ICYMI Multiple Sclerosis

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

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

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

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

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

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

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

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

—Erik Greb

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

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

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

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

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

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

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

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

—Erik Greb

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

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

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

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

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

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

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

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

—Erik Greb

Teriflunomide significantly reduced the annualized relapse rate in patients with relapsing-remitting multiple sclerosis (MS) by more than one-third, compared with placebo, in the second of two large, randomized, phase III trials that have been conducted with the drug.

The latest study—Teriflunomide Oral in People With Relapsing Multiple Sclerosis (TOWER)—demonstrated that the 14-mg dose of teriflunomide produced a 36% relative risk reduction in the annualized relapse rate, compared with placebo. A 7-mg dose of the oral MS agent yielded a 22% relative risk reduction. Teriflunomide 14 mg, but not 7 mg, was also associated with a significantly lower sustained disability accumulation than placebo.

“These data support the use of teriflunomide as an initial therapy for patients with relapsing-remitting MS and as an option for patients who are unable to tolerate other disease-modifying therapies,” Christian Confavreux, MD, of the Université Claude Bernard Lyon 1 in France, and associates wrote online ahead of print January 22 in Lancet Neurology.

The TOWER trial involved 1,169 patients with relapsing-remitting MS who were randomized to treatment—408 were assigned to teriflunomide 14 mg, 372 to teriflunomide 7 mg, and 389 to placebo. The mean age of patients at study entry was approximately 38—slightly more than 80% were white, 15% were Asian, and 2% were black.

The annualized relapse rates were 0.50 for patients treated with placebo, 0.32 for patients treated with teriflunomide 14 mg, and 0.39 for those treated with teriflunomide 7 mg. Absolute risk reductions for teriflunomide 14 mg and 7 mg versus placebo were –0.11 and –0.18, respectively.

A key secondary end point was sustained accumulation of disability. This outcome was defined as an increase of at least 1 point on the Expanded Disability Status Scale from baseline that persisted for at least 12 weeks. The hazard ratios for the time to sustained accumulation of disability were 0.68 for the 14-mg dose of teriflunomide and 0.95 for the 7-mg dose versus placebo.

“The safety and tolerability profile of teriflunomide ... was similar for both the 7-mg and 14-mg doses, including long-term treatment observations,” the investigators wrote. Common side effects in patients treated with teriflunomide were hair thinning and headache.

—Sara Freeman

Teriflunomide significantly reduced the annualized relapse rate in patients with relapsing-remitting multiple sclerosis (MS) by more than one-third, compared with placebo, in the second of two large, randomized, phase III trials that have been conducted with the drug.

The latest study—Teriflunomide Oral in People With Relapsing Multiple Sclerosis (TOWER)—demonstrated that the 14-mg dose of teriflunomide produced a 36% relative risk reduction in the annualized relapse rate, compared with placebo. A 7-mg dose of the oral MS agent yielded a 22% relative risk reduction. Teriflunomide 14 mg, but not 7 mg, was also associated with a significantly lower sustained disability accumulation than placebo.

“These data support the use of teriflunomide as an initial therapy for patients with relapsing-remitting MS and as an option for patients who are unable to tolerate other disease-modifying therapies,” Christian Confavreux, MD, of the Université Claude Bernard Lyon 1 in France, and associates wrote online ahead of print January 22 in Lancet Neurology.

The TOWER trial involved 1,169 patients with relapsing-remitting MS who were randomized to treatment—408 were assigned to teriflunomide 14 mg, 372 to teriflunomide 7 mg, and 389 to placebo. The mean age of patients at study entry was approximately 38—slightly more than 80% were white, 15% were Asian, and 2% were black.

The annualized relapse rates were 0.50 for patients treated with placebo, 0.32 for patients treated with teriflunomide 14 mg, and 0.39 for those treated with teriflunomide 7 mg. Absolute risk reductions for teriflunomide 14 mg and 7 mg versus placebo were –0.11 and –0.18, respectively.

A key secondary end point was sustained accumulation of disability. This outcome was defined as an increase of at least 1 point on the Expanded Disability Status Scale from baseline that persisted for at least 12 weeks. The hazard ratios for the time to sustained accumulation of disability were 0.68 for the 14-mg dose of teriflunomide and 0.95 for the 7-mg dose versus placebo.

“The safety and tolerability profile of teriflunomide ... was similar for both the 7-mg and 14-mg doses, including long-term treatment observations,” the investigators wrote. Common side effects in patients treated with teriflunomide were hair thinning and headache.

—Sara Freeman

Teriflunomide significantly reduced the annualized relapse rate in patients with relapsing-remitting multiple sclerosis (MS) by more than one-third, compared with placebo, in the second of two large, randomized, phase III trials that have been conducted with the drug.

The latest study—Teriflunomide Oral in People With Relapsing Multiple Sclerosis (TOWER)—demonstrated that the 14-mg dose of teriflunomide produced a 36% relative risk reduction in the annualized relapse rate, compared with placebo. A 7-mg dose of the oral MS agent yielded a 22% relative risk reduction. Teriflunomide 14 mg, but not 7 mg, was also associated with a significantly lower sustained disability accumulation than placebo.

“These data support the use of teriflunomide as an initial therapy for patients with relapsing-remitting MS and as an option for patients who are unable to tolerate other disease-modifying therapies,” Christian Confavreux, MD, of the Université Claude Bernard Lyon 1 in France, and associates wrote online ahead of print January 22 in Lancet Neurology.

The TOWER trial involved 1,169 patients with relapsing-remitting MS who were randomized to treatment—408 were assigned to teriflunomide 14 mg, 372 to teriflunomide 7 mg, and 389 to placebo. The mean age of patients at study entry was approximately 38—slightly more than 80% were white, 15% were Asian, and 2% were black.

The annualized relapse rates were 0.50 for patients treated with placebo, 0.32 for patients treated with teriflunomide 14 mg, and 0.39 for those treated with teriflunomide 7 mg. Absolute risk reductions for teriflunomide 14 mg and 7 mg versus placebo were –0.11 and –0.18, respectively.

A key secondary end point was sustained accumulation of disability. This outcome was defined as an increase of at least 1 point on the Expanded Disability Status Scale from baseline that persisted for at least 12 weeks. The hazard ratios for the time to sustained accumulation of disability were 0.68 for the 14-mg dose of teriflunomide and 0.95 for the 7-mg dose versus placebo.

“The safety and tolerability profile of teriflunomide ... was similar for both the 7-mg and 14-mg doses, including long-term treatment observations,” the investigators wrote. Common side effects in patients treated with teriflunomide were hair thinning and headache.

—Sara Freeman

Multiple sclerosis (MS) has a “striking” association with obesity at age 20 that strongly interacts with genetic susceptibility, according to an analysis of data from two case–control studies that examined environmental and genetic risk factors for MS and was published online ahead of print February 5 in Neurology.

This relationship between adolescent obesity and MS is of the same magnitude as the separate associations between MS and carriage of the high-risk HLA-DRB1*15 allele, absence of the protective HLA-A*02 allele, and smoking, according to Anna Karin Hedström, MD, of the Institute of Environmental Medicine, Karolinska Institutet, Stockholm, and colleagues.

“The biologic explanations for these interactions are far from clear, but the data open [the way] for mechanistically oriented studies,” the study authors stated.

Three previous studies have suggested that obesity in early life may be linked to an increased risk of developing MS later. Dr. Hedström and her colleagues examined this association using data from a Swedish population-based, case–control study and from a separate American case–control study.

In the Swedish study, 1,510 adults with incident MS who were treated at 40 clinics across the country during a seven-year period and 2,017 control subjects completed detailed questionnaires concerning environmental exposures and other factors. The controls were matched for age, sex, and area of residence, and all the participants gave blood samples for HLA typing.

The American study involved 937 white adults with prevalent MS who were members of a single large health maintenance organization covering northern California and 609 white control subjects matched for age, sex, and area of residence. All the participants completed computer-assisted telephone interviews regarding environmental exposures and lifestyle factors.

All the subjects in both studies reported what their height and weight had been at age 20, from which the investigators calculated BMI.

In both studies, participants whose BMI at age 20 was 27 kg/m² or greater showed an increased risk of developing MS later in life, compared with those whose BMI was 18.5 to 21 kg/m². The odds ratios (ORs) were 2.2 for subjects in the Swedish study and 1.8 for those in the American study, Dr. Hedström and her associates said.

Similarly, participants with a slightly lower but still above-normal BMI of 25 to 27 kg/m² had a modestly increased risk of developing MS later in life. The ORs were 1.4 in the Swedish study and 1.3 in the American study.

These ORs were unchanged when a sensitivity analysis was performed, including only the study subjects who had been genotyped.

Participants who carried the high-risk HLA-DRB1*15 gene, did not carry the protective HLA-A*02 gene, and had a BMI of 27 kg/m² or greater at age 20 had an OR of 16.2 for developing later MS, compared with those who had none of those risk factors. In contrast, subjects who had the same HLA profile but had not been obese at age 20 had an OR of 5.1.

The investigators proposed that the low-grade chronic inflammation associated with obesity, together with obesity’s adverse effects on autoimmunity, may increase the risk of HLA-related activation of T cells that attack the CNS.

Both studies were limited in that they were retrospective and relied on participants’ self-reports. In addition, Dr. Hedström and her associates modified the usual definition of obesity for the purposes of their study. The typical standard for obesity is a BMI of greater than 30 kg/m², not greater than 27 kg/m². However, the number of subjects at this level of BMI was too small in the Swedish cohort to allow accurate analysis, so the researchers combined the top two categories of BMI into one designation of obese.

—Mary Ann Moon

Multiple sclerosis (MS) has a “striking” association with obesity at age 20 that strongly interacts with genetic susceptibility, according to an analysis of data from two case–control studies that examined environmental and genetic risk factors for MS and was published online ahead of print February 5 in Neurology.

This relationship between adolescent obesity and MS is of the same magnitude as the separate associations between MS and carriage of the high-risk HLA-DRB1*15 allele, absence of the protective HLA-A*02 allele, and smoking, according to Anna Karin Hedström, MD, of the Institute of Environmental Medicine, Karolinska Institutet, Stockholm, and colleagues.

“The biologic explanations for these interactions are far from clear, but the data open [the way] for mechanistically oriented studies,” the study authors stated.

Three previous studies have suggested that obesity in early life may be linked to an increased risk of developing MS later. Dr. Hedström and her colleagues examined this association using data from a Swedish population-based, case–control study and from a separate American case–control study.

In the Swedish study, 1,510 adults with incident MS who were treated at 40 clinics across the country during a seven-year period and 2,017 control subjects completed detailed questionnaires concerning environmental exposures and other factors. The controls were matched for age, sex, and area of residence, and all the participants gave blood samples for HLA typing.

The American study involved 937 white adults with prevalent MS who were members of a single large health maintenance organization covering northern California and 609 white control subjects matched for age, sex, and area of residence. All the participants completed computer-assisted telephone interviews regarding environmental exposures and lifestyle factors.

All the subjects in both studies reported what their height and weight had been at age 20, from which the investigators calculated BMI.

In both studies, participants whose BMI at age 20 was 27 kg/m² or greater showed an increased risk of developing MS later in life, compared with those whose BMI was 18.5 to 21 kg/m². The odds ratios (ORs) were 2.2 for subjects in the Swedish study and 1.8 for those in the American study, Dr. Hedström and her associates said.

Similarly, participants with a slightly lower but still above-normal BMI of 25 to 27 kg/m² had a modestly increased risk of developing MS later in life. The ORs were 1.4 in the Swedish study and 1.3 in the American study.

These ORs were unchanged when a sensitivity analysis was performed, including only the study subjects who had been genotyped.

Participants who carried the high-risk HLA-DRB1*15 gene, did not carry the protective HLA-A*02 gene, and had a BMI of 27 kg/m² or greater at age 20 had an OR of 16.2 for developing later MS, compared with those who had none of those risk factors. In contrast, subjects who had the same HLA profile but had not been obese at age 20 had an OR of 5.1.

The investigators proposed that the low-grade chronic inflammation associated with obesity, together with obesity’s adverse effects on autoimmunity, may increase the risk of HLA-related activation of T cells that attack the CNS.

Both studies were limited in that they were retrospective and relied on participants’ self-reports. In addition, Dr. Hedström and her associates modified the usual definition of obesity for the purposes of their study. The typical standard for obesity is a BMI of greater than 30 kg/m², not greater than 27 kg/m². However, the number of subjects at this level of BMI was too small in the Swedish cohort to allow accurate analysis, so the researchers combined the top two categories of BMI into one designation of obese.

—Mary Ann Moon

Multiple sclerosis (MS) has a “striking” association with obesity at age 20 that strongly interacts with genetic susceptibility, according to an analysis of data from two case–control studies that examined environmental and genetic risk factors for MS and was published online ahead of print February 5 in Neurology.

This relationship between adolescent obesity and MS is of the same magnitude as the separate associations between MS and carriage of the high-risk HLA-DRB1*15 allele, absence of the protective HLA-A*02 allele, and smoking, according to Anna Karin Hedström, MD, of the Institute of Environmental Medicine, Karolinska Institutet, Stockholm, and colleagues.

“The biologic explanations for these interactions are far from clear, but the data open [the way] for mechanistically oriented studies,” the study authors stated.

Three previous studies have suggested that obesity in early life may be linked to an increased risk of developing MS later. Dr. Hedström and her colleagues examined this association using data from a Swedish population-based, case–control study and from a separate American case–control study.

In the Swedish study, 1,510 adults with incident MS who were treated at 40 clinics across the country during a seven-year period and 2,017 control subjects completed detailed questionnaires concerning environmental exposures and other factors. The controls were matched for age, sex, and area of residence, and all the participants gave blood samples for HLA typing.

The American study involved 937 white adults with prevalent MS who were members of a single large health maintenance organization covering northern California and 609 white control subjects matched for age, sex, and area of residence. All the participants completed computer-assisted telephone interviews regarding environmental exposures and lifestyle factors.

All the subjects in both studies reported what their height and weight had been at age 20, from which the investigators calculated BMI.

In both studies, participants whose BMI at age 20 was 27 kg/m² or greater showed an increased risk of developing MS later in life, compared with those whose BMI was 18.5 to 21 kg/m². The odds ratios (ORs) were 2.2 for subjects in the Swedish study and 1.8 for those in the American study, Dr. Hedström and her associates said.

Similarly, participants with a slightly lower but still above-normal BMI of 25 to 27 kg/m² had a modestly increased risk of developing MS later in life. The ORs were 1.4 in the Swedish study and 1.3 in the American study.

These ORs were unchanged when a sensitivity analysis was performed, including only the study subjects who had been genotyped.

Participants who carried the high-risk HLA-DRB1*15 gene, did not carry the protective HLA-A*02 gene, and had a BMI of 27 kg/m² or greater at age 20 had an OR of 16.2 for developing later MS, compared with those who had none of those risk factors. In contrast, subjects who had the same HLA profile but had not been obese at age 20 had an OR of 5.1.

The investigators proposed that the low-grade chronic inflammation associated with obesity, together with obesity’s adverse effects on autoimmunity, may increase the risk of HLA-related activation of T cells that attack the CNS.

Both studies were limited in that they were retrospective and relied on participants’ self-reports. In addition, Dr. Hedström and her associates modified the usual definition of obesity for the purposes of their study. The typical standard for obesity is a BMI of greater than 30 kg/m², not greater than 27 kg/m². However, the number of subjects at this level of BMI was too small in the Swedish cohort to allow accurate analysis, so the researchers combined the top two categories of BMI into one designation of obese.

—Mary Ann Moon

The FDA has declined to approve alemtuzumab for the treatment of multiple sclerosis (MS), citing a lack of well-controlled data from clinical studies indicating that the benefits outweigh the risks of treatment—a decision that Genzyme, the manufacturer, plans to appeal.

Genzyme announced in a December 30, 2013, statement that the FDA had sent a Complete Response Letter regarding alemtuzumab, an IV-infused monoclonal antibody that binds to the CD52 antigen present at high levels on the surface of T and B lymphocytes. Complete response letters are sent when the FDA decides against approval, with explanations of outstanding issues that need to be resolved.

The proposed indication for alemtuzumab is for treatment of relapsing-remitting MS, with a risk evaluation and mitigation strategy (REMS) that addresses the drug’s serious risks, which include immune thrombocytopenia and thyroid-related adverse events. The company’s proposed trade name for the MS indication for alemtuzumab is Lemtrada.

“The FDA has taken the position that Genzyme has not submitted evidence from adequate and well-controlled studies that demonstrate the benefits of Lemtrada outweigh its serious adverse effects,” according to the Genzyme statement. “The conclusion is related to the design of the completed [phase III] active comparator studies of Lemtrada in relapsing-remitting MS patients.” The FDA also said that one or more “additional active comparator clinical trials of different design and execution” are needed before alemtuzumab is approved for MS, the statement said.

In the statement, Genzyme said that it “strongly disagrees with the FDA’s conclusions and plans to appeal the agency’s decision.”

The FDA’s Concerns
FDA reviewers made their concerns about alemtuzumab clear at a meeting of the FDA’s Peripheral and Central Nervous System advisory committee in November 2013 and in documents provided before the meeting.

The FDA raised concerns about the elevated rates of serious adverse events in patients treated with alemtuzumab and the open-label design of the clinical trials, questioning whether bias had an impact on the efficacy results. Patients and clinicians were not blinded to the treatment in those studies, which compared alemtuzumab to subcutaneous interferon beta-1a (Rebif) in about 1,400 patients and found significant reductions in the relapse rates among those treated with alemtuzumab (49% and 55%), compared with those on Rebif.

The advisory panel did not vote specifically on whether to recommend approval for MS. But while panelists agreed that the unblinded studies were likely biased, the majority voted 12–6 that the manufacturer had provided substantial evidence that the drug was effective for the proposed indication. Several panelists said they would recommend the drug only for patients with severe MS, as a second- or third-line treatment.

Study Investigators Comment
In an interview, one of the investigators in the studies, Jonathan L. Carter, MD, Associate Professor of Neurology at the Mayo Clinic in Scottsdale, Arizona, said the decision is disappointing because patients “who have broken through the standard first-line therapies” have an unmet need for treatment.

Another investigator, Lily K. Jung Henson, MD, concurs. “I don’t think the FDA recognizes that there is a need for alternative therapies with mechanisms of action that patients who have failed multiple therapies need.” Dr. Henson is a neurologist at the Swedish Neuroscience Institute in Seattle. “I have—and most of us who have large patient populations have—patients who have failed everything else, including natalizumab [Tysabri], and are holding on, waiting for this drug to be released and now have no options.”

Dr. Carter acknowledged the FDA reviewers’ concerns about the effect of unblinding, although he pointed out that it can be difficult to maintain blinding of patients and clinicians in studies of products with marked side effects, such as infusion reactions. Despite the potential effects of unblinding on clinical outcome measures, however, he noted that MRI data showing less enhancing lesion activity in alemtuzumab-treated patients, compared with those on Rebif, supported the drug’s efficacy.

On the issue of blinding, another investigator, Christopher C. LaGanke, MD, added that the phase III alemtuzumab studies were rater blinded. “The Expanded Disability Status Scale scores were done by a blinded rater. The relapses were looked at by an adjudication panel that was blinded to any treatment that the patients may have had. The raters of the neurocognitive test, the MS Functional Composite Score, were blinded, and the MRI raters were blinded. So the main assessors were blinded to what the treatment was.” Due to the side effect profiles of the medications, however, patient blinding would have been extremely difficult. “We would like to have everyone blinded in the study. That’s a goal, but here it was not very feasible,” said Dr. LaGanke, who is a private neurologist at North Central Neurology Associates, as well as Director of the Joanne P. LaGanke Multiple Sclerosis Center, both in Cullman, Alabama.

“If the FDA was going to make this decision a priori given the lack of blinding of the study, then I’m concerned that they ethically allowed my patients to take the risk and the sacrifices that they did to enroll and maintain themselves in this study,” Dr. LaGanke said. “And the results were no surprise from the phase II study; so at the end of the day, this has been the most effective treatment we’ve had for relapsing MS, as far as several outcomes, of any of our approved medications, and there was no novel safety signal. It wasn’t that there were differences in the results that would have created a difference in their opinion. So that really concerns me. I feel badly for my patients who went through all of that for naught because of the trial design, because the trial could have been halted from the get go.”

Dr. Henson echoed Dr. LaGanke’s empathy for her own MS patients. “More than anything else, I feel really badly for my patients who have been waiting for this drug because truly it is now back to the drawing board.”

Dr. Carter notes that there is a segment of the MS population—those who are positive for the JC virus antibody and are considered at increased risk for progressive multifocal leukoencephalopathy (PML) with natalizumab (Tysabri) therapy—for whom the options are slim to none.

“There are a lot of patients for whom alemtuzumab is not the right drug,” said Dr. Henson. “It is not as though I am going to recommend this drug to all my patients.” She notes, however, that she has patients with severe MS who have no other options that they can use at this point. “Where I would use this drug is in patients with aggressive disease who have failed the first-line or second-line therapies. It is most likely going to be a third-line therapy for patients who have failed the injectables, failed the orals, and plus or minus failed natalizumab.”

Available Elsewhere, But Not Here
Alemtuzumab was approved by the FDA in 2001 and marketed as Campath for B-cell chronic lymphocytic leukemia in the United States. But in September 2012, the company took Campath off the market and is providing it free of charge to leukemia patients in a distribution program. Alemtuzumab has been approved for MS in the European Union, Canada, and Australia. “It is disappointing that we in this country do not have access to this medication,” said Dr. LaGanke.

“The implications of this drug being approved in other countries,” Dr. Henson added, “are that we are going to be forced to try to find some way to get these patients the medication, get it paid for, and then figure out how to monitor these patients. That’s just crazy.”

—Elizabeth Mechcatie & Glenn Williams

The FDA has declined to approve alemtuzumab for the treatment of multiple sclerosis (MS), citing a lack of well-controlled data from clinical studies indicating that the benefits outweigh the risks of treatment—a decision that Genzyme, the manufacturer, plans to appeal.

Genzyme announced in a December 30, 2013, statement that the FDA had sent a Complete Response Letter regarding alemtuzumab, an IV-infused monoclonal antibody that binds to the CD52 antigen present at high levels on the surface of T and B lymphocytes. Complete response letters are sent when the FDA decides against approval, with explanations of outstanding issues that need to be resolved.

The proposed indication for alemtuzumab is for treatment of relapsing-remitting MS, with a risk evaluation and mitigation strategy (REMS) that addresses the drug’s serious risks, which include immune thrombocytopenia and thyroid-related adverse events. The company’s proposed trade name for the MS indication for alemtuzumab is Lemtrada.

“The FDA has taken the position that Genzyme has not submitted evidence from adequate and well-controlled studies that demonstrate the benefits of Lemtrada outweigh its serious adverse effects,” according to the Genzyme statement. “The conclusion is related to the design of the completed [phase III] active comparator studies of Lemtrada in relapsing-remitting MS patients.” The FDA also said that one or more “additional active comparator clinical trials of different design and execution” are needed before alemtuzumab is approved for MS, the statement said.

In the statement, Genzyme said that it “strongly disagrees with the FDA’s conclusions and plans to appeal the agency’s decision.”

The FDA’s Concerns
FDA reviewers made their concerns about alemtuzumab clear at a meeting of the FDA’s Peripheral and Central Nervous System advisory committee in November 2013 and in documents provided before the meeting.

The FDA raised concerns about the elevated rates of serious adverse events in patients treated with alemtuzumab and the open-label design of the clinical trials, questioning whether bias had an impact on the efficacy results. Patients and clinicians were not blinded to the treatment in those studies, which compared alemtuzumab to subcutaneous interferon beta-1a (Rebif) in about 1,400 patients and found significant reductions in the relapse rates among those treated with alemtuzumab (49% and 55%), compared with those on Rebif.

The advisory panel did not vote specifically on whether to recommend approval for MS. But while panelists agreed that the unblinded studies were likely biased, the majority voted 12–6 that the manufacturer had provided substantial evidence that the drug was effective for the proposed indication. Several panelists said they would recommend the drug only for patients with severe MS, as a second- or third-line treatment.

Study Investigators Comment
In an interview, one of the investigators in the studies, Jonathan L. Carter, MD, Associate Professor of Neurology at the Mayo Clinic in Scottsdale, Arizona, said the decision is disappointing because patients “who have broken through the standard first-line therapies” have an unmet need for treatment.

Another investigator, Lily K. Jung Henson, MD, concurs. “I don’t think the FDA recognizes that there is a need for alternative therapies with mechanisms of action that patients who have failed multiple therapies need.” Dr. Henson is a neurologist at the Swedish Neuroscience Institute in Seattle. “I have—and most of us who have large patient populations have—patients who have failed everything else, including natalizumab [Tysabri], and are holding on, waiting for this drug to be released and now have no options.”

Dr. Carter acknowledged the FDA reviewers’ concerns about the effect of unblinding, although he pointed out that it can be difficult to maintain blinding of patients and clinicians in studies of products with marked side effects, such as infusion reactions. Despite the potential effects of unblinding on clinical outcome measures, however, he noted that MRI data showing less enhancing lesion activity in alemtuzumab-treated patients, compared with those on Rebif, supported the drug’s efficacy.

On the issue of blinding, another investigator, Christopher C. LaGanke, MD, added that the phase III alemtuzumab studies were rater blinded. “The Expanded Disability Status Scale scores were done by a blinded rater. The relapses were looked at by an adjudication panel that was blinded to any treatment that the patients may have had. The raters of the neurocognitive test, the MS Functional Composite Score, were blinded, and the MRI raters were blinded. So the main assessors were blinded to what the treatment was.” Due to the side effect profiles of the medications, however, patient blinding would have been extremely difficult. “We would like to have everyone blinded in the study. That’s a goal, but here it was not very feasible,” said Dr. LaGanke, who is a private neurologist at North Central Neurology Associates, as well as Director of the Joanne P. LaGanke Multiple Sclerosis Center, both in Cullman, Alabama.

“If the FDA was going to make this decision a priori given the lack of blinding of the study, then I’m concerned that they ethically allowed my patients to take the risk and the sacrifices that they did to enroll and maintain themselves in this study,” Dr. LaGanke said. “And the results were no surprise from the phase II study; so at the end of the day, this has been the most effective treatment we’ve had for relapsing MS, as far as several outcomes, of any of our approved medications, and there was no novel safety signal. It wasn’t that there were differences in the results that would have created a difference in their opinion. So that really concerns me. I feel badly for my patients who went through all of that for naught because of the trial design, because the trial could have been halted from the get go.”

Dr. Henson echoed Dr. LaGanke’s empathy for her own MS patients. “More than anything else, I feel really badly for my patients who have been waiting for this drug because truly it is now back to the drawing board.”

Dr. Carter notes that there is a segment of the MS population—those who are positive for the JC virus antibody and are considered at increased risk for progressive multifocal leukoencephalopathy (PML) with natalizumab (Tysabri) therapy—for whom the options are slim to none.

“There are a lot of patients for whom alemtuzumab is not the right drug,” said Dr. Henson. “It is not as though I am going to recommend this drug to all my patients.” She notes, however, that she has patients with severe MS who have no other options that they can use at this point. “Where I would use this drug is in patients with aggressive disease who have failed the first-line or second-line therapies. It is most likely going to be a third-line therapy for patients who have failed the injectables, failed the orals, and plus or minus failed natalizumab.”

Available Elsewhere, But Not Here
Alemtuzumab was approved by the FDA in 2001 and marketed as Campath for B-cell chronic lymphocytic leukemia in the United States. But in September 2012, the company took Campath off the market and is providing it free of charge to leukemia patients in a distribution program. Alemtuzumab has been approved for MS in the European Union, Canada, and Australia. “It is disappointing that we in this country do not have access to this medication,” said Dr. LaGanke.

“The implications of this drug being approved in other countries,” Dr. Henson added, “are that we are going to be forced to try to find some way to get these patients the medication, get it paid for, and then figure out how to monitor these patients. That’s just crazy.”

—Elizabeth Mechcatie & Glenn Williams

The FDA has declined to approve alemtuzumab for the treatment of multiple sclerosis (MS), citing a lack of well-controlled data from clinical studies indicating that the benefits outweigh the risks of treatment—a decision that Genzyme, the manufacturer, plans to appeal.

Genzyme announced in a December 30, 2013, statement that the FDA had sent a Complete Response Letter regarding alemtuzumab, an IV-infused monoclonal antibody that binds to the CD52 antigen present at high levels on the surface of T and B lymphocytes. Complete response letters are sent when the FDA decides against approval, with explanations of outstanding issues that need to be resolved.

The proposed indication for alemtuzumab is for treatment of relapsing-remitting MS, with a risk evaluation and mitigation strategy (REMS) that addresses the drug’s serious risks, which include immune thrombocytopenia and thyroid-related adverse events. The company’s proposed trade name for the MS indication for alemtuzumab is Lemtrada.

“The FDA has taken the position that Genzyme has not submitted evidence from adequate and well-controlled studies that demonstrate the benefits of Lemtrada outweigh its serious adverse effects,” according to the Genzyme statement. “The conclusion is related to the design of the completed [phase III] active comparator studies of Lemtrada in relapsing-remitting MS patients.” The FDA also said that one or more “additional active comparator clinical trials of different design and execution” are needed before alemtuzumab is approved for MS, the statement said.

In the statement, Genzyme said that it “strongly disagrees with the FDA’s conclusions and plans to appeal the agency’s decision.”

The FDA’s Concerns
FDA reviewers made their concerns about alemtuzumab clear at a meeting of the FDA’s Peripheral and Central Nervous System advisory committee in November 2013 and in documents provided before the meeting.

The FDA raised concerns about the elevated rates of serious adverse events in patients treated with alemtuzumab and the open-label design of the clinical trials, questioning whether bias had an impact on the efficacy results. Patients and clinicians were not blinded to the treatment in those studies, which compared alemtuzumab to subcutaneous interferon beta-1a (Rebif) in about 1,400 patients and found significant reductions in the relapse rates among those treated with alemtuzumab (49% and 55%), compared with those on Rebif.

The advisory panel did not vote specifically on whether to recommend approval for MS. But while panelists agreed that the unblinded studies were likely biased, the majority voted 12–6 that the manufacturer had provided substantial evidence that the drug was effective for the proposed indication. Several panelists said they would recommend the drug only for patients with severe MS, as a second- or third-line treatment.

Study Investigators Comment
In an interview, one of the investigators in the studies, Jonathan L. Carter, MD, Associate Professor of Neurology at the Mayo Clinic in Scottsdale, Arizona, said the decision is disappointing because patients “who have broken through the standard first-line therapies” have an unmet need for treatment.

Another investigator, Lily K. Jung Henson, MD, concurs. “I don’t think the FDA recognizes that there is a need for alternative therapies with mechanisms of action that patients who have failed multiple therapies need.” Dr. Henson is a neurologist at the Swedish Neuroscience Institute in Seattle. “I have—and most of us who have large patient populations have—patients who have failed everything else, including natalizumab [Tysabri], and are holding on, waiting for this drug to be released and now have no options.”

Dr. Carter acknowledged the FDA reviewers’ concerns about the effect of unblinding, although he pointed out that it can be difficult to maintain blinding of patients and clinicians in studies of products with marked side effects, such as infusion reactions. Despite the potential effects of unblinding on clinical outcome measures, however, he noted that MRI data showing less enhancing lesion activity in alemtuzumab-treated patients, compared with those on Rebif, supported the drug’s efficacy.

On the issue of blinding, another investigator, Christopher C. LaGanke, MD, added that the phase III alemtuzumab studies were rater blinded. “The Expanded Disability Status Scale scores were done by a blinded rater. The relapses were looked at by an adjudication panel that was blinded to any treatment that the patients may have had. The raters of the neurocognitive test, the MS Functional Composite Score, were blinded, and the MRI raters were blinded. So the main assessors were blinded to what the treatment was.” Due to the side effect profiles of the medications, however, patient blinding would have been extremely difficult. “We would like to have everyone blinded in the study. That’s a goal, but here it was not very feasible,” said Dr. LaGanke, who is a private neurologist at North Central Neurology Associates, as well as Director of the Joanne P. LaGanke Multiple Sclerosis Center, both in Cullman, Alabama.

“If the FDA was going to make this decision a priori given the lack of blinding of the study, then I’m concerned that they ethically allowed my patients to take the risk and the sacrifices that they did to enroll and maintain themselves in this study,” Dr. LaGanke said. “And the results were no surprise from the phase II study; so at the end of the day, this has been the most effective treatment we’ve had for relapsing MS, as far as several outcomes, of any of our approved medications, and there was no novel safety signal. It wasn’t that there were differences in the results that would have created a difference in their opinion. So that really concerns me. I feel badly for my patients who went through all of that for naught because of the trial design, because the trial could have been halted from the get go.”

Dr. Henson echoed Dr. LaGanke’s empathy for her own MS patients. “More than anything else, I feel really badly for my patients who have been waiting for this drug because truly it is now back to the drawing board.”

Dr. Carter notes that there is a segment of the MS population—those who are positive for the JC virus antibody and are considered at increased risk for progressive multifocal leukoencephalopathy (PML) with natalizumab (Tysabri) therapy—for whom the options are slim to none.

“There are a lot of patients for whom alemtuzumab is not the right drug,” said Dr. Henson. “It is not as though I am going to recommend this drug to all my patients.” She notes, however, that she has patients with severe MS who have no other options that they can use at this point. “Where I would use this drug is in patients with aggressive disease who have failed the first-line or second-line therapies. It is most likely going to be a third-line therapy for patients who have failed the injectables, failed the orals, and plus or minus failed natalizumab.”

Available Elsewhere, But Not Here
Alemtuzumab was approved by the FDA in 2001 and marketed as Campath for B-cell chronic lymphocytic leukemia in the United States. But in September 2012, the company took Campath off the market and is providing it free of charge to leukemia patients in a distribution program. Alemtuzumab has been approved for MS in the European Union, Canada, and Australia. “It is disappointing that we in this country do not have access to this medication,” said Dr. LaGanke.

“The implications of this drug being approved in other countries,” Dr. Henson added, “are that we are going to be forced to try to find some way to get these patients the medication, get it paid for, and then figure out how to monitor these patients. That’s just crazy.”

—Elizabeth Mechcatie & Glenn Williams

COPENHAGEN—In patients with multiple sclerosis (MS), IV immunoglobulin (IV Ig) infusions increase John Cunningham virus (JCV) antibody levels, which may result in seropositivity, according to a study presented at the 29th Congress of the European Committee for Treatment and Research in MS (ECTRIMS). This finding suggests that risk stratification rules based on JCV antibody status may not apply to patients recently treated with IV Ig.

The concentration of JCV antibodies is likely to decrease over time after IV Ig is discontinued. “The lack of consistent sampling in our patients prevents us from making firm conclusions as to the likelihood of return to innate (pre–IV Ig) JCV antibody levels after stopping IV Ig,” said Ilya Kister, MD, Assistant Professor of Neurology at New York University School of Medicine in New York City. He and his colleagues are investigating whether age, IV Ig therapy duration, JCV antibody concentration during IV Ig therapy, and time from IV Ig administration to JCV antibody testing affect JCV antibody concentration after IV Ig discontinuation.

The STRATIFY Trial
Dr. Kister and colleagues examined data for 102 patients with MS who participated in the STRATIFY-2 trial and had monthly infusions of IV Ig (0.7 g/kg) at any point during the trial. The researchers also analyzed results from the commercial STRATIFY JCV and STRATIFY JCV Dx SELECT assays for participants in STRATIFY-2 who had been exposed to IV Ig. The team calculated the relative concentration of polyclonal JCV antibodies as JCV monoclonal antibody equivalents by interpolating the optical density or index values for each sample against a reference curve prepared using a monoclonal antibody to JCV.

JCV Antibody Levels Decreased Over Time
Of the 1,251 patients enrolled in STRATIFY-2, 1,143 were not exposed to IV Ig, and 58% of these patients were seropositive for JCV antibody. In contrast, all 71 STRATIFY-2 enrollees who were tested for JCV antibodies within 30 days of IV Ig administration were seropositive. Sixteen of 25 (64%) STRATIFY-2 enrollees who were exposed to IV Ig more than 30 days after IV Ig administration were seropositive, which suggests that the level of JCV antibodies in IV Ig–exposed patients declines over time.

The median relative concentration of JCV antibodies was 0 µg/mL for patients not yet exposed to IV Ig. For patients receiving IV Ig, the median relative concentration of JCV antibodies was approximately 2 µg/mL. At 30 days after IV Ig exposure, the median relative concentration of JCV antibodies was less than 1 µg/mL.

The researchers observed a significant decrease or complete elimination of JCV antibody relative concentrations for many samples after discontinuation of IV Ig, which implies a reduction of passively transferred JCV antibody levels over time. “However, without pre–IV Ig samples, it is not possible to determine if subjects return to baseline levels or not,” said Dr. Kister.

—Erik Greb

COPENHAGEN—In patients with multiple sclerosis (MS), IV immunoglobulin (IV Ig) infusions increase John Cunningham virus (JCV) antibody levels, which may result in seropositivity, according to a study presented at the 29th Congress of the European Committee for Treatment and Research in MS (ECTRIMS). This finding suggests that risk stratification rules based on JCV antibody status may not apply to patients recently treated with IV Ig.

The concentration of JCV antibodies is likely to decrease over time after IV Ig is discontinued. “The lack of consistent sampling in our patients prevents us from making firm conclusions as to the likelihood of return to innate (pre–IV Ig) JCV antibody levels after stopping IV Ig,” said Ilya Kister, MD, Assistant Professor of Neurology at New York University School of Medicine in New York City. He and his colleagues are investigating whether age, IV Ig therapy duration, JCV antibody concentration during IV Ig therapy, and time from IV Ig administration to JCV antibody testing affect JCV antibody concentration after IV Ig discontinuation.

The STRATIFY Trial
Dr. Kister and colleagues examined data for 102 patients with MS who participated in the STRATIFY-2 trial and had monthly infusions of IV Ig (0.7 g/kg) at any point during the trial. The researchers also analyzed results from the commercial STRATIFY JCV and STRATIFY JCV Dx SELECT assays for participants in STRATIFY-2 who had been exposed to IV Ig. The team calculated the relative concentration of polyclonal JCV antibodies as JCV monoclonal antibody equivalents by interpolating the optical density or index values for each sample against a reference curve prepared using a monoclonal antibody to JCV.

JCV Antibody Levels Decreased Over Time
Of the 1,251 patients enrolled in STRATIFY-2, 1,143 were not exposed to IV Ig, and 58% of these patients were seropositive for JCV antibody. In contrast, all 71 STRATIFY-2 enrollees who were tested for JCV antibodies within 30 days of IV Ig administration were seropositive. Sixteen of 25 (64%) STRATIFY-2 enrollees who were exposed to IV Ig more than 30 days after IV Ig administration were seropositive, which suggests that the level of JCV antibodies in IV Ig–exposed patients declines over time.

The median relative concentration of JCV antibodies was 0 µg/mL for patients not yet exposed to IV Ig. For patients receiving IV Ig, the median relative concentration of JCV antibodies was approximately 2 µg/mL. At 30 days after IV Ig exposure, the median relative concentration of JCV antibodies was less than 1 µg/mL.

The researchers observed a significant decrease or complete elimination of JCV antibody relative concentrations for many samples after discontinuation of IV Ig, which implies a reduction of passively transferred JCV antibody levels over time. “However, without pre–IV Ig samples, it is not possible to determine if subjects return to baseline levels or not,” said Dr. Kister.

—Erik Greb

COPENHAGEN—In patients with multiple sclerosis (MS), IV immunoglobulin (IV Ig) infusions increase John Cunningham virus (JCV) antibody levels, which may result in seropositivity, according to a study presented at the 29th Congress of the European Committee for Treatment and Research in MS (ECTRIMS). This finding suggests that risk stratification rules based on JCV antibody status may not apply to patients recently treated with IV Ig.

The concentration of JCV antibodies is likely to decrease over time after IV Ig is discontinued. “The lack of consistent sampling in our patients prevents us from making firm conclusions as to the likelihood of return to innate (pre–IV Ig) JCV antibody levels after stopping IV Ig,” said Ilya Kister, MD, Assistant Professor of Neurology at New York University School of Medicine in New York City. He and his colleagues are investigating whether age, IV Ig therapy duration, JCV antibody concentration during IV Ig therapy, and time from IV Ig administration to JCV antibody testing affect JCV antibody concentration after IV Ig discontinuation.

The STRATIFY Trial
Dr. Kister and colleagues examined data for 102 patients with MS who participated in the STRATIFY-2 trial and had monthly infusions of IV Ig (0.7 g/kg) at any point during the trial. The researchers also analyzed results from the commercial STRATIFY JCV and STRATIFY JCV Dx SELECT assays for participants in STRATIFY-2 who had been exposed to IV Ig. The team calculated the relative concentration of polyclonal JCV antibodies as JCV monoclonal antibody equivalents by interpolating the optical density or index values for each sample against a reference curve prepared using a monoclonal antibody to JCV.

JCV Antibody Levels Decreased Over Time
Of the 1,251 patients enrolled in STRATIFY-2, 1,143 were not exposed to IV Ig, and 58% of these patients were seropositive for JCV antibody. In contrast, all 71 STRATIFY-2 enrollees who were tested for JCV antibodies within 30 days of IV Ig administration were seropositive. Sixteen of 25 (64%) STRATIFY-2 enrollees who were exposed to IV Ig more than 30 days after IV Ig administration were seropositive, which suggests that the level of JCV antibodies in IV Ig–exposed patients declines over time.

The median relative concentration of JCV antibodies was 0 µg/mL for patients not yet exposed to IV Ig. For patients receiving IV Ig, the median relative concentration of JCV antibodies was approximately 2 µg/mL. At 30 days after IV Ig exposure, the median relative concentration of JCV antibodies was less than 1 µg/mL.

The researchers observed a significant decrease or complete elimination of JCV antibody relative concentrations for many samples after discontinuation of IV Ig, which implies a reduction of passively transferred JCV antibody levels over time. “However, without pre–IV Ig samples, it is not possible to determine if subjects return to baseline levels or not,” said Dr. Kister.

—Erik Greb

COPENHAGEN—Levels of glutamate may decline almost 10 times faster over time in patients with secondary progressive multiple sclerosis (MS) than in healthy controls, according to a study presented at the 29th Congress of the European Committee for Treatment and Research in MS (ECTRIMS). Levels of glutamine and the combination of glutamate and glutamine also may decrease faster in patients with secondary progressive MS than in healthy controls.

“The combined decline of glutamate and glutamine suggests a loss of synapse function or a loss of synapses over time,” said Erin MacMillan, PhD, postdoctoral research fellow at the University of British Columbia in Vancouver. The two metabolites may offer new biomarkers of progression and feasible outcome measures for multicenter clinical trials in secondary progressive MS.

“Few longitudinal proton magnetic resonance spectroscopy (1H-MRS) studies have been performed in a cohort of progressive MS patients, and, to our knowledge, this is the first with sufficient spectral quality and data analysis methods to reliably detect both glutamate and glutamine,” she added.

Monitoring Metabolite Concentrations in Patients With MS
Dr. MacMillan and colleagues analyzed data for patients with secondary progressive MS who were enrolled in a clinical trial at the University of British Columbia. The investigators focused on 47 subjects who completed MRS scans for at least two time points, including baseline, year one, and year two. Participants (median age, 51.7; median Expanded Disability Status Scale score, 6.0) were not on other disease-modifying therapies within three months before the start of the trial.

The researchers used 1H-MRS to examine concentrations of glutamate, glutamine, the combination of glutamate and glutamine, myo-inositol, choline-containing compounds, and other metabolites in a primarily white-matter region inside the brain. Concentration differences from year one and year two to baseline were tested with the two-sided Wilcoxon signed rank test. Concentrations at all three time points for each metabolite were fit with a linear random effects model to allow for individual offsets but the same slope across subjects.

Concentrations of Most Metabolites Changed Little
Participants’ level of N-acetyl-aspartate + N-acetyl-aspartylglutamate (tNAA) had no significant relationship with time. In contrast, glutamate concentration decreased from approximately 6.5 mM at baseline to approximately 6 mM at year two. Its rate of decrease was 4.9% per year. Glutamine concentration declined from approximately 2.5 mM at baseline to approximately 2 mM at year two. Its rate of decrease was 13.1% per year.

The lack of change in tNAA, creatine and phosphocreatine, and choline-containing compounds over two years is consistent with a previous study of participants with primary progressive MS over three years, said Dr. MacMillan.

“Glutamate and glutamine, as measured by 1H-MRS, are promising new biomarkers of MS disease progression that may be more sensitive than current state-of-the-art techniques, such as brain atrophy,” Dr. MacMillan told Neurology Reviews. “These new biomarkers may prove to be better prognostic measures and determinants of treatment efficacy.

“We hope to repeat this study with two regions of interest—one clearly within the cortical gray matter, and one clearly within the white matter—to distinguish whether the changes we have seen with disease progression are taking place in the gray matter or the white matter,” she concluded.

—Erik Greb

COPENHAGEN—Levels of glutamate may decline almost 10 times faster over time in patients with secondary progressive multiple sclerosis (MS) than in healthy controls, according to a study presented at the 29th Congress of the European Committee for Treatment and Research in MS (ECTRIMS). Levels of glutamine and the combination of glutamate and glutamine also may decrease faster in patients with secondary progressive MS than in healthy controls.

“The combined decline of glutamate and glutamine suggests a loss of synapse function or a loss of synapses over time,” said Erin MacMillan, PhD, postdoctoral research fellow at the University of British Columbia in Vancouver. The two metabolites may offer new biomarkers of progression and feasible outcome measures for multicenter clinical trials in secondary progressive MS.

“Few longitudinal proton magnetic resonance spectroscopy (1H-MRS) studies have been performed in a cohort of progressive MS patients, and, to our knowledge, this is the first with sufficient spectral quality and data analysis methods to reliably detect both glutamate and glutamine,” she added.

Monitoring Metabolite Concentrations in Patients With MS
Dr. MacMillan and colleagues analyzed data for patients with secondary progressive MS who were enrolled in a clinical trial at the University of British Columbia. The investigators focused on 47 subjects who completed MRS scans for at least two time points, including baseline, year one, and year two. Participants (median age, 51.7; median Expanded Disability Status Scale score, 6.0) were not on other disease-modifying therapies within three months before the start of the trial.

The researchers used 1H-MRS to examine concentrations of glutamate, glutamine, the combination of glutamate and glutamine, myo-inositol, choline-containing compounds, and other metabolites in a primarily white-matter region inside the brain. Concentration differences from year one and year two to baseline were tested with the two-sided Wilcoxon signed rank test. Concentrations at all three time points for each metabolite were fit with a linear random effects model to allow for individual offsets but the same slope across subjects.

Concentrations of Most Metabolites Changed Little
Participants’ level of N-acetyl-aspartate + N-acetyl-aspartylglutamate (tNAA) had no significant relationship with time. In contrast, glutamate concentration decreased from approximately 6.5 mM at baseline to approximately 6 mM at year two. Its rate of decrease was 4.9% per year. Glutamine concentration declined from approximately 2.5 mM at baseline to approximately 2 mM at year two. Its rate of decrease was 13.1% per year.

The lack of change in tNAA, creatine and phosphocreatine, and choline-containing compounds over two years is consistent with a previous study of participants with primary progressive MS over three years, said Dr. MacMillan.

“Glutamate and glutamine, as measured by 1H-MRS, are promising new biomarkers of MS disease progression that may be more sensitive than current state-of-the-art techniques, such as brain atrophy,” Dr. MacMillan told Neurology Reviews. “These new biomarkers may prove to be better prognostic measures and determinants of treatment efficacy.

“We hope to repeat this study with two regions of interest—one clearly within the cortical gray matter, and one clearly within the white matter—to distinguish whether the changes we have seen with disease progression are taking place in the gray matter or the white matter,” she concluded.

—Erik Greb

COPENHAGEN—Levels of glutamate may decline almost 10 times faster over time in patients with secondary progressive multiple sclerosis (MS) than in healthy controls, according to a study presented at the 29th Congress of the European Committee for Treatment and Research in MS (ECTRIMS). Levels of glutamine and the combination of glutamate and glutamine also may decrease faster in patients with secondary progressive MS than in healthy controls.

“The combined decline of glutamate and glutamine suggests a loss of synapse function or a loss of synapses over time,” said Erin MacMillan, PhD, postdoctoral research fellow at the University of British Columbia in Vancouver. The two metabolites may offer new biomarkers of progression and feasible outcome measures for multicenter clinical trials in secondary progressive MS.

“Few longitudinal proton magnetic resonance spectroscopy (1H-MRS) studies have been performed in a cohort of progressive MS patients, and, to our knowledge, this is the first with sufficient spectral quality and data analysis methods to reliably detect both glutamate and glutamine,” she added.

Monitoring Metabolite Concentrations in Patients With MS
Dr. MacMillan and colleagues analyzed data for patients with secondary progressive MS who were enrolled in a clinical trial at the University of British Columbia. The investigators focused on 47 subjects who completed MRS scans for at least two time points, including baseline, year one, and year two. Participants (median age, 51.7; median Expanded Disability Status Scale score, 6.0) were not on other disease-modifying therapies within three months before the start of the trial.

The researchers used 1H-MRS to examine concentrations of glutamate, glutamine, the combination of glutamate and glutamine, myo-inositol, choline-containing compounds, and other metabolites in a primarily white-matter region inside the brain. Concentration differences from year one and year two to baseline were tested with the two-sided Wilcoxon signed rank test. Concentrations at all three time points for each metabolite were fit with a linear random effects model to allow for individual offsets but the same slope across subjects.

Concentrations of Most Metabolites Changed Little
Participants’ level of N-acetyl-aspartate + N-acetyl-aspartylglutamate (tNAA) had no significant relationship with time. In contrast, glutamate concentration decreased from approximately 6.5 mM at baseline to approximately 6 mM at year two. Its rate of decrease was 4.9% per year. Glutamine concentration declined from approximately 2.5 mM at baseline to approximately 2 mM at year two. Its rate of decrease was 13.1% per year.

The lack of change in tNAA, creatine and phosphocreatine, and choline-containing compounds over two years is consistent with a previous study of participants with primary progressive MS over three years, said Dr. MacMillan.

“Glutamate and glutamine, as measured by 1H-MRS, are promising new biomarkers of MS disease progression that may be more sensitive than current state-of-the-art techniques, such as brain atrophy,” Dr. MacMillan told Neurology Reviews. “These new biomarkers may prove to be better prognostic measures and determinants of treatment efficacy.

“We hope to repeat this study with two regions of interest—one clearly within the cortical gray matter, and one clearly within the white matter—to distinguish whether the changes we have seen with disease progression are taking place in the gray matter or the white matter,” she concluded.

—Erik Greb

COPENHAGEN—The interaction between smoking and Epstein–Barr virus (EBV), two risk factors for multiple sclerosis (MS), may depend on age, according to research presented at the 29th Congress of the European Committee for Treatment and Research in MS. Smoking and EBV appear to have a negative interaction in adults younger than 26 and a positive interaction in adults older than 26.

“The negative interaction in younger subjects suggests that EBV and smoking as risk factors for MS act independently from an etiologic perspective,” said Jonatan Salzer, MD, PhD, a physician at Umeå University in Sweden. “The positive interaction in older subjects may suggest that the two risk factors share a common pathophysiologic pathway, most obviously that smoking enhances the antibody response against EBV after several years with MS.”

Analysis of Prospectively Collected Blood Samples
In a nested case–control study, Dr. Salzer and colleagues analyzed prospectively collected biobank blood samples. Of the patient population, 192 persons subsequently developed MS and 384 participants served as matched controls. The researchers measured levels of cotinine, a nicotine metabolite, in the samples with an immunoassay. Anti-EBNA-1 IgG antibodies were measured using an enzyme-linked immunosorbent assay (ELISA).

The investigators considered participants with cotinine levels of 10 ng/mL or higher to be smokers. The group also divided anti-EBNA-1 IgG levels at the median among controls. Dr. Salzer and colleagues assessed interaction on the additive and multiplicative scales and estimated the effects of the risk factors across strata of each other.

Smoking and EBV Did Not Interact Significantly
When analyzing the entire cohort, the researchers found no statistically significant interactions between smoking and EBV. The mean level of anti-EBNA-1 IgG was higher among subjects with cotinine levels of 10 ng/mL or higher than among participants with cotinine levels lower than 10 ng/mL. The investigators found no heterogeneity of effects of one risk factor across strata of the other. When the researchers analyzed interaction on the additive and multiplicative scales, they found that the group of patients with both risk factors (ie, high levels of anti-EBNA-1 IgG and cotinine level of 10 ng/mL or greater) had a slightly higher odds ratio of MS than predicted by the independent effects of the risk factors.

An analysis restricted to younger subjects indicated that the odds ratio for the patients with both risk factors was in between that of the additive interaction and that of the multiplicative interaction. The effects of both risk factors showed nonsignificant signs of heterogeneity, however. Among older patients, the pattern of heterogeneity of effects across strata was the opposite of that among younger patients, the researchers reported.

—Erik Greb

COPENHAGEN—The interaction between smoking and Epstein–Barr virus (EBV), two risk factors for multiple sclerosis (MS), may depend on age, according to research presented at the 29th Congress of the European Committee for Treatment and Research in MS. Smoking and EBV appear to have a negative interaction in adults younger than 26 and a positive interaction in adults older than 26.

“The negative interaction in younger subjects suggests that EBV and smoking as risk factors for MS act independently from an etiologic perspective,” said Jonatan Salzer, MD, PhD, a physician at Umeå University in Sweden. “The positive interaction in older subjects may suggest that the two risk factors share a common pathophysiologic pathway, most obviously that smoking enhances the antibody response against EBV after several years with MS.”

Analysis of Prospectively Collected Blood Samples
In a nested case–control study, Dr. Salzer and colleagues analyzed prospectively collected biobank blood samples. Of the patient population, 192 persons subsequently developed MS and 384 participants served as matched controls. The researchers measured levels of cotinine, a nicotine metabolite, in the samples with an immunoassay. Anti-EBNA-1 IgG antibodies were measured using an enzyme-linked immunosorbent assay (ELISA).

The investigators considered participants with cotinine levels of 10 ng/mL or higher to be smokers. The group also divided anti-EBNA-1 IgG levels at the median among controls. Dr. Salzer and colleagues assessed interaction on the additive and multiplicative scales and estimated the effects of the risk factors across strata of each other.

Smoking and EBV Did Not Interact Significantly
When analyzing the entire cohort, the researchers found no statistically significant interactions between smoking and EBV. The mean level of anti-EBNA-1 IgG was higher among subjects with cotinine levels of 10 ng/mL or higher than among participants with cotinine levels lower than 10 ng/mL. The investigators found no heterogeneity of effects of one risk factor across strata of the other. When the researchers analyzed interaction on the additive and multiplicative scales, they found that the group of patients with both risk factors (ie, high levels of anti-EBNA-1 IgG and cotinine level of 10 ng/mL or greater) had a slightly higher odds ratio of MS than predicted by the independent effects of the risk factors.

An analysis restricted to younger subjects indicated that the odds ratio for the patients with both risk factors was in between that of the additive interaction and that of the multiplicative interaction. The effects of both risk factors showed nonsignificant signs of heterogeneity, however. Among older patients, the pattern of heterogeneity of effects across strata was the opposite of that among younger patients, the researchers reported.

—Erik Greb

COPENHAGEN—The interaction between smoking and Epstein–Barr virus (EBV), two risk factors for multiple sclerosis (MS), may depend on age, according to research presented at the 29th Congress of the European Committee for Treatment and Research in MS. Smoking and EBV appear to have a negative interaction in adults younger than 26 and a positive interaction in adults older than 26.

“The negative interaction in younger subjects suggests that EBV and smoking as risk factors for MS act independently from an etiologic perspective,” said Jonatan Salzer, MD, PhD, a physician at Umeå University in Sweden. “The positive interaction in older subjects may suggest that the two risk factors share a common pathophysiologic pathway, most obviously that smoking enhances the antibody response against EBV after several years with MS.”

Analysis of Prospectively Collected Blood Samples
In a nested case–control study, Dr. Salzer and colleagues analyzed prospectively collected biobank blood samples. Of the patient population, 192 persons subsequently developed MS and 384 participants served as matched controls. The researchers measured levels of cotinine, a nicotine metabolite, in the samples with an immunoassay. Anti-EBNA-1 IgG antibodies were measured using an enzyme-linked immunosorbent assay (ELISA).

The investigators considered participants with cotinine levels of 10 ng/mL or higher to be smokers. The group also divided anti-EBNA-1 IgG levels at the median among controls. Dr. Salzer and colleagues assessed interaction on the additive and multiplicative scales and estimated the effects of the risk factors across strata of each other.

Smoking and EBV Did Not Interact Significantly
When analyzing the entire cohort, the researchers found no statistically significant interactions between smoking and EBV. The mean level of anti-EBNA-1 IgG was higher among subjects with cotinine levels of 10 ng/mL or higher than among participants with cotinine levels lower than 10 ng/mL. The investigators found no heterogeneity of effects of one risk factor across strata of the other. When the researchers analyzed interaction on the additive and multiplicative scales, they found that the group of patients with both risk factors (ie, high levels of anti-EBNA-1 IgG and cotinine level of 10 ng/mL or greater) had a slightly higher odds ratio of MS than predicted by the independent effects of the risk factors.

An analysis restricted to younger subjects indicated that the odds ratio for the patients with both risk factors was in between that of the additive interaction and that of the multiplicative interaction. The effects of both risk factors showed nonsignificant signs of heterogeneity, however. Among older patients, the pattern of heterogeneity of effects across strata was the opposite of that among younger patients, the researchers reported.

—Erik Greb

COPENHAGEN—At the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Sten Fredrikson, MD, Professor of Neurology at the Department of Clinical Neuroscience at the Karolinska Institute in Stockholm, summarized the arguments for and against early MS treatment.

“As it turns out, MS is really a moving target,” he said. “It’s not the same thing now as [it was] 20 or 30 years ago.” Prof. Fredrikson pointed to recent updates to MS diagnostic criteria that allow for immediate diagnosis if the first MRI shows dissemination in space (DIS) and dissemination in time (DIT). “When we talk about early MS, it has probably been ongoing for quite a long time, not only in clinically isolated syndrome (CIS), but also before that, without any clinical symptoms,” he explained. This new diagnostic classification is called radiologically isolated syndrome (RIS).

The Arguments for Early Treatment
A comparison of the 2010 diagnostic criteria with the 2005 criteria showed that 30% of CIS patients can now be diagnosed as having MS after a single MRI. The significance of altering these diagnostic margins is not only that it moves up the diagnostic timeline for individual patients, but that it also reclassifies into a treatment category a large percentage of patients who previously would not have been treated. “The time to diagnosis differed significantly between the 2005 and 2010 criteria, so the conclusion will be that the CIS group will probably be reduced after the introduction of the new MS criteria, and we will have more relapsing-remitting cases,” Prof. Fredrikson explained.

The main presenting complaint for patients referred for an MRI that identifies RIS is headache, he reported. “About two-thirds of the patients with RIS show radiologic progression over the next five years, and about one-third develop neurologic symptoms,” said Prof. Fredrikson.

“The question that we come back to is, of course, should RIS also be treated?” Prof. Fredrikson looked at the current understanding of MS pathogenesis, according to which, inflammation appears to be dominant in early phases of the disease, while degeneration dominates in later, progressive disease. “The drugs we have are anti-inflammatory, which means [that] these drugs are most effective during the anti-inflammatory phase,” he said. The rationale for early treatment (ie, at the point of CIS or RIS) is the prevention of irreversible axonal damage that leads to later disability. Cognitive effects resulting from early gray matter changes also may be averted.

One of the interesting arguments for early treatment in MS comes from a knowledge base borrowed from hypertension studies, Prof. Fredrikson explained, where it has been established that the number of patients with mildly elevated blood pressure who need to be treated to prevent one stroke is 118. In studies of CIS, numbers needed to treat are reported in the BENEFIT and CHAMPS trials as six and seven patients, respectively. “This [result] speaks in favor of the treatments that we can offer the patients having clinical effect,” said Prof. Fredrikson.

Questions of long-term efficacy are beginning to be answered, he said, pointing to recent studies by Trojano et al and Tedeholm et al that indicate a longer time to progression, as well as a study by Goodin et al that showed improved long-term survival with earlier intervention.

The Arguments Against Early Treatment
Still, Prof. Fredrikson said, there are a number of arguments against early treatment, the most significant of which is the potential for misdiagnosis. “Everyone who has been working with the disease for some years has seen so-called typical CIS that has been caused by other reasons,” he explained, emphasizing that it is important when managing patients with CIS to exclude other pathologies. “One way of doing that is by looking for the red flags described by Miller et al,” he said.

Data from the BENEFIT trial show that 85% of CIS patients will develop MS within two years based on MRI findings. Long-term data are not yet available on CIS patients, but benign MS appears to be a rare phenomenon, said Prof. Fredrikson. Therefore, 15 to 20 years of disease-modifying therapy in these few patients may entail more risks than benefits.

Patient Selection Is Key
Prof. Fredrikson offered practical recommendations for early treatment approaches. Initiation of therapy is appropriate for patients whose symptoms have no explanation other than MS, and for CIS with demyelination, he said, noting that the decision to treat or not to treat is less clear in CIS with MRI not showing DIT and DIS. In these cases, he recommended repeating the MRI in three to six months, but noted that starting therapy is also an option. Finally, for patients with RIS who have clinical symptoms with no better explanation, the notion of treatment is more controversial. “There are no studies or evidence to indicate how to handle these patients,” concluded Prof. Fredrikson, suggesting that waiting three to six months before repeating the MRI to decide on treatment is the most reasonable approach.

“Can we select patients that will benefit from early treatment?” asked Prof. Fredrikson. “This is still an ongoing area, but in our practical everyday life, there is not enough evidence on these markers to select individual patients.”

—Linda Peckel

COPENHAGEN—At the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Sten Fredrikson, MD, Professor of Neurology at the Department of Clinical Neuroscience at the Karolinska Institute in Stockholm, summarized the arguments for and against early MS treatment.

“As it turns out, MS is really a moving target,” he said. “It’s not the same thing now as [it was] 20 or 30 years ago.” Prof. Fredrikson pointed to recent updates to MS diagnostic criteria that allow for immediate diagnosis if the first MRI shows dissemination in space (DIS) and dissemination in time (DIT). “When we talk about early MS, it has probably been ongoing for quite a long time, not only in clinically isolated syndrome (CIS), but also before that, without any clinical symptoms,” he explained. This new diagnostic classification is called radiologically isolated syndrome (RIS).

The Arguments for Early Treatment
A comparison of the 2010 diagnostic criteria with the 2005 criteria showed that 30% of CIS patients can now be diagnosed as having MS after a single MRI. The significance of altering these diagnostic margins is not only that it moves up the diagnostic timeline for individual patients, but that it also reclassifies into a treatment category a large percentage of patients who previously would not have been treated. “The time to diagnosis differed significantly between the 2005 and 2010 criteria, so the conclusion will be that the CIS group will probably be reduced after the introduction of the new MS criteria, and we will have more relapsing-remitting cases,” Prof. Fredrikson explained.

The main presenting complaint for patients referred for an MRI that identifies RIS is headache, he reported. “About two-thirds of the patients with RIS show radiologic progression over the next five years, and about one-third develop neurologic symptoms,” said Prof. Fredrikson.

“The question that we come back to is, of course, should RIS also be treated?” Prof. Fredrikson looked at the current understanding of MS pathogenesis, according to which, inflammation appears to be dominant in early phases of the disease, while degeneration dominates in later, progressive disease. “The drugs we have are anti-inflammatory, which means [that] these drugs are most effective during the anti-inflammatory phase,” he said. The rationale for early treatment (ie, at the point of CIS or RIS) is the prevention of irreversible axonal damage that leads to later disability. Cognitive effects resulting from early gray matter changes also may be averted.

One of the interesting arguments for early treatment in MS comes from a knowledge base borrowed from hypertension studies, Prof. Fredrikson explained, where it has been established that the number of patients with mildly elevated blood pressure who need to be treated to prevent one stroke is 118. In studies of CIS, numbers needed to treat are reported in the BENEFIT and CHAMPS trials as six and seven patients, respectively. “This [result] speaks in favor of the treatments that we can offer the patients having clinical effect,” said Prof. Fredrikson.

Questions of long-term efficacy are beginning to be answered, he said, pointing to recent studies by Trojano et al and Tedeholm et al that indicate a longer time to progression, as well as a study by Goodin et al that showed improved long-term survival with earlier intervention.

The Arguments Against Early Treatment
Still, Prof. Fredrikson said, there are a number of arguments against early treatment, the most significant of which is the potential for misdiagnosis. “Everyone who has been working with the disease for some years has seen so-called typical CIS that has been caused by other reasons,” he explained, emphasizing that it is important when managing patients with CIS to exclude other pathologies. “One way of doing that is by looking for the red flags described by Miller et al,” he said.

Data from the BENEFIT trial show that 85% of CIS patients will develop MS within two years based on MRI findings. Long-term data are not yet available on CIS patients, but benign MS appears to be a rare phenomenon, said Prof. Fredrikson. Therefore, 15 to 20 years of disease-modifying therapy in these few patients may entail more risks than benefits.

Patient Selection Is Key
Prof. Fredrikson offered practical recommendations for early treatment approaches. Initiation of therapy is appropriate for patients whose symptoms have no explanation other than MS, and for CIS with demyelination, he said, noting that the decision to treat or not to treat is less clear in CIS with MRI not showing DIT and DIS. In these cases, he recommended repeating the MRI in three to six months, but noted that starting therapy is also an option. Finally, for patients with RIS who have clinical symptoms with no better explanation, the notion of treatment is more controversial. “There are no studies or evidence to indicate how to handle these patients,” concluded Prof. Fredrikson, suggesting that waiting three to six months before repeating the MRI to decide on treatment is the most reasonable approach.

“Can we select patients that will benefit from early treatment?” asked Prof. Fredrikson. “This is still an ongoing area, but in our practical everyday life, there is not enough evidence on these markers to select individual patients.”

—Linda Peckel

COPENHAGEN—At the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Sten Fredrikson, MD, Professor of Neurology at the Department of Clinical Neuroscience at the Karolinska Institute in Stockholm, summarized the arguments for and against early MS treatment.

“As it turns out, MS is really a moving target,” he said. “It’s not the same thing now as [it was] 20 or 30 years ago.” Prof. Fredrikson pointed to recent updates to MS diagnostic criteria that allow for immediate diagnosis if the first MRI shows dissemination in space (DIS) and dissemination in time (DIT). “When we talk about early MS, it has probably been ongoing for quite a long time, not only in clinically isolated syndrome (CIS), but also before that, without any clinical symptoms,” he explained. This new diagnostic classification is called radiologically isolated syndrome (RIS).

The Arguments for Early Treatment
A comparison of the 2010 diagnostic criteria with the 2005 criteria showed that 30% of CIS patients can now be diagnosed as having MS after a single MRI. The significance of altering these diagnostic margins is not only that it moves up the diagnostic timeline for individual patients, but that it also reclassifies into a treatment category a large percentage of patients who previously would not have been treated. “The time to diagnosis differed significantly between the 2005 and 2010 criteria, so the conclusion will be that the CIS group will probably be reduced after the introduction of the new MS criteria, and we will have more relapsing-remitting cases,” Prof. Fredrikson explained.

The main presenting complaint for patients referred for an MRI that identifies RIS is headache, he reported. “About two-thirds of the patients with RIS show radiologic progression over the next five years, and about one-third develop neurologic symptoms,” said Prof. Fredrikson.

“The question that we come back to is, of course, should RIS also be treated?” Prof. Fredrikson looked at the current understanding of MS pathogenesis, according to which, inflammation appears to be dominant in early phases of the disease, while degeneration dominates in later, progressive disease. “The drugs we have are anti-inflammatory, which means [that] these drugs are most effective during the anti-inflammatory phase,” he said. The rationale for early treatment (ie, at the point of CIS or RIS) is the prevention of irreversible axonal damage that leads to later disability. Cognitive effects resulting from early gray matter changes also may be averted.

One of the interesting arguments for early treatment in MS comes from a knowledge base borrowed from hypertension studies, Prof. Fredrikson explained, where it has been established that the number of patients with mildly elevated blood pressure who need to be treated to prevent one stroke is 118. In studies of CIS, numbers needed to treat are reported in the BENEFIT and CHAMPS trials as six and seven patients, respectively. “This [result] speaks in favor of the treatments that we can offer the patients having clinical effect,” said Prof. Fredrikson.

Questions of long-term efficacy are beginning to be answered, he said, pointing to recent studies by Trojano et al and Tedeholm et al that indicate a longer time to progression, as well as a study by Goodin et al that showed improved long-term survival with earlier intervention.

The Arguments Against Early Treatment
Still, Prof. Fredrikson said, there are a number of arguments against early treatment, the most significant of which is the potential for misdiagnosis. “Everyone who has been working with the disease for some years has seen so-called typical CIS that has been caused by other reasons,” he explained, emphasizing that it is important when managing patients with CIS to exclude other pathologies. “One way of doing that is by looking for the red flags described by Miller et al,” he said.

Data from the BENEFIT trial show that 85% of CIS patients will develop MS within two years based on MRI findings. Long-term data are not yet available on CIS patients, but benign MS appears to be a rare phenomenon, said Prof. Fredrikson. Therefore, 15 to 20 years of disease-modifying therapy in these few patients may entail more risks than benefits.

Patient Selection Is Key
Prof. Fredrikson offered practical recommendations for early treatment approaches. Initiation of therapy is appropriate for patients whose symptoms have no explanation other than MS, and for CIS with demyelination, he said, noting that the decision to treat or not to treat is less clear in CIS with MRI not showing DIT and DIS. In these cases, he recommended repeating the MRI in three to six months, but noted that starting therapy is also an option. Finally, for patients with RIS who have clinical symptoms with no better explanation, the notion of treatment is more controversial. “There are no studies or evidence to indicate how to handle these patients,” concluded Prof. Fredrikson, suggesting that waiting three to six months before repeating the MRI to decide on treatment is the most reasonable approach.

“Can we select patients that will benefit from early treatment?” asked Prof. Fredrikson. “This is still an ongoing area, but in our practical everyday life, there is not enough evidence on these markers to select individual patients.”

—Linda Peckel