million people. The researchers determined rate ratios for psychiatric disease, comparing rates of schizophrenia and bipolar disorder in a cohort of all people in England admitted with MS (n = 82,176) with rates in a comparison cohort of patients admitted for various other, mainly minor, medical and surgical conditions (n = 9,818,240). Rates were based on person-days and were standardized by age (in five-year age groups), sex, calendar year of first recorded admission, region of residence, and quintile of patients’ Index of Multiple Deprivation score (as a measure of socioeconomic status), using the indirect method of standardization.

Patients with MS had significantly elevated risks for schizophrenia (rate ratio [RR] = 1.42); schizophrenia, schizotypal, and delusional disorders (RR = 2.08); and bipolar disorder (RR = 1.73). The researchers found these associations in males and females. The associations also were evident when the investigators identified a first schizophrenia or bipolar diagnosis at least a year after the first MS admission. The latter result suggests that the association is not a reflection of surveillance bias.

—Erik Greb

Does Overactive Bladder Correlate With MS Relapses or Progression?
Overactive bladder (OAB) with leakage is associated with a higher number of relapses and increased disease progression among patients with multiple sclerosis (MS), according to researchers.

Patients with OAB and leakage “should be closely monitored for indications of overall worsening function,” said Stacey S. Cofield, PhD, Associate Professor of Biostatistics at the University of Alabama at Birmingham, and colleagues.

Dr. Cofield and colleagues investigated the relationship between self-reported bladder dysfunction and relapses and severity of disability during five years of follow-up. The researchers examined data from the North American Research Committee on MS (NARCOMS) database, a voluntary registry for people with MS that involves an enrollment survey and semiannual updates. They included participants who responded to questions about bladder function in fall 2005. Eligible participants were US residents with no surgical alterations to the bladder who completed one or more update survey annually from 2005 through 2010.

The investigators classified respondents in 2005 as having wet OAB (ie, urgency with urgency-related leakage), dry OAB (ie, urgency without urgency-related leakage), or no OAB. They defined progression as a one-point increase in Patient-Determined Disease Steps (PDDS) from 2005 to 2010 and at 2010.

A total of 4,870 respondents were included in the analysis. Approximately 74% of respondents were female. About 94% of participants were Caucasian, and the population’s mean age was approximately 51. Respondents’ mean disease duration in 2005 was 12 years.

Of all respondents, 60.2% were classified as having wet OAB, 15.2% were classified as having dry OAB, and 24.6% were classified as having no OAB. Among participants with wet OAB, 50.8% reported slight incontinence, 30.6% reported moderate incontinence, and 18.7% reported great incontinence. In 2005, patients with wet OAB were older and had a longer disease duration than the other respondents.

The proportion of respondents reporting any relapse from 2005 to 2010 did not differ across groups, but patients with wet OAB were more likely to report more than three relapses and PDDS progression. From 2005 to 2010, 55% of patients with wet OAB reported three or more relapses, compared with 51% of patients with dry OAB and 52% of patients with no OAB. In the same period, 37% of respondents with wet OAB reported progression, compared with 33% of respondents with dry OAB and 28% of respondents with no OAB. In addition, older age and longer disease duration were associated significantly with PDDS progression.

A higher proportion of patients with wet OAB in 2005 reported being severely bothered by urinary or bladder, bowel, and sexual dysfunction in 2010. Approximately 21% of respondents with wet OAB were severely bothered by urinary or bladder dysfunction in 2010, compared with 6% of patients with dry OAB and 5% of patients with no OAB. Eleven percent of patients with wet OAB were severely bothered by bowel dysfunction in 2010, compared with 5% of patients with dry OAB and 5% of patients with no OAB. In addition, 25% of participants with wet OAB were severely bothered by sexual dysfunction in 2010, compared with 5% of participants with dry OAB and 13% of participants with no OAB.

—Erik Greb

BOSTON—Patients with multiple sclerosis (MS) have an increased risk of schizophrenia and bipolar disorder, researchers reported. In addition, the results of a retrospective analysis suggest that these disorders have shared etiologies.

“To our knowledge, this is the first large-scale study to test this association,” said Sreeram Ramagopalan, PhD, a research fellow at Evidera in London. “Caregivers should appropriately diagnose and manage these conditions in patients with MS.”

Recent studies have found similar risk factors for patients with schizophrenia, bipolar disorder, and MS, including immunogenetic associations, vitamin D deficiency, and infections. Dr. Ramagopalan and colleagues sought to test whether MS patients are at an increased risk of schizophrenia and bipolar disorder using the Hospital Episode Statistics database of hospital admissions in England.

The investigators analyzed a database of linked statistical records of hospital admissions and death certificates for all of England. The analysis included the years from 1999 to 2011 and examined data for 52 million people. The researchers determined rate ratios for psychiatric disease, comparing rates of schizophrenia and bipolar disorder in a cohort of all people in England admitted with MS (n = 82,176) with rates in a comparison cohort of patients admitted for various other, mainly minor, medical and surgical conditions (n = 9,818,240). Rates were based on person-days and were standardized by age (in five-year age groups), sex, calendar year of first recorded admission, region of residence, and quintile of patients’ Index of Multiple Deprivation score (as a measure of socioeconomic status), using the indirect method of standardization.

Patients with MS had significantly elevated risks for schizophrenia (rate ratio [RR] = 1.42); schizophrenia, schizotypal, and delusional disorders (RR = 2.08); and bipolar disorder (RR = 1.73). The researchers found these associations in males and females. The associations also were evident when the investigators identified a first schizophrenia or bipolar diagnosis at least a year after the first MS admission. The latter result suggests that the association is not a reflection of surveillance bias.

—Erik Greb

Does Overactive Bladder Correlate With MS Relapses or Progression?
Overactive bladder (OAB) with leakage is associated with a higher number of relapses and increased disease progression among patients with multiple sclerosis (MS), according to researchers.

Patients with OAB and leakage “should be closely monitored for indications of overall worsening function,” said Stacey S. Cofield, PhD, Associate Professor of Biostatistics at the University of Alabama at Birmingham, and colleagues.

Dr. Cofield and colleagues investigated the relationship between self-reported bladder dysfunction and relapses and severity of disability during five years of follow-up. The researchers examined data from the North American Research Committee on MS (NARCOMS) database, a voluntary registry for people with MS that involves an enrollment survey and semiannual updates. They included participants who responded to questions about bladder function in fall 2005. Eligible participants were US residents with no surgical alterations to the bladder who completed one or more update survey annually from 2005 through 2010.

The investigators classified respondents in 2005 as having wet OAB (ie, urgency with urgency-related leakage), dry OAB (ie, urgency without urgency-related leakage), or no OAB. They defined progression as a one-point increase in Patient-Determined Disease Steps (PDDS) from 2005 to 2010 and at 2010.

A total of 4,870 respondents were included in the analysis. Approximately 74% of respondents were female. About 94% of participants were Caucasian, and the population’s mean age was approximately 51. Respondents’ mean disease duration in 2005 was 12 years.

Of all respondents, 60.2% were classified as having wet OAB, 15.2% were classified as having dry OAB, and 24.6% were classified as having no OAB. Among participants with wet OAB, 50.8% reported slight incontinence, 30.6% reported moderate incontinence, and 18.7% reported great incontinence. In 2005, patients with wet OAB were older and had a longer disease duration than the other respondents.

The proportion of respondents reporting any relapse from 2005 to 2010 did not differ across groups, but patients with wet OAB were more likely to report more than three relapses and PDDS progression. From 2005 to 2010, 55% of patients with wet OAB reported three or more relapses, compared with 51% of patients with dry OAB and 52% of patients with no OAB. In the same period, 37% of respondents with wet OAB reported progression, compared with 33% of respondents with dry OAB and 28% of respondents with no OAB. In addition, older age and longer disease duration were associated significantly with PDDS progression.

A higher proportion of patients with wet OAB in 2005 reported being severely bothered by urinary or bladder, bowel, and sexual dysfunction in 2010. Approximately 21% of respondents with wet OAB were severely bothered by urinary or bladder dysfunction in 2010, compared with 6% of patients with dry OAB and 5% of patients with no OAB. Eleven percent of patients with wet OAB were severely bothered by bowel dysfunction in 2010, compared with 5% of patients with dry OAB and 5% of patients with no OAB. In addition, 25% of participants with wet OAB were severely bothered by sexual dysfunction in 2010, compared with 5% of participants with dry OAB and 13% of participants with no OAB.

—Erik Greb

BOSTON—Diet does not appear to contribute to the development of multiple sclerosis (MS), according to findings presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

None of three dietary indices measured at baseline—the Alternative Healthy Eating Index-2010 (AHEI-2010), the Alternate Mediterranean Diet Index (aMED), and the Dietary Approaches to Stop Hypertension Index (DASH)—was significantly associated with the risk of developing MS in two longitudinal cohort studies, Dalia Rotstein, MD, Clinical Fellow in Neurology, Brigham and Women’s Hospital, Cambridge, Massachusetts, reported. Dr. Rotstein’s group prospectively followed more than 185,000 women from the Nurses’ Health Study (NHS) and the NHS II.

After adjustment for known confounders of MS risk—including age, latitude of residence at age 15, BMI at age 18, pack-years of smoking, total energy intake, supplemental vitamin D intake, and ethnicity—the investigators found that the pooled relative risk of MS for the highest versus the lowest quintile of scores for each index was 0.89 for the AHEI-2010, 1.10 for aMED, and 1.30 for DASH.

A principal-components analysis identified two general dietary patterns among the subjects. One was a “Western” dietary pattern with high intake of red and processed meats, refined grains, and sweets, and the other was a “prudent” dietary pattern with high intake of vegetables, fruit, legumes, fish, poultry, and whole grains. Neither was associated with MS risk (relative risk for the highest vs lowest quintile of scores, 0.71 and 1.09, respectively). The results were similar when looking at mean cumulative dietary scores and when looking at the two cohorts separately.

An exception in the analysis using mean cumulative dietary score was for the Western dietary pattern, which was shown to have a significant inverse association with MS risk (relative risk, 0.66). “This just met statistical significance, and we believe that this result is an artifact,” Dr. Rotstein said.

Study participants completed semiquantitative food frequency questionnaires every four years, beginning in 1984 for the NHS and in 1991 for NHS II. The MS cases were documented as of 2004 for NHS (130 cases) and as of 2009 for NHS II (350 cases).

With the exception of studies on vitamin D intake, prior studies have yielded null or inconsistent results with respect to the role of diet in MS development, and most have been limited by a focus on individual dietary elements and by small sample size.

The current study is the first large, prospective, population-based study to investigate the relationship, and it shows no evidence of an association between overall dietary quality and MS, Dr. Rotstein said.

The study is limited by the inherent subjectivity in dietary scores and by a basis in population norms rather than ideal consumption patterns. Also, the study is conceived around recommendations for cardiovascular health, but other dietary patterns may be more relevant for immunologic health, she said, noting that additional study is needed to determine if dietary quality and individual dietary elements in the early years play a role in MS development.

—Sharon Worcester

BOSTON—Diet does not appear to contribute to the development of multiple sclerosis (MS), according to findings presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

None of three dietary indices measured at baseline—the Alternative Healthy Eating Index-2010 (AHEI-2010), the Alternate Mediterranean Diet Index (aMED), and the Dietary Approaches to Stop Hypertension Index (DASH)—was significantly associated with the risk of developing MS in two longitudinal cohort studies, Dalia Rotstein, MD, Clinical Fellow in Neurology, Brigham and Women’s Hospital, Cambridge, Massachusetts, reported. Dr. Rotstein’s group prospectively followed more than 185,000 women from the Nurses’ Health Study (NHS) and the NHS II.

After adjustment for known confounders of MS risk—including age, latitude of residence at age 15, BMI at age 18, pack-years of smoking, total energy intake, supplemental vitamin D intake, and ethnicity—the investigators found that the pooled relative risk of MS for the highest versus the lowest quintile of scores for each index was 0.89 for the AHEI-2010, 1.10 for aMED, and 1.30 for DASH.

A principal-components analysis identified two general dietary patterns among the subjects. One was a “Western” dietary pattern with high intake of red and processed meats, refined grains, and sweets, and the other was a “prudent” dietary pattern with high intake of vegetables, fruit, legumes, fish, poultry, and whole grains. Neither was associated with MS risk (relative risk for the highest vs lowest quintile of scores, 0.71 and 1.09, respectively). The results were similar when looking at mean cumulative dietary scores and when looking at the two cohorts separately.

An exception in the analysis using mean cumulative dietary score was for the Western dietary pattern, which was shown to have a significant inverse association with MS risk (relative risk, 0.66). “This just met statistical significance, and we believe that this result is an artifact,” Dr. Rotstein said.

Study participants completed semiquantitative food frequency questionnaires every four years, beginning in 1984 for the NHS and in 1991 for NHS II. The MS cases were documented as of 2004 for NHS (130 cases) and as of 2009 for NHS II (350 cases).

With the exception of studies on vitamin D intake, prior studies have yielded null or inconsistent results with respect to the role of diet in MS development, and most have been limited by a focus on individual dietary elements and by small sample size.

The current study is the first large, prospective, population-based study to investigate the relationship, and it shows no evidence of an association between overall dietary quality and MS, Dr. Rotstein said.

The study is limited by the inherent subjectivity in dietary scores and by a basis in population norms rather than ideal consumption patterns. Also, the study is conceived around recommendations for cardiovascular health, but other dietary patterns may be more relevant for immunologic health, she said, noting that additional study is needed to determine if dietary quality and individual dietary elements in the early years play a role in MS development.

—Sharon Worcester

BOSTON—Diet does not appear to contribute to the development of multiple sclerosis (MS), according to findings presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

None of three dietary indices measured at baseline—the Alternative Healthy Eating Index-2010 (AHEI-2010), the Alternate Mediterranean Diet Index (aMED), and the Dietary Approaches to Stop Hypertension Index (DASH)—was significantly associated with the risk of developing MS in two longitudinal cohort studies, Dalia Rotstein, MD, Clinical Fellow in Neurology, Brigham and Women’s Hospital, Cambridge, Massachusetts, reported. Dr. Rotstein’s group prospectively followed more than 185,000 women from the Nurses’ Health Study (NHS) and the NHS II.

After adjustment for known confounders of MS risk—including age, latitude of residence at age 15, BMI at age 18, pack-years of smoking, total energy intake, supplemental vitamin D intake, and ethnicity—the investigators found that the pooled relative risk of MS for the highest versus the lowest quintile of scores for each index was 0.89 for the AHEI-2010, 1.10 for aMED, and 1.30 for DASH.

A principal-components analysis identified two general dietary patterns among the subjects. One was a “Western” dietary pattern with high intake of red and processed meats, refined grains, and sweets, and the other was a “prudent” dietary pattern with high intake of vegetables, fruit, legumes, fish, poultry, and whole grains. Neither was associated with MS risk (relative risk for the highest vs lowest quintile of scores, 0.71 and 1.09, respectively). The results were similar when looking at mean cumulative dietary scores and when looking at the two cohorts separately.

An exception in the analysis using mean cumulative dietary score was for the Western dietary pattern, which was shown to have a significant inverse association with MS risk (relative risk, 0.66). “This just met statistical significance, and we believe that this result is an artifact,” Dr. Rotstein said.

Study participants completed semiquantitative food frequency questionnaires every four years, beginning in 1984 for the NHS and in 1991 for NHS II. The MS cases were documented as of 2004 for NHS (130 cases) and as of 2009 for NHS II (350 cases).

With the exception of studies on vitamin D intake, prior studies have yielded null or inconsistent results with respect to the role of diet in MS development, and most have been limited by a focus on individual dietary elements and by small sample size.

The current study is the first large, prospective, population-based study to investigate the relationship, and it shows no evidence of an association between overall dietary quality and MS, Dr. Rotstein said.

The study is limited by the inherent subjectivity in dietary scores and by a basis in population norms rather than ideal consumption patterns. Also, the study is conceived around recommendations for cardiovascular health, but other dietary patterns may be more relevant for immunologic health, she said, noting that additional study is needed to determine if dietary quality and individual dietary elements in the early years play a role in MS development.

—Sharon Worcester

BOSTON—Long-term treatment with interferon beta-1a or glatiramer acetate has the potential to be cost effective and to alter the natural history of relapsing-remitting multiple sclerosis (MS), according to findings from a six-year observational study presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

In 4,137 patients with relapsing-remitting MS who were followed for a median of six years, the observed increase in the Expanded Disability Status Scale (EDSS) scores was lower among treated patients than the increase seen in a natural history cohort that served as a comparator group (relative rates, 0.76 using a continuous Markov model and 0.61 using a multilevel model).

Results of Treatment Exceeded Predictions
The observed progression for utility—a quality of life measure derived from the EDSS scores, and the primary outcome of the study—was consistent with this finding (relative rates of 0.58 and 0.56, according to the two models, respectively), said Jacqueline Palace, BM, Consultant Neurologist at the University of Oxford, United Kingdom.

The researchers had predicted that treatment would reduce the observed progression for utility by 38%, compared with the natural history cohort. Data, however, indicated a reduction of about 42%, which was better than predicted, added Dr. Palace. A range of sensitivity analyses that examined the potential for various biases consistently demonstrated better outcomes in the treated patients, compared with the natural history cohort. If sustained over 20 years, the magnitude of the treatment effect observed in this study would be consistent with a predefined cost-effectiveness target of approximately $58,400 per quality-adjusted life-year, said Dr. Palace.

Patients included in this study were adults with a mean age of 38 and a mean age at disease onset of 31. Most participants (76%) were women. Mean disease duration was 7.7 years at baseline, and the patients had a mean of three relapses over the previous two years. Mean baseline EDSS score was 3.06.

The UK’s Risk-Sharing Scheme
“In 2002, the National Institute of Clinical Excellence [NICE], which is the UK body that sets the guidelines that decide [which drugs] should be available under the National Health Service [NHS], concluded that beta-interferon and glatiramer acetate were not cost-effective during the short-term, and thus it recommended that [they] couldn’t be available under the NHS at that stage,” explained Dr. Palace.

The NICE did state, however, that if the drugs’ effects were maintained over the long term, the drugs might be cost effective. The institute invited the Department of Health to “try and find a way to make the drugs available in a cost-effective manner,” said Dr. Palace. “This was the birth of the Risk-Sharing Scheme, and it is a way of providing disease-modifying therapies to patients cost effectively.”

At the start of the scheme, the drug prices were reduced according to a NICE model of cost efficacy. Prices were set at the equivalent of $58,400/quality-adjusted life-year. A price adjustment would have been required to achieve cost effectiveness if the outcomes of the treated patients had been worse than predicted. “We were allowed to reach this target over a 20-year lifespan, and the idea was to monitor a clinical cohort of patients, measuring their EDSS scores,” said Dr. Palace. The natural history dataset was used as a virtual placebo.

The investigation was the largest observational study to measure the effect and cost-effectiveness of interferon beta-1a and glatiramer acetate. The findings provide evidence that the treatment alters the natural history of relapsing-remitting MS, Dr. Palace concluded.

—Sharon Worcester

BOSTON—Long-term treatment with interferon beta-1a or glatiramer acetate has the potential to be cost effective and to alter the natural history of relapsing-remitting multiple sclerosis (MS), according to findings from a six-year observational study presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

In 4,137 patients with relapsing-remitting MS who were followed for a median of six years, the observed increase in the Expanded Disability Status Scale (EDSS) scores was lower among treated patients than the increase seen in a natural history cohort that served as a comparator group (relative rates, 0.76 using a continuous Markov model and 0.61 using a multilevel model).

Results of Treatment Exceeded Predictions
The observed progression for utility—a quality of life measure derived from the EDSS scores, and the primary outcome of the study—was consistent with this finding (relative rates of 0.58 and 0.56, according to the two models, respectively), said Jacqueline Palace, BM, Consultant Neurologist at the University of Oxford, United Kingdom.

The researchers had predicted that treatment would reduce the observed progression for utility by 38%, compared with the natural history cohort. Data, however, indicated a reduction of about 42%, which was better than predicted, added Dr. Palace. A range of sensitivity analyses that examined the potential for various biases consistently demonstrated better outcomes in the treated patients, compared with the natural history cohort. If sustained over 20 years, the magnitude of the treatment effect observed in this study would be consistent with a predefined cost-effectiveness target of approximately $58,400 per quality-adjusted life-year, said Dr. Palace.

Patients included in this study were adults with a mean age of 38 and a mean age at disease onset of 31. Most participants (76%) were women. Mean disease duration was 7.7 years at baseline, and the patients had a mean of three relapses over the previous two years. Mean baseline EDSS score was 3.06.

The UK’s Risk-Sharing Scheme
“In 2002, the National Institute of Clinical Excellence [NICE], which is the UK body that sets the guidelines that decide [which drugs] should be available under the National Health Service [NHS], concluded that beta-interferon and glatiramer acetate were not cost-effective during the short-term, and thus it recommended that [they] couldn’t be available under the NHS at that stage,” explained Dr. Palace.

The NICE did state, however, that if the drugs’ effects were maintained over the long term, the drugs might be cost effective. The institute invited the Department of Health to “try and find a way to make the drugs available in a cost-effective manner,” said Dr. Palace. “This was the birth of the Risk-Sharing Scheme, and it is a way of providing disease-modifying therapies to patients cost effectively.”

At the start of the scheme, the drug prices were reduced according to a NICE model of cost efficacy. Prices were set at the equivalent of $58,400/quality-adjusted life-year. A price adjustment would have been required to achieve cost effectiveness if the outcomes of the treated patients had been worse than predicted. “We were allowed to reach this target over a 20-year lifespan, and the idea was to monitor a clinical cohort of patients, measuring their EDSS scores,” said Dr. Palace. The natural history dataset was used as a virtual placebo.

The investigation was the largest observational study to measure the effect and cost-effectiveness of interferon beta-1a and glatiramer acetate. The findings provide evidence that the treatment alters the natural history of relapsing-remitting MS, Dr. Palace concluded.

—Sharon Worcester

BOSTON—Long-term treatment with interferon beta-1a or glatiramer acetate has the potential to be cost effective and to alter the natural history of relapsing-remitting multiple sclerosis (MS), according to findings from a six-year observational study presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

In 4,137 patients with relapsing-remitting MS who were followed for a median of six years, the observed increase in the Expanded Disability Status Scale (EDSS) scores was lower among treated patients than the increase seen in a natural history cohort that served as a comparator group (relative rates, 0.76 using a continuous Markov model and 0.61 using a multilevel model).

Results of Treatment Exceeded Predictions
The observed progression for utility—a quality of life measure derived from the EDSS scores, and the primary outcome of the study—was consistent with this finding (relative rates of 0.58 and 0.56, according to the two models, respectively), said Jacqueline Palace, BM, Consultant Neurologist at the University of Oxford, United Kingdom.

The researchers had predicted that treatment would reduce the observed progression for utility by 38%, compared with the natural history cohort. Data, however, indicated a reduction of about 42%, which was better than predicted, added Dr. Palace. A range of sensitivity analyses that examined the potential for various biases consistently demonstrated better outcomes in the treated patients, compared with the natural history cohort. If sustained over 20 years, the magnitude of the treatment effect observed in this study would be consistent with a predefined cost-effectiveness target of approximately $58,400 per quality-adjusted life-year, said Dr. Palace.

Patients included in this study were adults with a mean age of 38 and a mean age at disease onset of 31. Most participants (76%) were women. Mean disease duration was 7.7 years at baseline, and the patients had a mean of three relapses over the previous two years. Mean baseline EDSS score was 3.06.

The UK’s Risk-Sharing Scheme
“In 2002, the National Institute of Clinical Excellence [NICE], which is the UK body that sets the guidelines that decide [which drugs] should be available under the National Health Service [NHS], concluded that beta-interferon and glatiramer acetate were not cost-effective during the short-term, and thus it recommended that [they] couldn’t be available under the NHS at that stage,” explained Dr. Palace.

The NICE did state, however, that if the drugs’ effects were maintained over the long term, the drugs might be cost effective. The institute invited the Department of Health to “try and find a way to make the drugs available in a cost-effective manner,” said Dr. Palace. “This was the birth of the Risk-Sharing Scheme, and it is a way of providing disease-modifying therapies to patients cost effectively.”

At the start of the scheme, the drug prices were reduced according to a NICE model of cost efficacy. Prices were set at the equivalent of $58,400/quality-adjusted life-year. A price adjustment would have been required to achieve cost effectiveness if the outcomes of the treated patients had been worse than predicted. “We were allowed to reach this target over a 20-year lifespan, and the idea was to monitor a clinical cohort of patients, measuring their EDSS scores,” said Dr. Palace. The natural history dataset was used as a virtual placebo.

The investigation was the largest observational study to measure the effect and cost-effectiveness of interferon beta-1a and glatiramer acetate. The findings provide evidence that the treatment alters the natural history of relapsing-remitting MS, Dr. Palace concluded.

—Sharon Worcester

BOSTON—A novel compound called fluorosamine appears to promote remyelination and reduce inflammation in animal models of experimental autoimmune encephalomyelitis (EAE), according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. Results indicate that the molecule potentially could benefit patients with multiple sclerosis (MS).

V. Wee Yong, PhD, Professor and Head of Translational Neuroscience at the University of Calgary in Canada, and colleagues initiated EAE in animals and allowed them to develop signs of disability. The investigators began treating some of the animals with fluorosamine daily and some with vehicle daily. Disease severity was reduced among animals that received fluorosamine, compared with animals that received vehicle. “If we initiate treatment with fluorosamine at peak EAE, we find that while vehicle-treated animals continue to have significant disability, treatment with fluorosamine reduces clinical severity,” said Dr. Yong.

Investigating CSPGs
The current study follows the investigators’ previous examinations of chondroitin sulfate proteoglycans (CSPGs). This class of chemicals includes versican, aggrecan, neurocan, and brevican. In 2001, Sobel and colleagues found neurocan, veriscan, and aggrecan at the edge of an active MS lesion. In other conditions such as traumatic spinal cord injury, CSPGs have been identified as inhibitors of axonal regeneration.

To determine whether CSPGs affect remyelination, Dr. Yong and colleagues investigated a model of demyelination and remyelination in which lysolecithin was injected into an animal’s spinal cord dorsal column. Within three days of demyelination, the researchers found deposition of versican V1 around cells and in acellular areas in the extracellular matrix. In a later study, Dr. Yong and colleagues found that CSPGs were cleared during the process of remyelination that followed lysolecithin-induced demyelination. The group also found that reducing the deposition of CSPGs promoted remyelination.

In 2012, Dr. Yong’s group performed in vitro stripe assays of human oligodendrocyte precursor cells (OPCs). When the human OPCs were plated onto a setup in which stripes had been coated with bovine serum albumin, the OPCs flourished in environments with and without bovine serum albumin. In contrast, OPCs sent few processes into stripes coated with CSPGs. This finding emphasizes “the nonpermissive nature of the CSPGs,” said Dr. Yong.

The Development of Fluorosamine
To reduce the production of CSPGs following injury, Dr. Yong and colleagues designed fluorosamine. They found that peracetylating fluorosamine with many acetyl groups facilitated the compound’s entry into cells. In an in vitro proof-of-concept study, the investigators activated astrocytes with TGF-β to increase their production of CSPGs. When the astrocytes were incubated with peracetylated fluorosamine, the group observed a “robust downregulation of CSPG production by activated astrocytes,” said Dr. Yong.

In an in vivo proof-of-concept study, the researchers induced demyelination in animals by injecting their spinal cords with lysolecithin. After the animals received fluorosamine treatment, the investigators observed significantly reduced expression of versican in the injured spinal cords.

When the researchers stained tissue samples for oligodendrocytes using OLIG2 and GSTπ, they found a greater number of oligodendrocytes within lesions in animals that underwent lysolecithin-induced demyelination and subsequent treatment with fluorosamine than in animals with demyelination that were untreated. In addition, animals that were treated with fluorosamine had more myelinated profiles than untreated animals. A separate study indicated that fluorosamine reduced inflammation in tissue culture by inhibiting macrophage activation.

—Erik Greb

BOSTON—A novel compound called fluorosamine appears to promote remyelination and reduce inflammation in animal models of experimental autoimmune encephalomyelitis (EAE), according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. Results indicate that the molecule potentially could benefit patients with multiple sclerosis (MS).

V. Wee Yong, PhD, Professor and Head of Translational Neuroscience at the University of Calgary in Canada, and colleagues initiated EAE in animals and allowed them to develop signs of disability. The investigators began treating some of the animals with fluorosamine daily and some with vehicle daily. Disease severity was reduced among animals that received fluorosamine, compared with animals that received vehicle. “If we initiate treatment with fluorosamine at peak EAE, we find that while vehicle-treated animals continue to have significant disability, treatment with fluorosamine reduces clinical severity,” said Dr. Yong.

Investigating CSPGs
The current study follows the investigators’ previous examinations of chondroitin sulfate proteoglycans (CSPGs). This class of chemicals includes versican, aggrecan, neurocan, and brevican. In 2001, Sobel and colleagues found neurocan, veriscan, and aggrecan at the edge of an active MS lesion. In other conditions such as traumatic spinal cord injury, CSPGs have been identified as inhibitors of axonal regeneration.

To determine whether CSPGs affect remyelination, Dr. Yong and colleagues investigated a model of demyelination and remyelination in which lysolecithin was injected into an animal’s spinal cord dorsal column. Within three days of demyelination, the researchers found deposition of versican V1 around cells and in acellular areas in the extracellular matrix. In a later study, Dr. Yong and colleagues found that CSPGs were cleared during the process of remyelination that followed lysolecithin-induced demyelination. The group also found that reducing the deposition of CSPGs promoted remyelination.

In 2012, Dr. Yong’s group performed in vitro stripe assays of human oligodendrocyte precursor cells (OPCs). When the human OPCs were plated onto a setup in which stripes had been coated with bovine serum albumin, the OPCs flourished in environments with and without bovine serum albumin. In contrast, OPCs sent few processes into stripes coated with CSPGs. This finding emphasizes “the nonpermissive nature of the CSPGs,” said Dr. Yong.

The Development of Fluorosamine
To reduce the production of CSPGs following injury, Dr. Yong and colleagues designed fluorosamine. They found that peracetylating fluorosamine with many acetyl groups facilitated the compound’s entry into cells. In an in vitro proof-of-concept study, the investigators activated astrocytes with TGF-β to increase their production of CSPGs. When the astrocytes were incubated with peracetylated fluorosamine, the group observed a “robust downregulation of CSPG production by activated astrocytes,” said Dr. Yong.

In an in vivo proof-of-concept study, the researchers induced demyelination in animals by injecting their spinal cords with lysolecithin. After the animals received fluorosamine treatment, the investigators observed significantly reduced expression of versican in the injured spinal cords.

When the researchers stained tissue samples for oligodendrocytes using OLIG2 and GSTπ, they found a greater number of oligodendrocytes within lesions in animals that underwent lysolecithin-induced demyelination and subsequent treatment with fluorosamine than in animals with demyelination that were untreated. In addition, animals that were treated with fluorosamine had more myelinated profiles than untreated animals. A separate study indicated that fluorosamine reduced inflammation in tissue culture by inhibiting macrophage activation.

—Erik Greb

BOSTON—A novel compound called fluorosamine appears to promote remyelination and reduce inflammation in animal models of experimental autoimmune encephalomyelitis (EAE), according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. Results indicate that the molecule potentially could benefit patients with multiple sclerosis (MS).

V. Wee Yong, PhD, Professor and Head of Translational Neuroscience at the University of Calgary in Canada, and colleagues initiated EAE in animals and allowed them to develop signs of disability. The investigators began treating some of the animals with fluorosamine daily and some with vehicle daily. Disease severity was reduced among animals that received fluorosamine, compared with animals that received vehicle. “If we initiate treatment with fluorosamine at peak EAE, we find that while vehicle-treated animals continue to have significant disability, treatment with fluorosamine reduces clinical severity,” said Dr. Yong.

Investigating CSPGs
The current study follows the investigators’ previous examinations of chondroitin sulfate proteoglycans (CSPGs). This class of chemicals includes versican, aggrecan, neurocan, and brevican. In 2001, Sobel and colleagues found neurocan, veriscan, and aggrecan at the edge of an active MS lesion. In other conditions such as traumatic spinal cord injury, CSPGs have been identified as inhibitors of axonal regeneration.

To determine whether CSPGs affect remyelination, Dr. Yong and colleagues investigated a model of demyelination and remyelination in which lysolecithin was injected into an animal’s spinal cord dorsal column. Within three days of demyelination, the researchers found deposition of versican V1 around cells and in acellular areas in the extracellular matrix. In a later study, Dr. Yong and colleagues found that CSPGs were cleared during the process of remyelination that followed lysolecithin-induced demyelination. The group also found that reducing the deposition of CSPGs promoted remyelination.

In 2012, Dr. Yong’s group performed in vitro stripe assays of human oligodendrocyte precursor cells (OPCs). When the human OPCs were plated onto a setup in which stripes had been coated with bovine serum albumin, the OPCs flourished in environments with and without bovine serum albumin. In contrast, OPCs sent few processes into stripes coated with CSPGs. This finding emphasizes “the nonpermissive nature of the CSPGs,” said Dr. Yong.

The Development of Fluorosamine
To reduce the production of CSPGs following injury, Dr. Yong and colleagues designed fluorosamine. They found that peracetylating fluorosamine with many acetyl groups facilitated the compound’s entry into cells. In an in vitro proof-of-concept study, the investigators activated astrocytes with TGF-β to increase their production of CSPGs. When the astrocytes were incubated with peracetylated fluorosamine, the group observed a “robust downregulation of CSPG production by activated astrocytes,” said Dr. Yong.

In an in vivo proof-of-concept study, the researchers induced demyelination in animals by injecting their spinal cords with lysolecithin. After the animals received fluorosamine treatment, the investigators observed significantly reduced expression of versican in the injured spinal cords.

When the researchers stained tissue samples for oligodendrocytes using OLIG2 and GSTπ, they found a greater number of oligodendrocytes within lesions in animals that underwent lysolecithin-induced demyelination and subsequent treatment with fluorosamine than in animals with demyelination that were untreated. In addition, animals that were treated with fluorosamine had more myelinated profiles than untreated animals. A separate study indicated that fluorosamine reduced inflammation in tissue culture by inhibiting macrophage activation.

—Erik Greb

BOSTON—In addition to John Cunningham virus (JCV) index, L-selectin level can help neurologists make treatment decisions for individuals with multiple sclerosis (MS), according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The two biomarkers can help neurologists determine which patients are at highest risk of natalizumab-associated progressive multifocal leukoencephalopathy (PML).

More than 40% of patients with MS can be considered at high risk of PML if JCV index alone is taken into account. If only L-selectin level is considered, then between 5% and 15% of patients with MS are at high risk of PML. Taking both JCV index and L-selectin level into account results in a rate of approximately 4% of patients with MS who are at high risk of PML. “That is a further stratification of patients being at risk, with all the advantages and disadvantages that biomarkers and serial assessments would have,” said Heinz Wiendl, MD, Professor of Neurology at the University of Münster in Germany.

Compared with JCV index, L-selectin may have disadvantages as a biomarker. For example, a patient’s JCV index generally is stable, but his or her L-selectin level may fluctuate. Furthermore, it is easier to measure JCV index than L-selectin level, which must be assessed in fragile peripheral blood mononucleated cells.

Yet data indicate that the two biomarkers have comparable sensitivity (98% for JCV index and 91% for L-selectin). An advantage of L-selectin is that it can provide information about all patients, while JCV index only is informative in patients who have not previously had immune suppression, said Dr. Wiendl.

L-Selectin May Indicate PML Risk in Various Disorders
In a 2013 study of patients with MS without previous immune suppression, Plavina et al concluded that individuals with a JCV index greater than 0.9 are at higher risk of developing PML. In the same year, Schwab and colleagues found that patients with MS and an L-selectin value lower than 21.6 are at higher risk of developing PML.

These findings prompted Dr. Wiendl and colleagues to ask whether L-selectin was associated only with natalizumab. They examined 10 patients with HIV who previously had developed PML and found that nine had a low L-selectin value. The group concluded that L-selectin might have a connection to the development of PML in various disorders.

L-Selectin Decreases During Natalizumab Treatment
Dr. Wiendl’s group recruited 2,300 patients with MS to further investigate JCV index and L-selectin. Approximately 55% of the patients had JCV antibodies, and this result is consistent with the literature. Approximately 41% of the cohort had a JCV index greater than 0.9 and were thus at higher risk of developing PML, said Dr. Wiendl.

In analyses of all patients and of only patients who had JCV antibodies, JCV index did not change during treatment with natalizumab. “This [finding] is rather good news for a biomarker because it’s pretty stable all the time,” said Dr. Wiendl. The investigators also found a clear correlation of JCV index with age, “which is a phenomenon that is mainly to be explained by seroconversion.”

The researchers also assessed patients’ L-selectin values. Early in the study, they found that 10 of 11 patients who later developed PML had low L-selectin values. The investigators went on to measure each patient as many as six times. After Dr. Wiendl’s group had screened approximately 800 patients, they calculated that with current protocols and cohorts, L-selectin had a specificity of approximately 89% and a sensitivity of approximately 91% for indicating risk of PML.

By examining the series of measurements for individual patients, the investigators gained additional information about both biomarkers. In one patient who previously had immune suppression and later developed PML, JCV index was low. The result indicates that JCV index is not a reliable indicator of PML risk among patients with previous immune suppression, said Dr. Wiendl.

Another patient had a normal L-selectin value that later decreased, and the patient subsequently developed PML. This patient’s JCV index was consistently high throughout all measurements. One patient with high L-selectin values and high JC index developed PML.

L-Selectin in Clinical Practice
The data indicate that a single measurement of a low L-selectin level confers a higher risk of PML. A patient’s L-selectin level will not necessarily stay low, however; it may recover. This fluctuation underscores the importance of repeated assessments, said Dr. Wiendl. L-selectin is “a dynamic marker that can change,” he added.

In addition, JCV index seems to correlate with L-selectin expression levels. Patients with high JCV index are likely to have a low L-selectin level, but the two biomarkers may not be correlated biologically, said Dr. Wiendl.

Treatment decisions are influenced by unchangeable factors, such as previous immune suppression, and dynamic biomarkers, such as treatment duration and JCV antibody seropositivity. “Then you have two additional parameters that might be helpful for individual treatment decisions: JCV index and L-selectin,” concluded Dr. Wiendl.

—Erik Greb

BOSTON—In addition to John Cunningham virus (JCV) index, L-selectin level can help neurologists make treatment decisions for individuals with multiple sclerosis (MS), according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The two biomarkers can help neurologists determine which patients are at highest risk of natalizumab-associated progressive multifocal leukoencephalopathy (PML).

More than 40% of patients with MS can be considered at high risk of PML if JCV index alone is taken into account. If only L-selectin level is considered, then between 5% and 15% of patients with MS are at high risk of PML. Taking both JCV index and L-selectin level into account results in a rate of approximately 4% of patients with MS who are at high risk of PML. “That is a further stratification of patients being at risk, with all the advantages and disadvantages that biomarkers and serial assessments would have,” said Heinz Wiendl, MD, Professor of Neurology at the University of Münster in Germany.

Compared with JCV index, L-selectin may have disadvantages as a biomarker. For example, a patient’s JCV index generally is stable, but his or her L-selectin level may fluctuate. Furthermore, it is easier to measure JCV index than L-selectin level, which must be assessed in fragile peripheral blood mononucleated cells.

Yet data indicate that the two biomarkers have comparable sensitivity (98% for JCV index and 91% for L-selectin). An advantage of L-selectin is that it can provide information about all patients, while JCV index only is informative in patients who have not previously had immune suppression, said Dr. Wiendl.

L-Selectin May Indicate PML Risk in Various Disorders
In a 2013 study of patients with MS without previous immune suppression, Plavina et al concluded that individuals with a JCV index greater than 0.9 are at higher risk of developing PML. In the same year, Schwab and colleagues found that patients with MS and an L-selectin value lower than 21.6 are at higher risk of developing PML.

These findings prompted Dr. Wiendl and colleagues to ask whether L-selectin was associated only with natalizumab. They examined 10 patients with HIV who previously had developed PML and found that nine had a low L-selectin value. The group concluded that L-selectin might have a connection to the development of PML in various disorders.

L-Selectin Decreases During Natalizumab Treatment
Dr. Wiendl’s group recruited 2,300 patients with MS to further investigate JCV index and L-selectin. Approximately 55% of the patients had JCV antibodies, and this result is consistent with the literature. Approximately 41% of the cohort had a JCV index greater than 0.9 and were thus at higher risk of developing PML, said Dr. Wiendl.

In analyses of all patients and of only patients who had JCV antibodies, JCV index did not change during treatment with natalizumab. “This [finding] is rather good news for a biomarker because it’s pretty stable all the time,” said Dr. Wiendl. The investigators also found a clear correlation of JCV index with age, “which is a phenomenon that is mainly to be explained by seroconversion.”

The researchers also assessed patients’ L-selectin values. Early in the study, they found that 10 of 11 patients who later developed PML had low L-selectin values. The investigators went on to measure each patient as many as six times. After Dr. Wiendl’s group had screened approximately 800 patients, they calculated that with current protocols and cohorts, L-selectin had a specificity of approximately 89% and a sensitivity of approximately 91% for indicating risk of PML.

By examining the series of measurements for individual patients, the investigators gained additional information about both biomarkers. In one patient who previously had immune suppression and later developed PML, JCV index was low. The result indicates that JCV index is not a reliable indicator of PML risk among patients with previous immune suppression, said Dr. Wiendl.

Another patient had a normal L-selectin value that later decreased, and the patient subsequently developed PML. This patient’s JCV index was consistently high throughout all measurements. One patient with high L-selectin values and high JC index developed PML.

L-Selectin in Clinical Practice
The data indicate that a single measurement of a low L-selectin level confers a higher risk of PML. A patient’s L-selectin level will not necessarily stay low, however; it may recover. This fluctuation underscores the importance of repeated assessments, said Dr. Wiendl. L-selectin is “a dynamic marker that can change,” he added.

In addition, JCV index seems to correlate with L-selectin expression levels. Patients with high JCV index are likely to have a low L-selectin level, but the two biomarkers may not be correlated biologically, said Dr. Wiendl.

Treatment decisions are influenced by unchangeable factors, such as previous immune suppression, and dynamic biomarkers, such as treatment duration and JCV antibody seropositivity. “Then you have two additional parameters that might be helpful for individual treatment decisions: JCV index and L-selectin,” concluded Dr. Wiendl.

—Erik Greb

BOSTON—In addition to John Cunningham virus (JCV) index, L-selectin level can help neurologists make treatment decisions for individuals with multiple sclerosis (MS), according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The two biomarkers can help neurologists determine which patients are at highest risk of natalizumab-associated progressive multifocal leukoencephalopathy (PML).

More than 40% of patients with MS can be considered at high risk of PML if JCV index alone is taken into account. If only L-selectin level is considered, then between 5% and 15% of patients with MS are at high risk of PML. Taking both JCV index and L-selectin level into account results in a rate of approximately 4% of patients with MS who are at high risk of PML. “That is a further stratification of patients being at risk, with all the advantages and disadvantages that biomarkers and serial assessments would have,” said Heinz Wiendl, MD, Professor of Neurology at the University of Münster in Germany.

Compared with JCV index, L-selectin may have disadvantages as a biomarker. For example, a patient’s JCV index generally is stable, but his or her L-selectin level may fluctuate. Furthermore, it is easier to measure JCV index than L-selectin level, which must be assessed in fragile peripheral blood mononucleated cells.

Yet data indicate that the two biomarkers have comparable sensitivity (98% for JCV index and 91% for L-selectin). An advantage of L-selectin is that it can provide information about all patients, while JCV index only is informative in patients who have not previously had immune suppression, said Dr. Wiendl.

L-Selectin May Indicate PML Risk in Various Disorders
In a 2013 study of patients with MS without previous immune suppression, Plavina et al concluded that individuals with a JCV index greater than 0.9 are at higher risk of developing PML. In the same year, Schwab and colleagues found that patients with MS and an L-selectin value lower than 21.6 are at higher risk of developing PML.

These findings prompted Dr. Wiendl and colleagues to ask whether L-selectin was associated only with natalizumab. They examined 10 patients with HIV who previously had developed PML and found that nine had a low L-selectin value. The group concluded that L-selectin might have a connection to the development of PML in various disorders.

L-Selectin Decreases During Natalizumab Treatment
Dr. Wiendl’s group recruited 2,300 patients with MS to further investigate JCV index and L-selectin. Approximately 55% of the patients had JCV antibodies, and this result is consistent with the literature. Approximately 41% of the cohort had a JCV index greater than 0.9 and were thus at higher risk of developing PML, said Dr. Wiendl.

In analyses of all patients and of only patients who had JCV antibodies, JCV index did not change during treatment with natalizumab. “This [finding] is rather good news for a biomarker because it’s pretty stable all the time,” said Dr. Wiendl. The investigators also found a clear correlation of JCV index with age, “which is a phenomenon that is mainly to be explained by seroconversion.”

The researchers also assessed patients’ L-selectin values. Early in the study, they found that 10 of 11 patients who later developed PML had low L-selectin values. The investigators went on to measure each patient as many as six times. After Dr. Wiendl’s group had screened approximately 800 patients, they calculated that with current protocols and cohorts, L-selectin had a specificity of approximately 89% and a sensitivity of approximately 91% for indicating risk of PML.

By examining the series of measurements for individual patients, the investigators gained additional information about both biomarkers. In one patient who previously had immune suppression and later developed PML, JCV index was low. The result indicates that JCV index is not a reliable indicator of PML risk among patients with previous immune suppression, said Dr. Wiendl.

Another patient had a normal L-selectin value that later decreased, and the patient subsequently developed PML. This patient’s JCV index was consistently high throughout all measurements. One patient with high L-selectin values and high JC index developed PML.

L-Selectin in Clinical Practice
The data indicate that a single measurement of a low L-selectin level confers a higher risk of PML. A patient’s L-selectin level will not necessarily stay low, however; it may recover. This fluctuation underscores the importance of repeated assessments, said Dr. Wiendl. L-selectin is “a dynamic marker that can change,” he added.

In addition, JCV index seems to correlate with L-selectin expression levels. Patients with high JCV index are likely to have a low L-selectin level, but the two biomarkers may not be correlated biologically, said Dr. Wiendl.

Treatment decisions are influenced by unchangeable factors, such as previous immune suppression, and dynamic biomarkers, such as treatment duration and JCV antibody seropositivity. “Then you have two additional parameters that might be helpful for individual treatment decisions: JCV index and L-selectin,” concluded Dr. Wiendl.

—Erik Greb