Multiple Sclerosis

ORLANDO – Sepsis, pulmonary infections, aspiration, and ischemic heart disease accounted for the bulk of excess mortality seen in patients with multiple sclerosis, compared with the matched general population, in a large U.S. study.

"Increased awareness of these potentially fatal conditions for patients with MS can improve patient care by increasing physician vigilance and facilitating early intervention," Dr. Michael J. Corwin said at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Because MS is a chronic, progressive, incurable disease, the death certificates of MS patients often list MS as the underlying cause of death. Accepting that at face value would mean nearly two-thirds of excess mortality seen in the study was because of advanced MS, said Dr. Corwin. But with the use of a novel cause-of-death algorithm, he and his colleagues were able to identify key intermediate and potentially interruptible steps on the pathway from end-stage MS to death.

He presented a retrospective matched cohort study of 30,402 patients with MS and 89,818 matched non-MS comparators, all drawn from a large, national, U.S. commercial health-plan database. The mortality rate was doubled among the MS population: 5.2%, compared with 2.6% in controls. This translated to a death rate of 899 per 100,000 person-years in the MS group and 446 per 100,000 person-years in the control group, reported Dr. Corwin, an associate professor of pediatrics and epidemiology at Boston University’s Schools of Medicine and Public Health.

The study entailed detailed analysis of the death records of 1,579 MS patients and 2,332 matched controls. Because of the notorious lack of uniformity in the way death certificate data are recorded, it can be difficult to determine the immediate cause of death from these records, noted Dr. Corwin. Therefore, he and his coinvestigators developed the algorithm for doing so.

Specifically, the algorithm showed that infection accounted for 21% of the excess mortality in the MS population, cardiovascular disease 13%, and pulmonary disease 10%. Collectively, these three causes of death accounted for 44% of the excess mortality. Another 29% of the excess remained attributable to late-stage MS because of the lack of additional death record data that might have allowed a more specific categorization.

Delving more deeply into the principal causes of death, the investigators determined that sepsis was the No. 1 contributor to the excess mortality seen in the MS population. It accounted for 45 of the 453 excess deaths per 100,000 person-years. Sepsis was followed by pulmonary infection at 41, pulmonary aspiration at 27, and ischemic heart disease at 17.

The prominent role of pulmonary infections in contributing to excess mortality in patients with MS seen in this study confirms a finding from the 21-year follow-up of the landmark, multicenter, interferon beta-1b randomized treatment trial (BMJ Open 2012 Nov 30;2(6). pii: e001972 [doi: 10.1136/bmjopen-2012-001972]). Respiratory diseases were also the top cause of excess mortality found among MS patients in a recent, large, British, national population-based registry (Eur. J. Neurol. 2012;19:1007-14).

Dr. Corwin is a principal in Care-Safe, a consulting firm contracted by Bayer HealthCare Pharmaceuticals to conduct the U.S. study.

bjancin@frontlinemedcom.com

ORLANDO – Sepsis, pulmonary infections, aspiration, and ischemic heart disease accounted for the bulk of excess mortality seen in patients with multiple sclerosis, compared with the matched general population, in a large U.S. study.

"Increased awareness of these potentially fatal conditions for patients with MS can improve patient care by increasing physician vigilance and facilitating early intervention," Dr. Michael J. Corwin said at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Because MS is a chronic, progressive, incurable disease, the death certificates of MS patients often list MS as the underlying cause of death. Accepting that at face value would mean nearly two-thirds of excess mortality seen in the study was because of advanced MS, said Dr. Corwin. But with the use of a novel cause-of-death algorithm, he and his colleagues were able to identify key intermediate and potentially interruptible steps on the pathway from end-stage MS to death.

He presented a retrospective matched cohort study of 30,402 patients with MS and 89,818 matched non-MS comparators, all drawn from a large, national, U.S. commercial health-plan database. The mortality rate was doubled among the MS population: 5.2%, compared with 2.6% in controls. This translated to a death rate of 899 per 100,000 person-years in the MS group and 446 per 100,000 person-years in the control group, reported Dr. Corwin, an associate professor of pediatrics and epidemiology at Boston University’s Schools of Medicine and Public Health.

The study entailed detailed analysis of the death records of 1,579 MS patients and 2,332 matched controls. Because of the notorious lack of uniformity in the way death certificate data are recorded, it can be difficult to determine the immediate cause of death from these records, noted Dr. Corwin. Therefore, he and his coinvestigators developed the algorithm for doing so.

Specifically, the algorithm showed that infection accounted for 21% of the excess mortality in the MS population, cardiovascular disease 13%, and pulmonary disease 10%. Collectively, these three causes of death accounted for 44% of the excess mortality. Another 29% of the excess remained attributable to late-stage MS because of the lack of additional death record data that might have allowed a more specific categorization.

Delving more deeply into the principal causes of death, the investigators determined that sepsis was the No. 1 contributor to the excess mortality seen in the MS population. It accounted for 45 of the 453 excess deaths per 100,000 person-years. Sepsis was followed by pulmonary infection at 41, pulmonary aspiration at 27, and ischemic heart disease at 17.

The prominent role of pulmonary infections in contributing to excess mortality in patients with MS seen in this study confirms a finding from the 21-year follow-up of the landmark, multicenter, interferon beta-1b randomized treatment trial (BMJ Open 2012 Nov 30;2(6). pii: e001972 [doi: 10.1136/bmjopen-2012-001972]). Respiratory diseases were also the top cause of excess mortality found among MS patients in a recent, large, British, national population-based registry (Eur. J. Neurol. 2012;19:1007-14).

Dr. Corwin is a principal in Care-Safe, a consulting firm contracted by Bayer HealthCare Pharmaceuticals to conduct the U.S. study.

bjancin@frontlinemedcom.com

ORLANDO – Sepsis, pulmonary infections, aspiration, and ischemic heart disease accounted for the bulk of excess mortality seen in patients with multiple sclerosis, compared with the matched general population, in a large U.S. study.

"Increased awareness of these potentially fatal conditions for patients with MS can improve patient care by increasing physician vigilance and facilitating early intervention," Dr. Michael J. Corwin said at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Because MS is a chronic, progressive, incurable disease, the death certificates of MS patients often list MS as the underlying cause of death. Accepting that at face value would mean nearly two-thirds of excess mortality seen in the study was because of advanced MS, said Dr. Corwin. But with the use of a novel cause-of-death algorithm, he and his colleagues were able to identify key intermediate and potentially interruptible steps on the pathway from end-stage MS to death.

He presented a retrospective matched cohort study of 30,402 patients with MS and 89,818 matched non-MS comparators, all drawn from a large, national, U.S. commercial health-plan database. The mortality rate was doubled among the MS population: 5.2%, compared with 2.6% in controls. This translated to a death rate of 899 per 100,000 person-years in the MS group and 446 per 100,000 person-years in the control group, reported Dr. Corwin, an associate professor of pediatrics and epidemiology at Boston University’s Schools of Medicine and Public Health.

The study entailed detailed analysis of the death records of 1,579 MS patients and 2,332 matched controls. Because of the notorious lack of uniformity in the way death certificate data are recorded, it can be difficult to determine the immediate cause of death from these records, noted Dr. Corwin. Therefore, he and his coinvestigators developed the algorithm for doing so.

Specifically, the algorithm showed that infection accounted for 21% of the excess mortality in the MS population, cardiovascular disease 13%, and pulmonary disease 10%. Collectively, these three causes of death accounted for 44% of the excess mortality. Another 29% of the excess remained attributable to late-stage MS because of the lack of additional death record data that might have allowed a more specific categorization.

Delving more deeply into the principal causes of death, the investigators determined that sepsis was the No. 1 contributor to the excess mortality seen in the MS population. It accounted for 45 of the 453 excess deaths per 100,000 person-years. Sepsis was followed by pulmonary infection at 41, pulmonary aspiration at 27, and ischemic heart disease at 17.

The prominent role of pulmonary infections in contributing to excess mortality in patients with MS seen in this study confirms a finding from the 21-year follow-up of the landmark, multicenter, interferon beta-1b randomized treatment trial (BMJ Open 2012 Nov 30;2(6). pii: e001972 [doi: 10.1136/bmjopen-2012-001972]). Respiratory diseases were also the top cause of excess mortality found among MS patients in a recent, large, British, national population-based registry (Eur. J. Neurol. 2012;19:1007-14).

Dr. Corwin is a principal in Care-Safe, a consulting firm contracted by Bayer HealthCare Pharmaceuticals to conduct the U.S. study.

bjancin@frontlinemedcom.com

There has been much progress in multiple sclerosis research in the past decade. Researchers are now armed with more evidence that halting inflammation in the early stages of the disease can protect patients decades down the road. Dr. Stephen L. Hauser, chair of the department of neurology at the University of California, San Francisco, talks about the current state of MS research, the challenges, and the opportunities for progress.

There has been much progress in multiple sclerosis research in the past decade. Researchers are now armed with more evidence that halting inflammation in the early stages of the disease can protect patients decades down the road. Dr. Stephen L. Hauser, chair of the department of neurology at the University of California, San Francisco, talks about the current state of MS research, the challenges, and the opportunities for progress.

There has been much progress in multiple sclerosis research in the past decade. Researchers are now armed with more evidence that halting inflammation in the early stages of the disease can protect patients decades down the road. Dr. Stephen L. Hauser, chair of the department of neurology at the University of California, San Francisco, talks about the current state of MS research, the challenges, and the opportunities for progress.

ORLANDO – When neurologists select or switch medications for multiple sclerosis, they are most concerned with the drugs’ efficacy and patients’ relapse frequency, according to an online survey.

The survey, which included 63 neurologists and 39 multiple sclerosis specialists, also showed that the most commonly prescribed disease-modifying therapies were glatiramer acetate and subcutaneous and intramuscular interferon beta-1a.

The results of such a survey among physicians are "what you might expect," said Dr. Robert P. Lisak, professor of neurology at Wayne State University, Detroit, and president-elect of the Consortium of Multiple Sclerosis Centers (CMSC).

"I think you’ll see a lot of patients on those [drugs] in my own experience, because a lot of patients do very well on them, although there could be injection fatigue. But a lot of patients and physicians work on, ‘If it ain’t broke, don’t fix it.’ I think you’re going to see that people either get resistant, or finally get tired of the injection, and you’ll probably see an increasing shift towards the oral agents," he said. Meanwhile, insurance coverage and side effects are two issues to take into account, added Dr. Lisak, who was not involved with the survey.

So far, "little is known about how neurologists select available disease-modifying therapies (DMTs) for their patients," said Kristin A. Hanson, Pharm.D., of United BioSource, Dorval, Que., who presented her poster at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Dr. Hanson and colleagues sent out the online survey to members of a physician market research panel between December 2012 and January 2013.

All physicians, 81% of whom were male, lived in the United States and were treating at least 20 MS patients.

Respondents said that the most important medication attributes for patients starting their first DMT, in order, were efficacy, safety, tolerability, patient preference, and convenience.

Nearly 95% of the respondents said that they would switch medications if they observed an increase in relapse frequency. Other factors influencing the change in medication were worsening of MRI (75% of respondents) and worsening of disability (73%).

On average, 5.5% of the physicians’ patients were not on therapy for their condition, with individual physician reports ranging from 0% to 23% of patients not being on any therapy.

The study was supported by Novartis Pharmaceuticals. Dr. Hanson had no disclosures. Some of her coauthors are employees of Novartis, or have been speakers or advisors for Acorda, Avanir, Bayer, Genzyme/Sanofi, Novartis, Questcor, and Teva. Dr. Lisak has received research grants from and has been an advisor for several companies, including Avanir, Bayer, Novartis, Questcor, and Teva.

nmiller@frontlinemedcom.com

On Twitter @NaseemSMiller

ORLANDO – When neurologists select or switch medications for multiple sclerosis, they are most concerned with the drugs’ efficacy and patients’ relapse frequency, according to an online survey.

The survey, which included 63 neurologists and 39 multiple sclerosis specialists, also showed that the most commonly prescribed disease-modifying therapies were glatiramer acetate and subcutaneous and intramuscular interferon beta-1a.

The results of such a survey among physicians are "what you might expect," said Dr. Robert P. Lisak, professor of neurology at Wayne State University, Detroit, and president-elect of the Consortium of Multiple Sclerosis Centers (CMSC).

"I think you’ll see a lot of patients on those [drugs] in my own experience, because a lot of patients do very well on them, although there could be injection fatigue. But a lot of patients and physicians work on, ‘If it ain’t broke, don’t fix it.’ I think you’re going to see that people either get resistant, or finally get tired of the injection, and you’ll probably see an increasing shift towards the oral agents," he said. Meanwhile, insurance coverage and side effects are two issues to take into account, added Dr. Lisak, who was not involved with the survey.

So far, "little is known about how neurologists select available disease-modifying therapies (DMTs) for their patients," said Kristin A. Hanson, Pharm.D., of United BioSource, Dorval, Que., who presented her poster at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Dr. Hanson and colleagues sent out the online survey to members of a physician market research panel between December 2012 and January 2013.

All physicians, 81% of whom were male, lived in the United States and were treating at least 20 MS patients.

Respondents said that the most important medication attributes for patients starting their first DMT, in order, were efficacy, safety, tolerability, patient preference, and convenience.

Nearly 95% of the respondents said that they would switch medications if they observed an increase in relapse frequency. Other factors influencing the change in medication were worsening of MRI (75% of respondents) and worsening of disability (73%).

On average, 5.5% of the physicians’ patients were not on therapy for their condition, with individual physician reports ranging from 0% to 23% of patients not being on any therapy.

The study was supported by Novartis Pharmaceuticals. Dr. Hanson had no disclosures. Some of her coauthors are employees of Novartis, or have been speakers or advisors for Acorda, Avanir, Bayer, Genzyme/Sanofi, Novartis, Questcor, and Teva. Dr. Lisak has received research grants from and has been an advisor for several companies, including Avanir, Bayer, Novartis, Questcor, and Teva.

nmiller@frontlinemedcom.com

On Twitter @NaseemSMiller

ORLANDO – When neurologists select or switch medications for multiple sclerosis, they are most concerned with the drugs’ efficacy and patients’ relapse frequency, according to an online survey.

The survey, which included 63 neurologists and 39 multiple sclerosis specialists, also showed that the most commonly prescribed disease-modifying therapies were glatiramer acetate and subcutaneous and intramuscular interferon beta-1a.

The results of such a survey among physicians are "what you might expect," said Dr. Robert P. Lisak, professor of neurology at Wayne State University, Detroit, and president-elect of the Consortium of Multiple Sclerosis Centers (CMSC).

"I think you’ll see a lot of patients on those [drugs] in my own experience, because a lot of patients do very well on them, although there could be injection fatigue. But a lot of patients and physicians work on, ‘If it ain’t broke, don’t fix it.’ I think you’re going to see that people either get resistant, or finally get tired of the injection, and you’ll probably see an increasing shift towards the oral agents," he said. Meanwhile, insurance coverage and side effects are two issues to take into account, added Dr. Lisak, who was not involved with the survey.

So far, "little is known about how neurologists select available disease-modifying therapies (DMTs) for their patients," said Kristin A. Hanson, Pharm.D., of United BioSource, Dorval, Que., who presented her poster at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Dr. Hanson and colleagues sent out the online survey to members of a physician market research panel between December 2012 and January 2013.

All physicians, 81% of whom were male, lived in the United States and were treating at least 20 MS patients.

Respondents said that the most important medication attributes for patients starting their first DMT, in order, were efficacy, safety, tolerability, patient preference, and convenience.

Nearly 95% of the respondents said that they would switch medications if they observed an increase in relapse frequency. Other factors influencing the change in medication were worsening of MRI (75% of respondents) and worsening of disability (73%).

On average, 5.5% of the physicians’ patients were not on therapy for their condition, with individual physician reports ranging from 0% to 23% of patients not being on any therapy.

The study was supported by Novartis Pharmaceuticals. Dr. Hanson had no disclosures. Some of her coauthors are employees of Novartis, or have been speakers or advisors for Acorda, Avanir, Bayer, Genzyme/Sanofi, Novartis, Questcor, and Teva. Dr. Lisak has received research grants from and has been an advisor for several companies, including Avanir, Bayer, Novartis, Questcor, and Teva.

nmiller@frontlinemedcom.com

On Twitter @NaseemSMiller

SAN DIEGO – Fingolimod slows brain atrophy in patients with multiple sclerosis and is the only approved drug that does so within the first 6 months of treatment, according to Dr. Jeffrey Cohen of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio.

The findings come from a combined analysis of the drug’s three clinical trials: FREEDOMS (Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis) and FREEDOMS II, which pitted 0.5 mg and 1.25 mg daily against placebo for 2 years, and TRANSFORMS (FREEDOMS With Optional Extension Phase), which pitted those doses against weekly intramuscular interferon beta-1a (Avonex) for a year. Brain volumes were assessed by MRI SIENA (structural image evaluation, using normalization, of atrophy) at baseline and 6, 12, and 24 months. More than 3,000 patients 18-55 years old with clinically active relapsing-remitting MS participated.

"There was a consistent" 31%-36% reduction in the rate of brain volume loss with both doses of fingolimod (Gilenya) "as compared to placebo and interferon beta-1a. There was no clear-cut dose effect between the two" doses, said Dr. Cohen, the lead investigator and the director of the Mellen center’s experimental therapeutics program.

In the two trials with placebo arms, fingolimod patients had volume losses of about 0.85%, compared with 1.31% in placebo patients. In the remaining trial, brain volume loss was about 0.31% with fingolimod and about 0.45% with interferon beta-1a.

The "benefit was seen as early as 6 months, in both FREEDOMS and FREEDOMS II. In this analysis of the overall study cohort, there was no apparent early acceleration of brain volume loss, in other words, no pseudoatrophy," Dr. Cohen said at the annual meeting of the American Academy of Neurology.

Other approved MS therapies have shown either no significant effect on brain atrophy or a benefit only in the second year of treatment, as with natalizumab (Tysabri) and glatiramer acetate (Copaxone), he said.

The study investigators found that baseline brain atrophy correlated best with baseline T1 and T2 lesion volume, disability, age, and disease duration and severity. Both high baseline T2 lesion volume and active gadolinium-enhancing T1 lesions predicted brain volume loss during the trial. Volume loss in the study correlated best with worsening disability and increasing numbers of T2 lesions.

The drug seemed to protect brain volume in patients who got it, regardless of baseline characteristics.

There were weak correlations between accumulations of T2 lesions and disability during the study, perhaps because "brain volume and measures of disability don’t change much over 2 years," Dr. Cohen said.

Novartis, the maker of fingolimod, paid for the study. Dr. Cohen disclosed compensation or research support from Novartis, Biogen Idec, Genzyme, Lilly, Serono, and Teva.

aotto@frontlinemedcom.com

SAN DIEGO – Fingolimod slows brain atrophy in patients with multiple sclerosis and is the only approved drug that does so within the first 6 months of treatment, according to Dr. Jeffrey Cohen of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio.

The findings come from a combined analysis of the drug’s three clinical trials: FREEDOMS (Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis) and FREEDOMS II, which pitted 0.5 mg and 1.25 mg daily against placebo for 2 years, and TRANSFORMS (FREEDOMS With Optional Extension Phase), which pitted those doses against weekly intramuscular interferon beta-1a (Avonex) for a year. Brain volumes were assessed by MRI SIENA (structural image evaluation, using normalization, of atrophy) at baseline and 6, 12, and 24 months. More than 3,000 patients 18-55 years old with clinically active relapsing-remitting MS participated.

"There was a consistent" 31%-36% reduction in the rate of brain volume loss with both doses of fingolimod (Gilenya) "as compared to placebo and interferon beta-1a. There was no clear-cut dose effect between the two" doses, said Dr. Cohen, the lead investigator and the director of the Mellen center’s experimental therapeutics program.

In the two trials with placebo arms, fingolimod patients had volume losses of about 0.85%, compared with 1.31% in placebo patients. In the remaining trial, brain volume loss was about 0.31% with fingolimod and about 0.45% with interferon beta-1a.

The "benefit was seen as early as 6 months, in both FREEDOMS and FREEDOMS II. In this analysis of the overall study cohort, there was no apparent early acceleration of brain volume loss, in other words, no pseudoatrophy," Dr. Cohen said at the annual meeting of the American Academy of Neurology.

Other approved MS therapies have shown either no significant effect on brain atrophy or a benefit only in the second year of treatment, as with natalizumab (Tysabri) and glatiramer acetate (Copaxone), he said.

The study investigators found that baseline brain atrophy correlated best with baseline T1 and T2 lesion volume, disability, age, and disease duration and severity. Both high baseline T2 lesion volume and active gadolinium-enhancing T1 lesions predicted brain volume loss during the trial. Volume loss in the study correlated best with worsening disability and increasing numbers of T2 lesions.

The drug seemed to protect brain volume in patients who got it, regardless of baseline characteristics.

There were weak correlations between accumulations of T2 lesions and disability during the study, perhaps because "brain volume and measures of disability don’t change much over 2 years," Dr. Cohen said.

Novartis, the maker of fingolimod, paid for the study. Dr. Cohen disclosed compensation or research support from Novartis, Biogen Idec, Genzyme, Lilly, Serono, and Teva.

aotto@frontlinemedcom.com

SAN DIEGO – Fingolimod slows brain atrophy in patients with multiple sclerosis and is the only approved drug that does so within the first 6 months of treatment, according to Dr. Jeffrey Cohen of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio.

The findings come from a combined analysis of the drug’s three clinical trials: FREEDOMS (Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis) and FREEDOMS II, which pitted 0.5 mg and 1.25 mg daily against placebo for 2 years, and TRANSFORMS (FREEDOMS With Optional Extension Phase), which pitted those doses against weekly intramuscular interferon beta-1a (Avonex) for a year. Brain volumes were assessed by MRI SIENA (structural image evaluation, using normalization, of atrophy) at baseline and 6, 12, and 24 months. More than 3,000 patients 18-55 years old with clinically active relapsing-remitting MS participated.

"There was a consistent" 31%-36% reduction in the rate of brain volume loss with both doses of fingolimod (Gilenya) "as compared to placebo and interferon beta-1a. There was no clear-cut dose effect between the two" doses, said Dr. Cohen, the lead investigator and the director of the Mellen center’s experimental therapeutics program.

In the two trials with placebo arms, fingolimod patients had volume losses of about 0.85%, compared with 1.31% in placebo patients. In the remaining trial, brain volume loss was about 0.31% with fingolimod and about 0.45% with interferon beta-1a.

The "benefit was seen as early as 6 months, in both FREEDOMS and FREEDOMS II. In this analysis of the overall study cohort, there was no apparent early acceleration of brain volume loss, in other words, no pseudoatrophy," Dr. Cohen said at the annual meeting of the American Academy of Neurology.

Other approved MS therapies have shown either no significant effect on brain atrophy or a benefit only in the second year of treatment, as with natalizumab (Tysabri) and glatiramer acetate (Copaxone), he said.

The study investigators found that baseline brain atrophy correlated best with baseline T1 and T2 lesion volume, disability, age, and disease duration and severity. Both high baseline T2 lesion volume and active gadolinium-enhancing T1 lesions predicted brain volume loss during the trial. Volume loss in the study correlated best with worsening disability and increasing numbers of T2 lesions.

The drug seemed to protect brain volume in patients who got it, regardless of baseline characteristics.

There were weak correlations between accumulations of T2 lesions and disability during the study, perhaps because "brain volume and measures of disability don’t change much over 2 years," Dr. Cohen said.

Novartis, the maker of fingolimod, paid for the study. Dr. Cohen disclosed compensation or research support from Novartis, Biogen Idec, Genzyme, Lilly, Serono, and Teva.

aotto@frontlinemedcom.com

SAN DIEGO – A new adverse event may be emerging for dalfampridine – trigeminal neuralgia in multiple sclerosis patients with a preexisting trigeminal injury, or worsening of the condition in those who already have it, according to Dr. Gary Birnbaum, director of the Multiple Sclerosis Treatment and Research Center at the Minneapolis Clinic of Neurology.

Within a month of starting the drug at his clinic, three women with well-controlled trigeminal neuralgia "had very significant increases in the severity of their trigeminal pain," he said.

Stopping the drug brought some temporary relief to two, but they soon relapsed and their pain is now "very, very difficult to control," requiring substantially higher pain medication doses than before, he said.

In the third woman, the pain continued despite stopping the drug and no longer responded to pain medication. It was so severe that she contemplated suicide; she eventually had a trigeminal rhizotomy.

They had "very, very severe pain after" starting dalfampridine (Ampyra), "and it didn’t get better" when it was stopped. "That is what’s disquieting about it," Dr. Birnbaum said at the American Academy of Neurology (AAN) annual meeting.

A fourth patient developed trigeminal neuralgia after 18 months on the drug; the side of his face had only been numb previously. He now requires pain medications for the condition. Brain MRIs of all four patients were stable.

"Irreversible injury [appears] to have occurred in our three patients, and perhaps even in the fourth. Dalfampridine needs to be used with caution in multiple sclerosis patients with preexisting trigeminal neuralgia as well as in those with evidence of preexisting trigeminal nerve injuries," Dr. Birnbaum said.

When prescribing the drug, "I have to tell [patients] now that there’s a possibility that their trigeminal neuralgia may get worse, and it may not get better if they stop [the drug]. They have to take that into consideration," he said in an interview.

The four cases are not the first to be reported since the potassium channel blocker was approved for MS in 2010 to improve walking.

Investigators from the Mayo Clinic in Scottsdale, Ariz., reported two cases at AAN’s 2012 annual conference, both within a month of starting the drug and both in patients whose trigeminal neuralgia had been in remission. One patient responded to pain medications, the other needed a rhizotomy.

"As I talk to [physicians] about these data," people come up and say, "I’ve seen the same thing," Dr. Birnbaum said.

Dalfampridine improves action potential conduction in demyelinated axons. Perhaps when sensory nerves – such as the trigeminal – have a preexisting injury, that effect can lead to a type of "metabolic exhaustion" that makes the injury worse.

"Could there be a similar phenomenon with motor nerves? Perhaps one sees an initial improvement in motor function, but in the long term could this perhaps be deleterious? I have no data to support that, but the implication is that [it’s] a possibility," he said.

Dr. Birnbaum is a paid consultant to TEVA, Serono, Genzyme, Questcor, and Biogen Idec. Biogen Idec and Hoffman-LaRoche have both supported his research.

aotto@frontlinemedcom.com

SAN DIEGO – A new adverse event may be emerging for dalfampridine – trigeminal neuralgia in multiple sclerosis patients with a preexisting trigeminal injury, or worsening of the condition in those who already have it, according to Dr. Gary Birnbaum, director of the Multiple Sclerosis Treatment and Research Center at the Minneapolis Clinic of Neurology.

Within a month of starting the drug at his clinic, three women with well-controlled trigeminal neuralgia "had very significant increases in the severity of their trigeminal pain," he said.

Stopping the drug brought some temporary relief to two, but they soon relapsed and their pain is now "very, very difficult to control," requiring substantially higher pain medication doses than before, he said.

In the third woman, the pain continued despite stopping the drug and no longer responded to pain medication. It was so severe that she contemplated suicide; she eventually had a trigeminal rhizotomy.

They had "very, very severe pain after" starting dalfampridine (Ampyra), "and it didn’t get better" when it was stopped. "That is what’s disquieting about it," Dr. Birnbaum said at the American Academy of Neurology (AAN) annual meeting.

A fourth patient developed trigeminal neuralgia after 18 months on the drug; the side of his face had only been numb previously. He now requires pain medications for the condition. Brain MRIs of all four patients were stable.

"Irreversible injury [appears] to have occurred in our three patients, and perhaps even in the fourth. Dalfampridine needs to be used with caution in multiple sclerosis patients with preexisting trigeminal neuralgia as well as in those with evidence of preexisting trigeminal nerve injuries," Dr. Birnbaum said.

When prescribing the drug, "I have to tell [patients] now that there’s a possibility that their trigeminal neuralgia may get worse, and it may not get better if they stop [the drug]. They have to take that into consideration," he said in an interview.

The four cases are not the first to be reported since the potassium channel blocker was approved for MS in 2010 to improve walking.

Investigators from the Mayo Clinic in Scottsdale, Ariz., reported two cases at AAN’s 2012 annual conference, both within a month of starting the drug and both in patients whose trigeminal neuralgia had been in remission. One patient responded to pain medications, the other needed a rhizotomy.

"As I talk to [physicians] about these data," people come up and say, "I’ve seen the same thing," Dr. Birnbaum said.

Dalfampridine improves action potential conduction in demyelinated axons. Perhaps when sensory nerves – such as the trigeminal – have a preexisting injury, that effect can lead to a type of "metabolic exhaustion" that makes the injury worse.

"Could there be a similar phenomenon with motor nerves? Perhaps one sees an initial improvement in motor function, but in the long term could this perhaps be deleterious? I have no data to support that, but the implication is that [it’s] a possibility," he said.

Dr. Birnbaum is a paid consultant to TEVA, Serono, Genzyme, Questcor, and Biogen Idec. Biogen Idec and Hoffman-LaRoche have both supported his research.

aotto@frontlinemedcom.com

SAN DIEGO – A new adverse event may be emerging for dalfampridine – trigeminal neuralgia in multiple sclerosis patients with a preexisting trigeminal injury, or worsening of the condition in those who already have it, according to Dr. Gary Birnbaum, director of the Multiple Sclerosis Treatment and Research Center at the Minneapolis Clinic of Neurology.

Within a month of starting the drug at his clinic, three women with well-controlled trigeminal neuralgia "had very significant increases in the severity of their trigeminal pain," he said.

Stopping the drug brought some temporary relief to two, but they soon relapsed and their pain is now "very, very difficult to control," requiring substantially higher pain medication doses than before, he said.

In the third woman, the pain continued despite stopping the drug and no longer responded to pain medication. It was so severe that she contemplated suicide; she eventually had a trigeminal rhizotomy.

They had "very, very severe pain after" starting dalfampridine (Ampyra), "and it didn’t get better" when it was stopped. "That is what’s disquieting about it," Dr. Birnbaum said at the American Academy of Neurology (AAN) annual meeting.

A fourth patient developed trigeminal neuralgia after 18 months on the drug; the side of his face had only been numb previously. He now requires pain medications for the condition. Brain MRIs of all four patients were stable.

"Irreversible injury [appears] to have occurred in our three patients, and perhaps even in the fourth. Dalfampridine needs to be used with caution in multiple sclerosis patients with preexisting trigeminal neuralgia as well as in those with evidence of preexisting trigeminal nerve injuries," Dr. Birnbaum said.

When prescribing the drug, "I have to tell [patients] now that there’s a possibility that their trigeminal neuralgia may get worse, and it may not get better if they stop [the drug]. They have to take that into consideration," he said in an interview.

The four cases are not the first to be reported since the potassium channel blocker was approved for MS in 2010 to improve walking.

Investigators from the Mayo Clinic in Scottsdale, Ariz., reported two cases at AAN’s 2012 annual conference, both within a month of starting the drug and both in patients whose trigeminal neuralgia had been in remission. One patient responded to pain medications, the other needed a rhizotomy.

"As I talk to [physicians] about these data," people come up and say, "I’ve seen the same thing," Dr. Birnbaum said.

Dalfampridine improves action potential conduction in demyelinated axons. Perhaps when sensory nerves – such as the trigeminal – have a preexisting injury, that effect can lead to a type of "metabolic exhaustion" that makes the injury worse.

"Could there be a similar phenomenon with motor nerves? Perhaps one sees an initial improvement in motor function, but in the long term could this perhaps be deleterious? I have no data to support that, but the implication is that [it’s] a possibility," he said.

Dr. Birnbaum is a paid consultant to TEVA, Serono, Genzyme, Questcor, and Biogen Idec. Biogen Idec and Hoffman-LaRoche have both supported his research.

aotto@frontlinemedcom.com

SAN DIEGO – Thinner multiple sclerosis patients may be at higher risk for natalizumab-induced progressive multifocal leukoencephalopathy, according to researchers from the Rocky Mountain Multiple Sclerosis Research Group in Salt Lake City.

The risk may derive from the drug’s higher mean plasma concentrations and the greater saturation of lymphocyte receptors in such patients, lead investigator Dr. John Foley suggested.

He and his team reviewed 38 natalizumab (Tysabri)-induced progressive multifocal leukoencephalopathy (PML) cases – 11.5% of the current global total – and found that 24 of the patients were 70 kg or less and 29 were 80 kg or less. The median weight of the PML patients was 64 kg, substantially lower than the weight of the average MS patient, at least at the Rocky Mountain clinic.

At 60 kg or less, "there is a striking elevation in PML cases. [The] incidence definitely trends towards patients with lower body weights," said Dr. Foley, founder of the clinic.

To further explore the issue, his team also analyzed clinical data from 301 of its own natalizumab patients, plus data from 826 patients in the Swedish Natalizumab Registry, 799 patients from phase III trials, and patients from other sources.

In doing so, they also found that patients weighing less than 75 kg tend to develop higher plasma concentrations of the monoclonal antibody over time and are more likely to saturate 95% or more of the lymphocyte receptors that natalizumab targets, exceeding the saturation goal of about 85%.

Patients who weighed no more than 70 kg had mean plasma concentrations of about 45 mcg/mL, whereas those over 150 kg had a mean level of less than 10 mcg/mL. Meanwhile, saturations appeared to escalate with concentration per patient-kilogram in a linear fashion from a mean of 85%-95%. "When you look at 95%-plus saturators, you see stratification into this real high-concentration and low-weight group," Dr. Foley said at the annual meeting of the American Academy of Neurology.

The findings led him to theorize that thinner patients are more at risk for PML because the higher saturations they develop block not only myelin-destroying lymphocytes from entering the central nervous system, as intended, but also lymphocytes that fight the JC virus, the cause of PML in those who carry it.

"We think there’s a link between serum concentration and saturation of lymphocytes in general, and that excessive saturation leads to near-complete stoppage of [lymphocyte] trafficking from blood vessels into brain parenchyma." Perhaps "we reach a threshold where we not only impede the cells that are programmed to cause MS, but also the trafficking of the cells that are programmed to kill viruses. We need to figure out what the optimal balance is," he said in an interview.

For now, "how we are approaching this is [by] dose-extending high-risk, JC virus antibody–positive populations out to 5-6 weeks, instead of dosing every 4 weeks," as the natalizumab label indicates. It "reduces concentrations in the last few weeks, and saturations decline. It may well be a viable approach for PML risk reduction," Dr. Foley said.

At the Rocky Mountain clinic, 14 patients who took natalizumab every 6 weeks had mean concentrations of 18.7 mcg/mL and saturations of 83.5%, whereas a group of about 160 patients on a 4-week dosing schedule had mean concentrations of 33.6 mcg/mL and saturations of 89.3%.

"You really want to avoid these high-concentration, high-saturation environments," he said.

The work was funded by the maker of natalizumab, Biogen Idec, and its distributor, Elan Pharmaceuticals. Dr. Foley is a scientific adviser to and a speaker for Biogen.

aotto@frontlinemedcom.com

SAN DIEGO – Thinner multiple sclerosis patients may be at higher risk for natalizumab-induced progressive multifocal leukoencephalopathy, according to researchers from the Rocky Mountain Multiple Sclerosis Research Group in Salt Lake City.

The risk may derive from the drug’s higher mean plasma concentrations and the greater saturation of lymphocyte receptors in such patients, lead investigator Dr. John Foley suggested.

He and his team reviewed 38 natalizumab (Tysabri)-induced progressive multifocal leukoencephalopathy (PML) cases – 11.5% of the current global total – and found that 24 of the patients were 70 kg or less and 29 were 80 kg or less. The median weight of the PML patients was 64 kg, substantially lower than the weight of the average MS patient, at least at the Rocky Mountain clinic.

At 60 kg or less, "there is a striking elevation in PML cases. [The] incidence definitely trends towards patients with lower body weights," said Dr. Foley, founder of the clinic.

To further explore the issue, his team also analyzed clinical data from 301 of its own natalizumab patients, plus data from 826 patients in the Swedish Natalizumab Registry, 799 patients from phase III trials, and patients from other sources.

In doing so, they also found that patients weighing less than 75 kg tend to develop higher plasma concentrations of the monoclonal antibody over time and are more likely to saturate 95% or more of the lymphocyte receptors that natalizumab targets, exceeding the saturation goal of about 85%.

Patients who weighed no more than 70 kg had mean plasma concentrations of about 45 mcg/mL, whereas those over 150 kg had a mean level of less than 10 mcg/mL. Meanwhile, saturations appeared to escalate with concentration per patient-kilogram in a linear fashion from a mean of 85%-95%. "When you look at 95%-plus saturators, you see stratification into this real high-concentration and low-weight group," Dr. Foley said at the annual meeting of the American Academy of Neurology.

The findings led him to theorize that thinner patients are more at risk for PML because the higher saturations they develop block not only myelin-destroying lymphocytes from entering the central nervous system, as intended, but also lymphocytes that fight the JC virus, the cause of PML in those who carry it.

"We think there’s a link between serum concentration and saturation of lymphocytes in general, and that excessive saturation leads to near-complete stoppage of [lymphocyte] trafficking from blood vessels into brain parenchyma." Perhaps "we reach a threshold where we not only impede the cells that are programmed to cause MS, but also the trafficking of the cells that are programmed to kill viruses. We need to figure out what the optimal balance is," he said in an interview.

For now, "how we are approaching this is [by] dose-extending high-risk, JC virus antibody–positive populations out to 5-6 weeks, instead of dosing every 4 weeks," as the natalizumab label indicates. It "reduces concentrations in the last few weeks, and saturations decline. It may well be a viable approach for PML risk reduction," Dr. Foley said.

At the Rocky Mountain clinic, 14 patients who took natalizumab every 6 weeks had mean concentrations of 18.7 mcg/mL and saturations of 83.5%, whereas a group of about 160 patients on a 4-week dosing schedule had mean concentrations of 33.6 mcg/mL and saturations of 89.3%.

"You really want to avoid these high-concentration, high-saturation environments," he said.

The work was funded by the maker of natalizumab, Biogen Idec, and its distributor, Elan Pharmaceuticals. Dr. Foley is a scientific adviser to and a speaker for Biogen.

aotto@frontlinemedcom.com

SAN DIEGO – Thinner multiple sclerosis patients may be at higher risk for natalizumab-induced progressive multifocal leukoencephalopathy, according to researchers from the Rocky Mountain Multiple Sclerosis Research Group in Salt Lake City.

The risk may derive from the drug’s higher mean plasma concentrations and the greater saturation of lymphocyte receptors in such patients, lead investigator Dr. John Foley suggested.

He and his team reviewed 38 natalizumab (Tysabri)-induced progressive multifocal leukoencephalopathy (PML) cases – 11.5% of the current global total – and found that 24 of the patients were 70 kg or less and 29 were 80 kg or less. The median weight of the PML patients was 64 kg, substantially lower than the weight of the average MS patient, at least at the Rocky Mountain clinic.

At 60 kg or less, "there is a striking elevation in PML cases. [The] incidence definitely trends towards patients with lower body weights," said Dr. Foley, founder of the clinic.

To further explore the issue, his team also analyzed clinical data from 301 of its own natalizumab patients, plus data from 826 patients in the Swedish Natalizumab Registry, 799 patients from phase III trials, and patients from other sources.

In doing so, they also found that patients weighing less than 75 kg tend to develop higher plasma concentrations of the monoclonal antibody over time and are more likely to saturate 95% or more of the lymphocyte receptors that natalizumab targets, exceeding the saturation goal of about 85%.

Patients who weighed no more than 70 kg had mean plasma concentrations of about 45 mcg/mL, whereas those over 150 kg had a mean level of less than 10 mcg/mL. Meanwhile, saturations appeared to escalate with concentration per patient-kilogram in a linear fashion from a mean of 85%-95%. "When you look at 95%-plus saturators, you see stratification into this real high-concentration and low-weight group," Dr. Foley said at the annual meeting of the American Academy of Neurology.

The findings led him to theorize that thinner patients are more at risk for PML because the higher saturations they develop block not only myelin-destroying lymphocytes from entering the central nervous system, as intended, but also lymphocytes that fight the JC virus, the cause of PML in those who carry it.

"We think there’s a link between serum concentration and saturation of lymphocytes in general, and that excessive saturation leads to near-complete stoppage of [lymphocyte] trafficking from blood vessels into brain parenchyma." Perhaps "we reach a threshold where we not only impede the cells that are programmed to cause MS, but also the trafficking of the cells that are programmed to kill viruses. We need to figure out what the optimal balance is," he said in an interview.

For now, "how we are approaching this is [by] dose-extending high-risk, JC virus antibody–positive populations out to 5-6 weeks, instead of dosing every 4 weeks," as the natalizumab label indicates. It "reduces concentrations in the last few weeks, and saturations decline. It may well be a viable approach for PML risk reduction," Dr. Foley said.

At the Rocky Mountain clinic, 14 patients who took natalizumab every 6 weeks had mean concentrations of 18.7 mcg/mL and saturations of 83.5%, whereas a group of about 160 patients on a 4-week dosing schedule had mean concentrations of 33.6 mcg/mL and saturations of 89.3%.

"You really want to avoid these high-concentration, high-saturation environments," he said.

The work was funded by the maker of natalizumab, Biogen Idec, and its distributor, Elan Pharmaceuticals. Dr. Foley is a scientific adviser to and a speaker for Biogen.

aotto@frontlinemedcom.com

Use of all glucocorticoids is associated with a two- to threefold increased risk of venous thromboembolism, depending on the type of glucocorticoid, the route of administration, and other factors, according to a report published online April 1 in JAMA Internal Medicine.

Systemic glucocorticoids, as compared with inhaled ones or glucocorticoids that act on the intestines, were associated with the highest risk of VTE. New use was linked to higher risk than continuing or past use, and the VTE risk increased as the dose of glucocorticoids increased, said Sigrun A. Johannesdottir of the department of clinical epidemiology, Aarhus (the Netherlands) University Hospital, and her associates.

These findings are from a population-based case-control study, which cannot prove a cause-and-effect relationship. Moreover, it is difficult to statistically account for all the confounding effects of patients’ underlying disease – the reason they were taking glucocorticoids in the first place – because such disorders raise the risk of VTE directly or cause immobility that in turn can lead to VTE.

However, the timing of this adverse effect, the strength of the association across all types of glucocorticoids, and the fact that the association persisted after the data were adjusted to account for multiple confounders all "increase our confidence that the results reflect a true biological effect," the investigators said.

"Clinicians should be aware of this association," they noted.

Ms. Johannesdottir and her colleagues used data from several Danish national medical registries to identify all adults who were diagnosed with VTE in Denmark in 2005-2012, all patients who filled prescriptions for glucocorticoids during the study period, and all indications for the drugs as well as all relevant comorbidities. They matched 10 control subjects for age and sex from the general population to each study subject.

A total of 38,765 VTE cases and 387,650 controls were included in this study. The median age was 67 years, and slightly more than half of those studied were women.

All glucocorticoid users were found to be at increased risk for VTE, particularly for pulmonary embolism, compared with nonusers, the researchers said.

Systemic glucocorticoids, including betamethasone, methylprednisolone, prednisolone, prednisone, triamcinolone, and hydrocortisone, raised VTE risk to the highest degree. (No patients filled prescriptions for dexamethasone in this study.)

Inhaled corticosteroids and corticosteroids that act on the intestines also raised VTE risk significantly. Among the systemic glucocorticoids, prednisolone and prednisone raised VTE risk the most.

New use of glucocorticoids was associated with the highest risk of VTE, but current use, continuing use, and former use also raised the risk significantly. Oral formulations were associated with the highest risk of VTE, but injectable formulations also raised the risk significantly, Ms. Johannesdottir and her associates reported (JAMA Intern. Med. 2013 April 1 [doi:10.1001/jamainternmed.2013.122]).

In particular, new use of systemic glucocorticoids was associated with the highest risk for VTE, with an estimated incidence rate ratio of 3.06, compared with nonuse of glucocorticoids.

The risk of VTE also rose with increasing cumulative doses of all glucocorticoids.

In further analyses, elevated risk for VTE persisted across all the subgroups that were examined.

The findings did not change appreciably in a sensitivity analysis that included only subjects who took glucocorticoids for at least 5 years.

"The temporality of the association (i.e., the strongest effect at initiation of therapy and the absence of an effect after discontinuation) is in line with an effect on coagulation," Ms. Johannesdottir and her associates said.

This study was supported by the Clinical Epidemiological Research Foundation at Aarhus University Hospital. No relevant conflicts of interest were reported.

Use of all glucocorticoids is associated with a two- to threefold increased risk of venous thromboembolism, depending on the type of glucocorticoid, the route of administration, and other factors, according to a report published online April 1 in JAMA Internal Medicine.

Systemic glucocorticoids, as compared with inhaled ones or glucocorticoids that act on the intestines, were associated with the highest risk of VTE. New use was linked to higher risk than continuing or past use, and the VTE risk increased as the dose of glucocorticoids increased, said Sigrun A. Johannesdottir of the department of clinical epidemiology, Aarhus (the Netherlands) University Hospital, and her associates.

These findings are from a population-based case-control study, which cannot prove a cause-and-effect relationship. Moreover, it is difficult to statistically account for all the confounding effects of patients’ underlying disease – the reason they were taking glucocorticoids in the first place – because such disorders raise the risk of VTE directly or cause immobility that in turn can lead to VTE.

However, the timing of this adverse effect, the strength of the association across all types of glucocorticoids, and the fact that the association persisted after the data were adjusted to account for multiple confounders all "increase our confidence that the results reflect a true biological effect," the investigators said.

"Clinicians should be aware of this association," they noted.

Ms. Johannesdottir and her colleagues used data from several Danish national medical registries to identify all adults who were diagnosed with VTE in Denmark in 2005-2012, all patients who filled prescriptions for glucocorticoids during the study period, and all indications for the drugs as well as all relevant comorbidities. They matched 10 control subjects for age and sex from the general population to each study subject.

A total of 38,765 VTE cases and 387,650 controls were included in this study. The median age was 67 years, and slightly more than half of those studied were women.

All glucocorticoid users were found to be at increased risk for VTE, particularly for pulmonary embolism, compared with nonusers, the researchers said.

Systemic glucocorticoids, including betamethasone, methylprednisolone, prednisolone, prednisone, triamcinolone, and hydrocortisone, raised VTE risk to the highest degree. (No patients filled prescriptions for dexamethasone in this study.)

Inhaled corticosteroids and corticosteroids that act on the intestines also raised VTE risk significantly. Among the systemic glucocorticoids, prednisolone and prednisone raised VTE risk the most.

New use of glucocorticoids was associated with the highest risk of VTE, but current use, continuing use, and former use also raised the risk significantly. Oral formulations were associated with the highest risk of VTE, but injectable formulations also raised the risk significantly, Ms. Johannesdottir and her associates reported (JAMA Intern. Med. 2013 April 1 [doi:10.1001/jamainternmed.2013.122]).

In particular, new use of systemic glucocorticoids was associated with the highest risk for VTE, with an estimated incidence rate ratio of 3.06, compared with nonuse of glucocorticoids.

The risk of VTE also rose with increasing cumulative doses of all glucocorticoids.

In further analyses, elevated risk for VTE persisted across all the subgroups that were examined.

The findings did not change appreciably in a sensitivity analysis that included only subjects who took glucocorticoids for at least 5 years.

"The temporality of the association (i.e., the strongest effect at initiation of therapy and the absence of an effect after discontinuation) is in line with an effect on coagulation," Ms. Johannesdottir and her associates said.

This study was supported by the Clinical Epidemiological Research Foundation at Aarhus University Hospital. No relevant conflicts of interest were reported.

Use of all glucocorticoids is associated with a two- to threefold increased risk of venous thromboembolism, depending on the type of glucocorticoid, the route of administration, and other factors, according to a report published online April 1 in JAMA Internal Medicine.

Systemic glucocorticoids, as compared with inhaled ones or glucocorticoids that act on the intestines, were associated with the highest risk of VTE. New use was linked to higher risk than continuing or past use, and the VTE risk increased as the dose of glucocorticoids increased, said Sigrun A. Johannesdottir of the department of clinical epidemiology, Aarhus (the Netherlands) University Hospital, and her associates.

These findings are from a population-based case-control study, which cannot prove a cause-and-effect relationship. Moreover, it is difficult to statistically account for all the confounding effects of patients’ underlying disease – the reason they were taking glucocorticoids in the first place – because such disorders raise the risk of VTE directly or cause immobility that in turn can lead to VTE.

However, the timing of this adverse effect, the strength of the association across all types of glucocorticoids, and the fact that the association persisted after the data were adjusted to account for multiple confounders all "increase our confidence that the results reflect a true biological effect," the investigators said.

"Clinicians should be aware of this association," they noted.

Ms. Johannesdottir and her colleagues used data from several Danish national medical registries to identify all adults who were diagnosed with VTE in Denmark in 2005-2012, all patients who filled prescriptions for glucocorticoids during the study period, and all indications for the drugs as well as all relevant comorbidities. They matched 10 control subjects for age and sex from the general population to each study subject.

A total of 38,765 VTE cases and 387,650 controls were included in this study. The median age was 67 years, and slightly more than half of those studied were women.

All glucocorticoid users were found to be at increased risk for VTE, particularly for pulmonary embolism, compared with nonusers, the researchers said.

Systemic glucocorticoids, including betamethasone, methylprednisolone, prednisolone, prednisone, triamcinolone, and hydrocortisone, raised VTE risk to the highest degree. (No patients filled prescriptions for dexamethasone in this study.)

Inhaled corticosteroids and corticosteroids that act on the intestines also raised VTE risk significantly. Among the systemic glucocorticoids, prednisolone and prednisone raised VTE risk the most.

New use of glucocorticoids was associated with the highest risk of VTE, but current use, continuing use, and former use also raised the risk significantly. Oral formulations were associated with the highest risk of VTE, but injectable formulations also raised the risk significantly, Ms. Johannesdottir and her associates reported (JAMA Intern. Med. 2013 April 1 [doi:10.1001/jamainternmed.2013.122]).

In particular, new use of systemic glucocorticoids was associated with the highest risk for VTE, with an estimated incidence rate ratio of 3.06, compared with nonuse of glucocorticoids.

The risk of VTE also rose with increasing cumulative doses of all glucocorticoids.

In further analyses, elevated risk for VTE persisted across all the subgroups that were examined.

The findings did not change appreciably in a sensitivity analysis that included only subjects who took glucocorticoids for at least 5 years.

"The temporality of the association (i.e., the strongest effect at initiation of therapy and the absence of an effect after discontinuation) is in line with an effect on coagulation," Ms. Johannesdottir and her associates said.

This study was supported by the Clinical Epidemiological Research Foundation at Aarhus University Hospital. No relevant conflicts of interest were reported.

LYON, FRANCE—Researchers are uncovering an increasing amount of evidence that vitamin D plays a role in multiple sclerosis (MS), according to a review presented at the 28th Congress of the European Committee for Treatment and Research in MS. Recent findings indicate that vitamin D may be influential during interactions between genes and the environment and may have long-term epigenetic effects.

Sreeram Ramagopalan, postdoctoral fellow at Oxford University in the United Kingdom, described the results of various investigations that shed further light on how vitamin D levels may affect gene expression and, ultimately, the risk of developing MS.

A Threshold Effect on Activation of the Vitamin D Receptor
To investigate the relationship between vitamin D receptor binding and vitamin D levels in serum, Dr. Ramagopalan and his colleagues examined nine healthy individuals. Using flow sorting and chromatin immunoprecipitation sequencing, the researchers observed a strong correlation between serum hydroxyvitamin D levels and vitamin D receptor binding in the subjects' CD4+ T-cells. "There seems to be a threshold effect on activation of the vitamin D receptor," said Dr. Ramagopalan.

Healthy individuals with serum 25-hydroxyvitamin D levels greater than 75 nmol/L had a mean of approximately 4,500 vitamin D receptor binding sites. Individuals with serum vitamin D levels lower than 75 nmol/L had a mean of approximately 500 binding sites.

A hierarchical clustering analysis revealed that individuals with serum hydroxyvitamin D levels greater than 75 nmol/L tended to have intronic and intragenic binding sites. Promoter-based binding sites were more common in subjects with lower levels of hydroxyvitamin D. The Vitamin D Council recommends a minimum serum vitamin D level of 75 nmol/L for health, noted Dr. Ramagopalan.

Further testing indicated that vitamin D receptor binding sites were highly enriched for genes associated with MS in individuals with serum hydroxyvitamin D levels greater than 75 nmol/L. The investigators found no enrichment for vitamin D receptor binding sites in individuals who had serum hydroxyvitamin D levels lower than 75 nmol/L. In addition, the researchers detected "a big difference in gene expression, and this also related to MS-associated genes," between individuals with serum hydroxyvitamin D levels above and below 75 nmol/L, said Dr. Ramagopalan.

Methylation May Affect Vitamin D's Influence on MS
Dr. Ramagopalan and his colleagues are examining sets of twins as part of ongoing studies of the epigenetics of MS. Each set includes one twin with MS and one without. Recently, the investigators studied DNA methylation in the twins' CD4+ T-cells using an Illumina 27k array, which covers approximately 0.1% of DNA methylone. They found "about 120 differentially methylated regions or methylation-variable positions," including hypomethylation and hypermethylation in the affected twins, said Dr. Ramagopalan.

After examining three of these twin pairs to determine whether vitamin D receptor binding was affected by DNA methylation, the group found that methylation at promoter sites correlated with the absence of vitamin D receptor binding. Conversely, lack of methylation correlated with high levels of vitamin D receptor binding. Methylation associated with MS also appeared to affect vitamin D receptor binding. In affected twins, hypermethylation correlated with little or no vitamin D receptor binding. "Methylation associated with MS may affect the influence of vitamin D in patients with MS," said Dr. Ramagopalan.

Vitamin D May Influence the Expression of Thousands of Genes
These results extend and complement the findings of Dr. Ramagopalan's previous studies. In 2010, he and his colleagues investigated whether the vitamin D receptor was more or less likely to bind to genes associated with 47 diseases. The researchers found that genes associated with autoimmune diseases such as type 1 diabetes, Crohn's disease, MS, and colorectal cancer were unusually enriched for vitamin D receptor binding sites.

At the time, approximately 10 genes were associated with MS, and more have been associated with the disease since then. In the group's updated analysis, performed in 2012, 80% of the more than 60 MS-associated genes had vitamin D receptor binding near them.

The vitamin D receptor tends to bind to intragenic or intronic binding sites, and Dr. Ramagopalan's group wanted to understand how this tendency affects gene expression. The investigators found that vitamin D receptors bound to strong enhancer sites and active promoter sites at more than 60 times the rate that would result from chance. "This suggested that the binding of vitamin D receptors to these regions should influence gene expression," said Dr. Ramagopalan. The investigators also found that when the Epstein–Barr virus protein EBNA-3 was knocked out, vitamin D was associated with the differential expression of approximately 4,000 genes.

In subsequent studies, the researchers exposed in utero mice to vitamin D deficiency. The number and type of genes expressed were different in these mice, compared with control mice. Genes that were upregulated in mice exposed to vitamin D deficiency were also upregulated in their offspring, and the same correspondence was true for genes that were downregulated in the parent mice. "This suggests that vitamin D impacts gene expression until adulthood, and this impact also lasts until the next generation," said Dr. Ramagopalan. "We're actively trying to study the mechanism and how this potentially may relate to complex disease."

LYON, FRANCE—Researchers are uncovering an increasing amount of evidence that vitamin D plays a role in multiple sclerosis (MS), according to a review presented at the 28th Congress of the European Committee for Treatment and Research in MS. Recent findings indicate that vitamin D may be influential during interactions between genes and the environment and may have long-term epigenetic effects.

Sreeram Ramagopalan, postdoctoral fellow at Oxford University in the United Kingdom, described the results of various investigations that shed further light on how vitamin D levels may affect gene expression and, ultimately, the risk of developing MS.

A Threshold Effect on Activation of the Vitamin D Receptor
To investigate the relationship between vitamin D receptor binding and vitamin D levels in serum, Dr. Ramagopalan and his colleagues examined nine healthy individuals. Using flow sorting and chromatin immunoprecipitation sequencing, the researchers observed a strong correlation between serum hydroxyvitamin D levels and vitamin D receptor binding in the subjects' CD4+ T-cells. "There seems to be a threshold effect on activation of the vitamin D receptor," said Dr. Ramagopalan.

Healthy individuals with serum 25-hydroxyvitamin D levels greater than 75 nmol/L had a mean of approximately 4,500 vitamin D receptor binding sites. Individuals with serum vitamin D levels lower than 75 nmol/L had a mean of approximately 500 binding sites.

A hierarchical clustering analysis revealed that individuals with serum hydroxyvitamin D levels greater than 75 nmol/L tended to have intronic and intragenic binding sites. Promoter-based binding sites were more common in subjects with lower levels of hydroxyvitamin D. The Vitamin D Council recommends a minimum serum vitamin D level of 75 nmol/L for health, noted Dr. Ramagopalan.

Further testing indicated that vitamin D receptor binding sites were highly enriched for genes associated with MS in individuals with serum hydroxyvitamin D levels greater than 75 nmol/L. The investigators found no enrichment for vitamin D receptor binding sites in individuals who had serum hydroxyvitamin D levels lower than 75 nmol/L. In addition, the researchers detected "a big difference in gene expression, and this also related to MS-associated genes," between individuals with serum hydroxyvitamin D levels above and below 75 nmol/L, said Dr. Ramagopalan.

Methylation May Affect Vitamin D's Influence on MS
Dr. Ramagopalan and his colleagues are examining sets of twins as part of ongoing studies of the epigenetics of MS. Each set includes one twin with MS and one without. Recently, the investigators studied DNA methylation in the twins' CD4+ T-cells using an Illumina 27k array, which covers approximately 0.1% of DNA methylone. They found "about 120 differentially methylated regions or methylation-variable positions," including hypomethylation and hypermethylation in the affected twins, said Dr. Ramagopalan.

After examining three of these twin pairs to determine whether vitamin D receptor binding was affected by DNA methylation, the group found that methylation at promoter sites correlated with the absence of vitamin D receptor binding. Conversely, lack of methylation correlated with high levels of vitamin D receptor binding. Methylation associated with MS also appeared to affect vitamin D receptor binding. In affected twins, hypermethylation correlated with little or no vitamin D receptor binding. "Methylation associated with MS may affect the influence of vitamin D in patients with MS," said Dr. Ramagopalan.

Vitamin D May Influence the Expression of Thousands of Genes
These results extend and complement the findings of Dr. Ramagopalan's previous studies. In 2010, he and his colleagues investigated whether the vitamin D receptor was more or less likely to bind to genes associated with 47 diseases. The researchers found that genes associated with autoimmune diseases such as type 1 diabetes, Crohn's disease, MS, and colorectal cancer were unusually enriched for vitamin D receptor binding sites.

At the time, approximately 10 genes were associated with MS, and more have been associated with the disease since then. In the group's updated analysis, performed in 2012, 80% of the more than 60 MS-associated genes had vitamin D receptor binding near them.

The vitamin D receptor tends to bind to intragenic or intronic binding sites, and Dr. Ramagopalan's group wanted to understand how this tendency affects gene expression. The investigators found that vitamin D receptors bound to strong enhancer sites and active promoter sites at more than 60 times the rate that would result from chance. "This suggested that the binding of vitamin D receptors to these regions should influence gene expression," said Dr. Ramagopalan. The investigators also found that when the Epstein–Barr virus protein EBNA-3 was knocked out, vitamin D was associated with the differential expression of approximately 4,000 genes.

In subsequent studies, the researchers exposed in utero mice to vitamin D deficiency. The number and type of genes expressed were different in these mice, compared with control mice. Genes that were upregulated in mice exposed to vitamin D deficiency were also upregulated in their offspring, and the same correspondence was true for genes that were downregulated in the parent mice. "This suggests that vitamin D impacts gene expression until adulthood, and this impact also lasts until the next generation," said Dr. Ramagopalan. "We're actively trying to study the mechanism and how this potentially may relate to complex disease."

LYON, FRANCE—Researchers are uncovering an increasing amount of evidence that vitamin D plays a role in multiple sclerosis (MS), according to a review presented at the 28th Congress of the European Committee for Treatment and Research in MS. Recent findings indicate that vitamin D may be influential during interactions between genes and the environment and may have long-term epigenetic effects.

Sreeram Ramagopalan, postdoctoral fellow at Oxford University in the United Kingdom, described the results of various investigations that shed further light on how vitamin D levels may affect gene expression and, ultimately, the risk of developing MS.

A Threshold Effect on Activation of the Vitamin D Receptor
To investigate the relationship between vitamin D receptor binding and vitamin D levels in serum, Dr. Ramagopalan and his colleagues examined nine healthy individuals. Using flow sorting and chromatin immunoprecipitation sequencing, the researchers observed a strong correlation between serum hydroxyvitamin D levels and vitamin D receptor binding in the subjects' CD4+ T-cells. "There seems to be a threshold effect on activation of the vitamin D receptor," said Dr. Ramagopalan.

Healthy individuals with serum 25-hydroxyvitamin D levels greater than 75 nmol/L had a mean of approximately 4,500 vitamin D receptor binding sites. Individuals with serum vitamin D levels lower than 75 nmol/L had a mean of approximately 500 binding sites.

A hierarchical clustering analysis revealed that individuals with serum hydroxyvitamin D levels greater than 75 nmol/L tended to have intronic and intragenic binding sites. Promoter-based binding sites were more common in subjects with lower levels of hydroxyvitamin D. The Vitamin D Council recommends a minimum serum vitamin D level of 75 nmol/L for health, noted Dr. Ramagopalan.

Further testing indicated that vitamin D receptor binding sites were highly enriched for genes associated with MS in individuals with serum hydroxyvitamin D levels greater than 75 nmol/L. The investigators found no enrichment for vitamin D receptor binding sites in individuals who had serum hydroxyvitamin D levels lower than 75 nmol/L. In addition, the researchers detected "a big difference in gene expression, and this also related to MS-associated genes," between individuals with serum hydroxyvitamin D levels above and below 75 nmol/L, said Dr. Ramagopalan.

Methylation May Affect Vitamin D's Influence on MS
Dr. Ramagopalan and his colleagues are examining sets of twins as part of ongoing studies of the epigenetics of MS. Each set includes one twin with MS and one without. Recently, the investigators studied DNA methylation in the twins' CD4+ T-cells using an Illumina 27k array, which covers approximately 0.1% of DNA methylone. They found "about 120 differentially methylated regions or methylation-variable positions," including hypomethylation and hypermethylation in the affected twins, said Dr. Ramagopalan.

After examining three of these twin pairs to determine whether vitamin D receptor binding was affected by DNA methylation, the group found that methylation at promoter sites correlated with the absence of vitamin D receptor binding. Conversely, lack of methylation correlated with high levels of vitamin D receptor binding. Methylation associated with MS also appeared to affect vitamin D receptor binding. In affected twins, hypermethylation correlated with little or no vitamin D receptor binding. "Methylation associated with MS may affect the influence of vitamin D in patients with MS," said Dr. Ramagopalan.

Vitamin D May Influence the Expression of Thousands of Genes
These results extend and complement the findings of Dr. Ramagopalan's previous studies. In 2010, he and his colleagues investigated whether the vitamin D receptor was more or less likely to bind to genes associated with 47 diseases. The researchers found that genes associated with autoimmune diseases such as type 1 diabetes, Crohn's disease, MS, and colorectal cancer were unusually enriched for vitamin D receptor binding sites.

At the time, approximately 10 genes were associated with MS, and more have been associated with the disease since then. In the group's updated analysis, performed in 2012, 80% of the more than 60 MS-associated genes had vitamin D receptor binding near them.

The vitamin D receptor tends to bind to intragenic or intronic binding sites, and Dr. Ramagopalan's group wanted to understand how this tendency affects gene expression. The investigators found that vitamin D receptors bound to strong enhancer sites and active promoter sites at more than 60 times the rate that would result from chance. "This suggested that the binding of vitamin D receptors to these regions should influence gene expression," said Dr. Ramagopalan. The investigators also found that when the Epstein–Barr virus protein EBNA-3 was knocked out, vitamin D was associated with the differential expression of approximately 4,000 genes.

In subsequent studies, the researchers exposed in utero mice to vitamin D deficiency. The number and type of genes expressed were different in these mice, compared with control mice. Genes that were upregulated in mice exposed to vitamin D deficiency were also upregulated in their offspring, and the same correspondence was true for genes that were downregulated in the parent mice. "This suggests that vitamin D impacts gene expression until adulthood, and this impact also lasts until the next generation," said Dr. Ramagopalan. "We're actively trying to study the mechanism and how this potentially may relate to complex disease."