Multiple Sclerosis Hub

Intramuscular interferon beta-1 was the first-line MS treatment with the highest adherence rate; natalizumab was the second-line treatment with the highest adherence rate and it had the lowest rate of patients switching to a third drug, researchers found.

SAN ANTONIO—Patients may adhere more to intramuscular (IM) interferon beta-1a than to other first-line disease-modifying therapies (DMTs) for multiple sclerosis (MS), according to a study presented at the 24th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

“These results may be attributable to less frequent administration required for IM interferon beta-1a,” reported Rachel Halpern, PhD, of i3 Innovus, Eden Prairie, Minnesota, and colleagues. “Multiple factors are considered when selecting a first-line DMT for MS; given the importance of adherence in the management of MS, adherence should be one of those factors.”

Dr. Halpern’s team also performed analyses on second-line treatments and found that natalizumab was associated with the highest rate of patient adherence and the lowest rate of patients who switched to a third treatment. Like IM interferon beta-1a, natalizumab requires relatively infrequent administration.

The first-line and second-line studies were based on medical and pharmacy claims data and included both unadjusted analyses and regression analyses with adjustment for demographic and pre-index clinical characteristics. Adherence was defined as a medication-possession ratio of at least 80%, and persistence was defined as the “number of days until the earlier of last DMT claim before a minimum 60-day gap in therapy or last DMT claim during postindex.”

First-Line Treatments

The first-line study included 2,305 patients initiating treatment by taking IM interferon beta-1a once weekly, 894 taking subcutaneous (SC) interferon beta-1b every other day, 2,270 taking glatiramer acetate daily, and 1,211 taking SC interferon beta-1a three times weekly.

The unadjusted adherence rates were 62.3% for IM interferon beta-1a, 52.2% for SC interferon beta-1b, 55.4% for glatiramer acetate, and 58.5% for SC interferon beta-1a. Compared with IM interferon beta-1a, all the other treatments had significantly lower adjusted odds of adherence, at 0.66 for SC interferon beta-1b, 0.75 for glatiramer acetate, and 0.84 for SC interferon beta-1a.

The number of mean persistence days was 508 for IM interferon beta-1a, 482 for SC interferon beta-1b, and 471 for both glatiramer acetate and SC interferon beta-1a. In addition, the regression-adjusted persistence failure ratio of SC interferon beta-1a relative to IM interferon beta-1a was significantly high, at 1.12.

Second-Line Treatments

Second-line treatment analyses included 288 patients taking natalizumab, 429 taking IM interferon beta-1a, 415 taking SC interferon beta-1b, 1,067 taking glatiramer acetate, and 872 taking SC interferon beta-1a. Among these groups, the unadjusted adherence rates were 74.7% for natalizumab, 60.8% for IM interferon beta-1a, 55.4% for SC interferon beta-1b, 54.6% for glatiramer acetate, and 60.3% for SC interferon beta-1a. Adjusted odds of adherence relative to natalizumab were significantly lower for all the other drugs, at 0.56 for IM interferon beta-1a, 0.43 for SC interferon beta-1b, 0.42 for glatiramer acetate, and 0.54 for SC interferon beta-1a. Furthermore, SC interferon beta-1b, glatiramer acetate, and SC interferon beta-1a had significantly higher regression-adjusted persistence failure ratios relative to natalizumab, at 1.27, 1.27, and 1.24, respectively.

In the switching analysis, 10.4% of patients taking natalizumab, 23.5% of those taking IM interferon beta-1a, 23.1% of those taking SC interferon beta-1b, 16.9% of those on glatiramer acetate, and 21.8% of those taking SC interferon beta-1a switched to a third drug. Regression-adjusted switching relative to natalizumab was significantly more likely for IM interferon beta-1a, SC interferon beta-1b, and SC interferon beta-1a, at 1.74, 1.77, and 1.62, respectively. “Switching between DMTs often indicates problems with tolerance or effectiveness,” the researchers noted.

Intramuscular interferon beta-1 was the first-line MS treatment with the highest adherence rate; natalizumab was the second-line treatment with the highest adherence rate and it had the lowest rate of patients switching to a third drug, researchers found.

SAN ANTONIO—Patients may adhere more to intramuscular (IM) interferon beta-1a than to other first-line disease-modifying therapies (DMTs) for multiple sclerosis (MS), according to a study presented at the 24th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

“These results may be attributable to less frequent administration required for IM interferon beta-1a,” reported Rachel Halpern, PhD, of i3 Innovus, Eden Prairie, Minnesota, and colleagues. “Multiple factors are considered when selecting a first-line DMT for MS; given the importance of adherence in the management of MS, adherence should be one of those factors.”

Dr. Halpern’s team also performed analyses on second-line treatments and found that natalizumab was associated with the highest rate of patient adherence and the lowest rate of patients who switched to a third treatment. Like IM interferon beta-1a, natalizumab requires relatively infrequent administration.

The first-line and second-line studies were based on medical and pharmacy claims data and included both unadjusted analyses and regression analyses with adjustment for demographic and pre-index clinical characteristics. Adherence was defined as a medication-possession ratio of at least 80%, and persistence was defined as the “number of days until the earlier of last DMT claim before a minimum 60-day gap in therapy or last DMT claim during postindex.”

First-Line Treatments

The first-line study included 2,305 patients initiating treatment by taking IM interferon beta-1a once weekly, 894 taking subcutaneous (SC) interferon beta-1b every other day, 2,270 taking glatiramer acetate daily, and 1,211 taking SC interferon beta-1a three times weekly.

The unadjusted adherence rates were 62.3% for IM interferon beta-1a, 52.2% for SC interferon beta-1b, 55.4% for glatiramer acetate, and 58.5% for SC interferon beta-1a. Compared with IM interferon beta-1a, all the other treatments had significantly lower adjusted odds of adherence, at 0.66 for SC interferon beta-1b, 0.75 for glatiramer acetate, and 0.84 for SC interferon beta-1a.

The number of mean persistence days was 508 for IM interferon beta-1a, 482 for SC interferon beta-1b, and 471 for both glatiramer acetate and SC interferon beta-1a. In addition, the regression-adjusted persistence failure ratio of SC interferon beta-1a relative to IM interferon beta-1a was significantly high, at 1.12.

Second-Line Treatments

Second-line treatment analyses included 288 patients taking natalizumab, 429 taking IM interferon beta-1a, 415 taking SC interferon beta-1b, 1,067 taking glatiramer acetate, and 872 taking SC interferon beta-1a. Among these groups, the unadjusted adherence rates were 74.7% for natalizumab, 60.8% for IM interferon beta-1a, 55.4% for SC interferon beta-1b, 54.6% for glatiramer acetate, and 60.3% for SC interferon beta-1a. Adjusted odds of adherence relative to natalizumab were significantly lower for all the other drugs, at 0.56 for IM interferon beta-1a, 0.43 for SC interferon beta-1b, 0.42 for glatiramer acetate, and 0.54 for SC interferon beta-1a. Furthermore, SC interferon beta-1b, glatiramer acetate, and SC interferon beta-1a had significantly higher regression-adjusted persistence failure ratios relative to natalizumab, at 1.27, 1.27, and 1.24, respectively.

In the switching analysis, 10.4% of patients taking natalizumab, 23.5% of those taking IM interferon beta-1a, 23.1% of those taking SC interferon beta-1b, 16.9% of those on glatiramer acetate, and 21.8% of those taking SC interferon beta-1a switched to a third drug. Regression-adjusted switching relative to natalizumab was significantly more likely for IM interferon beta-1a, SC interferon beta-1b, and SC interferon beta-1a, at 1.74, 1.77, and 1.62, respectively. “Switching between DMTs often indicates problems with tolerance or effectiveness,” the researchers noted.

Intramuscular interferon beta-1 was the first-line MS treatment with the highest adherence rate; natalizumab was the second-line treatment with the highest adherence rate and it had the lowest rate of patients switching to a third drug, researchers found.

SAN ANTONIO—Patients may adhere more to intramuscular (IM) interferon beta-1a than to other first-line disease-modifying therapies (DMTs) for multiple sclerosis (MS), according to a study presented at the 24th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

“These results may be attributable to less frequent administration required for IM interferon beta-1a,” reported Rachel Halpern, PhD, of i3 Innovus, Eden Prairie, Minnesota, and colleagues. “Multiple factors are considered when selecting a first-line DMT for MS; given the importance of adherence in the management of MS, adherence should be one of those factors.”

Dr. Halpern’s team also performed analyses on second-line treatments and found that natalizumab was associated with the highest rate of patient adherence and the lowest rate of patients who switched to a third treatment. Like IM interferon beta-1a, natalizumab requires relatively infrequent administration.

The first-line and second-line studies were based on medical and pharmacy claims data and included both unadjusted analyses and regression analyses with adjustment for demographic and pre-index clinical characteristics. Adherence was defined as a medication-possession ratio of at least 80%, and persistence was defined as the “number of days until the earlier of last DMT claim before a minimum 60-day gap in therapy or last DMT claim during postindex.”

First-Line Treatments

The first-line study included 2,305 patients initiating treatment by taking IM interferon beta-1a once weekly, 894 taking subcutaneous (SC) interferon beta-1b every other day, 2,270 taking glatiramer acetate daily, and 1,211 taking SC interferon beta-1a three times weekly.

The unadjusted adherence rates were 62.3% for IM interferon beta-1a, 52.2% for SC interferon beta-1b, 55.4% for glatiramer acetate, and 58.5% for SC interferon beta-1a. Compared with IM interferon beta-1a, all the other treatments had significantly lower adjusted odds of adherence, at 0.66 for SC interferon beta-1b, 0.75 for glatiramer acetate, and 0.84 for SC interferon beta-1a.

The number of mean persistence days was 508 for IM interferon beta-1a, 482 for SC interferon beta-1b, and 471 for both glatiramer acetate and SC interferon beta-1a. In addition, the regression-adjusted persistence failure ratio of SC interferon beta-1a relative to IM interferon beta-1a was significantly high, at 1.12.

Second-Line Treatments

Second-line treatment analyses included 288 patients taking natalizumab, 429 taking IM interferon beta-1a, 415 taking SC interferon beta-1b, 1,067 taking glatiramer acetate, and 872 taking SC interferon beta-1a. Among these groups, the unadjusted adherence rates were 74.7% for natalizumab, 60.8% for IM interferon beta-1a, 55.4% for SC interferon beta-1b, 54.6% for glatiramer acetate, and 60.3% for SC interferon beta-1a. Adjusted odds of adherence relative to natalizumab were significantly lower for all the other drugs, at 0.56 for IM interferon beta-1a, 0.43 for SC interferon beta-1b, 0.42 for glatiramer acetate, and 0.54 for SC interferon beta-1a. Furthermore, SC interferon beta-1b, glatiramer acetate, and SC interferon beta-1a had significantly higher regression-adjusted persistence failure ratios relative to natalizumab, at 1.27, 1.27, and 1.24, respectively.

In the switching analysis, 10.4% of patients taking natalizumab, 23.5% of those taking IM interferon beta-1a, 23.1% of those taking SC interferon beta-1b, 16.9% of those on glatiramer acetate, and 21.8% of those taking SC interferon beta-1a switched to a third drug. Regression-adjusted switching relative to natalizumab was significantly more likely for IM interferon beta-1a, SC interferon beta-1b, and SC interferon beta-1a, at 1.74, 1.77, and 1.62, respectively. “Switching between DMTs often indicates problems with tolerance or effectiveness,” the researchers noted.

Female migraineurs have higher rates of multiple sclerosis than those who do not experience headaches.

Toronto—Women with migraines have a 48% higher risk of developing multiple sclerosis (MS) than those who do not have migraines, according to research presented at the 62nd Annual Meeting of the American Academy of Neurology. Using data from the Nurses Health Study II (NHS-2), investigators determined that the absolute risk of developing MS was 0.46% for women with migraines and 0.30% for those without, making it a “modest predictor of MS compared to the established risk factors.”

In a prospective cohort study, Ilya Kister, MD, of the MS Care Center, Department of Neurology, New York University School of Medicine in New York City, and colleagues examined the relationship between migraine and MS in the large population-based NHS-2 dataset, which included more than 116,000 female registered nurses from 14 states, who were ages 25 to 42 in 1989. At enrollment, 140 subjects had pre-existing MS (prevalent group), and an additional 375 women were diagnosed with MS after enrollment (incident group). Of the incident group, symptom onset was before 1989 in 92 women, after 1989 in 240 women (new onset), and unknown in 43 women.

Investigators used Cox proportional hazard regression to estimate rate ratios for being diagnosed with MS in women with and without pre-existing migraine, and adjusted for age, latitude of residence at age 15, ethnicity (Scandinavian, Southern European, other Caucasian, and other), smoking history in pack years, BMI at age 18, and supplemental vitamin D in 1991.

At baseline, 17,893 women (15.4%) reported a physician diagnosis of migraine. The researchers found that this group had a 47% greater risk of being diagnosed with MS in the next six years. An additional 6,407 women reported a diagnosis of migraine by 1995, for a cumulative migraine prevalence of 20.9%. For the cumulative total, investigators found a 1.48 increased risk of new onset MS than those who did not have migraine.

“Migraine is a very common disorder, reported by about 18% of women in the US, so it is not surprising that many women with MS report migraines as well,” Dr. Kister told Neurology Reviews. “There is likely an association between migraine in MS, but we are not sure what the causes are. It is possible that in some small minority of women, migraine headache is actually an early symptom of MS.”

Dr. Kister noted that migraine appears to be a lesser predictor of MS than is low vitamin D status, history of infectious mononucleosis, or positive DRB1*1501 haplotype. Investigators also observed a trend for MS patients to develop migraines at a higher rate than for non-MS patients, but it did not reach statistical significance.

“The literature on MS/migraine connection is conflicted—some studies show that migraine is more common among MS patients than in the general population, and others don’t show it is more common,” Dr. Kister noted. “While our study found women with migraine were more likely to develop MS later on, about a 50% relative risk, it is important to note the absolute risk of MS in women migraineurs was still very small. More than 99% of migraineurs will not develop MS.”  

—Rebecca K. Abma

Suggested Reading

La Mantia L. Headache and multiple sclerosis: clinical and therapeutic correlations. Neurol Sci. 2009;30(Suppl 1):S23-S26.

Female migraineurs have higher rates of multiple sclerosis than those who do not experience headaches.

Toronto—Women with migraines have a 48% higher risk of developing multiple sclerosis (MS) than those who do not have migraines, according to research presented at the 62nd Annual Meeting of the American Academy of Neurology. Using data from the Nurses Health Study II (NHS-2), investigators determined that the absolute risk of developing MS was 0.46% for women with migraines and 0.30% for those without, making it a “modest predictor of MS compared to the established risk factors.”

In a prospective cohort study, Ilya Kister, MD, of the MS Care Center, Department of Neurology, New York University School of Medicine in New York City, and colleagues examined the relationship between migraine and MS in the large population-based NHS-2 dataset, which included more than 116,000 female registered nurses from 14 states, who were ages 25 to 42 in 1989. At enrollment, 140 subjects had pre-existing MS (prevalent group), and an additional 375 women were diagnosed with MS after enrollment (incident group). Of the incident group, symptom onset was before 1989 in 92 women, after 1989 in 240 women (new onset), and unknown in 43 women.

Investigators used Cox proportional hazard regression to estimate rate ratios for being diagnosed with MS in women with and without pre-existing migraine, and adjusted for age, latitude of residence at age 15, ethnicity (Scandinavian, Southern European, other Caucasian, and other), smoking history in pack years, BMI at age 18, and supplemental vitamin D in 1991.

At baseline, 17,893 women (15.4%) reported a physician diagnosis of migraine. The researchers found that this group had a 47% greater risk of being diagnosed with MS in the next six years. An additional 6,407 women reported a diagnosis of migraine by 1995, for a cumulative migraine prevalence of 20.9%. For the cumulative total, investigators found a 1.48 increased risk of new onset MS than those who did not have migraine.

“Migraine is a very common disorder, reported by about 18% of women in the US, so it is not surprising that many women with MS report migraines as well,” Dr. Kister told Neurology Reviews. “There is likely an association between migraine in MS, but we are not sure what the causes are. It is possible that in some small minority of women, migraine headache is actually an early symptom of MS.”

Dr. Kister noted that migraine appears to be a lesser predictor of MS than is low vitamin D status, history of infectious mononucleosis, or positive DRB1*1501 haplotype. Investigators also observed a trend for MS patients to develop migraines at a higher rate than for non-MS patients, but it did not reach statistical significance.

“The literature on MS/migraine connection is conflicted—some studies show that migraine is more common among MS patients than in the general population, and others don’t show it is more common,” Dr. Kister noted. “While our study found women with migraine were more likely to develop MS later on, about a 50% relative risk, it is important to note the absolute risk of MS in women migraineurs was still very small. More than 99% of migraineurs will not develop MS.”  

—Rebecca K. Abma

Suggested Reading

La Mantia L. Headache and multiple sclerosis: clinical and therapeutic correlations. Neurol Sci. 2009;30(Suppl 1):S23-S26.

Female migraineurs have higher rates of multiple sclerosis than those who do not experience headaches.

Toronto—Women with migraines have a 48% higher risk of developing multiple sclerosis (MS) than those who do not have migraines, according to research presented at the 62nd Annual Meeting of the American Academy of Neurology. Using data from the Nurses Health Study II (NHS-2), investigators determined that the absolute risk of developing MS was 0.46% for women with migraines and 0.30% for those without, making it a “modest predictor of MS compared to the established risk factors.”

In a prospective cohort study, Ilya Kister, MD, of the MS Care Center, Department of Neurology, New York University School of Medicine in New York City, and colleagues examined the relationship between migraine and MS in the large population-based NHS-2 dataset, which included more than 116,000 female registered nurses from 14 states, who were ages 25 to 42 in 1989. At enrollment, 140 subjects had pre-existing MS (prevalent group), and an additional 375 women were diagnosed with MS after enrollment (incident group). Of the incident group, symptom onset was before 1989 in 92 women, after 1989 in 240 women (new onset), and unknown in 43 women.

Investigators used Cox proportional hazard regression to estimate rate ratios for being diagnosed with MS in women with and without pre-existing migraine, and adjusted for age, latitude of residence at age 15, ethnicity (Scandinavian, Southern European, other Caucasian, and other), smoking history in pack years, BMI at age 18, and supplemental vitamin D in 1991.

At baseline, 17,893 women (15.4%) reported a physician diagnosis of migraine. The researchers found that this group had a 47% greater risk of being diagnosed with MS in the next six years. An additional 6,407 women reported a diagnosis of migraine by 1995, for a cumulative migraine prevalence of 20.9%. For the cumulative total, investigators found a 1.48 increased risk of new onset MS than those who did not have migraine.

“Migraine is a very common disorder, reported by about 18% of women in the US, so it is not surprising that many women with MS report migraines as well,” Dr. Kister told Neurology Reviews. “There is likely an association between migraine in MS, but we are not sure what the causes are. It is possible that in some small minority of women, migraine headache is actually an early symptom of MS.”

Dr. Kister noted that migraine appears to be a lesser predictor of MS than is low vitamin D status, history of infectious mononucleosis, or positive DRB1*1501 haplotype. Investigators also observed a trend for MS patients to develop migraines at a higher rate than for non-MS patients, but it did not reach statistical significance.

“The literature on MS/migraine connection is conflicted—some studies show that migraine is more common among MS patients than in the general population, and others don’t show it is more common,” Dr. Kister noted. “While our study found women with migraine were more likely to develop MS later on, about a 50% relative risk, it is important to note the absolute risk of MS in women migraineurs was still very small. More than 99% of migraineurs will not develop MS.”  

—Rebecca K. Abma

Suggested Reading

La Mantia L. Headache and multiple sclerosis: clinical and therapeutic correlations. Neurol Sci. 2009;30(Suppl 1):S23-S26.

SAN ANTONIO—Stem cell therapy for multiple sclerosis (MS) is “on the threshold of clinical translation,” Neil Scolding, PhD, reported at the 24th Annual Meeting of the Consortium of MS Centers. “Our increasing knowledge of stem cells—bone marrow stem cells in particular—has emerged [during the past decade] in parallel with our increasing knowledge of MS.” Dr. Scolding is a Professor of Neurology at the Institute of Clinical Neuroscience, University of Bristol, United Kingdom.

“MS appears to be a disease that is particularly amenable for reparative therapy,” he said. “We’ve known for quite a while that bone marrow–derived stem cells, and adult stem cells in general, are able to achieve reparative effects by calling on a number of different functions…. [They] can stimulate or reprogram repair both directly and through a range of other noncanonical mechanisms, including fusion, immune modulation, neuroprotection, growth factor production, reduced scar formation, effects on local repair and other cells, and transdifferentiation.”

In particular, mesenchymal stem cells (MSC)—nonhaematopoietic stem cells derived from bone marrow, skin, and adipose tissue—appear very promising for the future of MS therapy, he said. Their potential immunomodulatory and reparative properties are being investigated in a number of centers worldwide.

Although the precise mechanism of immunomodulation in MSCs is not clearly understood, research indicates that these cells suppress T- and B-cell functions and natural killer cells. Studies in experimental autoimmune encephalomyelitis (EAE) mice showed decreased inflammatory infiltrates in the CNS and a reduction in demyelination after MSC transplantation.

Using MSCs in EAE mice, Dr. Scolding’s and other research teams have found that tissue damage was reduced, with a very pronounced effect on the suppression of EAE, with “evidence suggesting both a peripheral and a central role for these cells,” he explained.

Research has shown that oligodentrocyte progenitor cells—endogenous neural precursors capable of generating more myelin—exist within lesions. “We know [there is] a certain amount of spontaneous myelin repair already occurring in MS, … [which] means that any cell therapy needs to enhance something that is happening already rather than starting from scratch,” Dr. Scolding noted.

Precisely how MSCs reverse myelin damage is unclear. Initial evidence suggested that MSCs could turn into oligodendrocytes. “It’s certainly true that these cells express antigens that we associate with neuronal or glial markers, such as nestin, βIII-tubulin, GFAP, and the oligodendrocyte marker 04. And it is possible to manipulate the cell populations to increase the proportions expressing those antigens,” Dr. Scolding said. “But what we haven’t been able to show is any suggestion that these cells might turn into process-bearing oligodendrocytes that are functionally capable of making myelin.” He added that the current “consensus is that maybe the MSCs themselves may not be able to make oligodendrocytes,” but rather have an indirect effect on the endogenous repair processes.

“Whatever the mechanism is, it is quite clear that bone marrow cells injected intravenously can promote remyelination,” he said, adding he believes it is due to a “myelin promoting effect and not just a direct consequence of immune processes suppressing inflammation.”

In addition to their anti-inflammatory properties, MSCs possess the apparent ability to home in on lesions, migrating toward chemokines expressed in the lesions. “These cells are capable of finding their way to inflammation [and are] apparently attracted to damaged tissue,” Dr. Scolding reported.

“These cells have powerful neuroprotective properties,” he added, pointing to research showing that bone marrow stromal cells reduce axonal loss in EAE mice. In addition, investigators found MSCs secrete brain-derived neurotrophic factor and superoxide dismutase, both of which can promote neuronal survival. In addition, he noted, circulating bone marrow stem cells enter the brain and spinal cord and may contribute to the repair of damaged tissue.

Another attractive aspect of MSC therapy is the potential to use a patient’s own bone marrow. In the May 5 online Clinical Pharmacology and Therapeutics, Dr. Scolding and colleagues published results of the phase I Study of Intravenous Autologous Marrow in Multiple Sclerosis (SIAMMS) assessing the safety and feasibility of IV autologous bone marrow cell therapy without immunosuppressive preconditioning.

During the 12-month study of six subjects with relapsing-progressive MS, subjects’ clinical disability scores either improved or had no change. Electrophysiologic tests, however, showed statistically significant improvements in all patients. The treatment was well-tolerated by subjects and not associated with any serious side effects.

“The lack of serious adverse effects and the suggestion of a beneficial effect in this small sample of patients with progressive disease justify conducting a larger phase II/III study to make a fuller assessment of the efficacy of mobilization of autologous bone marrow in patients with MS,” Dr. Scolding and colleagues concluded.

—Rebecca K. Abma

Suggested Reading
Freedman MS, Bar-Or A, Atkins HL, et al. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult Scler. 2010;16(4):503-510.

Mallam E, Kemp K, Wilkins A, et al. Characterization of in vitro expanded bone marrow-derived mesenchymal stem cells from patients with multiple sclerosis. Mult Scler. 2010 Jun 11; [Epub ahead of print].

Martino G, Franklin RJ, Van Evercooren AB, et al. Stem cell transplantation in multiple sclerosis: current status and future prospects. Nat Rev Neurol. 2010;6(5):247-255.

Rice CM, Mallam EA, Whone AL, et al. Safety and feasibility of autologous bone marrow cellular therapy in relapsing-progressive multiple sclerosis. Clin Pharmacol Ther. 2010;87(6):679-685.

SAN ANTONIO—Stem cell therapy for multiple sclerosis (MS) is “on the threshold of clinical translation,” Neil Scolding, PhD, reported at the 24th Annual Meeting of the Consortium of MS Centers. “Our increasing knowledge of stem cells—bone marrow stem cells in particular—has emerged [during the past decade] in parallel with our increasing knowledge of MS.” Dr. Scolding is a Professor of Neurology at the Institute of Clinical Neuroscience, University of Bristol, United Kingdom.

“MS appears to be a disease that is particularly amenable for reparative therapy,” he said. “We’ve known for quite a while that bone marrow–derived stem cells, and adult stem cells in general, are able to achieve reparative effects by calling on a number of different functions…. [They] can stimulate or reprogram repair both directly and through a range of other noncanonical mechanisms, including fusion, immune modulation, neuroprotection, growth factor production, reduced scar formation, effects on local repair and other cells, and transdifferentiation.”

In particular, mesenchymal stem cells (MSC)—nonhaematopoietic stem cells derived from bone marrow, skin, and adipose tissue—appear very promising for the future of MS therapy, he said. Their potential immunomodulatory and reparative properties are being investigated in a number of centers worldwide.

Although the precise mechanism of immunomodulation in MSCs is not clearly understood, research indicates that these cells suppress T- and B-cell functions and natural killer cells. Studies in experimental autoimmune encephalomyelitis (EAE) mice showed decreased inflammatory infiltrates in the CNS and a reduction in demyelination after MSC transplantation.

Using MSCs in EAE mice, Dr. Scolding’s and other research teams have found that tissue damage was reduced, with a very pronounced effect on the suppression of EAE, with “evidence suggesting both a peripheral and a central role for these cells,” he explained.

Research has shown that oligodentrocyte progenitor cells—endogenous neural precursors capable of generating more myelin—exist within lesions. “We know [there is] a certain amount of spontaneous myelin repair already occurring in MS, … [which] means that any cell therapy needs to enhance something that is happening already rather than starting from scratch,” Dr. Scolding noted.

Precisely how MSCs reverse myelin damage is unclear. Initial evidence suggested that MSCs could turn into oligodendrocytes. “It’s certainly true that these cells express antigens that we associate with neuronal or glial markers, such as nestin, βIII-tubulin, GFAP, and the oligodendrocyte marker 04. And it is possible to manipulate the cell populations to increase the proportions expressing those antigens,” Dr. Scolding said. “But what we haven’t been able to show is any suggestion that these cells might turn into process-bearing oligodendrocytes that are functionally capable of making myelin.” He added that the current “consensus is that maybe the MSCs themselves may not be able to make oligodendrocytes,” but rather have an indirect effect on the endogenous repair processes.

“Whatever the mechanism is, it is quite clear that bone marrow cells injected intravenously can promote remyelination,” he said, adding he believes it is due to a “myelin promoting effect and not just a direct consequence of immune processes suppressing inflammation.”

In addition to their anti-inflammatory properties, MSCs possess the apparent ability to home in on lesions, migrating toward chemokines expressed in the lesions. “These cells are capable of finding their way to inflammation [and are] apparently attracted to damaged tissue,” Dr. Scolding reported.

“These cells have powerful neuroprotective properties,” he added, pointing to research showing that bone marrow stromal cells reduce axonal loss in EAE mice. In addition, investigators found MSCs secrete brain-derived neurotrophic factor and superoxide dismutase, both of which can promote neuronal survival. In addition, he noted, circulating bone marrow stem cells enter the brain and spinal cord and may contribute to the repair of damaged tissue.

Another attractive aspect of MSC therapy is the potential to use a patient’s own bone marrow. In the May 5 online Clinical Pharmacology and Therapeutics, Dr. Scolding and colleagues published results of the phase I Study of Intravenous Autologous Marrow in Multiple Sclerosis (SIAMMS) assessing the safety and feasibility of IV autologous bone marrow cell therapy without immunosuppressive preconditioning.

During the 12-month study of six subjects with relapsing-progressive MS, subjects’ clinical disability scores either improved or had no change. Electrophysiologic tests, however, showed statistically significant improvements in all patients. The treatment was well-tolerated by subjects and not associated with any serious side effects.

“The lack of serious adverse effects and the suggestion of a beneficial effect in this small sample of patients with progressive disease justify conducting a larger phase II/III study to make a fuller assessment of the efficacy of mobilization of autologous bone marrow in patients with MS,” Dr. Scolding and colleagues concluded.

—Rebecca K. Abma

Suggested Reading
Freedman MS, Bar-Or A, Atkins HL, et al. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult Scler. 2010;16(4):503-510.

Mallam E, Kemp K, Wilkins A, et al. Characterization of in vitro expanded bone marrow-derived mesenchymal stem cells from patients with multiple sclerosis. Mult Scler. 2010 Jun 11; [Epub ahead of print].

Martino G, Franklin RJ, Van Evercooren AB, et al. Stem cell transplantation in multiple sclerosis: current status and future prospects. Nat Rev Neurol. 2010;6(5):247-255.

Rice CM, Mallam EA, Whone AL, et al. Safety and feasibility of autologous bone marrow cellular therapy in relapsing-progressive multiple sclerosis. Clin Pharmacol Ther. 2010;87(6):679-685.

SAN ANTONIO—Stem cell therapy for multiple sclerosis (MS) is “on the threshold of clinical translation,” Neil Scolding, PhD, reported at the 24th Annual Meeting of the Consortium of MS Centers. “Our increasing knowledge of stem cells—bone marrow stem cells in particular—has emerged [during the past decade] in parallel with our increasing knowledge of MS.” Dr. Scolding is a Professor of Neurology at the Institute of Clinical Neuroscience, University of Bristol, United Kingdom.

“MS appears to be a disease that is particularly amenable for reparative therapy,” he said. “We’ve known for quite a while that bone marrow–derived stem cells, and adult stem cells in general, are able to achieve reparative effects by calling on a number of different functions…. [They] can stimulate or reprogram repair both directly and through a range of other noncanonical mechanisms, including fusion, immune modulation, neuroprotection, growth factor production, reduced scar formation, effects on local repair and other cells, and transdifferentiation.”

In particular, mesenchymal stem cells (MSC)—nonhaematopoietic stem cells derived from bone marrow, skin, and adipose tissue—appear very promising for the future of MS therapy, he said. Their potential immunomodulatory and reparative properties are being investigated in a number of centers worldwide.

Although the precise mechanism of immunomodulation in MSCs is not clearly understood, research indicates that these cells suppress T- and B-cell functions and natural killer cells. Studies in experimental autoimmune encephalomyelitis (EAE) mice showed decreased inflammatory infiltrates in the CNS and a reduction in demyelination after MSC transplantation.

Using MSCs in EAE mice, Dr. Scolding’s and other research teams have found that tissue damage was reduced, with a very pronounced effect on the suppression of EAE, with “evidence suggesting both a peripheral and a central role for these cells,” he explained.

Research has shown that oligodentrocyte progenitor cells—endogenous neural precursors capable of generating more myelin—exist within lesions. “We know [there is] a certain amount of spontaneous myelin repair already occurring in MS, … [which] means that any cell therapy needs to enhance something that is happening already rather than starting from scratch,” Dr. Scolding noted.

Precisely how MSCs reverse myelin damage is unclear. Initial evidence suggested that MSCs could turn into oligodendrocytes. “It’s certainly true that these cells express antigens that we associate with neuronal or glial markers, such as nestin, βIII-tubulin, GFAP, and the oligodendrocyte marker 04. And it is possible to manipulate the cell populations to increase the proportions expressing those antigens,” Dr. Scolding said. “But what we haven’t been able to show is any suggestion that these cells might turn into process-bearing oligodendrocytes that are functionally capable of making myelin.” He added that the current “consensus is that maybe the MSCs themselves may not be able to make oligodendrocytes,” but rather have an indirect effect on the endogenous repair processes.

“Whatever the mechanism is, it is quite clear that bone marrow cells injected intravenously can promote remyelination,” he said, adding he believes it is due to a “myelin promoting effect and not just a direct consequence of immune processes suppressing inflammation.”

In addition to their anti-inflammatory properties, MSCs possess the apparent ability to home in on lesions, migrating toward chemokines expressed in the lesions. “These cells are capable of finding their way to inflammation [and are] apparently attracted to damaged tissue,” Dr. Scolding reported.

“These cells have powerful neuroprotective properties,” he added, pointing to research showing that bone marrow stromal cells reduce axonal loss in EAE mice. In addition, investigators found MSCs secrete brain-derived neurotrophic factor and superoxide dismutase, both of which can promote neuronal survival. In addition, he noted, circulating bone marrow stem cells enter the brain and spinal cord and may contribute to the repair of damaged tissue.

Another attractive aspect of MSC therapy is the potential to use a patient’s own bone marrow. In the May 5 online Clinical Pharmacology and Therapeutics, Dr. Scolding and colleagues published results of the phase I Study of Intravenous Autologous Marrow in Multiple Sclerosis (SIAMMS) assessing the safety and feasibility of IV autologous bone marrow cell therapy without immunosuppressive preconditioning.

During the 12-month study of six subjects with relapsing-progressive MS, subjects’ clinical disability scores either improved or had no change. Electrophysiologic tests, however, showed statistically significant improvements in all patients. The treatment was well-tolerated by subjects and not associated with any serious side effects.

“The lack of serious adverse effects and the suggestion of a beneficial effect in this small sample of patients with progressive disease justify conducting a larger phase II/III study to make a fuller assessment of the efficacy of mobilization of autologous bone marrow in patients with MS,” Dr. Scolding and colleagues concluded.

—Rebecca K. Abma

Suggested Reading
Freedman MS, Bar-Or A, Atkins HL, et al. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult Scler. 2010;16(4):503-510.

Mallam E, Kemp K, Wilkins A, et al. Characterization of in vitro expanded bone marrow-derived mesenchymal stem cells from patients with multiple sclerosis. Mult Scler. 2010 Jun 11; [Epub ahead of print].

Martino G, Franklin RJ, Van Evercooren AB, et al. Stem cell transplantation in multiple sclerosis: current status and future prospects. Nat Rev Neurol. 2010;6(5):247-255.

Rice CM, Mallam EA, Whone AL, et al. Safety and feasibility of autologous bone marrow cellular therapy in relapsing-progressive multiple sclerosis. Clin Pharmacol Ther. 2010;87(6):679-685.

Episodes of involuntary laughing and crying, known as pseudobulbar affect, were safely and effectively treated with dextromethorphan and quinidine.

TORONTO—A combination of dextromethorphan and quinidine appears to be an effective, safe, and well-tolerated treatment for pseudobulbar affect, said Erik P. Pioro, MD, at the 62nd Annual Meeting of the American Academy of Neurology.

Pseudobulbar affect—common among patients with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and other neurologic conditions—involves involuntary, sudden, and frequent episodes of laughing or crying.

“These episodes are very exaggerated and are often incongruent or inconsistent with what the individual may be feeling inside,” said Dr. Pioro, Director of the Section for ALS and Related Disorders at the Cleveland Clinic. “Some patients whom I’ve followed have been at a funeral and, instead of crying or being sad, suddenly started giggling or laughing. So one can imagine how socially paralyzing and incapacitating this condition can be.”

At present, there is no FDA-approved treatment for the condition. “Primarily, antidepressant medications are the mainstay now that they are being used off-label for treating pseudobulbar affect,” said Dr. Pioro. “Sometimes the antidepressants work reasonably well; other times, not so well. It’s quite variable.… In addition, the side-effect profiles of some of the antidepressants are really quite poor.”

Dextromethorphan and Quinidine Treatment

Dr. Pioro and colleagues tested the dextromethorphan and quinidine treatment in a 12-week, placebo-controlled, double-blind trial and a 12-week open-label extension. The treatment showed better results than placebo during the double-blind phase, continued benefits during the open-label phase, and a “very low” incidence of serious adverse events, according to Dr. Pioro.

Avanir Pharmaceuticals (Aliso Viejo, California) hopes to gain FDA approval for the treatment in the fourth quarter of 2010 and to make it available to pseudobulbar affect patients in the first quarter of 2011. The company plans to offer two doses: a combination of dextromethorphan 30 mg with quinidine 10 mg and a combination of dextromethorphan 20 mg with quinidine 10 mg.

The medication would be available in capsules taken orally twice daily in single-tablet form, according to Dr. Pioro. For elderly or more fragile patients with pseudobulbar affect, he said, “one may choose to start with the lower 20 mg/10 mg dosing first, see how they do, and if they don’t improve or they could use more improvement, to titrate up from there.”

The company had previously requested FDA approval for a combination of dextromethorphan 30 mg and quinidine 30 mg, but the FDA expressed concerns about that treatment’s tolerability and potential to cause cardiac arrhythmias in situations such as dosing errors or drug interactions, according to Dr. Pioro. Dextromethorphan is an NMDA receptor antagonist, and quinidine is a CYP2D6 inhibitor that increases concentrations of dextromethorphan in the plasma. Quinidine has the potential to be pro-arrhythmic at doses 60 to 100 times higher than the amount contained in the new combination.

The company agreed to reformulate to reduce the amount of quinidine in the combination by 67% and conduct a confirmatory Phase III trial to demonstrate safety, tolerability, and efficacy to support approval.

Double-Blind Efficacy

A total of 326 patients, all of whom had pseudobulbar affect and MS or ALS, entered the double-blind trial. To be eligible, the subjects had to have a score of at least 13 on the Center for Neurologic Study–Lability Scale (CNS–LS), a validated indicator of pseudobulbar symptom severity. CNS–LS scores range from 7 to 35, with higher scores indicating more severe symptoms; 13 is considered to correspond with the threshold for the clinical manifestation of symptoms.

At screening, the patients were randomized (1:1:1) into three groups: 110 received dextromethorphan 30 mg and quinidine 10 mg, 107 received dextromethorphan 20 mg and quinidine 10 mg, and 109 received placebo once daily for the first week and twice daily for the remaining 11 weeks. Patient data, including number of daily laughing or crying episodes, CNS–LS scores, and electrocardiograms, were collected during visits at baseline and weeks two, four, eight, and 12. However, beginning one week prior to randomization, patients began recording the number of daily episodes they experienced, which served as the “pre-treatment” baseline values.

The results indicated that treatment was associated with a reduction in laughing and crying episodes—the trial’s primary end point. Each treatment group had about a 47% to 48% benefit over placebo in reducing episode rates over the 12-week study course.

Treatment also was associated with a reduction in CNS–LS scores—the trial’s secondary end point. At baseline, those scores were 19.8 for the dextromethorphan 30-mg group, 21.0 for the dextromethorphan 20-mg group, and 19.9 for the placebo group. At week two, they had decreased to 13.1 for the dextromethorphan 30-mg group, 14.6 for the dextromethorphan 20-mg group, and 15.4 for the placebo group. And at week 12, the scores were 11.8 for the dextromethorphan 30-mg group, 12.8 for the dextromethorphan 20-mg group, and 14.3 for the placebo group.

“There was a very high placebo effect, which was somewhat surprising,” said Dr. Pioro. Nevertheless, he added, “Whatever effect placebo had, this combination was significantly better.”

Open-Label Efficacy

Of the 283 patients who completed the double-blind trial, 253 (89%) entered the open-label extension: 94 from the trial’s dextromethorphan 30-mg group, 76 from its dextromethorphan 20-mg group, and 83 from its placebo group. Some of these patients began the extension immediately after completing the double-blind trial, but about half chose to delay up to two weeks between completing the double-blind trial and enrolling in the extension.

In the extension, all patients received dextromethorphan 30 mg and quinidine 10 mg twice daily for 12 weeks. The researchers obtained the patients’ data at baseline and weeks two, six, and 12.

The patients’ mean CNS–LS score decreased from 13.8 at the extension’s baseline to 11.2 at week 12—a decrease that Dr. Pioro called “highly significant.” He also noted that patients who had received placebo during the double-blind phase showed the most improvement during the open-label phase: The mean CNS–LS score reductions were approximately 2.6 in patients originally from the dextromethorphan 30-mg group, 2.4 in those originally from the dextromethorphan 20-mg group, and 3.1 in those originally from the placebo group.

Safety and Tolerability

Asked how the trial and extension would alleviate the FDA’s concerns about cardiovascular safety, Dr. Pioro said, “There were no cardiovascular serious adverse events at all, in either the double-blind or the open-label phase.”

During the trial, the patients showed small changes from baseline to week 12 in mean QT interval (QTcF) with a Fridericia correction (a formula for adjusting QT intervals for heart rate). Those changes were 4.8 msec in the dextromethorphan 30-mg group, 1.0 msec in the dextromethorphan 20-mg group, and 1.0 msec in the placebo group. No patients in the treatment groups had QTcF interval increases greater than 60 msec or absolute QTcF interval greater than 480 msec, however. The researchers concluded from the double-blind phase that the treatment has low pro-arrhythmic potential.

During the open-label extension, 73.5% of patients—72.3% of those previously treated with dextromethorphan 30 mg, 75% of those previously treated with dextromethorphan 20 mg, and 73.5% of those previously treated with placebo—reported adverse events. However, 5.5% of patients—6.4%, 6.6%, and 3.6% from the previous dextromethorphan 30-mg, previous dextromethorphan 20-mg, and previous placebo groups, respectively—reported serious adverse events.

The rates of adverse event-related discontinuations during the open-label extension were 5.5% overall and 6.4%, 3.9%, and 2.4% for patients previously treated with dextromethorphan 30 mg, dextromethorphan 20 mg, and placebo, respectively. Dr. Pioro noted that some patients “didn’t complete because of death … which occurred in the ALS patient population, as one might expect. Other individuals were unable to either tolerate the medication because of adverse events—most commonly, mild to moderate dizziness, nausea, [and] diarrhea. Overall, however, both formulations of the drug combination were found to be safe and well-tolerated.”

—Jack Baney

Episodes of involuntary laughing and crying, known as pseudobulbar affect, were safely and effectively treated with dextromethorphan and quinidine.

TORONTO—A combination of dextromethorphan and quinidine appears to be an effective, safe, and well-tolerated treatment for pseudobulbar affect, said Erik P. Pioro, MD, at the 62nd Annual Meeting of the American Academy of Neurology.

Pseudobulbar affect—common among patients with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and other neurologic conditions—involves involuntary, sudden, and frequent episodes of laughing or crying.

“These episodes are very exaggerated and are often incongruent or inconsistent with what the individual may be feeling inside,” said Dr. Pioro, Director of the Section for ALS and Related Disorders at the Cleveland Clinic. “Some patients whom I’ve followed have been at a funeral and, instead of crying or being sad, suddenly started giggling or laughing. So one can imagine how socially paralyzing and incapacitating this condition can be.”

At present, there is no FDA-approved treatment for the condition. “Primarily, antidepressant medications are the mainstay now that they are being used off-label for treating pseudobulbar affect,” said Dr. Pioro. “Sometimes the antidepressants work reasonably well; other times, not so well. It’s quite variable.… In addition, the side-effect profiles of some of the antidepressants are really quite poor.”

Dextromethorphan and Quinidine Treatment

Dr. Pioro and colleagues tested the dextromethorphan and quinidine treatment in a 12-week, placebo-controlled, double-blind trial and a 12-week open-label extension. The treatment showed better results than placebo during the double-blind phase, continued benefits during the open-label phase, and a “very low” incidence of serious adverse events, according to Dr. Pioro.

Avanir Pharmaceuticals (Aliso Viejo, California) hopes to gain FDA approval for the treatment in the fourth quarter of 2010 and to make it available to pseudobulbar affect patients in the first quarter of 2011. The company plans to offer two doses: a combination of dextromethorphan 30 mg with quinidine 10 mg and a combination of dextromethorphan 20 mg with quinidine 10 mg.

The medication would be available in capsules taken orally twice daily in single-tablet form, according to Dr. Pioro. For elderly or more fragile patients with pseudobulbar affect, he said, “one may choose to start with the lower 20 mg/10 mg dosing first, see how they do, and if they don’t improve or they could use more improvement, to titrate up from there.”

The company had previously requested FDA approval for a combination of dextromethorphan 30 mg and quinidine 30 mg, but the FDA expressed concerns about that treatment’s tolerability and potential to cause cardiac arrhythmias in situations such as dosing errors or drug interactions, according to Dr. Pioro. Dextromethorphan is an NMDA receptor antagonist, and quinidine is a CYP2D6 inhibitor that increases concentrations of dextromethorphan in the plasma. Quinidine has the potential to be pro-arrhythmic at doses 60 to 100 times higher than the amount contained in the new combination.

The company agreed to reformulate to reduce the amount of quinidine in the combination by 67% and conduct a confirmatory Phase III trial to demonstrate safety, tolerability, and efficacy to support approval.

Double-Blind Efficacy

A total of 326 patients, all of whom had pseudobulbar affect and MS or ALS, entered the double-blind trial. To be eligible, the subjects had to have a score of at least 13 on the Center for Neurologic Study–Lability Scale (CNS–LS), a validated indicator of pseudobulbar symptom severity. CNS–LS scores range from 7 to 35, with higher scores indicating more severe symptoms; 13 is considered to correspond with the threshold for the clinical manifestation of symptoms.

At screening, the patients were randomized (1:1:1) into three groups: 110 received dextromethorphan 30 mg and quinidine 10 mg, 107 received dextromethorphan 20 mg and quinidine 10 mg, and 109 received placebo once daily for the first week and twice daily for the remaining 11 weeks. Patient data, including number of daily laughing or crying episodes, CNS–LS scores, and electrocardiograms, were collected during visits at baseline and weeks two, four, eight, and 12. However, beginning one week prior to randomization, patients began recording the number of daily episodes they experienced, which served as the “pre-treatment” baseline values.

The results indicated that treatment was associated with a reduction in laughing and crying episodes—the trial’s primary end point. Each treatment group had about a 47% to 48% benefit over placebo in reducing episode rates over the 12-week study course.

Treatment also was associated with a reduction in CNS–LS scores—the trial’s secondary end point. At baseline, those scores were 19.8 for the dextromethorphan 30-mg group, 21.0 for the dextromethorphan 20-mg group, and 19.9 for the placebo group. At week two, they had decreased to 13.1 for the dextromethorphan 30-mg group, 14.6 for the dextromethorphan 20-mg group, and 15.4 for the placebo group. And at week 12, the scores were 11.8 for the dextromethorphan 30-mg group, 12.8 for the dextromethorphan 20-mg group, and 14.3 for the placebo group.

“There was a very high placebo effect, which was somewhat surprising,” said Dr. Pioro. Nevertheless, he added, “Whatever effect placebo had, this combination was significantly better.”

Open-Label Efficacy

Of the 283 patients who completed the double-blind trial, 253 (89%) entered the open-label extension: 94 from the trial’s dextromethorphan 30-mg group, 76 from its dextromethorphan 20-mg group, and 83 from its placebo group. Some of these patients began the extension immediately after completing the double-blind trial, but about half chose to delay up to two weeks between completing the double-blind trial and enrolling in the extension.

In the extension, all patients received dextromethorphan 30 mg and quinidine 10 mg twice daily for 12 weeks. The researchers obtained the patients’ data at baseline and weeks two, six, and 12.

The patients’ mean CNS–LS score decreased from 13.8 at the extension’s baseline to 11.2 at week 12—a decrease that Dr. Pioro called “highly significant.” He also noted that patients who had received placebo during the double-blind phase showed the most improvement during the open-label phase: The mean CNS–LS score reductions were approximately 2.6 in patients originally from the dextromethorphan 30-mg group, 2.4 in those originally from the dextromethorphan 20-mg group, and 3.1 in those originally from the placebo group.

Safety and Tolerability

Asked how the trial and extension would alleviate the FDA’s concerns about cardiovascular safety, Dr. Pioro said, “There were no cardiovascular serious adverse events at all, in either the double-blind or the open-label phase.”

During the trial, the patients showed small changes from baseline to week 12 in mean QT interval (QTcF) with a Fridericia correction (a formula for adjusting QT intervals for heart rate). Those changes were 4.8 msec in the dextromethorphan 30-mg group, 1.0 msec in the dextromethorphan 20-mg group, and 1.0 msec in the placebo group. No patients in the treatment groups had QTcF interval increases greater than 60 msec or absolute QTcF interval greater than 480 msec, however. The researchers concluded from the double-blind phase that the treatment has low pro-arrhythmic potential.

During the open-label extension, 73.5% of patients—72.3% of those previously treated with dextromethorphan 30 mg, 75% of those previously treated with dextromethorphan 20 mg, and 73.5% of those previously treated with placebo—reported adverse events. However, 5.5% of patients—6.4%, 6.6%, and 3.6% from the previous dextromethorphan 30-mg, previous dextromethorphan 20-mg, and previous placebo groups, respectively—reported serious adverse events.

The rates of adverse event-related discontinuations during the open-label extension were 5.5% overall and 6.4%, 3.9%, and 2.4% for patients previously treated with dextromethorphan 30 mg, dextromethorphan 20 mg, and placebo, respectively. Dr. Pioro noted that some patients “didn’t complete because of death … which occurred in the ALS patient population, as one might expect. Other individuals were unable to either tolerate the medication because of adverse events—most commonly, mild to moderate dizziness, nausea, [and] diarrhea. Overall, however, both formulations of the drug combination were found to be safe and well-tolerated.”

—Jack Baney

Episodes of involuntary laughing and crying, known as pseudobulbar affect, were safely and effectively treated with dextromethorphan and quinidine.

TORONTO—A combination of dextromethorphan and quinidine appears to be an effective, safe, and well-tolerated treatment for pseudobulbar affect, said Erik P. Pioro, MD, at the 62nd Annual Meeting of the American Academy of Neurology.

Pseudobulbar affect—common among patients with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and other neurologic conditions—involves involuntary, sudden, and frequent episodes of laughing or crying.

“These episodes are very exaggerated and are often incongruent or inconsistent with what the individual may be feeling inside,” said Dr. Pioro, Director of the Section for ALS and Related Disorders at the Cleveland Clinic. “Some patients whom I’ve followed have been at a funeral and, instead of crying or being sad, suddenly started giggling or laughing. So one can imagine how socially paralyzing and incapacitating this condition can be.”

At present, there is no FDA-approved treatment for the condition. “Primarily, antidepressant medications are the mainstay now that they are being used off-label for treating pseudobulbar affect,” said Dr. Pioro. “Sometimes the antidepressants work reasonably well; other times, not so well. It’s quite variable.… In addition, the side-effect profiles of some of the antidepressants are really quite poor.”

Dextromethorphan and Quinidine Treatment

Dr. Pioro and colleagues tested the dextromethorphan and quinidine treatment in a 12-week, placebo-controlled, double-blind trial and a 12-week open-label extension. The treatment showed better results than placebo during the double-blind phase, continued benefits during the open-label phase, and a “very low” incidence of serious adverse events, according to Dr. Pioro.

Avanir Pharmaceuticals (Aliso Viejo, California) hopes to gain FDA approval for the treatment in the fourth quarter of 2010 and to make it available to pseudobulbar affect patients in the first quarter of 2011. The company plans to offer two doses: a combination of dextromethorphan 30 mg with quinidine 10 mg and a combination of dextromethorphan 20 mg with quinidine 10 mg.

The medication would be available in capsules taken orally twice daily in single-tablet form, according to Dr. Pioro. For elderly or more fragile patients with pseudobulbar affect, he said, “one may choose to start with the lower 20 mg/10 mg dosing first, see how they do, and if they don’t improve or they could use more improvement, to titrate up from there.”

The company had previously requested FDA approval for a combination of dextromethorphan 30 mg and quinidine 30 mg, but the FDA expressed concerns about that treatment’s tolerability and potential to cause cardiac arrhythmias in situations such as dosing errors or drug interactions, according to Dr. Pioro. Dextromethorphan is an NMDA receptor antagonist, and quinidine is a CYP2D6 inhibitor that increases concentrations of dextromethorphan in the plasma. Quinidine has the potential to be pro-arrhythmic at doses 60 to 100 times higher than the amount contained in the new combination.

The company agreed to reformulate to reduce the amount of quinidine in the combination by 67% and conduct a confirmatory Phase III trial to demonstrate safety, tolerability, and efficacy to support approval.

Double-Blind Efficacy

A total of 326 patients, all of whom had pseudobulbar affect and MS or ALS, entered the double-blind trial. To be eligible, the subjects had to have a score of at least 13 on the Center for Neurologic Study–Lability Scale (CNS–LS), a validated indicator of pseudobulbar symptom severity. CNS–LS scores range from 7 to 35, with higher scores indicating more severe symptoms; 13 is considered to correspond with the threshold for the clinical manifestation of symptoms.

At screening, the patients were randomized (1:1:1) into three groups: 110 received dextromethorphan 30 mg and quinidine 10 mg, 107 received dextromethorphan 20 mg and quinidine 10 mg, and 109 received placebo once daily for the first week and twice daily for the remaining 11 weeks. Patient data, including number of daily laughing or crying episodes, CNS–LS scores, and electrocardiograms, were collected during visits at baseline and weeks two, four, eight, and 12. However, beginning one week prior to randomization, patients began recording the number of daily episodes they experienced, which served as the “pre-treatment” baseline values.

The results indicated that treatment was associated with a reduction in laughing and crying episodes—the trial’s primary end point. Each treatment group had about a 47% to 48% benefit over placebo in reducing episode rates over the 12-week study course.

Treatment also was associated with a reduction in CNS–LS scores—the trial’s secondary end point. At baseline, those scores were 19.8 for the dextromethorphan 30-mg group, 21.0 for the dextromethorphan 20-mg group, and 19.9 for the placebo group. At week two, they had decreased to 13.1 for the dextromethorphan 30-mg group, 14.6 for the dextromethorphan 20-mg group, and 15.4 for the placebo group. And at week 12, the scores were 11.8 for the dextromethorphan 30-mg group, 12.8 for the dextromethorphan 20-mg group, and 14.3 for the placebo group.

“There was a very high placebo effect, which was somewhat surprising,” said Dr. Pioro. Nevertheless, he added, “Whatever effect placebo had, this combination was significantly better.”

Open-Label Efficacy

Of the 283 patients who completed the double-blind trial, 253 (89%) entered the open-label extension: 94 from the trial’s dextromethorphan 30-mg group, 76 from its dextromethorphan 20-mg group, and 83 from its placebo group. Some of these patients began the extension immediately after completing the double-blind trial, but about half chose to delay up to two weeks between completing the double-blind trial and enrolling in the extension.

In the extension, all patients received dextromethorphan 30 mg and quinidine 10 mg twice daily for 12 weeks. The researchers obtained the patients’ data at baseline and weeks two, six, and 12.

The patients’ mean CNS–LS score decreased from 13.8 at the extension’s baseline to 11.2 at week 12—a decrease that Dr. Pioro called “highly significant.” He also noted that patients who had received placebo during the double-blind phase showed the most improvement during the open-label phase: The mean CNS–LS score reductions were approximately 2.6 in patients originally from the dextromethorphan 30-mg group, 2.4 in those originally from the dextromethorphan 20-mg group, and 3.1 in those originally from the placebo group.

Safety and Tolerability

Asked how the trial and extension would alleviate the FDA’s concerns about cardiovascular safety, Dr. Pioro said, “There were no cardiovascular serious adverse events at all, in either the double-blind or the open-label phase.”

During the trial, the patients showed small changes from baseline to week 12 in mean QT interval (QTcF) with a Fridericia correction (a formula for adjusting QT intervals for heart rate). Those changes were 4.8 msec in the dextromethorphan 30-mg group, 1.0 msec in the dextromethorphan 20-mg group, and 1.0 msec in the placebo group. No patients in the treatment groups had QTcF interval increases greater than 60 msec or absolute QTcF interval greater than 480 msec, however. The researchers concluded from the double-blind phase that the treatment has low pro-arrhythmic potential.

During the open-label extension, 73.5% of patients—72.3% of those previously treated with dextromethorphan 30 mg, 75% of those previously treated with dextromethorphan 20 mg, and 73.5% of those previously treated with placebo—reported adverse events. However, 5.5% of patients—6.4%, 6.6%, and 3.6% from the previous dextromethorphan 30-mg, previous dextromethorphan 20-mg, and previous placebo groups, respectively—reported serious adverse events.

The rates of adverse event-related discontinuations during the open-label extension were 5.5% overall and 6.4%, 3.9%, and 2.4% for patients previously treated with dextromethorphan 30 mg, dextromethorphan 20 mg, and placebo, respectively. Dr. Pioro noted that some patients “didn’t complete because of death … which occurred in the ALS patient population, as one might expect. Other individuals were unable to either tolerate the medication because of adverse events—most commonly, mild to moderate dizziness, nausea, [and] diarrhea. Overall, however, both formulations of the drug combination were found to be safe and well-tolerated.”

—Jack Baney

In addition to physical symptoms, multiple sclerosis (MS) may have significant effects on emotions. Some of these may be reactions to living with a chronic, unpredictable disease, while others may be due to the disease itself—demyelination and nerve fiber damage can result in emotional changes.

In addition to physical symptoms, multiple sclerosis (MS) may have significant effects on emotions. Some of these may be reactions to living with a chronic, unpredictable disease, while others may be due to the disease itself—demyelination and nerve fiber damage can result in emotional changes.

In addition to physical symptoms, multiple sclerosis (MS) may have significant effects on emotions. Some of these may be reactions to living with a chronic, unpredictable disease, while others may be due to the disease itself—demyelination and nerve fiber damage can result in emotional changes.

TORONTO—Annualized relapse rates in patients with relapsing-remitting multiple sclerosis (MS) were more than 50% lower in subjects taking oral fingolimod (FTY720) than in those taking a placebo, according to research presented at the 62nd Annual Meeting of the American Academy of Neurology. The medication also reduced the risk of disability progression by 30% and significantly decreased the number of new or enlarged T2 lesions and gadolinium-enhancing lesions, per 24-month results of the phase III FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) trial.

Oral fingolimod, a sphingosine 1-phosphate receptor (S1PR) modulator, is the first in a novel class of drugs under evaluation for the treatment of relapsing and progressive forms of MS. S1PR modulators work to retain circulating lymphocytes in the lymph nodes, thereby reducing the recirculation of autoreactive lymphocytes and preventing penetration of these lymphocytes into the CNS.

Fingolimod Versus Placebo

The double-blind, placebo-controlled multicenter FREEDOMS study randomized 1,083 patients (mean age, 40.5) to receive once-daily doses of either 1.25-mg fingolimod, 0.5-mg fingolimod, or a placebo. For the primary end point of annualized relapse rate, both doses of fingolimod were superior to placebo, with a 54% reduction in relapses for the lower dose and a 60% reduction in the higher dose. For the key secondary end point of time to three-month confirmed disability progression, measured by a 1-point increase in the Expanded Disability Status Scale (EDSS), a 30% risk reduction was reported in the 0.5-mg dose, and 32% in the 1.25-mg dose, compared with placebo.

“Overall, 1.25-mg fingolimod did not offer any advantages regarding efficacy, and it had a slightly higher array of side effects; therefore, 0.5 mg is the dosage that we will submit an application for [FDA] approval at this time,” announced Ludwig Kappos, MD, of the Department of Neurology, University Hospital, University of Basel, Switzerland.

The second phase of the study, which was presented in 2006, showed a “clear cut effect on inflammatory outcomes on MRI,” Dr. Kappos noted. “Five years of follow-up support these effects…. Approximately 99.5% of patients remaining in the study do not show MRI activity and have a low annualized relapse rate at approximately 0.2, [which is equivalent to] one relapse every five years.”

The phase III, 24-month MRI inflammatory activity results favored fingolimod over placebo, with 50.5% of the 0.5-mg fingolimod group and 51.9% of the 1.25-mg group free from new or newly enlarged T2 lesions, compared with 21.2% of the placebo group, reported Ernst-Wilhelm Radue, MD, Director of Medical Image Analysis Center, University Hospital Basel, Switzerland. In addition, more patients were free from gadolinium-enhanced lesions with fingolimod (89.7% and 89.8%), compared with placebo (65.1%).

Fingolimod Versus Interferon

A second study, the Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS), compared both doses of fingolimod to intramuscular interferon beta-1a and found that the oral medicine reduced annualized relapse rates by up to 50%, compared with injectable interferon.

The 12-month phase III study of 1,153 patients also found that fewer patients experienced relapses requiring steroid treatment and/or hospitalization when treated with fingolimod than when treated with interferon beta-1a. Patients in both fingolimod groups also had significantly less deterioration of the ability to perform daily activities, based on the Patient-Reported Indices for Multiple Sclerosis (PRIMUS)–Activities scores, compared with the interferon group.

A 24-month optional extension study to assess the safety and efficacy—both clinically and on MRI—is under way and involves 89% of the patients who completed the core TRANSFORMS study. Patients who were taking weekly interferon beta-1a injections have been switched to daily oral fingolimod, and those who took fingolimod in the earlier phase of the trial have continued on the medication. Following the results of the FREEDOMS II trial, all subjects in the TRANSFORMS extension study are taking the 0.5-mg dose.

Safety and Tolerability

Of the 1,272 patients initially enrolled in the FREEDOMS trial, 81% completed the study. Those who discontinued the trial were proportionately lower in the 0.5-mg fingolimod group (19%), compared with the 1.25-mg dose (31%) or placebo (28%) groups.

The percentages of patients reporting any adverse events were similar for both fingolimod groups (94%) and placebo (93%). Serious adverse events were reported in 10% of patients taking 0.5-mg fingolimod, 12% of those taking 1.25-mg fingolimod, and 13% of the placebo group. Serious infectious adverse events occurred in 1.6% of the 0.5-mg group, 2.6% of the 1.25-mg group, and 1.9% of the placebo group.

Malignant neoplasms were reported in 10 patients in the placebo group and four patients in each active group. Seven cases of macular edema occurred, all in patients on the 1.25-mg dose. A transient heart rate decrease at the beginning of treatment, minor increases in blood pressure, and increases in liver enzymes were also observed.

“These results confirm that fingolimod is generally well tolerated,” the researchers reported. “The 0.5-mg dose was generally better tolerated than the 1.25-mg dose, [and was] associated with fewer bradycardia and serious adverse events and no cases of macular edema.”

—Rebecca K. Abma
Suggested Reading

Cohen JA, Barkhof F, Comi G, et al; TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402-415.

Kappos L, Radue EW, O’Connor P, et al; FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401.

More Oral MS Drugs in the Pipeline
TORONTO—A number of other oral MS drugs are also in development and were reported on at the 62nd Annual Meeting of the American Academy of Neurology.

Cladribine, an adenosine deaminase-resistant purine nucleoside that targets CD4+ T cells and spares B cells and natural killer cells, is taken as short cycles (once daily for five days), which are then repeated monthly for a total of two (3.5-mg/kg) or four (5.25-mg/kg) cycles in the first year and two cycles in the second year. In the 96-month Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study of 1,326 patients with relapsing-remitting MS, Gavin Giovannoni, PhD, Chair of Neurology, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry and the Department of Neurology, Barts and The London NHS Trust, reported that treatment with cladribine in either 3.5-mg/kg or 5.25-mg/kg doses offered significant treatment benefits over placebo, with consistent reductions in the annualized relapse rate and decreases in health care costs. When examining the data for complete disease remission, the investigators found that 71.8% of patients taking 3.5 mg and 70.4% of those taking 5.25 mg were relapse- and disease-progression free, compared with 52.6% of the placebo group. When the third end point of MRI-activity was added, 43.0% of the 3.5-mg group and 44.3% of the 5.25-mg group were disease-activity free, compared with 16% of the placebo group. Cladribine developer Merck Serono SA, Geneva, Switzerland, was issued a refuse to file letter from the FDA late last year.

Teriflunomide, an FDA-approved arthritis treatment from Sanofi-Aventis, Bridgewater, New Jersey, is currently in phase III trials for relapsing-remitting MS. Research presented at the conference noted, “the immunomodulatory effects of teriflunomide are associated with a reduction in the infiltration of macrophages, B cells, and T cells, and an increased survival of oligodendrocytes in the spinal cord. Therefore, teriflunomide treatment could potentially delay neurodegeneration in MS by preventing the loss of myelin and oligodendrocytes.” A six-month, placebo-controlled study of teriflunomide combined with glatiramer acetate found that both 7-mg and 14-mg daily doses improved disease control as measured by MRI scans compared to placebo.

BG-12 is oral dimethyl fumarate taken two to three times a day. Researchers suspect that it may act via the nuclear factor-E2–related factor 2 (Nrf2) transcription pathway. Biogen Idec, Inc, Cambridge, Massachusetts, is conducting two large, phase III trials: Determination of the Efficacy and Safety of Oral Fumarate in Relapsing Remitting MS (DEFINE), a randomized, double-blind, placebo-controlled study of 1,237 patients; and Comparator and an Oral Fumarate in Relapsing Remitting Multiple Sclerosis (CONFIRM), a randomized, double-blind, placebo-controlled and active reference (glatiramer acetate) trial of 1,431 patients.

BAF312, a second-generation S1P receptor modulator, from Novartis Pharma, Basel, Switzerland, selectively targets S1P1 and S1P5 receptors, and is currently in phase II trials. Researchers reported that BAF312 “reverses chronic neurologic paralysis and reduces inflammation and demyelination in EAE mice, and thus may represent a promising treatment modality for inflammatory autoimmune diseases like MS.”

—Rebecca K. Abma

Suggested Reading
Rammohan KW, Shoemaker J. Emerging multiple sclerosis oral therapies. Neurology. 2010;74(Suppl 1):S47-S53.

TORONTO—Annualized relapse rates in patients with relapsing-remitting multiple sclerosis (MS) were more than 50% lower in subjects taking oral fingolimod (FTY720) than in those taking a placebo, according to research presented at the 62nd Annual Meeting of the American Academy of Neurology. The medication also reduced the risk of disability progression by 30% and significantly decreased the number of new or enlarged T2 lesions and gadolinium-enhancing lesions, per 24-month results of the phase III FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) trial.

Oral fingolimod, a sphingosine 1-phosphate receptor (S1PR) modulator, is the first in a novel class of drugs under evaluation for the treatment of relapsing and progressive forms of MS. S1PR modulators work to retain circulating lymphocytes in the lymph nodes, thereby reducing the recirculation of autoreactive lymphocytes and preventing penetration of these lymphocytes into the CNS.

Fingolimod Versus Placebo

The double-blind, placebo-controlled multicenter FREEDOMS study randomized 1,083 patients (mean age, 40.5) to receive once-daily doses of either 1.25-mg fingolimod, 0.5-mg fingolimod, or a placebo. For the primary end point of annualized relapse rate, both doses of fingolimod were superior to placebo, with a 54% reduction in relapses for the lower dose and a 60% reduction in the higher dose. For the key secondary end point of time to three-month confirmed disability progression, measured by a 1-point increase in the Expanded Disability Status Scale (EDSS), a 30% risk reduction was reported in the 0.5-mg dose, and 32% in the 1.25-mg dose, compared with placebo.

“Overall, 1.25-mg fingolimod did not offer any advantages regarding efficacy, and it had a slightly higher array of side effects; therefore, 0.5 mg is the dosage that we will submit an application for [FDA] approval at this time,” announced Ludwig Kappos, MD, of the Department of Neurology, University Hospital, University of Basel, Switzerland.

The second phase of the study, which was presented in 2006, showed a “clear cut effect on inflammatory outcomes on MRI,” Dr. Kappos noted. “Five years of follow-up support these effects…. Approximately 99.5% of patients remaining in the study do not show MRI activity and have a low annualized relapse rate at approximately 0.2, [which is equivalent to] one relapse every five years.”

The phase III, 24-month MRI inflammatory activity results favored fingolimod over placebo, with 50.5% of the 0.5-mg fingolimod group and 51.9% of the 1.25-mg group free from new or newly enlarged T2 lesions, compared with 21.2% of the placebo group, reported Ernst-Wilhelm Radue, MD, Director of Medical Image Analysis Center, University Hospital Basel, Switzerland. In addition, more patients were free from gadolinium-enhanced lesions with fingolimod (89.7% and 89.8%), compared with placebo (65.1%).

Fingolimod Versus Interferon

A second study, the Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS), compared both doses of fingolimod to intramuscular interferon beta-1a and found that the oral medicine reduced annualized relapse rates by up to 50%, compared with injectable interferon.

The 12-month phase III study of 1,153 patients also found that fewer patients experienced relapses requiring steroid treatment and/or hospitalization when treated with fingolimod than when treated with interferon beta-1a. Patients in both fingolimod groups also had significantly less deterioration of the ability to perform daily activities, based on the Patient-Reported Indices for Multiple Sclerosis (PRIMUS)–Activities scores, compared with the interferon group.

A 24-month optional extension study to assess the safety and efficacy—both clinically and on MRI—is under way and involves 89% of the patients who completed the core TRANSFORMS study. Patients who were taking weekly interferon beta-1a injections have been switched to daily oral fingolimod, and those who took fingolimod in the earlier phase of the trial have continued on the medication. Following the results of the FREEDOMS II trial, all subjects in the TRANSFORMS extension study are taking the 0.5-mg dose.

Safety and Tolerability

Of the 1,272 patients initially enrolled in the FREEDOMS trial, 81% completed the study. Those who discontinued the trial were proportionately lower in the 0.5-mg fingolimod group (19%), compared with the 1.25-mg dose (31%) or placebo (28%) groups.

The percentages of patients reporting any adverse events were similar for both fingolimod groups (94%) and placebo (93%). Serious adverse events were reported in 10% of patients taking 0.5-mg fingolimod, 12% of those taking 1.25-mg fingolimod, and 13% of the placebo group. Serious infectious adverse events occurred in 1.6% of the 0.5-mg group, 2.6% of the 1.25-mg group, and 1.9% of the placebo group.

Malignant neoplasms were reported in 10 patients in the placebo group and four patients in each active group. Seven cases of macular edema occurred, all in patients on the 1.25-mg dose. A transient heart rate decrease at the beginning of treatment, minor increases in blood pressure, and increases in liver enzymes were also observed.

“These results confirm that fingolimod is generally well tolerated,” the researchers reported. “The 0.5-mg dose was generally better tolerated than the 1.25-mg dose, [and was] associated with fewer bradycardia and serious adverse events and no cases of macular edema.”

—Rebecca K. Abma
Suggested Reading

Cohen JA, Barkhof F, Comi G, et al; TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402-415.

Kappos L, Radue EW, O’Connor P, et al; FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401.

More Oral MS Drugs in the Pipeline
TORONTO—A number of other oral MS drugs are also in development and were reported on at the 62nd Annual Meeting of the American Academy of Neurology.

Cladribine, an adenosine deaminase-resistant purine nucleoside that targets CD4+ T cells and spares B cells and natural killer cells, is taken as short cycles (once daily for five days), which are then repeated monthly for a total of two (3.5-mg/kg) or four (5.25-mg/kg) cycles in the first year and two cycles in the second year. In the 96-month Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study of 1,326 patients with relapsing-remitting MS, Gavin Giovannoni, PhD, Chair of Neurology, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry and the Department of Neurology, Barts and The London NHS Trust, reported that treatment with cladribine in either 3.5-mg/kg or 5.25-mg/kg doses offered significant treatment benefits over placebo, with consistent reductions in the annualized relapse rate and decreases in health care costs. When examining the data for complete disease remission, the investigators found that 71.8% of patients taking 3.5 mg and 70.4% of those taking 5.25 mg were relapse- and disease-progression free, compared with 52.6% of the placebo group. When the third end point of MRI-activity was added, 43.0% of the 3.5-mg group and 44.3% of the 5.25-mg group were disease-activity free, compared with 16% of the placebo group. Cladribine developer Merck Serono SA, Geneva, Switzerland, was issued a refuse to file letter from the FDA late last year.

Teriflunomide, an FDA-approved arthritis treatment from Sanofi-Aventis, Bridgewater, New Jersey, is currently in phase III trials for relapsing-remitting MS. Research presented at the conference noted, “the immunomodulatory effects of teriflunomide are associated with a reduction in the infiltration of macrophages, B cells, and T cells, and an increased survival of oligodendrocytes in the spinal cord. Therefore, teriflunomide treatment could potentially delay neurodegeneration in MS by preventing the loss of myelin and oligodendrocytes.” A six-month, placebo-controlled study of teriflunomide combined with glatiramer acetate found that both 7-mg and 14-mg daily doses improved disease control as measured by MRI scans compared to placebo.

BG-12 is oral dimethyl fumarate taken two to three times a day. Researchers suspect that it may act via the nuclear factor-E2–related factor 2 (Nrf2) transcription pathway. Biogen Idec, Inc, Cambridge, Massachusetts, is conducting two large, phase III trials: Determination of the Efficacy and Safety of Oral Fumarate in Relapsing Remitting MS (DEFINE), a randomized, double-blind, placebo-controlled study of 1,237 patients; and Comparator and an Oral Fumarate in Relapsing Remitting Multiple Sclerosis (CONFIRM), a randomized, double-blind, placebo-controlled and active reference (glatiramer acetate) trial of 1,431 patients.

BAF312, a second-generation S1P receptor modulator, from Novartis Pharma, Basel, Switzerland, selectively targets S1P1 and S1P5 receptors, and is currently in phase II trials. Researchers reported that BAF312 “reverses chronic neurologic paralysis and reduces inflammation and demyelination in EAE mice, and thus may represent a promising treatment modality for inflammatory autoimmune diseases like MS.”

—Rebecca K. Abma

Suggested Reading
Rammohan KW, Shoemaker J. Emerging multiple sclerosis oral therapies. Neurology. 2010;74(Suppl 1):S47-S53.

TORONTO—Annualized relapse rates in patients with relapsing-remitting multiple sclerosis (MS) were more than 50% lower in subjects taking oral fingolimod (FTY720) than in those taking a placebo, according to research presented at the 62nd Annual Meeting of the American Academy of Neurology. The medication also reduced the risk of disability progression by 30% and significantly decreased the number of new or enlarged T2 lesions and gadolinium-enhancing lesions, per 24-month results of the phase III FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) trial.

Oral fingolimod, a sphingosine 1-phosphate receptor (S1PR) modulator, is the first in a novel class of drugs under evaluation for the treatment of relapsing and progressive forms of MS. S1PR modulators work to retain circulating lymphocytes in the lymph nodes, thereby reducing the recirculation of autoreactive lymphocytes and preventing penetration of these lymphocytes into the CNS.

Fingolimod Versus Placebo

The double-blind, placebo-controlled multicenter FREEDOMS study randomized 1,083 patients (mean age, 40.5) to receive once-daily doses of either 1.25-mg fingolimod, 0.5-mg fingolimod, or a placebo. For the primary end point of annualized relapse rate, both doses of fingolimod were superior to placebo, with a 54% reduction in relapses for the lower dose and a 60% reduction in the higher dose. For the key secondary end point of time to three-month confirmed disability progression, measured by a 1-point increase in the Expanded Disability Status Scale (EDSS), a 30% risk reduction was reported in the 0.5-mg dose, and 32% in the 1.25-mg dose, compared with placebo.

“Overall, 1.25-mg fingolimod did not offer any advantages regarding efficacy, and it had a slightly higher array of side effects; therefore, 0.5 mg is the dosage that we will submit an application for [FDA] approval at this time,” announced Ludwig Kappos, MD, of the Department of Neurology, University Hospital, University of Basel, Switzerland.

The second phase of the study, which was presented in 2006, showed a “clear cut effect on inflammatory outcomes on MRI,” Dr. Kappos noted. “Five years of follow-up support these effects…. Approximately 99.5% of patients remaining in the study do not show MRI activity and have a low annualized relapse rate at approximately 0.2, [which is equivalent to] one relapse every five years.”

The phase III, 24-month MRI inflammatory activity results favored fingolimod over placebo, with 50.5% of the 0.5-mg fingolimod group and 51.9% of the 1.25-mg group free from new or newly enlarged T2 lesions, compared with 21.2% of the placebo group, reported Ernst-Wilhelm Radue, MD, Director of Medical Image Analysis Center, University Hospital Basel, Switzerland. In addition, more patients were free from gadolinium-enhanced lesions with fingolimod (89.7% and 89.8%), compared with placebo (65.1%).

Fingolimod Versus Interferon

A second study, the Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS), compared both doses of fingolimod to intramuscular interferon beta-1a and found that the oral medicine reduced annualized relapse rates by up to 50%, compared with injectable interferon.

The 12-month phase III study of 1,153 patients also found that fewer patients experienced relapses requiring steroid treatment and/or hospitalization when treated with fingolimod than when treated with interferon beta-1a. Patients in both fingolimod groups also had significantly less deterioration of the ability to perform daily activities, based on the Patient-Reported Indices for Multiple Sclerosis (PRIMUS)–Activities scores, compared with the interferon group.

A 24-month optional extension study to assess the safety and efficacy—both clinically and on MRI—is under way and involves 89% of the patients who completed the core TRANSFORMS study. Patients who were taking weekly interferon beta-1a injections have been switched to daily oral fingolimod, and those who took fingolimod in the earlier phase of the trial have continued on the medication. Following the results of the FREEDOMS II trial, all subjects in the TRANSFORMS extension study are taking the 0.5-mg dose.

Safety and Tolerability

Of the 1,272 patients initially enrolled in the FREEDOMS trial, 81% completed the study. Those who discontinued the trial were proportionately lower in the 0.5-mg fingolimod group (19%), compared with the 1.25-mg dose (31%) or placebo (28%) groups.

The percentages of patients reporting any adverse events were similar for both fingolimod groups (94%) and placebo (93%). Serious adverse events were reported in 10% of patients taking 0.5-mg fingolimod, 12% of those taking 1.25-mg fingolimod, and 13% of the placebo group. Serious infectious adverse events occurred in 1.6% of the 0.5-mg group, 2.6% of the 1.25-mg group, and 1.9% of the placebo group.

Malignant neoplasms were reported in 10 patients in the placebo group and four patients in each active group. Seven cases of macular edema occurred, all in patients on the 1.25-mg dose. A transient heart rate decrease at the beginning of treatment, minor increases in blood pressure, and increases in liver enzymes were also observed.

“These results confirm that fingolimod is generally well tolerated,” the researchers reported. “The 0.5-mg dose was generally better tolerated than the 1.25-mg dose, [and was] associated with fewer bradycardia and serious adverse events and no cases of macular edema.”

—Rebecca K. Abma
Suggested Reading

Cohen JA, Barkhof F, Comi G, et al; TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402-415.

Kappos L, Radue EW, O’Connor P, et al; FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401.

More Oral MS Drugs in the Pipeline
TORONTO—A number of other oral MS drugs are also in development and were reported on at the 62nd Annual Meeting of the American Academy of Neurology.

Cladribine, an adenosine deaminase-resistant purine nucleoside that targets CD4+ T cells and spares B cells and natural killer cells, is taken as short cycles (once daily for five days), which are then repeated monthly for a total of two (3.5-mg/kg) or four (5.25-mg/kg) cycles in the first year and two cycles in the second year. In the 96-month Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study of 1,326 patients with relapsing-remitting MS, Gavin Giovannoni, PhD, Chair of Neurology, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry and the Department of Neurology, Barts and The London NHS Trust, reported that treatment with cladribine in either 3.5-mg/kg or 5.25-mg/kg doses offered significant treatment benefits over placebo, with consistent reductions in the annualized relapse rate and decreases in health care costs. When examining the data for complete disease remission, the investigators found that 71.8% of patients taking 3.5 mg and 70.4% of those taking 5.25 mg were relapse- and disease-progression free, compared with 52.6% of the placebo group. When the third end point of MRI-activity was added, 43.0% of the 3.5-mg group and 44.3% of the 5.25-mg group were disease-activity free, compared with 16% of the placebo group. Cladribine developer Merck Serono SA, Geneva, Switzerland, was issued a refuse to file letter from the FDA late last year.

Teriflunomide, an FDA-approved arthritis treatment from Sanofi-Aventis, Bridgewater, New Jersey, is currently in phase III trials for relapsing-remitting MS. Research presented at the conference noted, “the immunomodulatory effects of teriflunomide are associated with a reduction in the infiltration of macrophages, B cells, and T cells, and an increased survival of oligodendrocytes in the spinal cord. Therefore, teriflunomide treatment could potentially delay neurodegeneration in MS by preventing the loss of myelin and oligodendrocytes.” A six-month, placebo-controlled study of teriflunomide combined with glatiramer acetate found that both 7-mg and 14-mg daily doses improved disease control as measured by MRI scans compared to placebo.

BG-12 is oral dimethyl fumarate taken two to three times a day. Researchers suspect that it may act via the nuclear factor-E2–related factor 2 (Nrf2) transcription pathway. Biogen Idec, Inc, Cambridge, Massachusetts, is conducting two large, phase III trials: Determination of the Efficacy and Safety of Oral Fumarate in Relapsing Remitting MS (DEFINE), a randomized, double-blind, placebo-controlled study of 1,237 patients; and Comparator and an Oral Fumarate in Relapsing Remitting Multiple Sclerosis (CONFIRM), a randomized, double-blind, placebo-controlled and active reference (glatiramer acetate) trial of 1,431 patients.

BAF312, a second-generation S1P receptor modulator, from Novartis Pharma, Basel, Switzerland, selectively targets S1P1 and S1P5 receptors, and is currently in phase II trials. Researchers reported that BAF312 “reverses chronic neurologic paralysis and reduces inflammation and demyelination in EAE mice, and thus may represent a promising treatment modality for inflammatory autoimmune diseases like MS.”

—Rebecca K. Abma

Suggested Reading
Rammohan KW, Shoemaker J. Emerging multiple sclerosis oral therapies. Neurology. 2010;74(Suppl 1):S47-S53.

BOSTON—Patients with tuberous sclerosis complex (TSC) may benefit from novel therapies targeting idoleamine 2,3-dioxygenase (IDO) and major vault protein (MVP), researchers at Wayne State University in Detroit reported at the American Epilepsy Society meeting. Carlos Batista, a graduate student in the Translational Neuroscience Program, and colleagues studied cortical tubers that were surgically removed from 12 children with TSC and found elevated tryptophan metabolism and expressions of IDO and MVP.

“Cortical tubers express large numbers of activated microglia, macrophages, and T lymphocytes, thus suggesting activation of inflammatory pathways,” the researchers noted. “Under conditions that cause activation of inflammatory pathways, IDO (the rate-limiting enzyme of tryptophan metabolism by the kynurenine pathway in the brain) is induced by IFN-γ.”

Furthermore, MVP, which is associated with multidrug resistance, is also induced by IFN-γ. Researchers hypothesized and found that the effect of inflammation on MVP and IDO in epileptogenic tumors may be different in TSC1 and TSC2 mutations. Patients with TSC2 had a higher expression of MVP than those with TSC1, which may explain the more severe course of the disease in TSC2 patients.

BOSTON—Patients with tuberous sclerosis complex (TSC) may benefit from novel therapies targeting idoleamine 2,3-dioxygenase (IDO) and major vault protein (MVP), researchers at Wayne State University in Detroit reported at the American Epilepsy Society meeting. Carlos Batista, a graduate student in the Translational Neuroscience Program, and colleagues studied cortical tubers that were surgically removed from 12 children with TSC and found elevated tryptophan metabolism and expressions of IDO and MVP.

“Cortical tubers express large numbers of activated microglia, macrophages, and T lymphocytes, thus suggesting activation of inflammatory pathways,” the researchers noted. “Under conditions that cause activation of inflammatory pathways, IDO (the rate-limiting enzyme of tryptophan metabolism by the kynurenine pathway in the brain) is induced by IFN-γ.”

Furthermore, MVP, which is associated with multidrug resistance, is also induced by IFN-γ. Researchers hypothesized and found that the effect of inflammation on MVP and IDO in epileptogenic tumors may be different in TSC1 and TSC2 mutations. Patients with TSC2 had a higher expression of MVP than those with TSC1, which may explain the more severe course of the disease in TSC2 patients.

BOSTON—Patients with tuberous sclerosis complex (TSC) may benefit from novel therapies targeting idoleamine 2,3-dioxygenase (IDO) and major vault protein (MVP), researchers at Wayne State University in Detroit reported at the American Epilepsy Society meeting. Carlos Batista, a graduate student in the Translational Neuroscience Program, and colleagues studied cortical tubers that were surgically removed from 12 children with TSC and found elevated tryptophan metabolism and expressions of IDO and MVP.

“Cortical tubers express large numbers of activated microglia, macrophages, and T lymphocytes, thus suggesting activation of inflammatory pathways,” the researchers noted. “Under conditions that cause activation of inflammatory pathways, IDO (the rate-limiting enzyme of tryptophan metabolism by the kynurenine pathway in the brain) is induced by IFN-γ.”

Furthermore, MVP, which is associated with multidrug resistance, is also induced by IFN-γ. Researchers hypothesized and found that the effect of inflammation on MVP and IDO in epileptogenic tumors may be different in TSC1 and TSC2 mutations. Patients with TSC2 had a higher expression of MVP than those with TSC1, which may explain the more severe course of the disease in TSC2 patients.

25th Congress of the European Committee for Treatment and Research in MS (ECTRIMS), Dusseldorf, Germany

Fewer Injection Site Reactions Occur in Patients Using Interferon Beta-1a IM
Data from an observational phase IV study of 499 patients—the Swiss MS Skin Project—showed that patients with multiple sclerosis (MS) taking interferon beta-1a IM reported significantly fewer injection site reactions, compared with patients who took interferon beta-1b, glatiramer acetate, or interferon beta-1a. The study also found that patients taking interferon beta-1a IM were less likely to have missed a dose due to an injection site reaction in the four weeks prior to first assessment than those patients on other interferon therapies.

“This study showed that treatment with interferon beta-1a IM leads to fewer injection site reactions, which is an important factor in improving compliance,” said Karsten Beer, lead investigator for the study and a private neurologist in Wil, Switzerland. “As the only once-weekly injection treatment, interferon beta-1a IM offers people with relapsing MS an easy-to-use and highly effective treatment option. Convenience of an MS therapy is an important consideration for patients, as they do not want a therapy that will interfere with their daily lives.”

The Swiss MS Skin Project was designed to determine the frequency of injection site reactions, including skin necrosis and lipoatrophy, in patients taking interferon beta-1a IM, interferon beta-1b, glatiramer acetate, or interferon beta-1a. Injection site reactions are believed to reduce treatment compliance among patients. The study enrolled nearly 500 patients on interferon beta-1a IM, interferon beta-1b, glatiramer acetate, or interferon beta-1a for a minimum of two years (mean treatment duration, 5.9 years) and followed patients for one year.

At the first assessment, significantly fewer patients who took interferon beta-1a IM experienced injection site reactions (13.4% vs 57.7% of those who used interferon beta-1b, 30.4% for glatiramer acetate, and 67.9% for interferon beta-1a); necrosis (0% vs 5.7% for interferon beta-1b, 0% for glatiramer acetate, and 6.0% for interferon beta-1a); and lipoatrophy (1.2 % vs 8.9% for interferon beta-1b, 13.0% for glatiramer acetate, and 10.3% for interferon beta-1a).

No patients who used interferon beta-1a IM missed a dose in the four weeks prior to first assessment due to injection site reactions (vs 5.7% of patients using interferon beta-1b, 4.3% for glatiramer acetate, and 7.1% for interferon beta-1a). These percentages were statistically significant, compared with use of interferon beta-1b and interferon beta-1a. In addition, significantly more patients remained on interferon beta-1a IM throughout the one-year trial (86.6% vs 79.7% of subjects who used interferon beta-1b, 60.9% for glatiramer acetate, and 83.2% for interferon beta-1a) than on any other treatment.

Patients Taking Natalizumab Report Improvement in Physical and Psychologic Well-Being
Patients with multiple sclerosis (MS) taking natalizumab experienced an improvement in both their physical function and psychologic well-being, according to six-month results of an ongoing, one-year longitudinal, observational, patient-reported outcomes study. The study, which was the first to assess patient experiences with natalizumab in usual-care settings, found that patients who used natalizumab reported an improvement in their overall quality of life.

“The symptoms that a patient with MS deals with on a daily basis result in significant psychologic and physical effects that can adversely impact their quality of life,” said William Stuart, MD, Medical Director of the Multiple Sclerosis Center of Atlanta. “In a previous pivotal trial, natalizumab not only showed a reduction in relapse rates and disability progression, but also improved quality of life. Results from this observational study further demonstrate the impact of natalizumab on improving MS patients’ well-being as reported by patients who live with this disease every day.”

The trial assessed health outcomes from patients’ perspectives before starting natalizumab and after the third, sixth, and 12th infusions of the drug. A majority of the patients in the study are female (76.3%), with a mean age of 46.6 and mean disease duration of 10 years.

After six natalizumab infusions, patients reported statistically significant improvement in disease-specific quality of life, measured with use of the MS Impact Scale-29 (MSIS-29), which assesses the physical impact of MS in terms of mobility and self-care, as well as the psychologic impact of MS in terms of anxiety/depression, with lower scores indicating better quality of life. Patients also reported statistically significant improvement in general health-related quality of life, as measured by the 12-item Short Form Scale (SF-12) health survey, which assesses the physical and mental health, with higher scores indicating better quality of life.

Both scales assess patient experience of the physical and psychologic aspects of quality of life. For the MSIS-29 subscales, statistically significant improvements were observed over time for both the physical (baseline, 46.87; third infusion, 39.60; sixth infusion, 39.27) and psychologic (baseline, 41.56; third infusion, 33.77; sixth infusion, 33.20) impact scores.

SF-12 physical component summary score (baseline, 34.20; third infusion, 36.05; sixth infusion, 36.34) and the SF-12 mental component summary score (baseline, 43.25; third infusion, 47.35; sixth infusion, 47.92) showed statistically significant improvements over time.
[Editor’s note: For more information on natalizumab, please see a related news story and commentary on page 5.]

Genetic Targets for Potential MS Therapies
Two genes in mice were associated with good CNS repair in multiple sclerosis (MS). The findings may help researchers develop more effective therapies and predict outcomes for patients with MS.

“Most MS genetic studies have looked at disease susceptibility—or why some people get MS and others do not,” said Allan Bieber, PhD, Assistant Professor of Neurology at the Mayo Clinic in Rochester, Minnesota. “This study asked, among those who have MS, why some do well with the disease while others do poorly, and what might be the genetic determinants of this difference in outcome.”

Dr. Bieber and a team of Mayo Clinic researchers used two different strains of mice with a chronic, progressive MS-like disease. One strain of mice progressed to paralysis and death. The other strain underwent the initial damage induction phase of the disease and then had spontaneous repair of the damage to the CNS and retained most neurologic function. Using the genetic mapping techniques that are available for mice, the team mapped two strong genetic determinants of good disease outcome.

“It’s possible that the identification of these genes may provide the first important clue as to why some patients with MS do well, while others do not,” said Dr. Bieber. “The genetic data indicate that good CNS repair results from stimulation of one genetic pathway and inhibition of another genetic pathway. While we’re still in the early stages of this research, it could eventually lead to the development of useful therapies that stimulate or inhibit these genetic pathways in patients with MS.”

According to Dr. Bieber, the research suggests that there may be a small number of strong genetic determinants for CNS repair following demyelinating disease, rather than a larger number of weak determinants.

“If that’s true, it may be possible to map the most important genetic determinants of CNS repair in patients with MS and define a reparative genotype that could predict patients’ outcomes,” said Moses Rodriguez, MD, Professor of Neurology and Director of the Mayo Clinic’s Center for Multiple Sclerosis and Central Nervous System Demyelinating Diseases Research and Therapeutics. “Such a diagnostic tool would be a great benefit to patients with MS and is consistent with the concepts of individualized medicine.”

Research Supports the Importance of Early Treatment in Patients With MS
Findings from two observational studies—CogniCIS and CogniMS—revealed that depression and fatigue occur alongside cognitive deficits, even early in the disease. Data from these studies showed that relatives were able to detect even minor changes in cognitive performance at an early stage of the disease, which the patients themselves did not report.

“Cognitive impairment in patients with multiple sclerosis (MS) is not sufficiently recognized, in spite of the significant negative impact it can have on patients’ lives,” said Dawn Langdon, PhD, Neuropsychology Lead and Reader in Neuropsychology, Royal Holloway, University of London, UK, and lead investigator of CogniCIS and CogniMS. “These studies will help us construct a more complete picture of the development and impact of cognitive decline in early MS. Such findings, added to the existing evidence, will have important implications for physicians when making management decisions.”

The CogniCIS study collected cognitive and psychosocial data from 394 patients with clinically isolated syndrome (CIS). A subset of 130 European patients with CIS and 60 of their relatives completed the MS Neuropsychological Questionnaire (MSNQ), which asks about cognitive difficulties. Preliminary results presented showed that scores on the MSNQ from patients with CIS and their relatives correlated more with the patients’ level of depression, fatigue, and quality of life rather than performance in cognitive tests.

The CogniMS study included psychosocial data from 1,509 patients with early MS. A subset of 274 patients and 178 of their relatives completed the MSNQ. According to preliminary findings from the trial, relatives’ reports of the patients’ cognition correlated with some cognitive test scores, obtained by patients; patient self-reported cognitive deficits were not closely related to objective test scores. Similar to results from CogniCIS, the CogniMS findings suggest that self-reported cognitive deficits in an early MS population are not specific to cognition, and are influenced by the patients’ psychologic situation.

25th Congress of the European Committee for Treatment and Research in MS (ECTRIMS), Dusseldorf, Germany

Fewer Injection Site Reactions Occur in Patients Using Interferon Beta-1a IM
Data from an observational phase IV study of 499 patients—the Swiss MS Skin Project—showed that patients with multiple sclerosis (MS) taking interferon beta-1a IM reported significantly fewer injection site reactions, compared with patients who took interferon beta-1b, glatiramer acetate, or interferon beta-1a. The study also found that patients taking interferon beta-1a IM were less likely to have missed a dose due to an injection site reaction in the four weeks prior to first assessment than those patients on other interferon therapies.

“This study showed that treatment with interferon beta-1a IM leads to fewer injection site reactions, which is an important factor in improving compliance,” said Karsten Beer, lead investigator for the study and a private neurologist in Wil, Switzerland. “As the only once-weekly injection treatment, interferon beta-1a IM offers people with relapsing MS an easy-to-use and highly effective treatment option. Convenience of an MS therapy is an important consideration for patients, as they do not want a therapy that will interfere with their daily lives.”

The Swiss MS Skin Project was designed to determine the frequency of injection site reactions, including skin necrosis and lipoatrophy, in patients taking interferon beta-1a IM, interferon beta-1b, glatiramer acetate, or interferon beta-1a. Injection site reactions are believed to reduce treatment compliance among patients. The study enrolled nearly 500 patients on interferon beta-1a IM, interferon beta-1b, glatiramer acetate, or interferon beta-1a for a minimum of two years (mean treatment duration, 5.9 years) and followed patients for one year.

At the first assessment, significantly fewer patients who took interferon beta-1a IM experienced injection site reactions (13.4% vs 57.7% of those who used interferon beta-1b, 30.4% for glatiramer acetate, and 67.9% for interferon beta-1a); necrosis (0% vs 5.7% for interferon beta-1b, 0% for glatiramer acetate, and 6.0% for interferon beta-1a); and lipoatrophy (1.2 % vs 8.9% for interferon beta-1b, 13.0% for glatiramer acetate, and 10.3% for interferon beta-1a).

No patients who used interferon beta-1a IM missed a dose in the four weeks prior to first assessment due to injection site reactions (vs 5.7% of patients using interferon beta-1b, 4.3% for glatiramer acetate, and 7.1% for interferon beta-1a). These percentages were statistically significant, compared with use of interferon beta-1b and interferon beta-1a. In addition, significantly more patients remained on interferon beta-1a IM throughout the one-year trial (86.6% vs 79.7% of subjects who used interferon beta-1b, 60.9% for glatiramer acetate, and 83.2% for interferon beta-1a) than on any other treatment.

Patients Taking Natalizumab Report Improvement in Physical and Psychologic Well-Being
Patients with multiple sclerosis (MS) taking natalizumab experienced an improvement in both their physical function and psychologic well-being, according to six-month results of an ongoing, one-year longitudinal, observational, patient-reported outcomes study. The study, which was the first to assess patient experiences with natalizumab in usual-care settings, found that patients who used natalizumab reported an improvement in their overall quality of life.

“The symptoms that a patient with MS deals with on a daily basis result in significant psychologic and physical effects that can adversely impact their quality of life,” said William Stuart, MD, Medical Director of the Multiple Sclerosis Center of Atlanta. “In a previous pivotal trial, natalizumab not only showed a reduction in relapse rates and disability progression, but also improved quality of life. Results from this observational study further demonstrate the impact of natalizumab on improving MS patients’ well-being as reported by patients who live with this disease every day.”

The trial assessed health outcomes from patients’ perspectives before starting natalizumab and after the third, sixth, and 12th infusions of the drug. A majority of the patients in the study are female (76.3%), with a mean age of 46.6 and mean disease duration of 10 years.

After six natalizumab infusions, patients reported statistically significant improvement in disease-specific quality of life, measured with use of the MS Impact Scale-29 (MSIS-29), which assesses the physical impact of MS in terms of mobility and self-care, as well as the psychologic impact of MS in terms of anxiety/depression, with lower scores indicating better quality of life. Patients also reported statistically significant improvement in general health-related quality of life, as measured by the 12-item Short Form Scale (SF-12) health survey, which assesses the physical and mental health, with higher scores indicating better quality of life.

Both scales assess patient experience of the physical and psychologic aspects of quality of life. For the MSIS-29 subscales, statistically significant improvements were observed over time for both the physical (baseline, 46.87; third infusion, 39.60; sixth infusion, 39.27) and psychologic (baseline, 41.56; third infusion, 33.77; sixth infusion, 33.20) impact scores.

SF-12 physical component summary score (baseline, 34.20; third infusion, 36.05; sixth infusion, 36.34) and the SF-12 mental component summary score (baseline, 43.25; third infusion, 47.35; sixth infusion, 47.92) showed statistically significant improvements over time.
[Editor’s note: For more information on natalizumab, please see a related news story and commentary on page 5.]

Genetic Targets for Potential MS Therapies
Two genes in mice were associated with good CNS repair in multiple sclerosis (MS). The findings may help researchers develop more effective therapies and predict outcomes for patients with MS.

“Most MS genetic studies have looked at disease susceptibility—or why some people get MS and others do not,” said Allan Bieber, PhD, Assistant Professor of Neurology at the Mayo Clinic in Rochester, Minnesota. “This study asked, among those who have MS, why some do well with the disease while others do poorly, and what might be the genetic determinants of this difference in outcome.”

Dr. Bieber and a team of Mayo Clinic researchers used two different strains of mice with a chronic, progressive MS-like disease. One strain of mice progressed to paralysis and death. The other strain underwent the initial damage induction phase of the disease and then had spontaneous repair of the damage to the CNS and retained most neurologic function. Using the genetic mapping techniques that are available for mice, the team mapped two strong genetic determinants of good disease outcome.

“It’s possible that the identification of these genes may provide the first important clue as to why some patients with MS do well, while others do not,” said Dr. Bieber. “The genetic data indicate that good CNS repair results from stimulation of one genetic pathway and inhibition of another genetic pathway. While we’re still in the early stages of this research, it could eventually lead to the development of useful therapies that stimulate or inhibit these genetic pathways in patients with MS.”

According to Dr. Bieber, the research suggests that there may be a small number of strong genetic determinants for CNS repair following demyelinating disease, rather than a larger number of weak determinants.

“If that’s true, it may be possible to map the most important genetic determinants of CNS repair in patients with MS and define a reparative genotype that could predict patients’ outcomes,” said Moses Rodriguez, MD, Professor of Neurology and Director of the Mayo Clinic’s Center for Multiple Sclerosis and Central Nervous System Demyelinating Diseases Research and Therapeutics. “Such a diagnostic tool would be a great benefit to patients with MS and is consistent with the concepts of individualized medicine.”

Research Supports the Importance of Early Treatment in Patients With MS
Findings from two observational studies—CogniCIS and CogniMS—revealed that depression and fatigue occur alongside cognitive deficits, even early in the disease. Data from these studies showed that relatives were able to detect even minor changes in cognitive performance at an early stage of the disease, which the patients themselves did not report.

“Cognitive impairment in patients with multiple sclerosis (MS) is not sufficiently recognized, in spite of the significant negative impact it can have on patients’ lives,” said Dawn Langdon, PhD, Neuropsychology Lead and Reader in Neuropsychology, Royal Holloway, University of London, UK, and lead investigator of CogniCIS and CogniMS. “These studies will help us construct a more complete picture of the development and impact of cognitive decline in early MS. Such findings, added to the existing evidence, will have important implications for physicians when making management decisions.”

The CogniCIS study collected cognitive and psychosocial data from 394 patients with clinically isolated syndrome (CIS). A subset of 130 European patients with CIS and 60 of their relatives completed the MS Neuropsychological Questionnaire (MSNQ), which asks about cognitive difficulties. Preliminary results presented showed that scores on the MSNQ from patients with CIS and their relatives correlated more with the patients’ level of depression, fatigue, and quality of life rather than performance in cognitive tests.

The CogniMS study included psychosocial data from 1,509 patients with early MS. A subset of 274 patients and 178 of their relatives completed the MSNQ. According to preliminary findings from the trial, relatives’ reports of the patients’ cognition correlated with some cognitive test scores, obtained by patients; patient self-reported cognitive deficits were not closely related to objective test scores. Similar to results from CogniCIS, the CogniMS findings suggest that self-reported cognitive deficits in an early MS population are not specific to cognition, and are influenced by the patients’ psychologic situation.

25th Congress of the European Committee for Treatment and Research in MS (ECTRIMS), Dusseldorf, Germany

Fewer Injection Site Reactions Occur in Patients Using Interferon Beta-1a IM
Data from an observational phase IV study of 499 patients—the Swiss MS Skin Project—showed that patients with multiple sclerosis (MS) taking interferon beta-1a IM reported significantly fewer injection site reactions, compared with patients who took interferon beta-1b, glatiramer acetate, or interferon beta-1a. The study also found that patients taking interferon beta-1a IM were less likely to have missed a dose due to an injection site reaction in the four weeks prior to first assessment than those patients on other interferon therapies.

“This study showed that treatment with interferon beta-1a IM leads to fewer injection site reactions, which is an important factor in improving compliance,” said Karsten Beer, lead investigator for the study and a private neurologist in Wil, Switzerland. “As the only once-weekly injection treatment, interferon beta-1a IM offers people with relapsing MS an easy-to-use and highly effective treatment option. Convenience of an MS therapy is an important consideration for patients, as they do not want a therapy that will interfere with their daily lives.”

The Swiss MS Skin Project was designed to determine the frequency of injection site reactions, including skin necrosis and lipoatrophy, in patients taking interferon beta-1a IM, interferon beta-1b, glatiramer acetate, or interferon beta-1a. Injection site reactions are believed to reduce treatment compliance among patients. The study enrolled nearly 500 patients on interferon beta-1a IM, interferon beta-1b, glatiramer acetate, or interferon beta-1a for a minimum of two years (mean treatment duration, 5.9 years) and followed patients for one year.

At the first assessment, significantly fewer patients who took interferon beta-1a IM experienced injection site reactions (13.4% vs 57.7% of those who used interferon beta-1b, 30.4% for glatiramer acetate, and 67.9% for interferon beta-1a); necrosis (0% vs 5.7% for interferon beta-1b, 0% for glatiramer acetate, and 6.0% for interferon beta-1a); and lipoatrophy (1.2 % vs 8.9% for interferon beta-1b, 13.0% for glatiramer acetate, and 10.3% for interferon beta-1a).

No patients who used interferon beta-1a IM missed a dose in the four weeks prior to first assessment due to injection site reactions (vs 5.7% of patients using interferon beta-1b, 4.3% for glatiramer acetate, and 7.1% for interferon beta-1a). These percentages were statistically significant, compared with use of interferon beta-1b and interferon beta-1a. In addition, significantly more patients remained on interferon beta-1a IM throughout the one-year trial (86.6% vs 79.7% of subjects who used interferon beta-1b, 60.9% for glatiramer acetate, and 83.2% for interferon beta-1a) than on any other treatment.

Patients Taking Natalizumab Report Improvement in Physical and Psychologic Well-Being
Patients with multiple sclerosis (MS) taking natalizumab experienced an improvement in both their physical function and psychologic well-being, according to six-month results of an ongoing, one-year longitudinal, observational, patient-reported outcomes study. The study, which was the first to assess patient experiences with natalizumab in usual-care settings, found that patients who used natalizumab reported an improvement in their overall quality of life.

“The symptoms that a patient with MS deals with on a daily basis result in significant psychologic and physical effects that can adversely impact their quality of life,” said William Stuart, MD, Medical Director of the Multiple Sclerosis Center of Atlanta. “In a previous pivotal trial, natalizumab not only showed a reduction in relapse rates and disability progression, but also improved quality of life. Results from this observational study further demonstrate the impact of natalizumab on improving MS patients’ well-being as reported by patients who live with this disease every day.”

The trial assessed health outcomes from patients’ perspectives before starting natalizumab and after the third, sixth, and 12th infusions of the drug. A majority of the patients in the study are female (76.3%), with a mean age of 46.6 and mean disease duration of 10 years.

After six natalizumab infusions, patients reported statistically significant improvement in disease-specific quality of life, measured with use of the MS Impact Scale-29 (MSIS-29), which assesses the physical impact of MS in terms of mobility and self-care, as well as the psychologic impact of MS in terms of anxiety/depression, with lower scores indicating better quality of life. Patients also reported statistically significant improvement in general health-related quality of life, as measured by the 12-item Short Form Scale (SF-12) health survey, which assesses the physical and mental health, with higher scores indicating better quality of life.

Both scales assess patient experience of the physical and psychologic aspects of quality of life. For the MSIS-29 subscales, statistically significant improvements were observed over time for both the physical (baseline, 46.87; third infusion, 39.60; sixth infusion, 39.27) and psychologic (baseline, 41.56; third infusion, 33.77; sixth infusion, 33.20) impact scores.

SF-12 physical component summary score (baseline, 34.20; third infusion, 36.05; sixth infusion, 36.34) and the SF-12 mental component summary score (baseline, 43.25; third infusion, 47.35; sixth infusion, 47.92) showed statistically significant improvements over time.
[Editor’s note: For more information on natalizumab, please see a related news story and commentary on page 5.]

Genetic Targets for Potential MS Therapies
Two genes in mice were associated with good CNS repair in multiple sclerosis (MS). The findings may help researchers develop more effective therapies and predict outcomes for patients with MS.

“Most MS genetic studies have looked at disease susceptibility—or why some people get MS and others do not,” said Allan Bieber, PhD, Assistant Professor of Neurology at the Mayo Clinic in Rochester, Minnesota. “This study asked, among those who have MS, why some do well with the disease while others do poorly, and what might be the genetic determinants of this difference in outcome.”

Dr. Bieber and a team of Mayo Clinic researchers used two different strains of mice with a chronic, progressive MS-like disease. One strain of mice progressed to paralysis and death. The other strain underwent the initial damage induction phase of the disease and then had spontaneous repair of the damage to the CNS and retained most neurologic function. Using the genetic mapping techniques that are available for mice, the team mapped two strong genetic determinants of good disease outcome.

“It’s possible that the identification of these genes may provide the first important clue as to why some patients with MS do well, while others do not,” said Dr. Bieber. “The genetic data indicate that good CNS repair results from stimulation of one genetic pathway and inhibition of another genetic pathway. While we’re still in the early stages of this research, it could eventually lead to the development of useful therapies that stimulate or inhibit these genetic pathways in patients with MS.”

According to Dr. Bieber, the research suggests that there may be a small number of strong genetic determinants for CNS repair following demyelinating disease, rather than a larger number of weak determinants.

“If that’s true, it may be possible to map the most important genetic determinants of CNS repair in patients with MS and define a reparative genotype that could predict patients’ outcomes,” said Moses Rodriguez, MD, Professor of Neurology and Director of the Mayo Clinic’s Center for Multiple Sclerosis and Central Nervous System Demyelinating Diseases Research and Therapeutics. “Such a diagnostic tool would be a great benefit to patients with MS and is consistent with the concepts of individualized medicine.”

Research Supports the Importance of Early Treatment in Patients With MS
Findings from two observational studies—CogniCIS and CogniMS—revealed that depression and fatigue occur alongside cognitive deficits, even early in the disease. Data from these studies showed that relatives were able to detect even minor changes in cognitive performance at an early stage of the disease, which the patients themselves did not report.

“Cognitive impairment in patients with multiple sclerosis (MS) is not sufficiently recognized, in spite of the significant negative impact it can have on patients’ lives,” said Dawn Langdon, PhD, Neuropsychology Lead and Reader in Neuropsychology, Royal Holloway, University of London, UK, and lead investigator of CogniCIS and CogniMS. “These studies will help us construct a more complete picture of the development and impact of cognitive decline in early MS. Such findings, added to the existing evidence, will have important implications for physicians when making management decisions.”

The CogniCIS study collected cognitive and psychosocial data from 394 patients with clinically isolated syndrome (CIS). A subset of 130 European patients with CIS and 60 of their relatives completed the MS Neuropsychological Questionnaire (MSNQ), which asks about cognitive difficulties. Preliminary results presented showed that scores on the MSNQ from patients with CIS and their relatives correlated more with the patients’ level of depression, fatigue, and quality of life rather than performance in cognitive tests.

The CogniMS study included psychosocial data from 1,509 patients with early MS. A subset of 274 patients and 178 of their relatives completed the MSNQ. According to preliminary findings from the trial, relatives’ reports of the patients’ cognition correlated with some cognitive test scores, obtained by patients; patient self-reported cognitive deficits were not closely related to objective test scores. Similar to results from CogniCIS, the CogniMS findings suggest that self-reported cognitive deficits in an early MS population are not specific to cognition, and are influenced by the patients’ psychologic situation.

Revised clinical practice guidelines for MRI in MS incorporate new information and practice recommendations that will help patients, physicians, and care providers, according to an international working group of MS researchers.

ATLANTA—Revised guidelines regarding an MRI protocol for the diagnosis and follow-up of multiple sclerosis (MS) were presented at the 2009 Annual Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS). “The new guidelines incorporate new information and practice recommendations that will benefit patients and will be useful for physicians and care providers,” stated Anthony Traboulsee, MD, Assistant Professor of Neurology at the University of British Columbia, Vancouver, Canada, and a member of the working group of international neurologists and radiologists who devised the guidelines.
Standardized Protocol Recommendations
No specific recommendations were made for magnet size or strength, although scans should be of good quality, with adequate signal noise ratio and resolution. However, some of the lower field strength magnets or older machines will probably not be able to produce optimal images under these guidelines, noted Lael Stone, MD, Staff Neurologist at Cleveland Clinic’s Mellen Center, and member of the MS working group.
Core brain MRI sequences are listed as sagittal fluid attenuated inversion recovery (FLAIR); axial FLAIR; axial T2; and axial T1 pre- and post-gadolinium. Core spinal cord MRI sequences are listed as sagittal T2, sagittal proton density or short tau invasion recovery, and sagittal T1.
The guidelines also address the requisition, reporting, and storage of MRIs. Physicians should request the standardized brain and/or spinal cord protocol, indicate the clinical question being addressed, and make the radiologist and technologist aware of relevant medical history, physical findings, and MS medications, as well as the date and place of any previous MRIs. Radiologists should report the lesion number, location, size, shape, and character, as well as whether MRI criteria for dissemination in space and time are met. A comparison with previous studies for new lesion activity and atrophy should be performed whenever possible, assuming that the images are of comparable quality and acquisition. Copies of the MRI studies should be kept permanently, and digital media are the most sensible manner for archiving.
Clinical Indications
For patients with a clinically isolated syndrome (CIS) and suspected MS, the researchers recommend a brain MRI with and without a gadolinium contrast agent at baseline evaluation. They also recommend a spinal cord MRI if persisting uncertainty exists about the diagnosis and/or the findings on brain MRI are equivocal, and if presenting symptoms or signs are at the level of the spinal cord. During a follow-up examination, a brain MRI with and without a gadolinium contrast agent is advised to detect new disease activity.
In noting that an initial brain MRI is recommended when available, “We wanted to recognize that there are some areas of the world, and frankly also in the United States, where it’s very difficult to obtain an MRI for a variety of reasons,” said Dr. Stone.
Among patients with definite MS, the guidelines authors recommend a brain MRI with gadolinium at baseline evaluation and during follow-up. “To assess subclinical disease activity, [brain MRI with and without gadolinium contrast] should be considered every one to two years,” reported the authors. “The exact frequency may vary depending on clinical course and other clinical features.”
“You’ve heard over and over again that MS is a clinical diagnosis but with newer criteria,” commented Dr. Stone. “We are emphasizing the fact that clinically silent lesions on an MRI can count toward dissemination of time or space.”
Dr. Stone emphasized that the goal of setting an MRI frequency timeline was to recommend, not dictate. “We want to emphasize the fact that at least it should pass through one’s consciousness, as to the appropriateness,” she pointed out. “The exact frequency may vary depending on clinical course and other clinical features.” The reasons for follow-up with a brain MRI with and without gadolinium contrast—to evaluate an unexpected clinical worsening that causes concern for diagnosis, to reassess the original diagnosis, and to reassess before starting or modifying therapy—also support the new recommendation. “The threshold for defining a response on MRI that is clinically meaningful in the short term and long term, including the potential effects of newer quantitative techniques, is evolving,” Dr. Stone stated.”

Revised clinical practice guidelines for MRI in MS incorporate new information and practice recommendations that will help patients, physicians, and care providers, according to an international working group of MS researchers.

ATLANTA—Revised guidelines regarding an MRI protocol for the diagnosis and follow-up of multiple sclerosis (MS) were presented at the 2009 Annual Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS). “The new guidelines incorporate new information and practice recommendations that will benefit patients and will be useful for physicians and care providers,” stated Anthony Traboulsee, MD, Assistant Professor of Neurology at the University of British Columbia, Vancouver, Canada, and a member of the working group of international neurologists and radiologists who devised the guidelines.
Standardized Protocol Recommendations
No specific recommendations were made for magnet size or strength, although scans should be of good quality, with adequate signal noise ratio and resolution. However, some of the lower field strength magnets or older machines will probably not be able to produce optimal images under these guidelines, noted Lael Stone, MD, Staff Neurologist at Cleveland Clinic’s Mellen Center, and member of the MS working group.
Core brain MRI sequences are listed as sagittal fluid attenuated inversion recovery (FLAIR); axial FLAIR; axial T2; and axial T1 pre- and post-gadolinium. Core spinal cord MRI sequences are listed as sagittal T2, sagittal proton density or short tau invasion recovery, and sagittal T1.
The guidelines also address the requisition, reporting, and storage of MRIs. Physicians should request the standardized brain and/or spinal cord protocol, indicate the clinical question being addressed, and make the radiologist and technologist aware of relevant medical history, physical findings, and MS medications, as well as the date and place of any previous MRIs. Radiologists should report the lesion number, location, size, shape, and character, as well as whether MRI criteria for dissemination in space and time are met. A comparison with previous studies for new lesion activity and atrophy should be performed whenever possible, assuming that the images are of comparable quality and acquisition. Copies of the MRI studies should be kept permanently, and digital media are the most sensible manner for archiving.
Clinical Indications
For patients with a clinically isolated syndrome (CIS) and suspected MS, the researchers recommend a brain MRI with and without a gadolinium contrast agent at baseline evaluation. They also recommend a spinal cord MRI if persisting uncertainty exists about the diagnosis and/or the findings on brain MRI are equivocal, and if presenting symptoms or signs are at the level of the spinal cord. During a follow-up examination, a brain MRI with and without a gadolinium contrast agent is advised to detect new disease activity.
In noting that an initial brain MRI is recommended when available, “We wanted to recognize that there are some areas of the world, and frankly also in the United States, where it’s very difficult to obtain an MRI for a variety of reasons,” said Dr. Stone.
Among patients with definite MS, the guidelines authors recommend a brain MRI with gadolinium at baseline evaluation and during follow-up. “To assess subclinical disease activity, [brain MRI with and without gadolinium contrast] should be considered every one to two years,” reported the authors. “The exact frequency may vary depending on clinical course and other clinical features.”
“You’ve heard over and over again that MS is a clinical diagnosis but with newer criteria,” commented Dr. Stone. “We are emphasizing the fact that clinically silent lesions on an MRI can count toward dissemination of time or space.”
Dr. Stone emphasized that the goal of setting an MRI frequency timeline was to recommend, not dictate. “We want to emphasize the fact that at least it should pass through one’s consciousness, as to the appropriateness,” she pointed out. “The exact frequency may vary depending on clinical course and other clinical features.” The reasons for follow-up with a brain MRI with and without gadolinium contrast—to evaluate an unexpected clinical worsening that causes concern for diagnosis, to reassess the original diagnosis, and to reassess before starting or modifying therapy—also support the new recommendation. “The threshold for defining a response on MRI that is clinically meaningful in the short term and long term, including the potential effects of newer quantitative techniques, is evolving,” Dr. Stone stated.”

Revised clinical practice guidelines for MRI in MS incorporate new information and practice recommendations that will help patients, physicians, and care providers, according to an international working group of MS researchers.

ATLANTA—Revised guidelines regarding an MRI protocol for the diagnosis and follow-up of multiple sclerosis (MS) were presented at the 2009 Annual Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS). “The new guidelines incorporate new information and practice recommendations that will benefit patients and will be useful for physicians and care providers,” stated Anthony Traboulsee, MD, Assistant Professor of Neurology at the University of British Columbia, Vancouver, Canada, and a member of the working group of international neurologists and radiologists who devised the guidelines.
Standardized Protocol Recommendations
No specific recommendations were made for magnet size or strength, although scans should be of good quality, with adequate signal noise ratio and resolution. However, some of the lower field strength magnets or older machines will probably not be able to produce optimal images under these guidelines, noted Lael Stone, MD, Staff Neurologist at Cleveland Clinic’s Mellen Center, and member of the MS working group.
Core brain MRI sequences are listed as sagittal fluid attenuated inversion recovery (FLAIR); axial FLAIR; axial T2; and axial T1 pre- and post-gadolinium. Core spinal cord MRI sequences are listed as sagittal T2, sagittal proton density or short tau invasion recovery, and sagittal T1.
The guidelines also address the requisition, reporting, and storage of MRIs. Physicians should request the standardized brain and/or spinal cord protocol, indicate the clinical question being addressed, and make the radiologist and technologist aware of relevant medical history, physical findings, and MS medications, as well as the date and place of any previous MRIs. Radiologists should report the lesion number, location, size, shape, and character, as well as whether MRI criteria for dissemination in space and time are met. A comparison with previous studies for new lesion activity and atrophy should be performed whenever possible, assuming that the images are of comparable quality and acquisition. Copies of the MRI studies should be kept permanently, and digital media are the most sensible manner for archiving.
Clinical Indications
For patients with a clinically isolated syndrome (CIS) and suspected MS, the researchers recommend a brain MRI with and without a gadolinium contrast agent at baseline evaluation. They also recommend a spinal cord MRI if persisting uncertainty exists about the diagnosis and/or the findings on brain MRI are equivocal, and if presenting symptoms or signs are at the level of the spinal cord. During a follow-up examination, a brain MRI with and without a gadolinium contrast agent is advised to detect new disease activity.
In noting that an initial brain MRI is recommended when available, “We wanted to recognize that there are some areas of the world, and frankly also in the United States, where it’s very difficult to obtain an MRI for a variety of reasons,” said Dr. Stone.
Among patients with definite MS, the guidelines authors recommend a brain MRI with gadolinium at baseline evaluation and during follow-up. “To assess subclinical disease activity, [brain MRI with and without gadolinium contrast] should be considered every one to two years,” reported the authors. “The exact frequency may vary depending on clinical course and other clinical features.”
“You’ve heard over and over again that MS is a clinical diagnosis but with newer criteria,” commented Dr. Stone. “We are emphasizing the fact that clinically silent lesions on an MRI can count toward dissemination of time or space.”
Dr. Stone emphasized that the goal of setting an MRI frequency timeline was to recommend, not dictate. “We want to emphasize the fact that at least it should pass through one’s consciousness, as to the appropriateness,” she pointed out. “The exact frequency may vary depending on clinical course and other clinical features.” The reasons for follow-up with a brain MRI with and without gadolinium contrast—to evaluate an unexpected clinical worsening that causes concern for diagnosis, to reassess the original diagnosis, and to reassess before starting or modifying therapy—also support the new recommendation. “The threshold for defining a response on MRI that is clinically meaningful in the short term and long term, including the potential effects of newer quantitative techniques, is evolving,” Dr. Stone stated.”