Multiple Sclerosis Hub

ORLANDO—Patients with secondary progressive multiple sclerosis (SPMS) have impaired regulation, according to data presented at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS. Compared with healthy subjects, patients with SPMS have reduced frequencies of Tr1 precursors, Tr1 cells, and nT_reg cells. The nT_reg cells in patients with SPMS, however, maintain levels of FOXP3 and CD39 similar to those of healthy controls.

Healthy subjects examined with multicolor flow cytometry had greater numbers of inhibitory PD-L1+ and HLA-G+ monocytes than did patients with SPMS, said Lauren W. Collison, PhD, Director of Immunology at Opexa Therapeutics in The Woodlands, Texas. In patients with SPMS, the memory T cell compartment had increased levels of Th17 and decreased numbers of Th2 cells, compared with controls. Controls had higher levels of Th1 cells than of Th17 cells, but the opposite was true for patients with SPMS.

Using an acoustic focusing flow cytometer, Dr. Collison and colleagues characterized peripheral blood mononuclear cells from healthy subjects and patients with SPMS. They analyzed the samples with multicolor flow cytometry using 16 six-color marker panels.

The researchers determined specificity by comparing test molecules to isotype-matched controls or by preincubating test molecules with clonally matched purified blocking monoclonal antibodies. They performed t-test analysis to determine the statistical significance of any difference between means of healthy donors and of patients with SPMS.

The number of regulatory T cells, both adaptive/peripherally generated TR1 cells and natural/thymic derived nT_reg cells, was determined in healthy subjects and patients with SPMS. The mean percentage of TR1 precursor cells (CD4+CD18^brightCD49b+) and TR1 cells (CD4+CD45RA-LAG3+CD49b+) was significantly greater among healthy subjects, when compared to patients with SPMS. Non-TR1 cell numbers (CD8+CD18^brightCD49b+ or CD4+CD45RA-LAG3+CD49b+) were similar for both groups.

Healthy donors also trended toward a greater frequency of CD4+ nT_regs. A greater percentage of CD4+ T cells were FOXP3 nT_reg cells in controls, compared with patients with SPMS. The mean fluorescence intensity of FOXP3 nT_reg cells was similar for both subject groups.

Similarly, a greater percentage of CD4+ T cells in healthy donors was CD25^bright nT_reg cells, when compared with patients with SPMS. However, among CD4+ nT_reg cells, CD39 expression was comparable in healthy donors and subjects with SPMS.

—Erik Greb
Senior Associate Editor

ORLANDO—Patients with secondary progressive multiple sclerosis (SPMS) have impaired regulation, according to data presented at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS. Compared with healthy subjects, patients with SPMS have reduced frequencies of Tr1 precursors, Tr1 cells, and nT_reg cells. The nT_reg cells in patients with SPMS, however, maintain levels of FOXP3 and CD39 similar to those of healthy controls.

Healthy subjects examined with multicolor flow cytometry had greater numbers of inhibitory PD-L1+ and HLA-G+ monocytes than did patients with SPMS, said Lauren W. Collison, PhD, Director of Immunology at Opexa Therapeutics in The Woodlands, Texas. In patients with SPMS, the memory T cell compartment had increased levels of Th17 and decreased numbers of Th2 cells, compared with controls. Controls had higher levels of Th1 cells than of Th17 cells, but the opposite was true for patients with SPMS.

Using an acoustic focusing flow cytometer, Dr. Collison and colleagues characterized peripheral blood mononuclear cells from healthy subjects and patients with SPMS. They analyzed the samples with multicolor flow cytometry using 16 six-color marker panels.

The researchers determined specificity by comparing test molecules to isotype-matched controls or by preincubating test molecules with clonally matched purified blocking monoclonal antibodies. They performed t-test analysis to determine the statistical significance of any difference between means of healthy donors and of patients with SPMS.

The number of regulatory T cells, both adaptive/peripherally generated TR1 cells and natural/thymic derived nT_reg cells, was determined in healthy subjects and patients with SPMS. The mean percentage of TR1 precursor cells (CD4+CD18^brightCD49b+) and TR1 cells (CD4+CD45RA-LAG3+CD49b+) was significantly greater among healthy subjects, when compared to patients with SPMS. Non-TR1 cell numbers (CD8+CD18^brightCD49b+ or CD4+CD45RA-LAG3+CD49b+) were similar for both groups.

Healthy donors also trended toward a greater frequency of CD4+ nT_regs. A greater percentage of CD4+ T cells were FOXP3 nT_reg cells in controls, compared with patients with SPMS. The mean fluorescence intensity of FOXP3 nT_reg cells was similar for both subject groups.

Similarly, a greater percentage of CD4+ T cells in healthy donors was CD25^bright nT_reg cells, when compared with patients with SPMS. However, among CD4+ nT_reg cells, CD39 expression was comparable in healthy donors and subjects with SPMS.

—Erik Greb
Senior Associate Editor

ORLANDO—Patients with secondary progressive multiple sclerosis (SPMS) have impaired regulation, according to data presented at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS. Compared with healthy subjects, patients with SPMS have reduced frequencies of Tr1 precursors, Tr1 cells, and nT_reg cells. The nT_reg cells in patients with SPMS, however, maintain levels of FOXP3 and CD39 similar to those of healthy controls.

Healthy subjects examined with multicolor flow cytometry had greater numbers of inhibitory PD-L1+ and HLA-G+ monocytes than did patients with SPMS, said Lauren W. Collison, PhD, Director of Immunology at Opexa Therapeutics in The Woodlands, Texas. In patients with SPMS, the memory T cell compartment had increased levels of Th17 and decreased numbers of Th2 cells, compared with controls. Controls had higher levels of Th1 cells than of Th17 cells, but the opposite was true for patients with SPMS.

Using an acoustic focusing flow cytometer, Dr. Collison and colleagues characterized peripheral blood mononuclear cells from healthy subjects and patients with SPMS. They analyzed the samples with multicolor flow cytometry using 16 six-color marker panels.

The researchers determined specificity by comparing test molecules to isotype-matched controls or by preincubating test molecules with clonally matched purified blocking monoclonal antibodies. They performed t-test analysis to determine the statistical significance of any difference between means of healthy donors and of patients with SPMS.

The number of regulatory T cells, both adaptive/peripherally generated TR1 cells and natural/thymic derived nT_reg cells, was determined in healthy subjects and patients with SPMS. The mean percentage of TR1 precursor cells (CD4+CD18^brightCD49b+) and TR1 cells (CD4+CD45RA-LAG3+CD49b+) was significantly greater among healthy subjects, when compared to patients with SPMS. Non-TR1 cell numbers (CD8+CD18^brightCD49b+ or CD4+CD45RA-LAG3+CD49b+) were similar for both groups.

Healthy donors also trended toward a greater frequency of CD4+ nT_regs. A greater percentage of CD4+ T cells were FOXP3 nT_reg cells in controls, compared with patients with SPMS. The mean fluorescence intensity of FOXP3 nT_reg cells was similar for both subject groups.

Similarly, a greater percentage of CD4+ T cells in healthy donors was CD25^bright nT_reg cells, when compared with patients with SPMS. However, among CD4+ nT_reg cells, CD39 expression was comparable in healthy donors and subjects with SPMS.

—Erik Greb
Senior Associate Editor

A large multicenter study published in the October issue of the Journal of Neurology, Neurosurgery and Psychiatry points to the complementary value of brain atrophy and lesion volumes for predicting long-term disability in multiple sclerosis (MS).

Although predictors of short- and medium-term clinical progression have been identified, the longer-term clinical prognostic value of brain atrophy measures and lesion volumes has been studied less extensively. “Our finding may help develop predictors of future disability in MS that could be used in clinical trials and eventually also for predicting the evolution of individual patients,” the researchers said.

Veronica Popescu, MD, MSc, of the Department of Radiology and Nuclear Medicine at VU University Medical Center in Amsterdam, and colleagues from the MAGNIMS study group sought to determine the prognostic value for 10-year disability of whole brain atrophy, central brain atrophy, and T2 lesion volumes in a large MS patient group, taking into account disease type, disease-modifying treatment, and initial clinical status. The researchers conducted a longitudinal, retrospective study with short-term serial MRI data and long-term clinical follow-up. Inclusion criteria comprised two MRI scans performed using the same protocol with a one- to two-year interval, baseline scan before January 1, 2000, and an MS diagnosis at 10 years of follow-up according to the McDonald criteria.

The researchers investigated long-term clinical associations with retrospective MR disease measures in 261 patients drawn from a multicenter MS group with all major disease subtypes and clinical follow-up at 10 years. Patients were categorized by baseline diagnosis as primary progressive (n = 77), secondary progressive (n = 69), relapsing-remitting (n = 97), and clinically isolated syndromes (n = 18). Relapse onset patients were classified as minimally impaired or moderately impaired based on their baseline disability, regardless of disease type.

Despite the characteristic variability among patients with MS, the most prominent predictive value was attributed to clinical variables such as baseline Expanded Disability Status Scale (EDSS), disease type, treatment, and imaging protocol. However, the researchers noted associations between MR measures—both cross-sectional and longitudinal—and clinical status 10 years later.

In the whole group, whole brain and central atrophy predicted EDSS at 10 years, corrected for imaging protocol, baseline EDSS, and treatment. The combined model with central atrophy and lesion volume change as MRI predictors predicted 10-year EDSS in the whole group and in the relapse onset group. In subgroups, central atrophy was predictive in the minimally impaired relapse onset patients, lesion volumes in moderately impaired relapse onset patients, and whole brain atrophy in primary progressive MS.

—Glenn S. Williams
Vice President/Group Editor

A large multicenter study published in the October issue of the Journal of Neurology, Neurosurgery and Psychiatry points to the complementary value of brain atrophy and lesion volumes for predicting long-term disability in multiple sclerosis (MS).

Although predictors of short- and medium-term clinical progression have been identified, the longer-term clinical prognostic value of brain atrophy measures and lesion volumes has been studied less extensively. “Our finding may help develop predictors of future disability in MS that could be used in clinical trials and eventually also for predicting the evolution of individual patients,” the researchers said.

Veronica Popescu, MD, MSc, of the Department of Radiology and Nuclear Medicine at VU University Medical Center in Amsterdam, and colleagues from the MAGNIMS study group sought to determine the prognostic value for 10-year disability of whole brain atrophy, central brain atrophy, and T2 lesion volumes in a large MS patient group, taking into account disease type, disease-modifying treatment, and initial clinical status. The researchers conducted a longitudinal, retrospective study with short-term serial MRI data and long-term clinical follow-up. Inclusion criteria comprised two MRI scans performed using the same protocol with a one- to two-year interval, baseline scan before January 1, 2000, and an MS diagnosis at 10 years of follow-up according to the McDonald criteria.

The researchers investigated long-term clinical associations with retrospective MR disease measures in 261 patients drawn from a multicenter MS group with all major disease subtypes and clinical follow-up at 10 years. Patients were categorized by baseline diagnosis as primary progressive (n = 77), secondary progressive (n = 69), relapsing-remitting (n = 97), and clinically isolated syndromes (n = 18). Relapse onset patients were classified as minimally impaired or moderately impaired based on their baseline disability, regardless of disease type.

Despite the characteristic variability among patients with MS, the most prominent predictive value was attributed to clinical variables such as baseline Expanded Disability Status Scale (EDSS), disease type, treatment, and imaging protocol. However, the researchers noted associations between MR measures—both cross-sectional and longitudinal—and clinical status 10 years later.

In the whole group, whole brain and central atrophy predicted EDSS at 10 years, corrected for imaging protocol, baseline EDSS, and treatment. The combined model with central atrophy and lesion volume change as MRI predictors predicted 10-year EDSS in the whole group and in the relapse onset group. In subgroups, central atrophy was predictive in the minimally impaired relapse onset patients, lesion volumes in moderately impaired relapse onset patients, and whole brain atrophy in primary progressive MS.

—Glenn S. Williams
Vice President/Group Editor

A large multicenter study published in the October issue of the Journal of Neurology, Neurosurgery and Psychiatry points to the complementary value of brain atrophy and lesion volumes for predicting long-term disability in multiple sclerosis (MS).

Although predictors of short- and medium-term clinical progression have been identified, the longer-term clinical prognostic value of brain atrophy measures and lesion volumes has been studied less extensively. “Our finding may help develop predictors of future disability in MS that could be used in clinical trials and eventually also for predicting the evolution of individual patients,” the researchers said.

Veronica Popescu, MD, MSc, of the Department of Radiology and Nuclear Medicine at VU University Medical Center in Amsterdam, and colleagues from the MAGNIMS study group sought to determine the prognostic value for 10-year disability of whole brain atrophy, central brain atrophy, and T2 lesion volumes in a large MS patient group, taking into account disease type, disease-modifying treatment, and initial clinical status. The researchers conducted a longitudinal, retrospective study with short-term serial MRI data and long-term clinical follow-up. Inclusion criteria comprised two MRI scans performed using the same protocol with a one- to two-year interval, baseline scan before January 1, 2000, and an MS diagnosis at 10 years of follow-up according to the McDonald criteria.

The researchers investigated long-term clinical associations with retrospective MR disease measures in 261 patients drawn from a multicenter MS group with all major disease subtypes and clinical follow-up at 10 years. Patients were categorized by baseline diagnosis as primary progressive (n = 77), secondary progressive (n = 69), relapsing-remitting (n = 97), and clinically isolated syndromes (n = 18). Relapse onset patients were classified as minimally impaired or moderately impaired based on their baseline disability, regardless of disease type.

Despite the characteristic variability among patients with MS, the most prominent predictive value was attributed to clinical variables such as baseline Expanded Disability Status Scale (EDSS), disease type, treatment, and imaging protocol. However, the researchers noted associations between MR measures—both cross-sectional and longitudinal—and clinical status 10 years later.

In the whole group, whole brain and central atrophy predicted EDSS at 10 years, corrected for imaging protocol, baseline EDSS, and treatment. The combined model with central atrophy and lesion volume change as MRI predictors predicted 10-year EDSS in the whole group and in the relapse onset group. In subgroups, central atrophy was predictive in the minimally impaired relapse onset patients, lesion volumes in moderately impaired relapse onset patients, and whole brain atrophy in primary progressive MS.

—Glenn S. Williams
Vice President/Group Editor

The first case of progressive multifocal leukoencephalopathy (PML) has been reported in a patient with multiple sclerosis (MS) treated with fingolimod who had not also been treated with natalizumab, according to the FDA.

The patient was diagnosed with PML after almost eight months of treatment with fingolimod, a sphingosine 1-phosphate receptor modulator that was approved in 2010 for treating relapsing forms of MS.

The patient received one month of treatment with interferon beta-1a and azathioprine prior to beginning fingolimod. Those drugs were stopped when treatment with fingolimod began. However, the patient was also treated with “multiple courses” of IV corticosteroids for several months before and during treatment with fingolimod.

Treatment with fingolimod was discontinued after the diagnosis of PML, made on the basis of clinical symptoms and detection of JC viral DNA in CSF, according to the FDA statement, which does not say whether the patient survived. The case was reported in Europe.

After several PML cases were reported in patients with MS treated with natalizumab months after it was approved in 2004, it was taken off the market in 2005 and reintroduced in June 2006 with measures to address the risk of PML, including a restricted distribution program.

The FDA is working with Novartis, the drug’s manufacturer, to investigate this case and will make recommendations when the evaluation has been completed, the statement said. The FDA is advising patients not to stop treatment with fingolimod before discussing this with their health care professionals.

The precautions and warnings section of the fingolimod label includes a statement that the treatment causes a dose-dependent reduction in peripheral lymphocyte count due to reversible sequestration of lymphocytes in lymphoid tissues, and the drug “may therefore increase the risk of infections, some serious in nature,” but PML is not mentioned. The label also says that the drug has not been administered with antineoplastic, immunosuppressive, or immune-modulating therapies used to treat MS and that use of fingolimod with any of these treatments “would be expected to increase the risk of immunosuppression.”

Fingolimod was approved with a risk evaluation and mitigation strategy addressing the serious risks associated with treatment, including bradyarrhythmia and atrioventricular block at the start of treatment, infections, macular edema, respiratory effects, hepatic effects, and fetal risk.

—Elizabeth Mechcatie
IMNG Medical News

The first case of progressive multifocal leukoencephalopathy (PML) has been reported in a patient with multiple sclerosis (MS) treated with fingolimod who had not also been treated with natalizumab, according to the FDA.

The patient was diagnosed with PML after almost eight months of treatment with fingolimod, a sphingosine 1-phosphate receptor modulator that was approved in 2010 for treating relapsing forms of MS.

The patient received one month of treatment with interferon beta-1a and azathioprine prior to beginning fingolimod. Those drugs were stopped when treatment with fingolimod began. However, the patient was also treated with “multiple courses” of IV corticosteroids for several months before and during treatment with fingolimod.

Treatment with fingolimod was discontinued after the diagnosis of PML, made on the basis of clinical symptoms and detection of JC viral DNA in CSF, according to the FDA statement, which does not say whether the patient survived. The case was reported in Europe.

After several PML cases were reported in patients with MS treated with natalizumab months after it was approved in 2004, it was taken off the market in 2005 and reintroduced in June 2006 with measures to address the risk of PML, including a restricted distribution program.

The FDA is working with Novartis, the drug’s manufacturer, to investigate this case and will make recommendations when the evaluation has been completed, the statement said. The FDA is advising patients not to stop treatment with fingolimod before discussing this with their health care professionals.

The precautions and warnings section of the fingolimod label includes a statement that the treatment causes a dose-dependent reduction in peripheral lymphocyte count due to reversible sequestration of lymphocytes in lymphoid tissues, and the drug “may therefore increase the risk of infections, some serious in nature,” but PML is not mentioned. The label also says that the drug has not been administered with antineoplastic, immunosuppressive, or immune-modulating therapies used to treat MS and that use of fingolimod with any of these treatments “would be expected to increase the risk of immunosuppression.”

Fingolimod was approved with a risk evaluation and mitigation strategy addressing the serious risks associated with treatment, including bradyarrhythmia and atrioventricular block at the start of treatment, infections, macular edema, respiratory effects, hepatic effects, and fetal risk.

—Elizabeth Mechcatie
IMNG Medical News

The first case of progressive multifocal leukoencephalopathy (PML) has been reported in a patient with multiple sclerosis (MS) treated with fingolimod who had not also been treated with natalizumab, according to the FDA.

The patient was diagnosed with PML after almost eight months of treatment with fingolimod, a sphingosine 1-phosphate receptor modulator that was approved in 2010 for treating relapsing forms of MS.

The patient received one month of treatment with interferon beta-1a and azathioprine prior to beginning fingolimod. Those drugs were stopped when treatment with fingolimod began. However, the patient was also treated with “multiple courses” of IV corticosteroids for several months before and during treatment with fingolimod.

Treatment with fingolimod was discontinued after the diagnosis of PML, made on the basis of clinical symptoms and detection of JC viral DNA in CSF, according to the FDA statement, which does not say whether the patient survived. The case was reported in Europe.

After several PML cases were reported in patients with MS treated with natalizumab months after it was approved in 2004, it was taken off the market in 2005 and reintroduced in June 2006 with measures to address the risk of PML, including a restricted distribution program.

The FDA is working with Novartis, the drug’s manufacturer, to investigate this case and will make recommendations when the evaluation has been completed, the statement said. The FDA is advising patients not to stop treatment with fingolimod before discussing this with their health care professionals.

The precautions and warnings section of the fingolimod label includes a statement that the treatment causes a dose-dependent reduction in peripheral lymphocyte count due to reversible sequestration of lymphocytes in lymphoid tissues, and the drug “may therefore increase the risk of infections, some serious in nature,” but PML is not mentioned. The label also says that the drug has not been administered with antineoplastic, immunosuppressive, or immune-modulating therapies used to treat MS and that use of fingolimod with any of these treatments “would be expected to increase the risk of immunosuppression.”

Fingolimod was approved with a risk evaluation and mitigation strategy addressing the serious risks associated with treatment, including bradyarrhythmia and atrioventricular block at the start of treatment, infections, macular edema, respiratory effects, hepatic effects, and fetal risk.

—Elizabeth Mechcatie
IMNG Medical News

ORLANDO—Cannabis may be a safe and effective therapy for pain and spasticity in patients with multiple sclerosis (MS), according to an overview presented at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS. The route of administration and the dose influence the drug’s physical and psychotropic effects.

Approximately 46% of patients with MS smoke marijuana for pain, tremor, insomnia, bladder problems, or spasticity, said Heidi Maloni, PhD, nurse practitioner at the Veterans Affairs Medical Center in Washington, DC. Although smoking the herbal form of cannabis is associated with several health concerns, oral and buccal sprays appear to entail fewer risks.

Nabiximols May Receive FDA Approval Soon
Nabiximols, a liquid extract of two strains of cloned Cannabis sativa, is formulated as an oromucosal spray that contains tetrahydrocannabinol (THC) and cannabidiol (CBD) in a 1:1 ratio. THC is the psychoactive chemical in marijuana, and CBD counteracts this psychoactive effect. Each spray of nabiximols contains 100 µL of cannabis, and the suggested maximum dose is 33.8 mg/day.

Three clinical trials conducted since 2010 suggest that nabiximols effectively reduces MS-related pain that otherwise resists pharmacologic intervention. Patients did not develop tolerance to nabiximols, and cessation of treatment was not associated with symptoms of withdrawal. In several clinical trials that included 930 patients who took nabiximols, 27.5% of patients who took the drug had dizziness, 13.1% had diarrhea, and 11% had fatigue. Less than 1% of patients had a cannabis high. Slow titration of the drug over 10 days helped to reduce the occurrence of serious adverse events.

Unlike smoked cannabis, nabiximols was not associated with memory impairment, sedation, or intoxication. The drug’s effect on pain intensity generally is evident within four weeks of treatment. The cost efficacy of nabiximols remains to be established, however. Authorities in the United Kingdom do not consider nabiximols to be cost effective when compared with baclofen and tizanidine.

The drug is an approved treatment for MS-related spasticity and pain in the United Kingdom, Canada, New Zealand, and eight European countries. The FDA is expected to approve the drug in December 2013, said Dr. Maloni.

Smoked Cannabis Is Associated With Cognitive Impairment
Unlike cannabis-based extracts such as nabiximols, which generally take 90 minutes to reach the brain and cause an effect, smoked cannabis reaches its peak concentration in the body in 10 minutes. In clinical trials of smoked cannabis, during which patients received between 4 and 128 mg/day of THC, pain intensity decreased by at least 30% for all participants. This result reflected an important improvement on quality of life, said Dr. Maloni. The medium dose of THC was as effective as the high dose.

In a 2012 study, scores on the visual analog scale of pain decreased by five points—a “huge” difference—among patients who smoked cannabis for MS-related pain, said Dr. Maloni. Mean scores on the Paced Auditory Serial Addition Test, however, decreased by eight points among patients who smoked cannabis, compared with controls.

A Canadian study published in Neurology compared patients with MS who smoked cannabis with patients who did not smoke it. Participants underwent cognitive testing after a 12-hour period during which no subject smoked cannabis. Scores on all aspects of cognition, including visuospatial ability, executive function, and short-term memory, were 30% worse for patients who smoked cannabis than for controls. Because MS itself can entail cognitive problems, smoked cannabis can be problematic for patients with the disease, said Dr. Maloni.

Smoked cannabis also entails other concerns. About 10% of people who smoke the drug develop dependence, and people who stop smoking it may have withdrawal symptoms. Smoked cannabis is associated with tachycardia, cardiovascular disease, and elevated blood pressure and heart rate. And because cannabis is an anticholinergic, it can cause problems for MS patients’ eyes. “You want to be careful with anything that’s going to dry them out,” said Dr. Maloni.

Oral Cannabis Is Least Popular Among Patients
Synthetic cannabis is available in oral tablets and capsules, but patients express the least satisfaction with this form of the drug because it is subject to the cytochrome P450 system and is metabolized by the liver, said Dr. Maloni. The bioavailability of oral cannabis ranges between 5% and 20%.

Dronabinol, a synthetic THC, is available in 2.5-, 5-, and 10-mg oral capsules. A 10- to 20-mg dose of THC has an analgesic effect equivalent to that of 60 to 120 mg of codeine. In one study, dronabinol was associated with subjective improvement in spasticity, pain, and relapse rate in patients with MS. Dronabinol is approved in the United States for the treatment of chemotherapy-related nausea and vomiting and the treatment of weight loss related to wasting syndromes.

Nabilone, a synthetic CB1 and CB2 receptor agonist, is also approved in the US for the treatment of chemotherapy-related nausea and vomiting. Studies of 0.5- to 1-mg doses of nabilone in patients with MS have not been robust, but the drug may have an effect in patients with fibromyalgia, said Dr. Maloni. A meta-analysis suggested that nabilone and dronabinol were associated with statistically significant differences in pain intensity.

Cannabis May Be an Alternative to Opioids
Physicians need guidance on prescribing cannabis for their patients, said Dr. Maloni. “Cannabis in an oral or buccal spray is safe, tolerable, and effective,” she added. The drug could provide an alternative to opioids and should be considered as a treatment for pain in MS when other accepted options have failed. Patients should be fully informed about their treatment, which should take place in the context of an ongoing relationship with their physician.

—Erik Greb
Senior Associate Editor

ORLANDO—Cannabis may be a safe and effective therapy for pain and spasticity in patients with multiple sclerosis (MS), according to an overview presented at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS. The route of administration and the dose influence the drug’s physical and psychotropic effects.

Approximately 46% of patients with MS smoke marijuana for pain, tremor, insomnia, bladder problems, or spasticity, said Heidi Maloni, PhD, nurse practitioner at the Veterans Affairs Medical Center in Washington, DC. Although smoking the herbal form of cannabis is associated with several health concerns, oral and buccal sprays appear to entail fewer risks.

Nabiximols May Receive FDA Approval Soon
Nabiximols, a liquid extract of two strains of cloned Cannabis sativa, is formulated as an oromucosal spray that contains tetrahydrocannabinol (THC) and cannabidiol (CBD) in a 1:1 ratio. THC is the psychoactive chemical in marijuana, and CBD counteracts this psychoactive effect. Each spray of nabiximols contains 100 µL of cannabis, and the suggested maximum dose is 33.8 mg/day.

Three clinical trials conducted since 2010 suggest that nabiximols effectively reduces MS-related pain that otherwise resists pharmacologic intervention. Patients did not develop tolerance to nabiximols, and cessation of treatment was not associated with symptoms of withdrawal. In several clinical trials that included 930 patients who took nabiximols, 27.5% of patients who took the drug had dizziness, 13.1% had diarrhea, and 11% had fatigue. Less than 1% of patients had a cannabis high. Slow titration of the drug over 10 days helped to reduce the occurrence of serious adverse events.

Unlike smoked cannabis, nabiximols was not associated with memory impairment, sedation, or intoxication. The drug’s effect on pain intensity generally is evident within four weeks of treatment. The cost efficacy of nabiximols remains to be established, however. Authorities in the United Kingdom do not consider nabiximols to be cost effective when compared with baclofen and tizanidine.

The drug is an approved treatment for MS-related spasticity and pain in the United Kingdom, Canada, New Zealand, and eight European countries. The FDA is expected to approve the drug in December 2013, said Dr. Maloni.

Smoked Cannabis Is Associated With Cognitive Impairment
Unlike cannabis-based extracts such as nabiximols, which generally take 90 minutes to reach the brain and cause an effect, smoked cannabis reaches its peak concentration in the body in 10 minutes. In clinical trials of smoked cannabis, during which patients received between 4 and 128 mg/day of THC, pain intensity decreased by at least 30% for all participants. This result reflected an important improvement on quality of life, said Dr. Maloni. The medium dose of THC was as effective as the high dose.

In a 2012 study, scores on the visual analog scale of pain decreased by five points—a “huge” difference—among patients who smoked cannabis for MS-related pain, said Dr. Maloni. Mean scores on the Paced Auditory Serial Addition Test, however, decreased by eight points among patients who smoked cannabis, compared with controls.

A Canadian study published in Neurology compared patients with MS who smoked cannabis with patients who did not smoke it. Participants underwent cognitive testing after a 12-hour period during which no subject smoked cannabis. Scores on all aspects of cognition, including visuospatial ability, executive function, and short-term memory, were 30% worse for patients who smoked cannabis than for controls. Because MS itself can entail cognitive problems, smoked cannabis can be problematic for patients with the disease, said Dr. Maloni.

Smoked cannabis also entails other concerns. About 10% of people who smoke the drug develop dependence, and people who stop smoking it may have withdrawal symptoms. Smoked cannabis is associated with tachycardia, cardiovascular disease, and elevated blood pressure and heart rate. And because cannabis is an anticholinergic, it can cause problems for MS patients’ eyes. “You want to be careful with anything that’s going to dry them out,” said Dr. Maloni.

Oral Cannabis Is Least Popular Among Patients
Synthetic cannabis is available in oral tablets and capsules, but patients express the least satisfaction with this form of the drug because it is subject to the cytochrome P450 system and is metabolized by the liver, said Dr. Maloni. The bioavailability of oral cannabis ranges between 5% and 20%.

Dronabinol, a synthetic THC, is available in 2.5-, 5-, and 10-mg oral capsules. A 10- to 20-mg dose of THC has an analgesic effect equivalent to that of 60 to 120 mg of codeine. In one study, dronabinol was associated with subjective improvement in spasticity, pain, and relapse rate in patients with MS. Dronabinol is approved in the United States for the treatment of chemotherapy-related nausea and vomiting and the treatment of weight loss related to wasting syndromes.

Nabilone, a synthetic CB1 and CB2 receptor agonist, is also approved in the US for the treatment of chemotherapy-related nausea and vomiting. Studies of 0.5- to 1-mg doses of nabilone in patients with MS have not been robust, but the drug may have an effect in patients with fibromyalgia, said Dr. Maloni. A meta-analysis suggested that nabilone and dronabinol were associated with statistically significant differences in pain intensity.

Cannabis May Be an Alternative to Opioids
Physicians need guidance on prescribing cannabis for their patients, said Dr. Maloni. “Cannabis in an oral or buccal spray is safe, tolerable, and effective,” she added. The drug could provide an alternative to opioids and should be considered as a treatment for pain in MS when other accepted options have failed. Patients should be fully informed about their treatment, which should take place in the context of an ongoing relationship with their physician.

—Erik Greb
Senior Associate Editor

ORLANDO—Cannabis may be a safe and effective therapy for pain and spasticity in patients with multiple sclerosis (MS), according to an overview presented at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS. The route of administration and the dose influence the drug’s physical and psychotropic effects.

Approximately 46% of patients with MS smoke marijuana for pain, tremor, insomnia, bladder problems, or spasticity, said Heidi Maloni, PhD, nurse practitioner at the Veterans Affairs Medical Center in Washington, DC. Although smoking the herbal form of cannabis is associated with several health concerns, oral and buccal sprays appear to entail fewer risks.

Nabiximols May Receive FDA Approval Soon
Nabiximols, a liquid extract of two strains of cloned Cannabis sativa, is formulated as an oromucosal spray that contains tetrahydrocannabinol (THC) and cannabidiol (CBD) in a 1:1 ratio. THC is the psychoactive chemical in marijuana, and CBD counteracts this psychoactive effect. Each spray of nabiximols contains 100 µL of cannabis, and the suggested maximum dose is 33.8 mg/day.

Three clinical trials conducted since 2010 suggest that nabiximols effectively reduces MS-related pain that otherwise resists pharmacologic intervention. Patients did not develop tolerance to nabiximols, and cessation of treatment was not associated with symptoms of withdrawal. In several clinical trials that included 930 patients who took nabiximols, 27.5% of patients who took the drug had dizziness, 13.1% had diarrhea, and 11% had fatigue. Less than 1% of patients had a cannabis high. Slow titration of the drug over 10 days helped to reduce the occurrence of serious adverse events.

Unlike smoked cannabis, nabiximols was not associated with memory impairment, sedation, or intoxication. The drug’s effect on pain intensity generally is evident within four weeks of treatment. The cost efficacy of nabiximols remains to be established, however. Authorities in the United Kingdom do not consider nabiximols to be cost effective when compared with baclofen and tizanidine.

The drug is an approved treatment for MS-related spasticity and pain in the United Kingdom, Canada, New Zealand, and eight European countries. The FDA is expected to approve the drug in December 2013, said Dr. Maloni.

Smoked Cannabis Is Associated With Cognitive Impairment
Unlike cannabis-based extracts such as nabiximols, which generally take 90 minutes to reach the brain and cause an effect, smoked cannabis reaches its peak concentration in the body in 10 minutes. In clinical trials of smoked cannabis, during which patients received between 4 and 128 mg/day of THC, pain intensity decreased by at least 30% for all participants. This result reflected an important improvement on quality of life, said Dr. Maloni. The medium dose of THC was as effective as the high dose.

In a 2012 study, scores on the visual analog scale of pain decreased by five points—a “huge” difference—among patients who smoked cannabis for MS-related pain, said Dr. Maloni. Mean scores on the Paced Auditory Serial Addition Test, however, decreased by eight points among patients who smoked cannabis, compared with controls.

A Canadian study published in Neurology compared patients with MS who smoked cannabis with patients who did not smoke it. Participants underwent cognitive testing after a 12-hour period during which no subject smoked cannabis. Scores on all aspects of cognition, including visuospatial ability, executive function, and short-term memory, were 30% worse for patients who smoked cannabis than for controls. Because MS itself can entail cognitive problems, smoked cannabis can be problematic for patients with the disease, said Dr. Maloni.

Smoked cannabis also entails other concerns. About 10% of people who smoke the drug develop dependence, and people who stop smoking it may have withdrawal symptoms. Smoked cannabis is associated with tachycardia, cardiovascular disease, and elevated blood pressure and heart rate. And because cannabis is an anticholinergic, it can cause problems for MS patients’ eyes. “You want to be careful with anything that’s going to dry them out,” said Dr. Maloni.

Oral Cannabis Is Least Popular Among Patients
Synthetic cannabis is available in oral tablets and capsules, but patients express the least satisfaction with this form of the drug because it is subject to the cytochrome P450 system and is metabolized by the liver, said Dr. Maloni. The bioavailability of oral cannabis ranges between 5% and 20%.

Dronabinol, a synthetic THC, is available in 2.5-, 5-, and 10-mg oral capsules. A 10- to 20-mg dose of THC has an analgesic effect equivalent to that of 60 to 120 mg of codeine. In one study, dronabinol was associated with subjective improvement in spasticity, pain, and relapse rate in patients with MS. Dronabinol is approved in the United States for the treatment of chemotherapy-related nausea and vomiting and the treatment of weight loss related to wasting syndromes.

Nabilone, a synthetic CB1 and CB2 receptor agonist, is also approved in the US for the treatment of chemotherapy-related nausea and vomiting. Studies of 0.5- to 1-mg doses of nabilone in patients with MS have not been robust, but the drug may have an effect in patients with fibromyalgia, said Dr. Maloni. A meta-analysis suggested that nabilone and dronabinol were associated with statistically significant differences in pain intensity.

Cannabis May Be an Alternative to Opioids
Physicians need guidance on prescribing cannabis for their patients, said Dr. Maloni. “Cannabis in an oral or buccal spray is safe, tolerable, and effective,” she added. The drug could provide an alternative to opioids and should be considered as a treatment for pain in MS when other accepted options have failed. Patients should be fully informed about their treatment, which should take place in the context of an ongoing relationship with their physician.

—Erik Greb
Senior Associate Editor

ORLANDO—After years of waiting, patients with multiple sclerosis (MS) can now choose between three approved oral agents. Patients’ choices will be improved, however, if they first investigate which of the three drugs would be most appropriate for them.

All three oral drugs—fingolimod, teriflunomide, and dimethyl fumarate—are “definitely” suitable as first-line therapy in selected newly diagnosed patients with MS, said Mariko Kita, MD, at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS.

But the three oral drugs are not interchangeable. Each has a different mechanism of action and its own side effect profile, emphasized Dr. Kita, Director of the Virginia Mason MS Center in Seattle and Director of the MS Clinical Trials Unit at Virginia Mason’s Benaroya Research Institute.

Few neurologists are prescribing an oral agent as a first-line therapy, partly because of cost and reimbursement issues, but mainly because most physicians do not believe that the oral agents’ safety profiles are fully understood. Most practitioners hesitate to administer new drugs. The hesitation may be understandable in light of the cautions added to the labels for natalizumab—considered the most effective of the injectable agents—and fingolimod—the first oral agent to receive marketing approval—shortly after they were introduced.

Nevertheless, physician experience with the oral medications is expected to grow quickly. Barring revelations of new side effects, observers anticipate that the use of oral agents for MS will surge within the next few years, leading to a corresponding decline in the popularity of injectable therapies.

Oral Therapies May Appeal to All Patients With MS
Demand for oral therapy will be high among all types of patients, predicted Dr. Kita. Newly diagnosed patients and individuals with a lengthy disease history who have tried all the available disease-modifying therapies with unsatisfactory results will be interested in oral medications, she said. The same will be true for patients who cannot tolerate a given first-line injectable agent or who experience breakthrough disease while using it. Likewise, patients who are stable on their current injectable disease-modifying therapy but are tired of injections or concerned about the parenteral therapy’s long-term risks will consider the oral drugs, added Dr. Kita.

Choosing an appropriate oral medication requires a focus on patient-specific factors, including comorbid conditions, reproductive status, and how the oral drug would fit into a long-term, staged therapy plan, she added.

Fingolimod
Fingolimod is best reserved for patients with MS who are otherwise relatively healthy, said Dr. Kita. It is a less favorable option for patients with diabetes, smokers, individuals with reduced pulmonary function, and those with an increased risk of infection, including people with a high Expanded Disability Status Scale score.

Fingolimod is a sphingosine-1-phosphate agonist. It sequesters lymphocytes in the lymph nodes so that they cannot participate in autoimmune activity. The testing required before initiating fingolimod therapy, the need for careful observation during the first dose, and the necessary ongoing monitoring for the duration of treatment make this a labor-intensive drug, said Dr. Kita.

Bearing those factors in mind, she continued, fingolimod is “reasonable” to use as a first-line agent or as a second-line agent in the setting of intolerance to prior therapy or of breakthrough disease on therapy.

Expectations for First- and Second-Line Therapies
“I would caution those who are reserving these oral agents as second-line [treatments] that we need to think about what we can reasonably expect from them,” said Dr. Kita. “If we’re moving to them as second-line [drugs] because of tolerability issues with first-line agents, yes, I think that’s most reasonable. But if we’re moving because of breakthrough disease, our experience with these agents in cases of failure with standard first-line therapies is very, very limited. Sure, the differing mechanism of action offers a reasonable alternative option, but the expectation that the oral [medication] will be better than a failed injectable [medication] has not yet been proven,” she added.

Choosing the Right Oral Drug
Of the three oral MS agents currently available in the US, dimethyl fumarate has the most benign side effect profile, which consists mostly of short-term flushing and gastrointestinal complaints. Dimethyl fumarate could gain broad use as a first-line drug in newly diagnosed patients and as a second-line therapy in patients intolerant to other agents or in patients experiencing breakthrough disease.

It remains unclear whether any of the available oral agents is the best choice after natalizumab discontinuation. In several studies, patients who took fingolimod after natalizumab discontinuation had a high relapse rate. No data exist yet about the effects of the two newer agents under these circumstances, Dr. Kita said.

Upcoming Oral Agents
The investigational oral agent furthest along in the developmental pipeline is laquinimod, a quinolone-3-carboxamide small molecule for which two phase III clinical trials have been completed. The European Medicines Agency is reviewing the drug for marketing approval. Teva, the drug’s manufacturer, has not yet applied to the FDA for approval in the United States.

Several second-generation sphingosine-1-phosphate agonists are in development. They are believed to act more selectively, and thus to entail a lower risk of compromising the immune system, than fingolimod. These agents include siponimod, ponesimod, and ONO-4641.

—Bruce Jancin
IMNG Medical News

ORLANDO—After years of waiting, patients with multiple sclerosis (MS) can now choose between three approved oral agents. Patients’ choices will be improved, however, if they first investigate which of the three drugs would be most appropriate for them.

All three oral drugs—fingolimod, teriflunomide, and dimethyl fumarate—are “definitely” suitable as first-line therapy in selected newly diagnosed patients with MS, said Mariko Kita, MD, at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS.

But the three oral drugs are not interchangeable. Each has a different mechanism of action and its own side effect profile, emphasized Dr. Kita, Director of the Virginia Mason MS Center in Seattle and Director of the MS Clinical Trials Unit at Virginia Mason’s Benaroya Research Institute.

Few neurologists are prescribing an oral agent as a first-line therapy, partly because of cost and reimbursement issues, but mainly because most physicians do not believe that the oral agents’ safety profiles are fully understood. Most practitioners hesitate to administer new drugs. The hesitation may be understandable in light of the cautions added to the labels for natalizumab—considered the most effective of the injectable agents—and fingolimod—the first oral agent to receive marketing approval—shortly after they were introduced.

Nevertheless, physician experience with the oral medications is expected to grow quickly. Barring revelations of new side effects, observers anticipate that the use of oral agents for MS will surge within the next few years, leading to a corresponding decline in the popularity of injectable therapies.

Oral Therapies May Appeal to All Patients With MS
Demand for oral therapy will be high among all types of patients, predicted Dr. Kita. Newly diagnosed patients and individuals with a lengthy disease history who have tried all the available disease-modifying therapies with unsatisfactory results will be interested in oral medications, she said. The same will be true for patients who cannot tolerate a given first-line injectable agent or who experience breakthrough disease while using it. Likewise, patients who are stable on their current injectable disease-modifying therapy but are tired of injections or concerned about the parenteral therapy’s long-term risks will consider the oral drugs, added Dr. Kita.

Choosing an appropriate oral medication requires a focus on patient-specific factors, including comorbid conditions, reproductive status, and how the oral drug would fit into a long-term, staged therapy plan, she added.

Fingolimod
Fingolimod is best reserved for patients with MS who are otherwise relatively healthy, said Dr. Kita. It is a less favorable option for patients with diabetes, smokers, individuals with reduced pulmonary function, and those with an increased risk of infection, including people with a high Expanded Disability Status Scale score.

Fingolimod is a sphingosine-1-phosphate agonist. It sequesters lymphocytes in the lymph nodes so that they cannot participate in autoimmune activity. The testing required before initiating fingolimod therapy, the need for careful observation during the first dose, and the necessary ongoing monitoring for the duration of treatment make this a labor-intensive drug, said Dr. Kita.

Bearing those factors in mind, she continued, fingolimod is “reasonable” to use as a first-line agent or as a second-line agent in the setting of intolerance to prior therapy or of breakthrough disease on therapy.

Expectations for First- and Second-Line Therapies
“I would caution those who are reserving these oral agents as second-line [treatments] that we need to think about what we can reasonably expect from them,” said Dr. Kita. “If we’re moving to them as second-line [drugs] because of tolerability issues with first-line agents, yes, I think that’s most reasonable. But if we’re moving because of breakthrough disease, our experience with these agents in cases of failure with standard first-line therapies is very, very limited. Sure, the differing mechanism of action offers a reasonable alternative option, but the expectation that the oral [medication] will be better than a failed injectable [medication] has not yet been proven,” she added.

Choosing the Right Oral Drug
Of the three oral MS agents currently available in the US, dimethyl fumarate has the most benign side effect profile, which consists mostly of short-term flushing and gastrointestinal complaints. Dimethyl fumarate could gain broad use as a first-line drug in newly diagnosed patients and as a second-line therapy in patients intolerant to other agents or in patients experiencing breakthrough disease.

It remains unclear whether any of the available oral agents is the best choice after natalizumab discontinuation. In several studies, patients who took fingolimod after natalizumab discontinuation had a high relapse rate. No data exist yet about the effects of the two newer agents under these circumstances, Dr. Kita said.

Upcoming Oral Agents
The investigational oral agent furthest along in the developmental pipeline is laquinimod, a quinolone-3-carboxamide small molecule for which two phase III clinical trials have been completed. The European Medicines Agency is reviewing the drug for marketing approval. Teva, the drug’s manufacturer, has not yet applied to the FDA for approval in the United States.

Several second-generation sphingosine-1-phosphate agonists are in development. They are believed to act more selectively, and thus to entail a lower risk of compromising the immune system, than fingolimod. These agents include siponimod, ponesimod, and ONO-4641.

—Bruce Jancin
IMNG Medical News

ORLANDO—After years of waiting, patients with multiple sclerosis (MS) can now choose between three approved oral agents. Patients’ choices will be improved, however, if they first investigate which of the three drugs would be most appropriate for them.

All three oral drugs—fingolimod, teriflunomide, and dimethyl fumarate—are “definitely” suitable as first-line therapy in selected newly diagnosed patients with MS, said Mariko Kita, MD, at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS.

But the three oral drugs are not interchangeable. Each has a different mechanism of action and its own side effect profile, emphasized Dr. Kita, Director of the Virginia Mason MS Center in Seattle and Director of the MS Clinical Trials Unit at Virginia Mason’s Benaroya Research Institute.

Few neurologists are prescribing an oral agent as a first-line therapy, partly because of cost and reimbursement issues, but mainly because most physicians do not believe that the oral agents’ safety profiles are fully understood. Most practitioners hesitate to administer new drugs. The hesitation may be understandable in light of the cautions added to the labels for natalizumab—considered the most effective of the injectable agents—and fingolimod—the first oral agent to receive marketing approval—shortly after they were introduced.

Nevertheless, physician experience with the oral medications is expected to grow quickly. Barring revelations of new side effects, observers anticipate that the use of oral agents for MS will surge within the next few years, leading to a corresponding decline in the popularity of injectable therapies.

Oral Therapies May Appeal to All Patients With MS
Demand for oral therapy will be high among all types of patients, predicted Dr. Kita. Newly diagnosed patients and individuals with a lengthy disease history who have tried all the available disease-modifying therapies with unsatisfactory results will be interested in oral medications, she said. The same will be true for patients who cannot tolerate a given first-line injectable agent or who experience breakthrough disease while using it. Likewise, patients who are stable on their current injectable disease-modifying therapy but are tired of injections or concerned about the parenteral therapy’s long-term risks will consider the oral drugs, added Dr. Kita.

Choosing an appropriate oral medication requires a focus on patient-specific factors, including comorbid conditions, reproductive status, and how the oral drug would fit into a long-term, staged therapy plan, she added.

Fingolimod
Fingolimod is best reserved for patients with MS who are otherwise relatively healthy, said Dr. Kita. It is a less favorable option for patients with diabetes, smokers, individuals with reduced pulmonary function, and those with an increased risk of infection, including people with a high Expanded Disability Status Scale score.

Fingolimod is a sphingosine-1-phosphate agonist. It sequesters lymphocytes in the lymph nodes so that they cannot participate in autoimmune activity. The testing required before initiating fingolimod therapy, the need for careful observation during the first dose, and the necessary ongoing monitoring for the duration of treatment make this a labor-intensive drug, said Dr. Kita.

Bearing those factors in mind, she continued, fingolimod is “reasonable” to use as a first-line agent or as a second-line agent in the setting of intolerance to prior therapy or of breakthrough disease on therapy.

Expectations for First- and Second-Line Therapies
“I would caution those who are reserving these oral agents as second-line [treatments] that we need to think about what we can reasonably expect from them,” said Dr. Kita. “If we’re moving to them as second-line [drugs] because of tolerability issues with first-line agents, yes, I think that’s most reasonable. But if we’re moving because of breakthrough disease, our experience with these agents in cases of failure with standard first-line therapies is very, very limited. Sure, the differing mechanism of action offers a reasonable alternative option, but the expectation that the oral [medication] will be better than a failed injectable [medication] has not yet been proven,” she added.

Choosing the Right Oral Drug
Of the three oral MS agents currently available in the US, dimethyl fumarate has the most benign side effect profile, which consists mostly of short-term flushing and gastrointestinal complaints. Dimethyl fumarate could gain broad use as a first-line drug in newly diagnosed patients and as a second-line therapy in patients intolerant to other agents or in patients experiencing breakthrough disease.

It remains unclear whether any of the available oral agents is the best choice after natalizumab discontinuation. In several studies, patients who took fingolimod after natalizumab discontinuation had a high relapse rate. No data exist yet about the effects of the two newer agents under these circumstances, Dr. Kita said.

Upcoming Oral Agents
The investigational oral agent furthest along in the developmental pipeline is laquinimod, a quinolone-3-carboxamide small molecule for which two phase III clinical trials have been completed. The European Medicines Agency is reviewing the drug for marketing approval. Teva, the drug’s manufacturer, has not yet applied to the FDA for approval in the United States.

Several second-generation sphingosine-1-phosphate agonists are in development. They are believed to act more selectively, and thus to entail a lower risk of compromising the immune system, than fingolimod. These agents include siponimod, ponesimod, and ONO-4641.

—Bruce Jancin
IMNG Medical News

ORLANDO—Among patients with multiple sclerosis (MS), treatment with a disease-modifying therapy (DMT) may be associated with more rapid development of autoimmune disease than remaining untreated, according to data presented at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS. In addition, irritable bowel syndrome (IBS) may be more prevalent among patients with MS who receive a DMT than among untreated patients.

Lynn Chouhfeh, MD, medical resident at the University at Buffalo, New York, and colleagues analyzed data from the New York State MS Consortium (NYSMSC) longitudinal registry to investigate the type and prevalence of comorbid autoimmune diseases in patients with MS treated with various DMTs. Eligible patients had at least five years of follow-up and clinically definite MS according to McDonald criteria. Patients with unknown DMT use before enrollment were excluded, as were patients with an autoimmune disease at the time of entry into the registry.

Of the 2,047 eligible patients, 281 developed an autoimmune disease after DMT initiation, and 33 patients who were DMT naïve developed an autoimmune disease. Autoimmune diseases included Crohn’s disease, myasthenia gravis, IBS, psoriasis, and rheumatoid arthritis, among others. DMT types included interferon beta-1a, interferon beta-1b, glatiramer acetate, and natalizumab, among others.

Rheumatoid Arthritis Was More Common Among Untreated Patients
The researchers found no demographic differences between the treated and untreated patients with MS. Approximately 91% of untreated patients were female, compared with 85% of treated patients. Mean age at registration was approximately 61 for untreated patients and 52 for patients who later received a DMT.

Thyroid disease was the most common autoimmune disease in both groups. The mean time from MS symptom onset to first comorbid autoimmune disease was significantly shorter among patients who received DMTs (192 months) than among untreated patients (262 months). The effect remained after adjusting for covariates in logistic regression modeling.

IBS was more common in the group of DMT users, compared with patients who were treatment naïve. Rheumatoid arthritis, however, was more common among untreated patients than among patients who received a DMT.

“Identifying risk factors associated with the development of autoimmune disease in the context of DMT use merits further understanding,” said Dr. Chouhfeh. “Our study results may contribute to identifying more appropriate personalized therapeutic management decisions for MS patients.”

Comorbid Autoimmune Disease May Increase Odds of MS Progression
A related study presented at the same meeting suggested that having a comorbid autoimmune disease significantly increases the odds of disease progression among patients with MS. Among individuals with relapsing-remitting MS, about 22% of patients with comorbid autoimmune disease developed secondary progressive MS, compared with 18% of patients without comorbid autoimmune disease. After adjusting for confounders, the investigators found that patients with comorbid autoimmune disease were 1.4 times as likely to develop secondary progressive MS than patients without comorbid autoimmune disease.

Katelyn S. Kavak, research scientist at the University at Buffalo, and colleagues analyzed data from the NYSMSC registry for 3,292 subjects with clinically definite relapsing-remitting MS and at least one follow-up. Eight types of autoimmune disease were reported in the database, including thryroid, lupus, psoriasis, and rheumatoid arthritis. Participants were considered to have a comorbid autoimmune disease if they ever reported having one or more such diseases at study enrollment or at follow-up.

The researchers compared subjects who reported having an autoimmune disease with those who did not to determine the effects of autoimmune disease on MS progression. The team conducted logistic regression analysis and controlled for age at symptom onset, sex, Expanded Disability Status Scale (EDSS) score at enrollment, and DMT use.

Progression Was More Prevalent Among Patients Using DMT
Compared with patients without comorbid autoimmune disease, patients with comorbid autoimmune disease were older at MS symptom onset (33 vs 31) and more likely to be female (84% vs 75%). EDSS score at enrollment did not differ between the two groups, but it was higher at the most recent follow-up among patients with comorbid autoimmune disease than among subjects without.

The researchers found no difference in race, education, or DMT use between the groups. But after results were stratified by DMT use, progression was significantly more prevalent in subjects using DMT than among subjects who did not use DMT.

“The increased susceptibility patients with MS have to other autoimmune diseases might be due to the effects of DMT use, as others have reported an increased susceptibility to thyroid issues in patients with MS after interferon treatment,” said Ms. Kavak. “Causality cannot be assumed in this study, and it has to be considered that subjects with a comorbid autoimmune disease might be different from those without a comorbid autoimmune disease. Subjects with a more severe form of relapsing-remitting MS may have a higher prevalence of medication use, which may not necessarily stop disease progression, but might induce autoimmune disease,” she added. “It would be of interest to investigate whether treating the autoimmune disease comorbidity would improve MS disease course.”

—Erik Greb
Senior Associate Editor

ORLANDO—Among patients with multiple sclerosis (MS), treatment with a disease-modifying therapy (DMT) may be associated with more rapid development of autoimmune disease than remaining untreated, according to data presented at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS. In addition, irritable bowel syndrome (IBS) may be more prevalent among patients with MS who receive a DMT than among untreated patients.

Lynn Chouhfeh, MD, medical resident at the University at Buffalo, New York, and colleagues analyzed data from the New York State MS Consortium (NYSMSC) longitudinal registry to investigate the type and prevalence of comorbid autoimmune diseases in patients with MS treated with various DMTs. Eligible patients had at least five years of follow-up and clinically definite MS according to McDonald criteria. Patients with unknown DMT use before enrollment were excluded, as were patients with an autoimmune disease at the time of entry into the registry.

Of the 2,047 eligible patients, 281 developed an autoimmune disease after DMT initiation, and 33 patients who were DMT naïve developed an autoimmune disease. Autoimmune diseases included Crohn’s disease, myasthenia gravis, IBS, psoriasis, and rheumatoid arthritis, among others. DMT types included interferon beta-1a, interferon beta-1b, glatiramer acetate, and natalizumab, among others.

Rheumatoid Arthritis Was More Common Among Untreated Patients
The researchers found no demographic differences between the treated and untreated patients with MS. Approximately 91% of untreated patients were female, compared with 85% of treated patients. Mean age at registration was approximately 61 for untreated patients and 52 for patients who later received a DMT.

Thyroid disease was the most common autoimmune disease in both groups. The mean time from MS symptom onset to first comorbid autoimmune disease was significantly shorter among patients who received DMTs (192 months) than among untreated patients (262 months). The effect remained after adjusting for covariates in logistic regression modeling.

IBS was more common in the group of DMT users, compared with patients who were treatment naïve. Rheumatoid arthritis, however, was more common among untreated patients than among patients who received a DMT.

“Identifying risk factors associated with the development of autoimmune disease in the context of DMT use merits further understanding,” said Dr. Chouhfeh. “Our study results may contribute to identifying more appropriate personalized therapeutic management decisions for MS patients.”

Comorbid Autoimmune Disease May Increase Odds of MS Progression
A related study presented at the same meeting suggested that having a comorbid autoimmune disease significantly increases the odds of disease progression among patients with MS. Among individuals with relapsing-remitting MS, about 22% of patients with comorbid autoimmune disease developed secondary progressive MS, compared with 18% of patients without comorbid autoimmune disease. After adjusting for confounders, the investigators found that patients with comorbid autoimmune disease were 1.4 times as likely to develop secondary progressive MS than patients without comorbid autoimmune disease.

Katelyn S. Kavak, research scientist at the University at Buffalo, and colleagues analyzed data from the NYSMSC registry for 3,292 subjects with clinically definite relapsing-remitting MS and at least one follow-up. Eight types of autoimmune disease were reported in the database, including thryroid, lupus, psoriasis, and rheumatoid arthritis. Participants were considered to have a comorbid autoimmune disease if they ever reported having one or more such diseases at study enrollment or at follow-up.

The researchers compared subjects who reported having an autoimmune disease with those who did not to determine the effects of autoimmune disease on MS progression. The team conducted logistic regression analysis and controlled for age at symptom onset, sex, Expanded Disability Status Scale (EDSS) score at enrollment, and DMT use.

Progression Was More Prevalent Among Patients Using DMT
Compared with patients without comorbid autoimmune disease, patients with comorbid autoimmune disease were older at MS symptom onset (33 vs 31) and more likely to be female (84% vs 75%). EDSS score at enrollment did not differ between the two groups, but it was higher at the most recent follow-up among patients with comorbid autoimmune disease than among subjects without.

The researchers found no difference in race, education, or DMT use between the groups. But after results were stratified by DMT use, progression was significantly more prevalent in subjects using DMT than among subjects who did not use DMT.

“The increased susceptibility patients with MS have to other autoimmune diseases might be due to the effects of DMT use, as others have reported an increased susceptibility to thyroid issues in patients with MS after interferon treatment,” said Ms. Kavak. “Causality cannot be assumed in this study, and it has to be considered that subjects with a comorbid autoimmune disease might be different from those without a comorbid autoimmune disease. Subjects with a more severe form of relapsing-remitting MS may have a higher prevalence of medication use, which may not necessarily stop disease progression, but might induce autoimmune disease,” she added. “It would be of interest to investigate whether treating the autoimmune disease comorbidity would improve MS disease course.”

—Erik Greb
Senior Associate Editor

ORLANDO—Among patients with multiple sclerosis (MS), treatment with a disease-modifying therapy (DMT) may be associated with more rapid development of autoimmune disease than remaining untreated, according to data presented at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS. In addition, irritable bowel syndrome (IBS) may be more prevalent among patients with MS who receive a DMT than among untreated patients.

Lynn Chouhfeh, MD, medical resident at the University at Buffalo, New York, and colleagues analyzed data from the New York State MS Consortium (NYSMSC) longitudinal registry to investigate the type and prevalence of comorbid autoimmune diseases in patients with MS treated with various DMTs. Eligible patients had at least five years of follow-up and clinically definite MS according to McDonald criteria. Patients with unknown DMT use before enrollment were excluded, as were patients with an autoimmune disease at the time of entry into the registry.

Of the 2,047 eligible patients, 281 developed an autoimmune disease after DMT initiation, and 33 patients who were DMT naïve developed an autoimmune disease. Autoimmune diseases included Crohn’s disease, myasthenia gravis, IBS, psoriasis, and rheumatoid arthritis, among others. DMT types included interferon beta-1a, interferon beta-1b, glatiramer acetate, and natalizumab, among others.

Rheumatoid Arthritis Was More Common Among Untreated Patients
The researchers found no demographic differences between the treated and untreated patients with MS. Approximately 91% of untreated patients were female, compared with 85% of treated patients. Mean age at registration was approximately 61 for untreated patients and 52 for patients who later received a DMT.

Thyroid disease was the most common autoimmune disease in both groups. The mean time from MS symptom onset to first comorbid autoimmune disease was significantly shorter among patients who received DMTs (192 months) than among untreated patients (262 months). The effect remained after adjusting for covariates in logistic regression modeling.

IBS was more common in the group of DMT users, compared with patients who were treatment naïve. Rheumatoid arthritis, however, was more common among untreated patients than among patients who received a DMT.

“Identifying risk factors associated with the development of autoimmune disease in the context of DMT use merits further understanding,” said Dr. Chouhfeh. “Our study results may contribute to identifying more appropriate personalized therapeutic management decisions for MS patients.”

Comorbid Autoimmune Disease May Increase Odds of MS Progression
A related study presented at the same meeting suggested that having a comorbid autoimmune disease significantly increases the odds of disease progression among patients with MS. Among individuals with relapsing-remitting MS, about 22% of patients with comorbid autoimmune disease developed secondary progressive MS, compared with 18% of patients without comorbid autoimmune disease. After adjusting for confounders, the investigators found that patients with comorbid autoimmune disease were 1.4 times as likely to develop secondary progressive MS than patients without comorbid autoimmune disease.

Katelyn S. Kavak, research scientist at the University at Buffalo, and colleagues analyzed data from the NYSMSC registry for 3,292 subjects with clinically definite relapsing-remitting MS and at least one follow-up. Eight types of autoimmune disease were reported in the database, including thryroid, lupus, psoriasis, and rheumatoid arthritis. Participants were considered to have a comorbid autoimmune disease if they ever reported having one or more such diseases at study enrollment or at follow-up.

The researchers compared subjects who reported having an autoimmune disease with those who did not to determine the effects of autoimmune disease on MS progression. The team conducted logistic regression analysis and controlled for age at symptom onset, sex, Expanded Disability Status Scale (EDSS) score at enrollment, and DMT use.

Progression Was More Prevalent Among Patients Using DMT
Compared with patients without comorbid autoimmune disease, patients with comorbid autoimmune disease were older at MS symptom onset (33 vs 31) and more likely to be female (84% vs 75%). EDSS score at enrollment did not differ between the two groups, but it was higher at the most recent follow-up among patients with comorbid autoimmune disease than among subjects without.

The researchers found no difference in race, education, or DMT use between the groups. But after results were stratified by DMT use, progression was significantly more prevalent in subjects using DMT than among subjects who did not use DMT.

“The increased susceptibility patients with MS have to other autoimmune diseases might be due to the effects of DMT use, as others have reported an increased susceptibility to thyroid issues in patients with MS after interferon treatment,” said Ms. Kavak. “Causality cannot be assumed in this study, and it has to be considered that subjects with a comorbid autoimmune disease might be different from those without a comorbid autoimmune disease. Subjects with a more severe form of relapsing-remitting MS may have a higher prevalence of medication use, which may not necessarily stop disease progression, but might induce autoimmune disease,” she added. “It would be of interest to investigate whether treating the autoimmune disease comorbidity would improve MS disease course.”

—Erik Greb
Senior Associate Editor

ORLANDO—The first-dose cardiovascular effects of fingolimod 0.5 mg may be transient in most patients with multiple sclerosis (MS). The effects begin to resolve within six hours after administration, according to analyses of two phase III trials and interim results of a phase IV study.

The analyses, which were presented at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS, confirmed that the initiation of treatment with fingolimod is associated with a decrease in heart rate and a slowing of atrioventricular conduction, especially in the first four to six hours. Previously reported cases of bradycardia and atrioventricular block have been mostly transient and self-limited, said the investigators.

All patients who receive fingolimod “should be observed and receive hourly pulse and blood pressure measurement for at least six hours after first dose and undergo ECG predose and after the six-hour observation,” according to the drug’s current prescribing information. The label for fingolimod was revised in May 2012 following reports of sudden or unexplained deaths in the United States and Europe after the drug’s 2010 approval for relapsing forms of MS.

Fingolimod Reduced Heart Rate at Five Hours
In the phase IV EPOC (Evaluate Patient Outcomes, Safety, and Tolerability of Fingolimod) study, 783 patients in the United States and Canada were randomized 3:1 to open-label treatment with once-daily fingolimod 0.5 mg or standard-of-care disease-modifying therapy (DMT) for six months. No patients had taken fingolimod previously, and all received at least one dose of the therapy. Subjects had received continuous treatment with a single standard-of-care DMT for six months or more. Patients’ mean age was 46, and most were white (82%) and female (76%). The mean duration of their MS symptoms was 12 years.

Patients’ mean sitting heart rate decreased from 74.1 bpm at baseline to 65.6 bpm at five hours after administration of fingolimod, said Bruce L. Hughes, MD, Director of Ruan MS Center in Des Moines, Iowa, and his colleagues. Heart rate began to recover by the sixth hour.

Most patients (98.6%) were discharged at six hours after treatment. Ten subjects required extended observations after the sixth hour, and three required a second day of observation and were subsequently discharged.

Twelve patients (1.5%) had bradycardia during the first-dose observation period. Of these patients, eight were symptomatic, four were asymptomatic, and none required treatment, according to the researchers. The mean heart rate in this group decreased to 56.3 ± 8.53 bpm and ranged from 38 to 64 bpm during bradycardia events. The patients recovered to 62.6 ± 9.46 bpm, ranging from 52 to 80 bpm, after the symptoms resolved.

Nearly 18% of the patients (137 of 783) underwent ECG at six hours postdose. In 28 subjects, the second ECG differed from the baseline ECG, and the most common new findings were first-degree atrioventricular block (11 patients) and sinus bradycardia (10 patients). There were no second-degree atrioventricular blocks. Other findings included late anterior hemiblock (one patient), atrial premature complex (two patients), and biphasic T waves (one patient).

Heart-Rate Decrease Was Greater for Patients Without Cardiac Factors
The two other studies reported at the meeting also analyzed the first-dose cardiovascular effects of fingolimod 0.5 mg. The FIRST trial was a four-month, open-label, phase IIIb study of 2,417 patients with relapsing MS, and the FREEDOMS II trial was a two-year, double-blind, placebo-controlled, phase III study of 1,083 patients.

In the FIRST trial, the lowest heart rate occurred at four to five hours postdose. The mean decrease was 7.4 bpm in patients without cardiac factors and 6.5 bpm in those with cardiac factors, said the researchers. The cardiac factors included beta-blocker or calcium channel blocker use (120 patients), resting heart rate of 45 to 54 bpm, Mobitz type I second-degree atrioventricular block, positive tilt test, and recurrent symptomatic bradycardia.

Simrat Randhawa, MD, from Novartis Pharmaceuticals, and her colleagues reported that the mean decrease in heart rate was 7.2 and 7.3 bpm in patients without and with concomitant beta-blocker or calcium channel blocker use, respectively. One patient had a greater than three-second pause in screening and postdose ECG results. One patient discontinued the study drug because of second-degree atrioventricular block, the authors reported.

In the FREEDOMS II trial, the clinician-observed mean maximal decrease in heart rate was 8.5 bpm among patients who received fingolimod. The incidence of Mobitz I second-degree atrioventricular block with fingolimod was 3.7%, compared with 2.0% for placebo. In addition, 2:1 atrioventricular block occurred in 2% of patients taking fingolimod and in no control patients.

Most first-occurrence, second-degree atrioventricular blocks were observed less than six hours after the first dose, according to the researchers. No Mobitz II or third-degree atrioventricular blocks were reported in FIRST or FREEDOMS II.

It is difficult to identify which patients should receive fingolimod, but less difficult to identify patients who should not receive it, said Robert P. Lisak, MD, Professor of Neurology at Wayne State University in Detroit and President-Elect of CMSC. “But once they’re on it, and if they don’t have other contraindications, they should be OK.”

—Naseem S. Miller
IMNG Medical News

ORLANDO—The first-dose cardiovascular effects of fingolimod 0.5 mg may be transient in most patients with multiple sclerosis (MS). The effects begin to resolve within six hours after administration, according to analyses of two phase III trials and interim results of a phase IV study.

The analyses, which were presented at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS, confirmed that the initiation of treatment with fingolimod is associated with a decrease in heart rate and a slowing of atrioventricular conduction, especially in the first four to six hours. Previously reported cases of bradycardia and atrioventricular block have been mostly transient and self-limited, said the investigators.

All patients who receive fingolimod “should be observed and receive hourly pulse and blood pressure measurement for at least six hours after first dose and undergo ECG predose and after the six-hour observation,” according to the drug’s current prescribing information. The label for fingolimod was revised in May 2012 following reports of sudden or unexplained deaths in the United States and Europe after the drug’s 2010 approval for relapsing forms of MS.

Fingolimod Reduced Heart Rate at Five Hours
In the phase IV EPOC (Evaluate Patient Outcomes, Safety, and Tolerability of Fingolimod) study, 783 patients in the United States and Canada were randomized 3:1 to open-label treatment with once-daily fingolimod 0.5 mg or standard-of-care disease-modifying therapy (DMT) for six months. No patients had taken fingolimod previously, and all received at least one dose of the therapy. Subjects had received continuous treatment with a single standard-of-care DMT for six months or more. Patients’ mean age was 46, and most were white (82%) and female (76%). The mean duration of their MS symptoms was 12 years.

Patients’ mean sitting heart rate decreased from 74.1 bpm at baseline to 65.6 bpm at five hours after administration of fingolimod, said Bruce L. Hughes, MD, Director of Ruan MS Center in Des Moines, Iowa, and his colleagues. Heart rate began to recover by the sixth hour.

Most patients (98.6%) were discharged at six hours after treatment. Ten subjects required extended observations after the sixth hour, and three required a second day of observation and were subsequently discharged.

Twelve patients (1.5%) had bradycardia during the first-dose observation period. Of these patients, eight were symptomatic, four were asymptomatic, and none required treatment, according to the researchers. The mean heart rate in this group decreased to 56.3 ± 8.53 bpm and ranged from 38 to 64 bpm during bradycardia events. The patients recovered to 62.6 ± 9.46 bpm, ranging from 52 to 80 bpm, after the symptoms resolved.

Nearly 18% of the patients (137 of 783) underwent ECG at six hours postdose. In 28 subjects, the second ECG differed from the baseline ECG, and the most common new findings were first-degree atrioventricular block (11 patients) and sinus bradycardia (10 patients). There were no second-degree atrioventricular blocks. Other findings included late anterior hemiblock (one patient), atrial premature complex (two patients), and biphasic T waves (one patient).

Heart-Rate Decrease Was Greater for Patients Without Cardiac Factors
The two other studies reported at the meeting also analyzed the first-dose cardiovascular effects of fingolimod 0.5 mg. The FIRST trial was a four-month, open-label, phase IIIb study of 2,417 patients with relapsing MS, and the FREEDOMS II trial was a two-year, double-blind, placebo-controlled, phase III study of 1,083 patients.

In the FIRST trial, the lowest heart rate occurred at four to five hours postdose. The mean decrease was 7.4 bpm in patients without cardiac factors and 6.5 bpm in those with cardiac factors, said the researchers. The cardiac factors included beta-blocker or calcium channel blocker use (120 patients), resting heart rate of 45 to 54 bpm, Mobitz type I second-degree atrioventricular block, positive tilt test, and recurrent symptomatic bradycardia.

Simrat Randhawa, MD, from Novartis Pharmaceuticals, and her colleagues reported that the mean decrease in heart rate was 7.2 and 7.3 bpm in patients without and with concomitant beta-blocker or calcium channel blocker use, respectively. One patient had a greater than three-second pause in screening and postdose ECG results. One patient discontinued the study drug because of second-degree atrioventricular block, the authors reported.

In the FREEDOMS II trial, the clinician-observed mean maximal decrease in heart rate was 8.5 bpm among patients who received fingolimod. The incidence of Mobitz I second-degree atrioventricular block with fingolimod was 3.7%, compared with 2.0% for placebo. In addition, 2:1 atrioventricular block occurred in 2% of patients taking fingolimod and in no control patients.

Most first-occurrence, second-degree atrioventricular blocks were observed less than six hours after the first dose, according to the researchers. No Mobitz II or third-degree atrioventricular blocks were reported in FIRST or FREEDOMS II.

It is difficult to identify which patients should receive fingolimod, but less difficult to identify patients who should not receive it, said Robert P. Lisak, MD, Professor of Neurology at Wayne State University in Detroit and President-Elect of CMSC. “But once they’re on it, and if they don’t have other contraindications, they should be OK.”

—Naseem S. Miller
IMNG Medical News

ORLANDO—The first-dose cardiovascular effects of fingolimod 0.5 mg may be transient in most patients with multiple sclerosis (MS). The effects begin to resolve within six hours after administration, according to analyses of two phase III trials and interim results of a phase IV study.

The analyses, which were presented at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS, confirmed that the initiation of treatment with fingolimod is associated with a decrease in heart rate and a slowing of atrioventricular conduction, especially in the first four to six hours. Previously reported cases of bradycardia and atrioventricular block have been mostly transient and self-limited, said the investigators.

All patients who receive fingolimod “should be observed and receive hourly pulse and blood pressure measurement for at least six hours after first dose and undergo ECG predose and after the six-hour observation,” according to the drug’s current prescribing information. The label for fingolimod was revised in May 2012 following reports of sudden or unexplained deaths in the United States and Europe after the drug’s 2010 approval for relapsing forms of MS.

Fingolimod Reduced Heart Rate at Five Hours
In the phase IV EPOC (Evaluate Patient Outcomes, Safety, and Tolerability of Fingolimod) study, 783 patients in the United States and Canada were randomized 3:1 to open-label treatment with once-daily fingolimod 0.5 mg or standard-of-care disease-modifying therapy (DMT) for six months. No patients had taken fingolimod previously, and all received at least one dose of the therapy. Subjects had received continuous treatment with a single standard-of-care DMT for six months or more. Patients’ mean age was 46, and most were white (82%) and female (76%). The mean duration of their MS symptoms was 12 years.

Patients’ mean sitting heart rate decreased from 74.1 bpm at baseline to 65.6 bpm at five hours after administration of fingolimod, said Bruce L. Hughes, MD, Director of Ruan MS Center in Des Moines, Iowa, and his colleagues. Heart rate began to recover by the sixth hour.

Most patients (98.6%) were discharged at six hours after treatment. Ten subjects required extended observations after the sixth hour, and three required a second day of observation and were subsequently discharged.

Twelve patients (1.5%) had bradycardia during the first-dose observation period. Of these patients, eight were symptomatic, four were asymptomatic, and none required treatment, according to the researchers. The mean heart rate in this group decreased to 56.3 ± 8.53 bpm and ranged from 38 to 64 bpm during bradycardia events. The patients recovered to 62.6 ± 9.46 bpm, ranging from 52 to 80 bpm, after the symptoms resolved.

Nearly 18% of the patients (137 of 783) underwent ECG at six hours postdose. In 28 subjects, the second ECG differed from the baseline ECG, and the most common new findings were first-degree atrioventricular block (11 patients) and sinus bradycardia (10 patients). There were no second-degree atrioventricular blocks. Other findings included late anterior hemiblock (one patient), atrial premature complex (two patients), and biphasic T waves (one patient).

Heart-Rate Decrease Was Greater for Patients Without Cardiac Factors
The two other studies reported at the meeting also analyzed the first-dose cardiovascular effects of fingolimod 0.5 mg. The FIRST trial was a four-month, open-label, phase IIIb study of 2,417 patients with relapsing MS, and the FREEDOMS II trial was a two-year, double-blind, placebo-controlled, phase III study of 1,083 patients.

In the FIRST trial, the lowest heart rate occurred at four to five hours postdose. The mean decrease was 7.4 bpm in patients without cardiac factors and 6.5 bpm in those with cardiac factors, said the researchers. The cardiac factors included beta-blocker or calcium channel blocker use (120 patients), resting heart rate of 45 to 54 bpm, Mobitz type I second-degree atrioventricular block, positive tilt test, and recurrent symptomatic bradycardia.

Simrat Randhawa, MD, from Novartis Pharmaceuticals, and her colleagues reported that the mean decrease in heart rate was 7.2 and 7.3 bpm in patients without and with concomitant beta-blocker or calcium channel blocker use, respectively. One patient had a greater than three-second pause in screening and postdose ECG results. One patient discontinued the study drug because of second-degree atrioventricular block, the authors reported.

In the FREEDOMS II trial, the clinician-observed mean maximal decrease in heart rate was 8.5 bpm among patients who received fingolimod. The incidence of Mobitz I second-degree atrioventricular block with fingolimod was 3.7%, compared with 2.0% for placebo. In addition, 2:1 atrioventricular block occurred in 2% of patients taking fingolimod and in no control patients.

Most first-occurrence, second-degree atrioventricular blocks were observed less than six hours after the first dose, according to the researchers. No Mobitz II or third-degree atrioventricular blocks were reported in FIRST or FREEDOMS II.

It is difficult to identify which patients should receive fingolimod, but less difficult to identify patients who should not receive it, said Robert P. Lisak, MD, Professor of Neurology at Wayne State University in Detroit and President-Elect of CMSC. “But once they’re on it, and if they don’t have other contraindications, they should be OK.”

—Naseem S. Miller
IMNG Medical News

ORLANDO—The flushing frequently reported in conjunction with oral dimethyl fumarate therapy for relapsing forms of multiple sclerosis (MS) is greatly reduced by aspirin pretreatment, J. Theodore Phillips, MD, PhD, reported at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS.

In contrast, slowed titration of dimethyl fumarate does not diminish the gastrointestinal adverse effects, which are common during the first two months of therapy, noted Dr. Phillips, Research Investigator at the MS Research Program, Baylor Institute for Immunology Research in Dallas.

Dr. Phillips was part of a consensus panel that presented recommendations for maximizing the tolerability of dimethyl fumarate, which was approved earlier this year as the third oral agent for the treatment of MS.

In an interview, Dr. Phillips said that the recommendations are largely based on expert opinion rather than on rigorous, evidence-based guidelines. After the pivotal phase III DEFINE and CONFIRM clinical trials were completed, he and four other study leaders decided to ask the investigators who had enrolled at least 10 patients in the trials how they had managed flushing and gastrointestinal upset problems. The flushing and gastrointestinal side effects were reported by 36% and 42%, respectively, of study patients randomized to the drug. The incidence decreased after the first month. These side effects were generally rated by investigators as mild to moderate in nature. Flushing resulted in study dropout of 2.5% of patients, and 4.3% discontinued because of gastrointestinal adverse events.

Thirty of the 84 invited clinical investigators completed the questionnaire. Investigators at Biogen Idec conducted their own randomized, double-blind, phase IIIb study in 172 healthy volunteers, the results of which have been incorporated into the panel’s recommendations. Participants in the eight-week trial were randomized to one of four treatment arms: dimethyl fumarate titrated in standard fashion for one week plus 325 mg of non–enteric-coated aspirin taken 30 minutes beforehand during weeks 1 to 4, replaced by aspirin placebo in weeks 5 to 8; dimethyl fumarate plus aspirin placebo during weeks 1 to 4; dimethyl fumarate slow-titrated during the course of three weeks; and double placebo.

Roughly 80% of subjects who received dimethyl fumarate without aspirin experienced flushing events self-assessed as mild to moderate. Although participants were taking both dimethyl fumarate and aspirin, their flushing frequency and severity were similar to those of participants receiving double placebo. Slow titration of dimethyl fumarate had no impact on gastrointestinal symptoms or flushing frequency or severity.

The panel’s recommendations for managing nausea or vomiting or abdominal pain were to advise taking the drug with food and consider prescribing a proton pump inhibitor or H2 receptor antagonist. Metoclopramide or domperidone is another recommended option for those with nausea or vomiting. For patients who experience medication-related diarrhea, the panel advised loperamide or other standard antidiarrheal agents.

“Vasocutaneous flushing and gastrointestinal upset in association with dosing of [dimethyl fumarate] could for obvious reasons affect a person’s enthusiasm for going on,” Dr. Phillips commented. “The main thing is for the physician to set expectations by acknowledging up front these issues as part of the risk–benefit discussion prior to initiating the drug. Tell the patient that if those side effects were to happen, we’ve got game plans to deal with them.”

—Bruce Jancin
IMNG Medical News

ORLANDO—The flushing frequently reported in conjunction with oral dimethyl fumarate therapy for relapsing forms of multiple sclerosis (MS) is greatly reduced by aspirin pretreatment, J. Theodore Phillips, MD, PhD, reported at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS.

In contrast, slowed titration of dimethyl fumarate does not diminish the gastrointestinal adverse effects, which are common during the first two months of therapy, noted Dr. Phillips, Research Investigator at the MS Research Program, Baylor Institute for Immunology Research in Dallas.

Dr. Phillips was part of a consensus panel that presented recommendations for maximizing the tolerability of dimethyl fumarate, which was approved earlier this year as the third oral agent for the treatment of MS.

In an interview, Dr. Phillips said that the recommendations are largely based on expert opinion rather than on rigorous, evidence-based guidelines. After the pivotal phase III DEFINE and CONFIRM clinical trials were completed, he and four other study leaders decided to ask the investigators who had enrolled at least 10 patients in the trials how they had managed flushing and gastrointestinal upset problems. The flushing and gastrointestinal side effects were reported by 36% and 42%, respectively, of study patients randomized to the drug. The incidence decreased after the first month. These side effects were generally rated by investigators as mild to moderate in nature. Flushing resulted in study dropout of 2.5% of patients, and 4.3% discontinued because of gastrointestinal adverse events.

Thirty of the 84 invited clinical investigators completed the questionnaire. Investigators at Biogen Idec conducted their own randomized, double-blind, phase IIIb study in 172 healthy volunteers, the results of which have been incorporated into the panel’s recommendations. Participants in the eight-week trial were randomized to one of four treatment arms: dimethyl fumarate titrated in standard fashion for one week plus 325 mg of non–enteric-coated aspirin taken 30 minutes beforehand during weeks 1 to 4, replaced by aspirin placebo in weeks 5 to 8; dimethyl fumarate plus aspirin placebo during weeks 1 to 4; dimethyl fumarate slow-titrated during the course of three weeks; and double placebo.

Roughly 80% of subjects who received dimethyl fumarate without aspirin experienced flushing events self-assessed as mild to moderate. Although participants were taking both dimethyl fumarate and aspirin, their flushing frequency and severity were similar to those of participants receiving double placebo. Slow titration of dimethyl fumarate had no impact on gastrointestinal symptoms or flushing frequency or severity.

The panel’s recommendations for managing nausea or vomiting or abdominal pain were to advise taking the drug with food and consider prescribing a proton pump inhibitor or H2 receptor antagonist. Metoclopramide or domperidone is another recommended option for those with nausea or vomiting. For patients who experience medication-related diarrhea, the panel advised loperamide or other standard antidiarrheal agents.

“Vasocutaneous flushing and gastrointestinal upset in association with dosing of [dimethyl fumarate] could for obvious reasons affect a person’s enthusiasm for going on,” Dr. Phillips commented. “The main thing is for the physician to set expectations by acknowledging up front these issues as part of the risk–benefit discussion prior to initiating the drug. Tell the patient that if those side effects were to happen, we’ve got game plans to deal with them.”

—Bruce Jancin
IMNG Medical News

ORLANDO—The flushing frequently reported in conjunction with oral dimethyl fumarate therapy for relapsing forms of multiple sclerosis (MS) is greatly reduced by aspirin pretreatment, J. Theodore Phillips, MD, PhD, reported at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS.

In contrast, slowed titration of dimethyl fumarate does not diminish the gastrointestinal adverse effects, which are common during the first two months of therapy, noted Dr. Phillips, Research Investigator at the MS Research Program, Baylor Institute for Immunology Research in Dallas.

Dr. Phillips was part of a consensus panel that presented recommendations for maximizing the tolerability of dimethyl fumarate, which was approved earlier this year as the third oral agent for the treatment of MS.

In an interview, Dr. Phillips said that the recommendations are largely based on expert opinion rather than on rigorous, evidence-based guidelines. After the pivotal phase III DEFINE and CONFIRM clinical trials were completed, he and four other study leaders decided to ask the investigators who had enrolled at least 10 patients in the trials how they had managed flushing and gastrointestinal upset problems. The flushing and gastrointestinal side effects were reported by 36% and 42%, respectively, of study patients randomized to the drug. The incidence decreased after the first month. These side effects were generally rated by investigators as mild to moderate in nature. Flushing resulted in study dropout of 2.5% of patients, and 4.3% discontinued because of gastrointestinal adverse events.

Thirty of the 84 invited clinical investigators completed the questionnaire. Investigators at Biogen Idec conducted their own randomized, double-blind, phase IIIb study in 172 healthy volunteers, the results of which have been incorporated into the panel’s recommendations. Participants in the eight-week trial were randomized to one of four treatment arms: dimethyl fumarate titrated in standard fashion for one week plus 325 mg of non–enteric-coated aspirin taken 30 minutes beforehand during weeks 1 to 4, replaced by aspirin placebo in weeks 5 to 8; dimethyl fumarate plus aspirin placebo during weeks 1 to 4; dimethyl fumarate slow-titrated during the course of three weeks; and double placebo.

Roughly 80% of subjects who received dimethyl fumarate without aspirin experienced flushing events self-assessed as mild to moderate. Although participants were taking both dimethyl fumarate and aspirin, their flushing frequency and severity were similar to those of participants receiving double placebo. Slow titration of dimethyl fumarate had no impact on gastrointestinal symptoms or flushing frequency or severity.

The panel’s recommendations for managing nausea or vomiting or abdominal pain were to advise taking the drug with food and consider prescribing a proton pump inhibitor or H2 receptor antagonist. Metoclopramide or domperidone is another recommended option for those with nausea or vomiting. For patients who experience medication-related diarrhea, the panel advised loperamide or other standard antidiarrheal agents.

“Vasocutaneous flushing and gastrointestinal upset in association with dosing of [dimethyl fumarate] could for obvious reasons affect a person’s enthusiasm for going on,” Dr. Phillips commented. “The main thing is for the physician to set expectations by acknowledging up front these issues as part of the risk–benefit discussion prior to initiating the drug. Tell the patient that if those side effects were to happen, we’ve got game plans to deal with them.”

—Bruce Jancin
IMNG Medical News