Multiple Sclerosis

NEW ORLEANS—Laquinimod, an oral, CNS-active therapy for multiple sclerosis (MS), significantly slows disability progression and brain atrophy, compared with placebo, according to research presented at the 64th Annual Meeting of the American Academy of Neurology. The drug’s safety profile suggests that “it may have an important role in the long-term management of MS,” said Timothy Vollmer, MD, Professor of Neurology and Director of Clinical Research at the University of Colorado School of Medicine in Aurora.

Laquinimod reduced the probability of three-month sustained disability by 34% with a hazard ratio of 0.658 and a highly significant P value. “From an exploratory standpoint, if you extend this definition to a six-month sustained disability progression, you get an even larger effect of 46%, again with a significant P value and a hazard ratio of 0.54,” said Dr. Vollmer.

After 24 months, laquinimod reduced the rate of cerebral atrophy by 30%, compared with placebo. “This effect was actually visible at month 12 and was already statistically significant,” observed Dr. Vollmer.

“This effect on disability seems somewhat out of proportion to what we would expect, based on the reduction of the inflammatory phase of the disease,” he continued. After 24 months, patients on laquinimod had a 21% lower annualized relapse rate than patients on placebo. At months 12 and 24, the researchers observed a 30% reduction in the number of gadolinium-enhancing lesions and a 24% reduction in new T2 lesions. These three results were highly statistically significant, but their effects were “modest,” said Dr. Vollmer.

Pooled Analyses of Two Trials
Dr. Vollmer and his colleagues performed pooled analyses of data from the Safety and Efficacy of Orally Administered Laquinimod Versus Placebo for Treatment of Relapsing Remitting Multiple Sclerosis (ALLEGRO) and Laquinimod Double Blind Placebo Controlled Study in RRMS Patients With a Rater Blinded Reference Arm of Interferon b-1a (BRAVO) phase III trials to assess the effect of laquinimod on relapse, disability, and brain atrophy in patients with MS. The ALLEGRO trial was a randomized, double-blinded, placebo-controlled study comparing 0.6 mg of laquinimod to placebo in patients with relapsing MS. The BRAVO trial was a randomized study that compared the same dose of laquinimod and placebo, but included an open-label comparator arm that was analyzed using a rater-blinded method. The two trials had similar study designs and shared the same primary outcome, secondary outcome, and exploratory end point.

The two patient data sets included almost 2,000 patients, approximately 50% of whom were randomized to laquinimod. About 21% of patients in the placebo arm ultimately were excluded from analysis, and 19% of patients in the laquinimod arm were excluded from analysis, mostly because of withdrawal of consent or failure to reconsent. Approximately 6.4% of the laquinimod group withdrew because of adverse events (primarily gastrointestinal side effects and abdominal pain), compared with 4.7% of the placebo group. About 80% of patients in both groups completed the protocol.

Trials Show Laquinimod’sPositive Safety Profile
Laquinimod was well tolerated among patients in the ALLEGRO and BRAVO trials. Approximately 9% of laquinimod and placebo patients reported experiencing serious adverse events. Six patients receiving laquinimod experienced appendicitis, the most commonly reported serious adverse event, compared with one patient on placebo. Three patients on laquinimod experienced malignant breast neoplasms, compared with one patient on placebo.

Overall, nearly 82% of patients receiving laquinimod experienced adverse events, compared with 76% of patients receiving placebo. Compared with control patients, those receiving laquinimod experienced higher rates of headache (15.1% vs 18.2%), back pain (8.2% vs 13.6%), arthralgia (6.0% vs 7.2%), increased liver enzymes (2.7% vs 5.9%), urinary tract infection (4.2% vs 5.7%), cough (3.1% vs 5.2%), and abdominal pain (2.6% vs 5.0%).

“Laquinimod’s toxicity-related liver function was very mild—0.7% of patients on laquinimod had elevated liver transaminase, compared with 0.4% of placebo,” Dr. Vollmer noted. “In all cases, they were mild elevations and resolved despite patients staying on therapy,” he added.  

NEW ORLEANS—Laquinimod, an oral, CNS-active therapy for multiple sclerosis (MS), significantly slows disability progression and brain atrophy, compared with placebo, according to research presented at the 64th Annual Meeting of the American Academy of Neurology. The drug’s safety profile suggests that “it may have an important role in the long-term management of MS,” said Timothy Vollmer, MD, Professor of Neurology and Director of Clinical Research at the University of Colorado School of Medicine in Aurora.

Laquinimod reduced the probability of three-month sustained disability by 34% with a hazard ratio of 0.658 and a highly significant P value. “From an exploratory standpoint, if you extend this definition to a six-month sustained disability progression, you get an even larger effect of 46%, again with a significant P value and a hazard ratio of 0.54,” said Dr. Vollmer.

After 24 months, laquinimod reduced the rate of cerebral atrophy by 30%, compared with placebo. “This effect was actually visible at month 12 and was already statistically significant,” observed Dr. Vollmer.

“This effect on disability seems somewhat out of proportion to what we would expect, based on the reduction of the inflammatory phase of the disease,” he continued. After 24 months, patients on laquinimod had a 21% lower annualized relapse rate than patients on placebo. At months 12 and 24, the researchers observed a 30% reduction in the number of gadolinium-enhancing lesions and a 24% reduction in new T2 lesions. These three results were highly statistically significant, but their effects were “modest,” said Dr. Vollmer.

Pooled Analyses of Two Trials
Dr. Vollmer and his colleagues performed pooled analyses of data from the Safety and Efficacy of Orally Administered Laquinimod Versus Placebo for Treatment of Relapsing Remitting Multiple Sclerosis (ALLEGRO) and Laquinimod Double Blind Placebo Controlled Study in RRMS Patients With a Rater Blinded Reference Arm of Interferon b-1a (BRAVO) phase III trials to assess the effect of laquinimod on relapse, disability, and brain atrophy in patients with MS. The ALLEGRO trial was a randomized, double-blinded, placebo-controlled study comparing 0.6 mg of laquinimod to placebo in patients with relapsing MS. The BRAVO trial was a randomized study that compared the same dose of laquinimod and placebo, but included an open-label comparator arm that was analyzed using a rater-blinded method. The two trials had similar study designs and shared the same primary outcome, secondary outcome, and exploratory end point.

The two patient data sets included almost 2,000 patients, approximately 50% of whom were randomized to laquinimod. About 21% of patients in the placebo arm ultimately were excluded from analysis, and 19% of patients in the laquinimod arm were excluded from analysis, mostly because of withdrawal of consent or failure to reconsent. Approximately 6.4% of the laquinimod group withdrew because of adverse events (primarily gastrointestinal side effects and abdominal pain), compared with 4.7% of the placebo group. About 80% of patients in both groups completed the protocol.

Trials Show Laquinimod’sPositive Safety Profile
Laquinimod was well tolerated among patients in the ALLEGRO and BRAVO trials. Approximately 9% of laquinimod and placebo patients reported experiencing serious adverse events. Six patients receiving laquinimod experienced appendicitis, the most commonly reported serious adverse event, compared with one patient on placebo. Three patients on laquinimod experienced malignant breast neoplasms, compared with one patient on placebo.

Overall, nearly 82% of patients receiving laquinimod experienced adverse events, compared with 76% of patients receiving placebo. Compared with control patients, those receiving laquinimod experienced higher rates of headache (15.1% vs 18.2%), back pain (8.2% vs 13.6%), arthralgia (6.0% vs 7.2%), increased liver enzymes (2.7% vs 5.9%), urinary tract infection (4.2% vs 5.7%), cough (3.1% vs 5.2%), and abdominal pain (2.6% vs 5.0%).

“Laquinimod’s toxicity-related liver function was very mild—0.7% of patients on laquinimod had elevated liver transaminase, compared with 0.4% of placebo,” Dr. Vollmer noted. “In all cases, they were mild elevations and resolved despite patients staying on therapy,” he added.  

NEW ORLEANS—Laquinimod, an oral, CNS-active therapy for multiple sclerosis (MS), significantly slows disability progression and brain atrophy, compared with placebo, according to research presented at the 64th Annual Meeting of the American Academy of Neurology. The drug’s safety profile suggests that “it may have an important role in the long-term management of MS,” said Timothy Vollmer, MD, Professor of Neurology and Director of Clinical Research at the University of Colorado School of Medicine in Aurora.

Laquinimod reduced the probability of three-month sustained disability by 34% with a hazard ratio of 0.658 and a highly significant P value. “From an exploratory standpoint, if you extend this definition to a six-month sustained disability progression, you get an even larger effect of 46%, again with a significant P value and a hazard ratio of 0.54,” said Dr. Vollmer.

After 24 months, laquinimod reduced the rate of cerebral atrophy by 30%, compared with placebo. “This effect was actually visible at month 12 and was already statistically significant,” observed Dr. Vollmer.

“This effect on disability seems somewhat out of proportion to what we would expect, based on the reduction of the inflammatory phase of the disease,” he continued. After 24 months, patients on laquinimod had a 21% lower annualized relapse rate than patients on placebo. At months 12 and 24, the researchers observed a 30% reduction in the number of gadolinium-enhancing lesions and a 24% reduction in new T2 lesions. These three results were highly statistically significant, but their effects were “modest,” said Dr. Vollmer.

Pooled Analyses of Two Trials
Dr. Vollmer and his colleagues performed pooled analyses of data from the Safety and Efficacy of Orally Administered Laquinimod Versus Placebo for Treatment of Relapsing Remitting Multiple Sclerosis (ALLEGRO) and Laquinimod Double Blind Placebo Controlled Study in RRMS Patients With a Rater Blinded Reference Arm of Interferon b-1a (BRAVO) phase III trials to assess the effect of laquinimod on relapse, disability, and brain atrophy in patients with MS. The ALLEGRO trial was a randomized, double-blinded, placebo-controlled study comparing 0.6 mg of laquinimod to placebo in patients with relapsing MS. The BRAVO trial was a randomized study that compared the same dose of laquinimod and placebo, but included an open-label comparator arm that was analyzed using a rater-blinded method. The two trials had similar study designs and shared the same primary outcome, secondary outcome, and exploratory end point.

The two patient data sets included almost 2,000 patients, approximately 50% of whom were randomized to laquinimod. About 21% of patients in the placebo arm ultimately were excluded from analysis, and 19% of patients in the laquinimod arm were excluded from analysis, mostly because of withdrawal of consent or failure to reconsent. Approximately 6.4% of the laquinimod group withdrew because of adverse events (primarily gastrointestinal side effects and abdominal pain), compared with 4.7% of the placebo group. About 80% of patients in both groups completed the protocol.

Trials Show Laquinimod’sPositive Safety Profile
Laquinimod was well tolerated among patients in the ALLEGRO and BRAVO trials. Approximately 9% of laquinimod and placebo patients reported experiencing serious adverse events. Six patients receiving laquinimod experienced appendicitis, the most commonly reported serious adverse event, compared with one patient on placebo. Three patients on laquinimod experienced malignant breast neoplasms, compared with one patient on placebo.

Overall, nearly 82% of patients receiving laquinimod experienced adverse events, compared with 76% of patients receiving placebo. Compared with control patients, those receiving laquinimod experienced higher rates of headache (15.1% vs 18.2%), back pain (8.2% vs 13.6%), arthralgia (6.0% vs 7.2%), increased liver enzymes (2.7% vs 5.9%), urinary tract infection (4.2% vs 5.7%), cough (3.1% vs 5.2%), and abdominal pain (2.6% vs 5.0%).

“Laquinimod’s toxicity-related liver function was very mild—0.7% of patients on laquinimod had elevated liver transaminase, compared with 0.4% of placebo,” Dr. Vollmer noted. “In all cases, they were mild elevations and resolved despite patients staying on therapy,” he added.  

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To read the accompanying article, please click here.

SAN DIEGO – Metronidazole-induced encephalopathy should be considered when patients on the antibiotic are worked up for suspected multiple sclerosis, according to a case study and literature review from researchers at the Mount Sinai School of Medicine in New York.

A Crohn’s disease patient in his mid-30s who had been on metronidazole for almost 7 years presented there with a years-long diagnosis of multiple sclerosis, but MS wasn’t his problem. Doctors at the center figured out he had metronidazole-induced encephalopathy (MIE).

He had been started on 500 mg three times daily for a few months in early 2004, and then restarted on the same regimen in mid-2005. His first neurologic attack – primarily gait ataxia and dysarthria, along with nonenhancing T2 hyperintensities on MRI – came about a month later. Nonetheless, he remained on 250 mg twice daily to 500 mg three times daily until early 2011, and suffered several more attacks, notably after dosage increases. His cumulative metronidazole dose was 2,133.5 g.

Forty-one days after the patient stopped taking metronidazole, his ataxia and dysarthria were almost completely resolved; 7 months later, he was almost clear on brain MRI, with only small residua. His sole remaining complaints were poor memory, attention, and motivation.

"Neurologists should be alert to the possibility of metronidazole-induced encephalopathy in the differential diagnosis of demyelinating disease, especially in view of its potential reversibility," said lead investigator Dr. Corey McGraw, a neurologist at the school’s Corinne Goldsmith Dickinson Center for Multiple Sclerosis.

It’s widely known that metronidazole can cause peripheral neuropathy, but it is much less known that it can also cause toxic encephalopathy that mimics demyelination, he said at the Fourth Cooperative Meeting on Multiple Sclerosis.

"This is an under-recognized neurologic disease among American neurologists. Most of the [63 reported] cases have been in Korea and India, where it may be more recognized. I and my much-more-senior colleagues had never heard of metronidazole-induced encephalopathy before this case. Neurologists are probably missing it," Dr. McGraw said.

The giveaway in the Crohn’s patient’s case was that he had the same signs and symptoms with each attack, whereas MS tends to migrate around the body.

In many ways, he was a typical MIE patient.

Of the 63 cases reviewed by Dr. McGraw, 44 (70%) had MRI T2 hyperintensities of the cerebellar dentate nuclei that were the same as those found in the Crohn’s disease patient, and 19 (30%) had T2 hyperintensities of the corpus callosum splenium. Those and other MIE findings are "classic for a toxic encephalopathy," he said at the meeting, which was sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Dysarthria and gait ataxia are common, too, as well as problems with mentation, arm coordination, leg strength, and seizures.

The cumulative mean metronidazole dose in the 63 cases was 106.1 g (range, 3-1,095 g). The mean time from first dose to first neurologic attack was 67 days (range, 2-730 days). Symptoms resolved in anywhere from 1 to 420 days after metronidazole was stopped.

The "wide ranges in time to clinical manifestations and total cumulative doses may obscure the appropriate diagnosis," Dr. McGraw noted.

Dr. McGraw said that he had no relevant disclosures.

SAN DIEGO – Metronidazole-induced encephalopathy should be considered when patients on the antibiotic are worked up for suspected multiple sclerosis, according to a case study and literature review from researchers at the Mount Sinai School of Medicine in New York.

A Crohn’s disease patient in his mid-30s who had been on metronidazole for almost 7 years presented there with a years-long diagnosis of multiple sclerosis, but MS wasn’t his problem. Doctors at the center figured out he had metronidazole-induced encephalopathy (MIE).

He had been started on 500 mg three times daily for a few months in early 2004, and then restarted on the same regimen in mid-2005. His first neurologic attack – primarily gait ataxia and dysarthria, along with nonenhancing T2 hyperintensities on MRI – came about a month later. Nonetheless, he remained on 250 mg twice daily to 500 mg three times daily until early 2011, and suffered several more attacks, notably after dosage increases. His cumulative metronidazole dose was 2,133.5 g.

Forty-one days after the patient stopped taking metronidazole, his ataxia and dysarthria were almost completely resolved; 7 months later, he was almost clear on brain MRI, with only small residua. His sole remaining complaints were poor memory, attention, and motivation.

"Neurologists should be alert to the possibility of metronidazole-induced encephalopathy in the differential diagnosis of demyelinating disease, especially in view of its potential reversibility," said lead investigator Dr. Corey McGraw, a neurologist at the school’s Corinne Goldsmith Dickinson Center for Multiple Sclerosis.

It’s widely known that metronidazole can cause peripheral neuropathy, but it is much less known that it can also cause toxic encephalopathy that mimics demyelination, he said at the Fourth Cooperative Meeting on Multiple Sclerosis.

"This is an under-recognized neurologic disease among American neurologists. Most of the [63 reported] cases have been in Korea and India, where it may be more recognized. I and my much-more-senior colleagues had never heard of metronidazole-induced encephalopathy before this case. Neurologists are probably missing it," Dr. McGraw said.

The giveaway in the Crohn’s patient’s case was that he had the same signs and symptoms with each attack, whereas MS tends to migrate around the body.

In many ways, he was a typical MIE patient.

Of the 63 cases reviewed by Dr. McGraw, 44 (70%) had MRI T2 hyperintensities of the cerebellar dentate nuclei that were the same as those found in the Crohn’s disease patient, and 19 (30%) had T2 hyperintensities of the corpus callosum splenium. Those and other MIE findings are "classic for a toxic encephalopathy," he said at the meeting, which was sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Dysarthria and gait ataxia are common, too, as well as problems with mentation, arm coordination, leg strength, and seizures.

The cumulative mean metronidazole dose in the 63 cases was 106.1 g (range, 3-1,095 g). The mean time from first dose to first neurologic attack was 67 days (range, 2-730 days). Symptoms resolved in anywhere from 1 to 420 days after metronidazole was stopped.

The "wide ranges in time to clinical manifestations and total cumulative doses may obscure the appropriate diagnosis," Dr. McGraw noted.

Dr. McGraw said that he had no relevant disclosures.

SAN DIEGO – Metronidazole-induced encephalopathy should be considered when patients on the antibiotic are worked up for suspected multiple sclerosis, according to a case study and literature review from researchers at the Mount Sinai School of Medicine in New York.

A Crohn’s disease patient in his mid-30s who had been on metronidazole for almost 7 years presented there with a years-long diagnosis of multiple sclerosis, but MS wasn’t his problem. Doctors at the center figured out he had metronidazole-induced encephalopathy (MIE).

He had been started on 500 mg three times daily for a few months in early 2004, and then restarted on the same regimen in mid-2005. His first neurologic attack – primarily gait ataxia and dysarthria, along with nonenhancing T2 hyperintensities on MRI – came about a month later. Nonetheless, he remained on 250 mg twice daily to 500 mg three times daily until early 2011, and suffered several more attacks, notably after dosage increases. His cumulative metronidazole dose was 2,133.5 g.

Forty-one days after the patient stopped taking metronidazole, his ataxia and dysarthria were almost completely resolved; 7 months later, he was almost clear on brain MRI, with only small residua. His sole remaining complaints were poor memory, attention, and motivation.

"Neurologists should be alert to the possibility of metronidazole-induced encephalopathy in the differential diagnosis of demyelinating disease, especially in view of its potential reversibility," said lead investigator Dr. Corey McGraw, a neurologist at the school’s Corinne Goldsmith Dickinson Center for Multiple Sclerosis.

It’s widely known that metronidazole can cause peripheral neuropathy, but it is much less known that it can also cause toxic encephalopathy that mimics demyelination, he said at the Fourth Cooperative Meeting on Multiple Sclerosis.

"This is an under-recognized neurologic disease among American neurologists. Most of the [63 reported] cases have been in Korea and India, where it may be more recognized. I and my much-more-senior colleagues had never heard of metronidazole-induced encephalopathy before this case. Neurologists are probably missing it," Dr. McGraw said.

The giveaway in the Crohn’s patient’s case was that he had the same signs and symptoms with each attack, whereas MS tends to migrate around the body.

In many ways, he was a typical MIE patient.

Of the 63 cases reviewed by Dr. McGraw, 44 (70%) had MRI T2 hyperintensities of the cerebellar dentate nuclei that were the same as those found in the Crohn’s disease patient, and 19 (30%) had T2 hyperintensities of the corpus callosum splenium. Those and other MIE findings are "classic for a toxic encephalopathy," he said at the meeting, which was sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Dysarthria and gait ataxia are common, too, as well as problems with mentation, arm coordination, leg strength, and seizures.

The cumulative mean metronidazole dose in the 63 cases was 106.1 g (range, 3-1,095 g). The mean time from first dose to first neurologic attack was 67 days (range, 2-730 days). Symptoms resolved in anywhere from 1 to 420 days after metronidazole was stopped.

The "wide ranges in time to clinical manifestations and total cumulative doses may obscure the appropriate diagnosis," Dr. McGraw noted.

Dr. McGraw said that he had no relevant disclosures.

SAN DIEGO – Tetrahydrocannabinol, the main active ingredient in marijuana, did not slow the progression of multiple sclerosis in a 3-year, randomized trial of 493 British patients with primary or secondary progressive forms of the disease.

Some patients with lower baseline EDSS (Expanded Disability Status Scale) scores appeared to have delayed progression, but the trial did not have enough statistical power to allow comparison of subgroups.

©ron hilton/iStockphoto.com

In the Cannabinoid Use in Progressive Inflammatory Brain Disease (CUPID) trial, investigators randomized 329 patients to 14-28 mg of tetrahydrocannabinol (THC)/day in capsule form based on weight, and 164 to placebo. Their mean baseline EDSS score was about 5.8 (range, 4.0-6.5). Patients were, on average, 52 years old; and about 60% were women.

None were on disease-modifying therapies, but most were on pain relievers and other medications for symptom relief. The patients agreed to otherwise abstain from marijuana during the study.

Compared with placebo, the hazard ratio for EDSS progression in the THC group – defined as a 1-point increase for patients starting at or below 5, and a half-point increase for those starting above – was 0.92 (95% CI, 0.68-1.23) after adjustment for disease type, age, and other variables.

There were no statistical differences in brain volume loss on MRI, Multiple Sclerosis Impact Scale scores, and several secondary outcomes, including the 25-foot timed walk and 9-hole peg tests.

On post hoc analysis, there was a hint of delayed progression in patients with baseline EDSS scores below 6; 26 (76%) of 34 placebo patients in that group progressed, compared with only 44 (58%) of 76 in the THC group.

"The lower EDSS scores do seem to suggest a treatment effect, but we did not have much power to detect that effect. I do think that there are probably going to be subgroups that do respond more than others," said lead investigator Dr. John Zajicek, a professor of clinical neuroscience at Plymouth (England) University.

Overall, he called the results "disappointing." Although "there is sufficient evidence to use cannabinoids" for relieving muscle stiffness, spasticity, pain, urinary disturbances, and other MS symptoms, it could be that THC simply does not slow progression in primary or secondary progressive MS. No drug has yet been proven to do so, Dr. Zajicek said at the Fourth Cooperative Meeting on Multiple Sclerosis.

The results might also have been obscured because there was very little progression in either the THC or placebo groups. "We were expecting 70% progression, but we got just over 40%, so most of the outcome measures did not change very much over 3 years. It’s very difficult to find a treatment effect when your outcome measures aren’t changing," he said.

About 60% of the THC patients complained of dizziness or lightheadedness, and 51% of thought or perception changes, both far more common than in the placebo group, but fewer THC patients reported musculoskeletal pain (26% vs. 37% in the placebo group) and fewer developed urinary tract infections (26% vs. 35%).

The meeting was sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis. Dr. Zajicek said he had no relevant disclosures.

SAN DIEGO – Tetrahydrocannabinol, the main active ingredient in marijuana, did not slow the progression of multiple sclerosis in a 3-year, randomized trial of 493 British patients with primary or secondary progressive forms of the disease.

Some patients with lower baseline EDSS (Expanded Disability Status Scale) scores appeared to have delayed progression, but the trial did not have enough statistical power to allow comparison of subgroups.

©ron hilton/iStockphoto.com

In the Cannabinoid Use in Progressive Inflammatory Brain Disease (CUPID) trial, investigators randomized 329 patients to 14-28 mg of tetrahydrocannabinol (THC)/day in capsule form based on weight, and 164 to placebo. Their mean baseline EDSS score was about 5.8 (range, 4.0-6.5). Patients were, on average, 52 years old; and about 60% were women.

None were on disease-modifying therapies, but most were on pain relievers and other medications for symptom relief. The patients agreed to otherwise abstain from marijuana during the study.

Compared with placebo, the hazard ratio for EDSS progression in the THC group – defined as a 1-point increase for patients starting at or below 5, and a half-point increase for those starting above – was 0.92 (95% CI, 0.68-1.23) after adjustment for disease type, age, and other variables.

There were no statistical differences in brain volume loss on MRI, Multiple Sclerosis Impact Scale scores, and several secondary outcomes, including the 25-foot timed walk and 9-hole peg tests.

On post hoc analysis, there was a hint of delayed progression in patients with baseline EDSS scores below 6; 26 (76%) of 34 placebo patients in that group progressed, compared with only 44 (58%) of 76 in the THC group.

"The lower EDSS scores do seem to suggest a treatment effect, but we did not have much power to detect that effect. I do think that there are probably going to be subgroups that do respond more than others," said lead investigator Dr. John Zajicek, a professor of clinical neuroscience at Plymouth (England) University.

Overall, he called the results "disappointing." Although "there is sufficient evidence to use cannabinoids" for relieving muscle stiffness, spasticity, pain, urinary disturbances, and other MS symptoms, it could be that THC simply does not slow progression in primary or secondary progressive MS. No drug has yet been proven to do so, Dr. Zajicek said at the Fourth Cooperative Meeting on Multiple Sclerosis.

The results might also have been obscured because there was very little progression in either the THC or placebo groups. "We were expecting 70% progression, but we got just over 40%, so most of the outcome measures did not change very much over 3 years. It’s very difficult to find a treatment effect when your outcome measures aren’t changing," he said.

About 60% of the THC patients complained of dizziness or lightheadedness, and 51% of thought or perception changes, both far more common than in the placebo group, but fewer THC patients reported musculoskeletal pain (26% vs. 37% in the placebo group) and fewer developed urinary tract infections (26% vs. 35%).

The meeting was sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis. Dr. Zajicek said he had no relevant disclosures.

SAN DIEGO – Tetrahydrocannabinol, the main active ingredient in marijuana, did not slow the progression of multiple sclerosis in a 3-year, randomized trial of 493 British patients with primary or secondary progressive forms of the disease.

Some patients with lower baseline EDSS (Expanded Disability Status Scale) scores appeared to have delayed progression, but the trial did not have enough statistical power to allow comparison of subgroups.

©ron hilton/iStockphoto.com

In the Cannabinoid Use in Progressive Inflammatory Brain Disease (CUPID) trial, investigators randomized 329 patients to 14-28 mg of tetrahydrocannabinol (THC)/day in capsule form based on weight, and 164 to placebo. Their mean baseline EDSS score was about 5.8 (range, 4.0-6.5). Patients were, on average, 52 years old; and about 60% were women.

None were on disease-modifying therapies, but most were on pain relievers and other medications for symptom relief. The patients agreed to otherwise abstain from marijuana during the study.

Compared with placebo, the hazard ratio for EDSS progression in the THC group – defined as a 1-point increase for patients starting at or below 5, and a half-point increase for those starting above – was 0.92 (95% CI, 0.68-1.23) after adjustment for disease type, age, and other variables.

There were no statistical differences in brain volume loss on MRI, Multiple Sclerosis Impact Scale scores, and several secondary outcomes, including the 25-foot timed walk and 9-hole peg tests.

On post hoc analysis, there was a hint of delayed progression in patients with baseline EDSS scores below 6; 26 (76%) of 34 placebo patients in that group progressed, compared with only 44 (58%) of 76 in the THC group.

"The lower EDSS scores do seem to suggest a treatment effect, but we did not have much power to detect that effect. I do think that there are probably going to be subgroups that do respond more than others," said lead investigator Dr. John Zajicek, a professor of clinical neuroscience at Plymouth (England) University.

Overall, he called the results "disappointing." Although "there is sufficient evidence to use cannabinoids" for relieving muscle stiffness, spasticity, pain, urinary disturbances, and other MS symptoms, it could be that THC simply does not slow progression in primary or secondary progressive MS. No drug has yet been proven to do so, Dr. Zajicek said at the Fourth Cooperative Meeting on Multiple Sclerosis.

The results might also have been obscured because there was very little progression in either the THC or placebo groups. "We were expecting 70% progression, but we got just over 40%, so most of the outcome measures did not change very much over 3 years. It’s very difficult to find a treatment effect when your outcome measures aren’t changing," he said.

About 60% of the THC patients complained of dizziness or lightheadedness, and 51% of thought or perception changes, both far more common than in the placebo group, but fewer THC patients reported musculoskeletal pain (26% vs. 37% in the placebo group) and fewer developed urinary tract infections (26% vs. 35%).

The meeting was sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis. Dr. Zajicek said he had no relevant disclosures.

NATIONAL HARBOR, MD. – Percutaneous balloon angioplasty improved flow dynamics in multiple sclerosis patients with chronic cerebrospinal venous insufficiency in a pilot study.

An association has been made recently between multiple sclerosis and chronic cerebrospinal venous insufficiency (CCSVI) that is characterized by stenosis and reflux of the principal extracranial venous drainage, including the internal jugular veins and the azygous veins. But there has been considerable debate about the validity of percutaneous balloon angioplasty in the treatment of this stenosis.

Dr. Manish Mehta of Albany (N.Y.) Medical College and his colleagues conducted the first angiographic study to quantitatively analyze the impact of percutaneous balloon angioplasty on flow dynamics across these lesions. Dr. Mehta shared their results at the Vascular Annual Meeting.

The researchers assessed 50 internal jugular veins (IJVs) from MS patients with CCSVI, as well as 12 IJVs from healthy volunteers, all of whom underwent detailed angiographic evaluation. The technical components of all venograms were standardized.

Quantitative analysis included the contrast time of flight from the mid-IJV to the superior vena cava, and the primary venous emptying time (PVET), quantified as greater than 50% of venous emptying from the IJV. The time of flight and PVET were recorded in patients with CCSVI prior to and subsequent to balloon angioplasty. The same data were recorded in the healthy controls. All data were collected prospectively, and statistical analysis was performed using two-tailed Student’s test.

Of the 50 CCSVI-MS patients who had IJV stenosis greater than 70% and reflux and who underwent balloon angioplasty, technical success (defined as less than 20% residual IJV stenosis) was achieved in 44 (78%). CCSVI patients were observed to have a significant improvement in both the time of flight and PVET following balloon angioplasty that paralleled those of healthy subjects without MS.

"The results of this prospective pilot study suggest an association between MS and CCSVI, which results in abnormally elevated time of flight and PVET through the IJV," Dr. Mehta said. "Furthermore, balloon angioplasty of these lesions improves the hemodynamic parameters so that they are comparable to" those of healthy non-MS patients."

Dr. Mehta stressed the need for randomized studies to further investigate this issue and said that this patient population is at high risk for a placebo effect with regard to their reported symptoms. He also stated that this treatment is being provided to many patients around the world and that the U.S. Food and Drug Administration has cautioned against its use outside of well-regulated trials due to lack of safety and efficacy data.

Dr. Mehta reported that he had nothing to disclose.

NATIONAL HARBOR, MD. – Percutaneous balloon angioplasty improved flow dynamics in multiple sclerosis patients with chronic cerebrospinal venous insufficiency in a pilot study.

An association has been made recently between multiple sclerosis and chronic cerebrospinal venous insufficiency (CCSVI) that is characterized by stenosis and reflux of the principal extracranial venous drainage, including the internal jugular veins and the azygous veins. But there has been considerable debate about the validity of percutaneous balloon angioplasty in the treatment of this stenosis.

Dr. Manish Mehta of Albany (N.Y.) Medical College and his colleagues conducted the first angiographic study to quantitatively analyze the impact of percutaneous balloon angioplasty on flow dynamics across these lesions. Dr. Mehta shared their results at the Vascular Annual Meeting.

The researchers assessed 50 internal jugular veins (IJVs) from MS patients with CCSVI, as well as 12 IJVs from healthy volunteers, all of whom underwent detailed angiographic evaluation. The technical components of all venograms were standardized.

Quantitative analysis included the contrast time of flight from the mid-IJV to the superior vena cava, and the primary venous emptying time (PVET), quantified as greater than 50% of venous emptying from the IJV. The time of flight and PVET were recorded in patients with CCSVI prior to and subsequent to balloon angioplasty. The same data were recorded in the healthy controls. All data were collected prospectively, and statistical analysis was performed using two-tailed Student’s test.

Of the 50 CCSVI-MS patients who had IJV stenosis greater than 70% and reflux and who underwent balloon angioplasty, technical success (defined as less than 20% residual IJV stenosis) was achieved in 44 (78%). CCSVI patients were observed to have a significant improvement in both the time of flight and PVET following balloon angioplasty that paralleled those of healthy subjects without MS.

"The results of this prospective pilot study suggest an association between MS and CCSVI, which results in abnormally elevated time of flight and PVET through the IJV," Dr. Mehta said. "Furthermore, balloon angioplasty of these lesions improves the hemodynamic parameters so that they are comparable to" those of healthy non-MS patients."

Dr. Mehta stressed the need for randomized studies to further investigate this issue and said that this patient population is at high risk for a placebo effect with regard to their reported symptoms. He also stated that this treatment is being provided to many patients around the world and that the U.S. Food and Drug Administration has cautioned against its use outside of well-regulated trials due to lack of safety and efficacy data.

Dr. Mehta reported that he had nothing to disclose.

NATIONAL HARBOR, MD. – Percutaneous balloon angioplasty improved flow dynamics in multiple sclerosis patients with chronic cerebrospinal venous insufficiency in a pilot study.

An association has been made recently between multiple sclerosis and chronic cerebrospinal venous insufficiency (CCSVI) that is characterized by stenosis and reflux of the principal extracranial venous drainage, including the internal jugular veins and the azygous veins. But there has been considerable debate about the validity of percutaneous balloon angioplasty in the treatment of this stenosis.

Dr. Manish Mehta of Albany (N.Y.) Medical College and his colleagues conducted the first angiographic study to quantitatively analyze the impact of percutaneous balloon angioplasty on flow dynamics across these lesions. Dr. Mehta shared their results at the Vascular Annual Meeting.

The researchers assessed 50 internal jugular veins (IJVs) from MS patients with CCSVI, as well as 12 IJVs from healthy volunteers, all of whom underwent detailed angiographic evaluation. The technical components of all venograms were standardized.

Quantitative analysis included the contrast time of flight from the mid-IJV to the superior vena cava, and the primary venous emptying time (PVET), quantified as greater than 50% of venous emptying from the IJV. The time of flight and PVET were recorded in patients with CCSVI prior to and subsequent to balloon angioplasty. The same data were recorded in the healthy controls. All data were collected prospectively, and statistical analysis was performed using two-tailed Student’s test.

Of the 50 CCSVI-MS patients who had IJV stenosis greater than 70% and reflux and who underwent balloon angioplasty, technical success (defined as less than 20% residual IJV stenosis) was achieved in 44 (78%). CCSVI patients were observed to have a significant improvement in both the time of flight and PVET following balloon angioplasty that paralleled those of healthy subjects without MS.

"The results of this prospective pilot study suggest an association between MS and CCSVI, which results in abnormally elevated time of flight and PVET through the IJV," Dr. Mehta said. "Furthermore, balloon angioplasty of these lesions improves the hemodynamic parameters so that they are comparable to" those of healthy non-MS patients."

Dr. Mehta stressed the need for randomized studies to further investigate this issue and said that this patient population is at high risk for a placebo effect with regard to their reported symptoms. He also stated that this treatment is being provided to many patients around the world and that the U.S. Food and Drug Administration has cautioned against its use outside of well-regulated trials due to lack of safety and efficacy data.

Dr. Mehta reported that he had nothing to disclose.

SAN DIEGO – An emergency department at an academic medical institution with a multiple sclerosis center missed diagnosing multiple sclerosis in nearly 40% of patients who were later diagnosed with the disease, calling into question what the rate of missed cases might be at smaller centers staffed by fewer specialists.

The retrospective study analyzed assessments for neurologic symptoms during 49 emergency department (ED) visits at the Mount Sinai School of Medicine in New York that were made by 49 people who were later diagnosed with MS. The researchers judged most of those presentations to be initial manifestations of the disease.

Just 30 of the visits (61%) resulted in a diagnosis of MS or demyelinating disease, either in the ED or on subsequent admission, Dr. Stephen Krieger said at the Fourth Cooperative Meeting on Multiple Sclerosis, which was sponsored by the Consortium of Multiple Sclerosis Centers and the America’s Committee for Treatment and Research in Multiple Sclerosis.

The diagnosis was missed in the remaining 19 (39%) visits, an important finding because early diagnosis and treatment leads to better MS outcomes. About a third of the patients involved in those visits still hadn’t been diagnosed 6 months later. It took more than a year to diagnose a few of them. "Those are the patients we have to look at to see what could have been done differently," said senior investigator Dr. Krieger, an MS specialist at the Corinne Goldsmith Dickinson Center for MS at Mount Sinai.

The risk of delayed diagnosis seemed to be greatest for men, the middle aged, and those with vague neurologic symptoms – all of whom are nontraditional MS patients – but the study didn’t have enough patients to demonstrate those findings statistically. Patients who were admitted from the ED, however, were more likely to be diagnosed quickly than were nonadmitted patients.

"Emergency department presentations for acute neurologic symptoms are an important opportunity to diagnose and treat clinically isolated syndrome and MS. There’s room to make that diagnosis more rapidly," Dr. Krieger said.

Even though the project was a single-center study, Dr. Krieger noted that Mount Sinai is an academic center with a busy neurology department, a neurology residency, and a multiple sclerosis center. In short, "we are sort of a best case scenario. A lot of other emergency departments without as much access to MS specialists may" have a harder time making a prompt diagnosis, he said.

His team plans to analyze demographic data and symptom presentations to develop robust predictive factors for delayed MS diagnoses.

Although the findings are concerning, Dr. Lael Stone, an MS specialist at the Cleveland Clinic, noted that the situation has improved in recent years. "It used to be that [the elapsed time between] first symptoms [and] diagnosis was on the order of 9 years. That has gone down dramatically," she said.

Even so, "we have a ways to go in terms of picking up MS in the [emergency department], which we should be able to do," she said at the meeting.

Vague and confusing neurologic symptoms remain a problem. The demyelinating disease neuromyelitis optica, for example, can present with month-long intractable vomiting, years before the condition is diagnosed.

"The intractable vomiting goes to the GI doctor or to the [ED]. I doubt that the [ED or GI specialist] thinks this might be neuromyelitis optica," she said.

Among the 49 ED visits for neurologic symptoms at Mount Sinai, almost half were for sensory symptoms; the remainder were for vision changes, weakness, balance problems, diplopia, and vertigo.

Bayer Healthcare Pharmaceuticals funded for the study. Dr. Krieger said he is a paid consultant for Acorda Therapeutics, Bayer Healthcare Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme, Novartis, and Questcor. He receives fees from Teva Neuroscience for non-CME services. Dr. Stone said she has no relevant disclosures.

SAN DIEGO – An emergency department at an academic medical institution with a multiple sclerosis center missed diagnosing multiple sclerosis in nearly 40% of patients who were later diagnosed with the disease, calling into question what the rate of missed cases might be at smaller centers staffed by fewer specialists.

The retrospective study analyzed assessments for neurologic symptoms during 49 emergency department (ED) visits at the Mount Sinai School of Medicine in New York that were made by 49 people who were later diagnosed with MS. The researchers judged most of those presentations to be initial manifestations of the disease.

Just 30 of the visits (61%) resulted in a diagnosis of MS or demyelinating disease, either in the ED or on subsequent admission, Dr. Stephen Krieger said at the Fourth Cooperative Meeting on Multiple Sclerosis, which was sponsored by the Consortium of Multiple Sclerosis Centers and the America’s Committee for Treatment and Research in Multiple Sclerosis.

The diagnosis was missed in the remaining 19 (39%) visits, an important finding because early diagnosis and treatment leads to better MS outcomes. About a third of the patients involved in those visits still hadn’t been diagnosed 6 months later. It took more than a year to diagnose a few of them. "Those are the patients we have to look at to see what could have been done differently," said senior investigator Dr. Krieger, an MS specialist at the Corinne Goldsmith Dickinson Center for MS at Mount Sinai.

The risk of delayed diagnosis seemed to be greatest for men, the middle aged, and those with vague neurologic symptoms – all of whom are nontraditional MS patients – but the study didn’t have enough patients to demonstrate those findings statistically. Patients who were admitted from the ED, however, were more likely to be diagnosed quickly than were nonadmitted patients.

"Emergency department presentations for acute neurologic symptoms are an important opportunity to diagnose and treat clinically isolated syndrome and MS. There’s room to make that diagnosis more rapidly," Dr. Krieger said.

Even though the project was a single-center study, Dr. Krieger noted that Mount Sinai is an academic center with a busy neurology department, a neurology residency, and a multiple sclerosis center. In short, "we are sort of a best case scenario. A lot of other emergency departments without as much access to MS specialists may" have a harder time making a prompt diagnosis, he said.

His team plans to analyze demographic data and symptom presentations to develop robust predictive factors for delayed MS diagnoses.

Although the findings are concerning, Dr. Lael Stone, an MS specialist at the Cleveland Clinic, noted that the situation has improved in recent years. "It used to be that [the elapsed time between] first symptoms [and] diagnosis was on the order of 9 years. That has gone down dramatically," she said.

Even so, "we have a ways to go in terms of picking up MS in the [emergency department], which we should be able to do," she said at the meeting.

Vague and confusing neurologic symptoms remain a problem. The demyelinating disease neuromyelitis optica, for example, can present with month-long intractable vomiting, years before the condition is diagnosed.

"The intractable vomiting goes to the GI doctor or to the [ED]. I doubt that the [ED or GI specialist] thinks this might be neuromyelitis optica," she said.

Among the 49 ED visits for neurologic symptoms at Mount Sinai, almost half were for sensory symptoms; the remainder were for vision changes, weakness, balance problems, diplopia, and vertigo.

Bayer Healthcare Pharmaceuticals funded for the study. Dr. Krieger said he is a paid consultant for Acorda Therapeutics, Bayer Healthcare Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme, Novartis, and Questcor. He receives fees from Teva Neuroscience for non-CME services. Dr. Stone said she has no relevant disclosures.

SAN DIEGO – An emergency department at an academic medical institution with a multiple sclerosis center missed diagnosing multiple sclerosis in nearly 40% of patients who were later diagnosed with the disease, calling into question what the rate of missed cases might be at smaller centers staffed by fewer specialists.

The retrospective study analyzed assessments for neurologic symptoms during 49 emergency department (ED) visits at the Mount Sinai School of Medicine in New York that were made by 49 people who were later diagnosed with MS. The researchers judged most of those presentations to be initial manifestations of the disease.

Just 30 of the visits (61%) resulted in a diagnosis of MS or demyelinating disease, either in the ED or on subsequent admission, Dr. Stephen Krieger said at the Fourth Cooperative Meeting on Multiple Sclerosis, which was sponsored by the Consortium of Multiple Sclerosis Centers and the America’s Committee for Treatment and Research in Multiple Sclerosis.

The diagnosis was missed in the remaining 19 (39%) visits, an important finding because early diagnosis and treatment leads to better MS outcomes. About a third of the patients involved in those visits still hadn’t been diagnosed 6 months later. It took more than a year to diagnose a few of them. "Those are the patients we have to look at to see what could have been done differently," said senior investigator Dr. Krieger, an MS specialist at the Corinne Goldsmith Dickinson Center for MS at Mount Sinai.

The risk of delayed diagnosis seemed to be greatest for men, the middle aged, and those with vague neurologic symptoms – all of whom are nontraditional MS patients – but the study didn’t have enough patients to demonstrate those findings statistically. Patients who were admitted from the ED, however, were more likely to be diagnosed quickly than were nonadmitted patients.

"Emergency department presentations for acute neurologic symptoms are an important opportunity to diagnose and treat clinically isolated syndrome and MS. There’s room to make that diagnosis more rapidly," Dr. Krieger said.

Even though the project was a single-center study, Dr. Krieger noted that Mount Sinai is an academic center with a busy neurology department, a neurology residency, and a multiple sclerosis center. In short, "we are sort of a best case scenario. A lot of other emergency departments without as much access to MS specialists may" have a harder time making a prompt diagnosis, he said.

His team plans to analyze demographic data and symptom presentations to develop robust predictive factors for delayed MS diagnoses.

Although the findings are concerning, Dr. Lael Stone, an MS specialist at the Cleveland Clinic, noted that the situation has improved in recent years. "It used to be that [the elapsed time between] first symptoms [and] diagnosis was on the order of 9 years. That has gone down dramatically," she said.

Even so, "we have a ways to go in terms of picking up MS in the [emergency department], which we should be able to do," she said at the meeting.

Vague and confusing neurologic symptoms remain a problem. The demyelinating disease neuromyelitis optica, for example, can present with month-long intractable vomiting, years before the condition is diagnosed.

"The intractable vomiting goes to the GI doctor or to the [ED]. I doubt that the [ED or GI specialist] thinks this might be neuromyelitis optica," she said.

Among the 49 ED visits for neurologic symptoms at Mount Sinai, almost half were for sensory symptoms; the remainder were for vision changes, weakness, balance problems, diplopia, and vertigo.

Bayer Healthcare Pharmaceuticals funded for the study. Dr. Krieger said he is a paid consultant for Acorda Therapeutics, Bayer Healthcare Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme, Novartis, and Questcor. He receives fees from Teva Neuroscience for non-CME services. Dr. Stone said she has no relevant disclosures.

NEW ORLEANS—Among treatment-naïve patients with relapsing–remitting multiple sclerosis (MS), alemtuzumab reduced the relapse rate by 55%, compared with interferon beta-1a, said Alasdair Coles, PhD, member of the Department of Clinical Neurosciences at Cambridge University in the United Kingdom, at the 64th Annual Meeting of the American Academy of Neurology. Eight percent of patients receiving alemtuzumab experienced sustained accumulation of disability, compared with 11% of patients receiving Rebif, but this difference was not statistically significant, according to findings from the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I (CARE-MS I) study.

“Perhaps most significantly,” the study provided evidence for alemtuzumab’s superiority “on reducing the rate of tissue loss, as measured by MRI, compared to the active drug Rebif,” said Dr. Coles. Alemtuzumab also had a superior effect on measures of neurologic impairment and on MRI measures of new inflammatory lesions, compared with that of Rebif.

In the two-year phase III trial, Dr. Coles and his colleagues randomized 581 treatment-naïve patients from 98 centers in 16 countries to alemtuzumab or interferon beta-1a to compare the clinical efficacy and safety outcomes of the two drugs. All patients had highly active relapsing–remitting MS but had not yet accumulated disability. Participants’ mean age was 33, and their mean Expanded Disability Status Scale (EDSS) score was 2. EDSS raters were blinded to treatment, and all relapses were adjudicated by an independent end point panel.

The annualized relapse rate was 0.18 for patients receiving alemtuzumab, compared with 0.39 for patients receiving interferon beta-1a. Approximately 78% of patients receiving alemtuzumab were relapse-free, compared with nearly 59% of patients receiving interferon beta-1a.

Alemtuzumab was associated with more adverse events than was interferon beta-1a, including infusion-associated symptoms such as headache, pyrexia, and rash. Premedication and further treatment with antihistamines and antipyretics ameliorated these symptoms.

“As we have come to expect, there was an excess of thyroid autoimmunities following alemtuzumab,” said Dr. Coles. In addition, three cases of idiopathic thrombocytopenic purpura occurred in the alemtuzumab arm, and one case occurred in the interferon beta-1a arm. The study’s risk-minimization program identified all cases, and appropriate treatment restored patients’ platelet counts and prevented sequelae.

NEW ORLEANS—Among treatment-naïve patients with relapsing–remitting multiple sclerosis (MS), alemtuzumab reduced the relapse rate by 55%, compared with interferon beta-1a, said Alasdair Coles, PhD, member of the Department of Clinical Neurosciences at Cambridge University in the United Kingdom, at the 64th Annual Meeting of the American Academy of Neurology. Eight percent of patients receiving alemtuzumab experienced sustained accumulation of disability, compared with 11% of patients receiving Rebif, but this difference was not statistically significant, according to findings from the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I (CARE-MS I) study.

“Perhaps most significantly,” the study provided evidence for alemtuzumab’s superiority “on reducing the rate of tissue loss, as measured by MRI, compared to the active drug Rebif,” said Dr. Coles. Alemtuzumab also had a superior effect on measures of neurologic impairment and on MRI measures of new inflammatory lesions, compared with that of Rebif.

In the two-year phase III trial, Dr. Coles and his colleagues randomized 581 treatment-naïve patients from 98 centers in 16 countries to alemtuzumab or interferon beta-1a to compare the clinical efficacy and safety outcomes of the two drugs. All patients had highly active relapsing–remitting MS but had not yet accumulated disability. Participants’ mean age was 33, and their mean Expanded Disability Status Scale (EDSS) score was 2. EDSS raters were blinded to treatment, and all relapses were adjudicated by an independent end point panel.

The annualized relapse rate was 0.18 for patients receiving alemtuzumab, compared with 0.39 for patients receiving interferon beta-1a. Approximately 78% of patients receiving alemtuzumab were relapse-free, compared with nearly 59% of patients receiving interferon beta-1a.

Alemtuzumab was associated with more adverse events than was interferon beta-1a, including infusion-associated symptoms such as headache, pyrexia, and rash. Premedication and further treatment with antihistamines and antipyretics ameliorated these symptoms.

“As we have come to expect, there was an excess of thyroid autoimmunities following alemtuzumab,” said Dr. Coles. In addition, three cases of idiopathic thrombocytopenic purpura occurred in the alemtuzumab arm, and one case occurred in the interferon beta-1a arm. The study’s risk-minimization program identified all cases, and appropriate treatment restored patients’ platelet counts and prevented sequelae.

NEW ORLEANS—Among treatment-naïve patients with relapsing–remitting multiple sclerosis (MS), alemtuzumab reduced the relapse rate by 55%, compared with interferon beta-1a, said Alasdair Coles, PhD, member of the Department of Clinical Neurosciences at Cambridge University in the United Kingdom, at the 64th Annual Meeting of the American Academy of Neurology. Eight percent of patients receiving alemtuzumab experienced sustained accumulation of disability, compared with 11% of patients receiving Rebif, but this difference was not statistically significant, according to findings from the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I (CARE-MS I) study.

“Perhaps most significantly,” the study provided evidence for alemtuzumab’s superiority “on reducing the rate of tissue loss, as measured by MRI, compared to the active drug Rebif,” said Dr. Coles. Alemtuzumab also had a superior effect on measures of neurologic impairment and on MRI measures of new inflammatory lesions, compared with that of Rebif.

In the two-year phase III trial, Dr. Coles and his colleagues randomized 581 treatment-naïve patients from 98 centers in 16 countries to alemtuzumab or interferon beta-1a to compare the clinical efficacy and safety outcomes of the two drugs. All patients had highly active relapsing–remitting MS but had not yet accumulated disability. Participants’ mean age was 33, and their mean Expanded Disability Status Scale (EDSS) score was 2. EDSS raters were blinded to treatment, and all relapses were adjudicated by an independent end point panel.

The annualized relapse rate was 0.18 for patients receiving alemtuzumab, compared with 0.39 for patients receiving interferon beta-1a. Approximately 78% of patients receiving alemtuzumab were relapse-free, compared with nearly 59% of patients receiving interferon beta-1a.

Alemtuzumab was associated with more adverse events than was interferon beta-1a, including infusion-associated symptoms such as headache, pyrexia, and rash. Premedication and further treatment with antihistamines and antipyretics ameliorated these symptoms.

“As we have come to expect, there was an excess of thyroid autoimmunities following alemtuzumab,” said Dr. Coles. In addition, three cases of idiopathic thrombocytopenic purpura occurred in the alemtuzumab arm, and one case occurred in the interferon beta-1a arm. The study’s risk-minimization program identified all cases, and appropriate treatment restored patients’ platelet counts and prevented sequelae.

NEW ORLEANS—Compared with interferon beta-1a, alemtuzumab reduced the annualized relapse rate by 49% among patients with relapsing–remitting multiple sclerosis (MS) who had relapsed on previous therapy, according to research presented at the 64th Annual Meeting of the American Academy of Neurology. Approximately 65% of patients taking alemtuzumab were relapse-free, compared with 47% of patients taking interferon beta-1a, per results from the phase III Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis II (CARE-MS II) study.

In addition, patients with relapsing–remitting MS taking alemtuzumab had a 12.7% risk of sustained accumulation of disability, while patients taking interferon had a 21% risk, said Jeffrey A. Cohen, MD, Director of Experimental Therapeutics at the Cleveland Clinic Mellen MS Center. This reduction represents a hazard ratio of 0.58, or 42% treatment effect, he noted.

During a two-year period, the average Expanded Disability Status Scale (EDSS) score decreased by 0.17 steps among patients taking alemtuzumab, compared with an increase of 0.24 steps among patients taking interferon. The net difference of 0.41 EDSS steps between the two groups after two years was statistically significant, said Dr. Cohen, as were the differences between each group’s scores at baseline and at 12 months.

Patients receiving alemtuzumab also experienced a 29% chance of sustained reduction of disability. Patients receiving interferon, in contrast, experienced a 13% chance of this outcome.

Comparing the Same Drugs in a New Patient Population
The results of the study were consistent with those of a previous phase III trial—Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I (CARE-MS I) (see sidebar). The two-year CARE-MS II trial, conducted by Dr. Cohen and colleagues, compared the effects of alemtuzumab and interferon beta-1a in patients who had relapsed on prior therapy. The study’s two primary efficacy end points were relapse rate and time to six-month sustained accumulation of disability. Additional end points included EDSS change from baseline and sustained reduction of disability, MRI lesion analyses, and normalized whole-brain volume, as measured by brain parenchymal fraction.

Eligible patients ages 18 to 55 were randomized to receive either 12 mg of alemtuzumab for five days at month 0 and for three days at month 12, or 44 µg of subcutaneous interferon beta-1a three times per week. To prevent side effects, the alemtuzumab patients received three days of IV methylprednisolone with each infusion course, and the same therapy was administered annually to the interferon patients. “Because of the distinct mode of administration and side-effect profiles, we felt that blinding of participants and treating clinicians was not feasible,” said Dr. Cohen.

The patients’ average EDSS score was 2.7, and participants had had an average of 1.5 relapses in the previous year. Approximately 80% of patients had previously received interferon therapy, 30% had received glatiramer acetate, and 20% had received both therapies.

Alemtuzumab Reduces the Number of T2 Lesions
Approximately 46% of patients receiving alemtuzumab had new or enlarging T2 lesions over two years, compared with 68% of patients receiving interferon. Although T2 lesion volume decreased in both patient groups, the difference was not statistically significant. Patients taking alemtuzumab experienced 23% less brain volume loss over two years, as measured by brain parenchymal fraction, compared with patients taking interferon beta-1a.

The overall incidence of adverse events was similar in both groups, as was the incidence of serious adverse events. Infections such as nasopharyngitis, sinusitis, and upper respiratory infection were somewhat more common among patients receiving alemtuzumab, as were serious infections such as pneumonia, appendicitis, and herpes zoster.

“This study showed superior efficacy of alemtuzumab, compared with interferon beta-1a, across multiple outcomes,” said Dr. Cohen. “This is now the third study demonstrating superior efficacy of alemtuzumab, and it’s important to note [that] all three of those studies were against an active comparator—subcutaneous interferon beta-1a—which itself is effective against relapses, disability, and MRI. The adverse event profile was consistent with [that of] previous studies, and a comprehensive monitoring program was successful in early detection, facilitating early treatment,” he concluded.

To hear an audiocast related to this news article, please click here.

To read a commentary on this news article, please click here.

NEW ORLEANS—Compared with interferon beta-1a, alemtuzumab reduced the annualized relapse rate by 49% among patients with relapsing–remitting multiple sclerosis (MS) who had relapsed on previous therapy, according to research presented at the 64th Annual Meeting of the American Academy of Neurology. Approximately 65% of patients taking alemtuzumab were relapse-free, compared with 47% of patients taking interferon beta-1a, per results from the phase III Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis II (CARE-MS II) study.

In addition, patients with relapsing–remitting MS taking alemtuzumab had a 12.7% risk of sustained accumulation of disability, while patients taking interferon had a 21% risk, said Jeffrey A. Cohen, MD, Director of Experimental Therapeutics at the Cleveland Clinic Mellen MS Center. This reduction represents a hazard ratio of 0.58, or 42% treatment effect, he noted.

During a two-year period, the average Expanded Disability Status Scale (EDSS) score decreased by 0.17 steps among patients taking alemtuzumab, compared with an increase of 0.24 steps among patients taking interferon. The net difference of 0.41 EDSS steps between the two groups after two years was statistically significant, said Dr. Cohen, as were the differences between each group’s scores at baseline and at 12 months.

Patients receiving alemtuzumab also experienced a 29% chance of sustained reduction of disability. Patients receiving interferon, in contrast, experienced a 13% chance of this outcome.

Comparing the Same Drugs in a New Patient Population
The results of the study were consistent with those of a previous phase III trial—Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I (CARE-MS I) (see sidebar). The two-year CARE-MS II trial, conducted by Dr. Cohen and colleagues, compared the effects of alemtuzumab and interferon beta-1a in patients who had relapsed on prior therapy. The study’s two primary efficacy end points were relapse rate and time to six-month sustained accumulation of disability. Additional end points included EDSS change from baseline and sustained reduction of disability, MRI lesion analyses, and normalized whole-brain volume, as measured by brain parenchymal fraction.

Eligible patients ages 18 to 55 were randomized to receive either 12 mg of alemtuzumab for five days at month 0 and for three days at month 12, or 44 µg of subcutaneous interferon beta-1a three times per week. To prevent side effects, the alemtuzumab patients received three days of IV methylprednisolone with each infusion course, and the same therapy was administered annually to the interferon patients. “Because of the distinct mode of administration and side-effect profiles, we felt that blinding of participants and treating clinicians was not feasible,” said Dr. Cohen.

The patients’ average EDSS score was 2.7, and participants had had an average of 1.5 relapses in the previous year. Approximately 80% of patients had previously received interferon therapy, 30% had received glatiramer acetate, and 20% had received both therapies.

Alemtuzumab Reduces the Number of T2 Lesions
Approximately 46% of patients receiving alemtuzumab had new or enlarging T2 lesions over two years, compared with 68% of patients receiving interferon. Although T2 lesion volume decreased in both patient groups, the difference was not statistically significant. Patients taking alemtuzumab experienced 23% less brain volume loss over two years, as measured by brain parenchymal fraction, compared with patients taking interferon beta-1a.

The overall incidence of adverse events was similar in both groups, as was the incidence of serious adverse events. Infections such as nasopharyngitis, sinusitis, and upper respiratory infection were somewhat more common among patients receiving alemtuzumab, as were serious infections such as pneumonia, appendicitis, and herpes zoster.

“This study showed superior efficacy of alemtuzumab, compared with interferon beta-1a, across multiple outcomes,” said Dr. Cohen. “This is now the third study demonstrating superior efficacy of alemtuzumab, and it’s important to note [that] all three of those studies were against an active comparator—subcutaneous interferon beta-1a—which itself is effective against relapses, disability, and MRI. The adverse event profile was consistent with [that of] previous studies, and a comprehensive monitoring program was successful in early detection, facilitating early treatment,” he concluded.

To hear an audiocast related to this news article, please click here.

To read a commentary on this news article, please click here.

NEW ORLEANS—Compared with interferon beta-1a, alemtuzumab reduced the annualized relapse rate by 49% among patients with relapsing–remitting multiple sclerosis (MS) who had relapsed on previous therapy, according to research presented at the 64th Annual Meeting of the American Academy of Neurology. Approximately 65% of patients taking alemtuzumab were relapse-free, compared with 47% of patients taking interferon beta-1a, per results from the phase III Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis II (CARE-MS II) study.

In addition, patients with relapsing–remitting MS taking alemtuzumab had a 12.7% risk of sustained accumulation of disability, while patients taking interferon had a 21% risk, said Jeffrey A. Cohen, MD, Director of Experimental Therapeutics at the Cleveland Clinic Mellen MS Center. This reduction represents a hazard ratio of 0.58, or 42% treatment effect, he noted.

During a two-year period, the average Expanded Disability Status Scale (EDSS) score decreased by 0.17 steps among patients taking alemtuzumab, compared with an increase of 0.24 steps among patients taking interferon. The net difference of 0.41 EDSS steps between the two groups after two years was statistically significant, said Dr. Cohen, as were the differences between each group’s scores at baseline and at 12 months.

Patients receiving alemtuzumab also experienced a 29% chance of sustained reduction of disability. Patients receiving interferon, in contrast, experienced a 13% chance of this outcome.

Comparing the Same Drugs in a New Patient Population
The results of the study were consistent with those of a previous phase III trial—Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I (CARE-MS I) (see sidebar). The two-year CARE-MS II trial, conducted by Dr. Cohen and colleagues, compared the effects of alemtuzumab and interferon beta-1a in patients who had relapsed on prior therapy. The study’s two primary efficacy end points were relapse rate and time to six-month sustained accumulation of disability. Additional end points included EDSS change from baseline and sustained reduction of disability, MRI lesion analyses, and normalized whole-brain volume, as measured by brain parenchymal fraction.

Eligible patients ages 18 to 55 were randomized to receive either 12 mg of alemtuzumab for five days at month 0 and for three days at month 12, or 44 µg of subcutaneous interferon beta-1a three times per week. To prevent side effects, the alemtuzumab patients received three days of IV methylprednisolone with each infusion course, and the same therapy was administered annually to the interferon patients. “Because of the distinct mode of administration and side-effect profiles, we felt that blinding of participants and treating clinicians was not feasible,” said Dr. Cohen.

The patients’ average EDSS score was 2.7, and participants had had an average of 1.5 relapses in the previous year. Approximately 80% of patients had previously received interferon therapy, 30% had received glatiramer acetate, and 20% had received both therapies.

Alemtuzumab Reduces the Number of T2 Lesions
Approximately 46% of patients receiving alemtuzumab had new or enlarging T2 lesions over two years, compared with 68% of patients receiving interferon. Although T2 lesion volume decreased in both patient groups, the difference was not statistically significant. Patients taking alemtuzumab experienced 23% less brain volume loss over two years, as measured by brain parenchymal fraction, compared with patients taking interferon beta-1a.

The overall incidence of adverse events was similar in both groups, as was the incidence of serious adverse events. Infections such as nasopharyngitis, sinusitis, and upper respiratory infection were somewhat more common among patients receiving alemtuzumab, as were serious infections such as pneumonia, appendicitis, and herpes zoster.

“This study showed superior efficacy of alemtuzumab, compared with interferon beta-1a, across multiple outcomes,” said Dr. Cohen. “This is now the third study demonstrating superior efficacy of alemtuzumab, and it’s important to note [that] all three of those studies were against an active comparator—subcutaneous interferon beta-1a—which itself is effective against relapses, disability, and MRI. The adverse event profile was consistent with [that of] previous studies, and a comprehensive monitoring program was successful in early detection, facilitating early treatment,” he concluded.

To hear an audiocast related to this news article, please click here.

To read a commentary on this news article, please click here.

Multiple sclerosis (MS) treatments have been available for more than a decade. Several disease-modifying therapies are approved and routinely used with various degrees of effectiveness, tolerability, and compliance. Treatment options have continued to evolve in effectiveness, frequency of administration, and routes of delivery, but more targeted, effective, and safe options are still needed.

The alemtuzumab clinical trial outcome data are exciting. Alemtuzumab represents another effective therapeutic option that will help MS clinicians treat their patients more effectively. This novel agent has demonstrated significant improvement in effectiveness not only for reduced relapse rates and MRI disease activity suppression, but also for reduction of accumulated disability. These impressive and significant gains across multiple outcomes have been accomplished when compared not to placebo, but to one of our mainstays in available treatment. This improved ability to deliver more effective treatment safely and easily, without the worry of ongoing compliance concerns, represents a great advantage in our ongoing fight to limit the damage that this disease causes to our patients, friends, and colleagues.

Multiple sclerosis (MS) treatments have been available for more than a decade. Several disease-modifying therapies are approved and routinely used with various degrees of effectiveness, tolerability, and compliance. Treatment options have continued to evolve in effectiveness, frequency of administration, and routes of delivery, but more targeted, effective, and safe options are still needed.

The alemtuzumab clinical trial outcome data are exciting. Alemtuzumab represents another effective therapeutic option that will help MS clinicians treat their patients more effectively. This novel agent has demonstrated significant improvement in effectiveness not only for reduced relapse rates and MRI disease activity suppression, but also for reduction of accumulated disability. These impressive and significant gains across multiple outcomes have been accomplished when compared not to placebo, but to one of our mainstays in available treatment. This improved ability to deliver more effective treatment safely and easily, without the worry of ongoing compliance concerns, represents a great advantage in our ongoing fight to limit the damage that this disease causes to our patients, friends, and colleagues.

Multiple sclerosis (MS) treatments have been available for more than a decade. Several disease-modifying therapies are approved and routinely used with various degrees of effectiveness, tolerability, and compliance. Treatment options have continued to evolve in effectiveness, frequency of administration, and routes of delivery, but more targeted, effective, and safe options are still needed.

The alemtuzumab clinical trial outcome data are exciting. Alemtuzumab represents another effective therapeutic option that will help MS clinicians treat their patients more effectively. This novel agent has demonstrated significant improvement in effectiveness not only for reduced relapse rates and MRI disease activity suppression, but also for reduction of accumulated disability. These impressive and significant gains across multiple outcomes have been accomplished when compared not to placebo, but to one of our mainstays in available treatment. This improved ability to deliver more effective treatment safely and easily, without the worry of ongoing compliance concerns, represents a great advantage in our ongoing fight to limit the damage that this disease causes to our patients, friends, and colleagues.

The risk of developing progressive multifocal leukoencephalopathy from natalizumab therapy appears to be greater than previously thought, being greatest in multiple sclerosis patients with certain risk factors, according to an updated analysis.

The analysis provides an algorithm that might help clinicians hone in on which patients are least or most likely to develop PML, and give them support in discussing risks and benefits, said Dr. Gary Bloomgren and his coauthors, all of whom work for Biogen Idec, which makes natalizumab (Tysabri).

Courtesy Biogen Idec

The algorithm took into account anti-JC virus antibody status; whether there was prior use of immunosuppressants; and duration of treatment. Positive anti-JC status, prior immunosuppressant use and longer treatment all have been previously identified as PML risk factors. But there has not been a physician-friendly way to stratify risk.

PML is an opportunistic brain infection caused by the JC virus. Previous estimates had put the incidence at about 1 case per 1,000. In April 2011, the Food and Drug Administration reported that 102 cases of PML had been reported among 82,732 patients treated with natalizumab worldwide.

But now that risk is 2.1 per 1,000, given that there have been 212 confirmed cases of PML among the 99,571 patients worldwide who have been treated with natalizumab, Dr. Bloomgren and his colleagues reported May 16 in the New England Journal of Medicine.

The incidence of PML rises to as much as 11.1 per 1,000 in multiple sclerosis patients who are positive for anti-JC virus antibodies, who have taken immunosuppressants before starting natalizumab, and who have taken the drug for 25-48 months.

Although this is a longer period of follow-up than has been reported previously, there were not enough data to calculate the risk beyond 4 years of treatment.

In January of this year, the FDA warned that anti–JC virus–positive status was associated with an increased risk, in addition to the other known risk factors for PML. The agency also estimated the incidence of PML for patients with those risk factors at 11.1 per 1,000.

Dr. Bloomgren and his associates based their calculations on data from Biogen Idec’s safety database, from clinical trials such as the Tysabri Global Observational Program in Safety study (TYGRIS-U.S. and TYGRIS–Rest of World) and from AFFIRM and STRATIFY-1. Data from an independent Swedish registry of patients with multiple sclerosis were also used (N. Engl. J. Med. 2012;366:1870-80).

The algorithm can help stratify risk and assist physicians in deciding whether to use natalizumab, the authors said. Avoiding PML is of great importance. The Biogen Idec researchers said that of the 212 confirmed PML cases, 46 of the patients had died, and that 23 of the 58 survivors for whom data was available had severe disability.

They noted that their risk estimates were limited by several factors, including the assumption that anti–JC-positive status was clearly associated with development of PML. This assumption was based on the fact that all 54 patients identified in the postmarketing setting had been anti–JC-positive before their PML diagnosis. But blood samples were not available for all patients with PML, and the anti-JC virus assay – which is now commercially available – has a small, but perceptible false negative rate.

In a commentary accompanying the study, Dr. Allan H. Ropper said that MS patients who test negative for anti-JC antibodies ostensibly can be reassured that it is safe to take natalizumab. But he noted that there are "basic limitations to serologic tests for JC virus, since there is no standard by which to judge the absence of the virus" (N. Engl. J. Med. 2012;366:1938-9).

Also, the seroprevalance of the virus increases with age, and patients can undergo seroconversion at any time, said Dr. Ropper, a neurologist at Brigham and Women’s Hospital, Boston. He urged retesting for any patients undergoing natalizumab therapy.

While it is not entirely clear why natalizumab is associated with PML, it appears that it may reactivate the JC virus and that it might possibly cause the emergence of a mutation in the virus that leads to the emergency of PML.

Dr. Ropper disclosed no financial conflicts, but reported that he is the associate editor of the New England Journal of Medicine.

Registry to Track PML Scheduled for Fall

With the incidence of progressive multifocal leukoencephalopathy on the rise, the National Institute of Neurological Disorders and Stroke plans to have a registry for the condition up and running by this fall.

The purpose of the registry is to acquire clinical information and biologic material for cases from all over the world, so that researchers can tease out the incidence, prevalence, and potential contributing factors, Eugene O. Major, Ph.D, chief of the laboratory of molecular medicine and neuroscience at the NINDS, said at the annual meeting of the American Academy of Neurology in New Orleans.

The research may also give rise to diagnostics and therapies for the condition, which has up to 50% mortality in the first few months after diagnosis, according to the NINDS.

PML is caused by the reactivation of infection with the JC virus.It is rare, and is most often seen in HIV-infected individuals, but is also seen in people who are undergoing chronic immunosuppression, as with certain cancers. But the disease has also been on the rise in multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus due to biologic therapies that appear to reactivate the JC virus. The NINDS estimates that 5% of HIV patients develop PML.

Much of the data in the registry will be collected through a network of cooperating clinical centers. But the registry, which will be web-based, will have several access points for reporting clinicians and a portal for the public as well, Dr. Major said. The public-facing side of the site will connect patients to the NINDS, its lab site, clinicaltrials.gov, and advocacy groups.

Neurologists and other clinicians will enter cases using a form that will give patients a random identifier. There will be space for narratives and for attaching MRI scans and lab results.

There will also be diagnostic criteria posted, which are currently under review by the AAN, Dr. Major said.

The aim is to conduct a pilot study using five academic medical centers and then have the registry publicly available in the fall, he said.

The risk of developing progressive multifocal leukoencephalopathy from natalizumab therapy appears to be greater than previously thought, being greatest in multiple sclerosis patients with certain risk factors, according to an updated analysis.

The analysis provides an algorithm that might help clinicians hone in on which patients are least or most likely to develop PML, and give them support in discussing risks and benefits, said Dr. Gary Bloomgren and his coauthors, all of whom work for Biogen Idec, which makes natalizumab (Tysabri).

Courtesy Biogen Idec

The algorithm took into account anti-JC virus antibody status; whether there was prior use of immunosuppressants; and duration of treatment. Positive anti-JC status, prior immunosuppressant use and longer treatment all have been previously identified as PML risk factors. But there has not been a physician-friendly way to stratify risk.

PML is an opportunistic brain infection caused by the JC virus. Previous estimates had put the incidence at about 1 case per 1,000. In April 2011, the Food and Drug Administration reported that 102 cases of PML had been reported among 82,732 patients treated with natalizumab worldwide.

But now that risk is 2.1 per 1,000, given that there have been 212 confirmed cases of PML among the 99,571 patients worldwide who have been treated with natalizumab, Dr. Bloomgren and his colleagues reported May 16 in the New England Journal of Medicine.

The incidence of PML rises to as much as 11.1 per 1,000 in multiple sclerosis patients who are positive for anti-JC virus antibodies, who have taken immunosuppressants before starting natalizumab, and who have taken the drug for 25-48 months.

Although this is a longer period of follow-up than has been reported previously, there were not enough data to calculate the risk beyond 4 years of treatment.

In January of this year, the FDA warned that anti–JC virus–positive status was associated with an increased risk, in addition to the other known risk factors for PML. The agency also estimated the incidence of PML for patients with those risk factors at 11.1 per 1,000.

Dr. Bloomgren and his associates based their calculations on data from Biogen Idec’s safety database, from clinical trials such as the Tysabri Global Observational Program in Safety study (TYGRIS-U.S. and TYGRIS–Rest of World) and from AFFIRM and STRATIFY-1. Data from an independent Swedish registry of patients with multiple sclerosis were also used (N. Engl. J. Med. 2012;366:1870-80).

The algorithm can help stratify risk and assist physicians in deciding whether to use natalizumab, the authors said. Avoiding PML is of great importance. The Biogen Idec researchers said that of the 212 confirmed PML cases, 46 of the patients had died, and that 23 of the 58 survivors for whom data was available had severe disability.

They noted that their risk estimates were limited by several factors, including the assumption that anti–JC-positive status was clearly associated with development of PML. This assumption was based on the fact that all 54 patients identified in the postmarketing setting had been anti–JC-positive before their PML diagnosis. But blood samples were not available for all patients with PML, and the anti-JC virus assay – which is now commercially available – has a small, but perceptible false negative rate.

In a commentary accompanying the study, Dr. Allan H. Ropper said that MS patients who test negative for anti-JC antibodies ostensibly can be reassured that it is safe to take natalizumab. But he noted that there are "basic limitations to serologic tests for JC virus, since there is no standard by which to judge the absence of the virus" (N. Engl. J. Med. 2012;366:1938-9).

Also, the seroprevalance of the virus increases with age, and patients can undergo seroconversion at any time, said Dr. Ropper, a neurologist at Brigham and Women’s Hospital, Boston. He urged retesting for any patients undergoing natalizumab therapy.

While it is not entirely clear why natalizumab is associated with PML, it appears that it may reactivate the JC virus and that it might possibly cause the emergence of a mutation in the virus that leads to the emergency of PML.

Dr. Ropper disclosed no financial conflicts, but reported that he is the associate editor of the New England Journal of Medicine.

Registry to Track PML Scheduled for Fall

With the incidence of progressive multifocal leukoencephalopathy on the rise, the National Institute of Neurological Disorders and Stroke plans to have a registry for the condition up and running by this fall.

The purpose of the registry is to acquire clinical information and biologic material for cases from all over the world, so that researchers can tease out the incidence, prevalence, and potential contributing factors, Eugene O. Major, Ph.D, chief of the laboratory of molecular medicine and neuroscience at the NINDS, said at the annual meeting of the American Academy of Neurology in New Orleans.

The research may also give rise to diagnostics and therapies for the condition, which has up to 50% mortality in the first few months after diagnosis, according to the NINDS.

PML is caused by the reactivation of infection with the JC virus.It is rare, and is most often seen in HIV-infected individuals, but is also seen in people who are undergoing chronic immunosuppression, as with certain cancers. But the disease has also been on the rise in multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus due to biologic therapies that appear to reactivate the JC virus. The NINDS estimates that 5% of HIV patients develop PML.

Much of the data in the registry will be collected through a network of cooperating clinical centers. But the registry, which will be web-based, will have several access points for reporting clinicians and a portal for the public as well, Dr. Major said. The public-facing side of the site will connect patients to the NINDS, its lab site, clinicaltrials.gov, and advocacy groups.

Neurologists and other clinicians will enter cases using a form that will give patients a random identifier. There will be space for narratives and for attaching MRI scans and lab results.

There will also be diagnostic criteria posted, which are currently under review by the AAN, Dr. Major said.

The aim is to conduct a pilot study using five academic medical centers and then have the registry publicly available in the fall, he said.

The risk of developing progressive multifocal leukoencephalopathy from natalizumab therapy appears to be greater than previously thought, being greatest in multiple sclerosis patients with certain risk factors, according to an updated analysis.

The analysis provides an algorithm that might help clinicians hone in on which patients are least or most likely to develop PML, and give them support in discussing risks and benefits, said Dr. Gary Bloomgren and his coauthors, all of whom work for Biogen Idec, which makes natalizumab (Tysabri).

Courtesy Biogen Idec

The algorithm took into account anti-JC virus antibody status; whether there was prior use of immunosuppressants; and duration of treatment. Positive anti-JC status, prior immunosuppressant use and longer treatment all have been previously identified as PML risk factors. But there has not been a physician-friendly way to stratify risk.

PML is an opportunistic brain infection caused by the JC virus. Previous estimates had put the incidence at about 1 case per 1,000. In April 2011, the Food and Drug Administration reported that 102 cases of PML had been reported among 82,732 patients treated with natalizumab worldwide.

But now that risk is 2.1 per 1,000, given that there have been 212 confirmed cases of PML among the 99,571 patients worldwide who have been treated with natalizumab, Dr. Bloomgren and his colleagues reported May 16 in the New England Journal of Medicine.

The incidence of PML rises to as much as 11.1 per 1,000 in multiple sclerosis patients who are positive for anti-JC virus antibodies, who have taken immunosuppressants before starting natalizumab, and who have taken the drug for 25-48 months.

Although this is a longer period of follow-up than has been reported previously, there were not enough data to calculate the risk beyond 4 years of treatment.

In January of this year, the FDA warned that anti–JC virus–positive status was associated with an increased risk, in addition to the other known risk factors for PML. The agency also estimated the incidence of PML for patients with those risk factors at 11.1 per 1,000.

Dr. Bloomgren and his associates based their calculations on data from Biogen Idec’s safety database, from clinical trials such as the Tysabri Global Observational Program in Safety study (TYGRIS-U.S. and TYGRIS–Rest of World) and from AFFIRM and STRATIFY-1. Data from an independent Swedish registry of patients with multiple sclerosis were also used (N. Engl. J. Med. 2012;366:1870-80).

The algorithm can help stratify risk and assist physicians in deciding whether to use natalizumab, the authors said. Avoiding PML is of great importance. The Biogen Idec researchers said that of the 212 confirmed PML cases, 46 of the patients had died, and that 23 of the 58 survivors for whom data was available had severe disability.

They noted that their risk estimates were limited by several factors, including the assumption that anti–JC-positive status was clearly associated with development of PML. This assumption was based on the fact that all 54 patients identified in the postmarketing setting had been anti–JC-positive before their PML diagnosis. But blood samples were not available for all patients with PML, and the anti-JC virus assay – which is now commercially available – has a small, but perceptible false negative rate.

In a commentary accompanying the study, Dr. Allan H. Ropper said that MS patients who test negative for anti-JC antibodies ostensibly can be reassured that it is safe to take natalizumab. But he noted that there are "basic limitations to serologic tests for JC virus, since there is no standard by which to judge the absence of the virus" (N. Engl. J. Med. 2012;366:1938-9).

Also, the seroprevalance of the virus increases with age, and patients can undergo seroconversion at any time, said Dr. Ropper, a neurologist at Brigham and Women’s Hospital, Boston. He urged retesting for any patients undergoing natalizumab therapy.

While it is not entirely clear why natalizumab is associated with PML, it appears that it may reactivate the JC virus and that it might possibly cause the emergence of a mutation in the virus that leads to the emergency of PML.

Dr. Ropper disclosed no financial conflicts, but reported that he is the associate editor of the New England Journal of Medicine.

Registry to Track PML Scheduled for Fall

With the incidence of progressive multifocal leukoencephalopathy on the rise, the National Institute of Neurological Disorders and Stroke plans to have a registry for the condition up and running by this fall.

The purpose of the registry is to acquire clinical information and biologic material for cases from all over the world, so that researchers can tease out the incidence, prevalence, and potential contributing factors, Eugene O. Major, Ph.D, chief of the laboratory of molecular medicine and neuroscience at the NINDS, said at the annual meeting of the American Academy of Neurology in New Orleans.

The research may also give rise to diagnostics and therapies for the condition, which has up to 50% mortality in the first few months after diagnosis, according to the NINDS.

PML is caused by the reactivation of infection with the JC virus.It is rare, and is most often seen in HIV-infected individuals, but is also seen in people who are undergoing chronic immunosuppression, as with certain cancers. But the disease has also been on the rise in multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus due to biologic therapies that appear to reactivate the JC virus. The NINDS estimates that 5% of HIV patients develop PML.

Much of the data in the registry will be collected through a network of cooperating clinical centers. But the registry, which will be web-based, will have several access points for reporting clinicians and a portal for the public as well, Dr. Major said. The public-facing side of the site will connect patients to the NINDS, its lab site, clinicaltrials.gov, and advocacy groups.

Neurologists and other clinicians will enter cases using a form that will give patients a random identifier. There will be space for narratives and for attaching MRI scans and lab results.

There will also be diagnostic criteria posted, which are currently under review by the AAN, Dr. Major said.

The aim is to conduct a pilot study using five academic medical centers and then have the registry publicly available in the fall, he said.