Neurology Reviews

Despite the ongoing epidemic of misuse, overuse, and diversion of opioids, the Food and Drug Administration has set a low bar for approval of these medications over the past 20 years, new research suggests.

Results of a cross-sectional study reveal that between 1997 and 2018, the majority of approvals of opioids for the treatment of chronic pain were based on pivotal trials that lacked critical safety and efficacy data.

The study results also show that the FDA did not require manufacturers to collect safety data on tolerance, withdrawal, overdose, misuse, and diversion in any rigorous fashion.

In addition, during the study period, 17 of the 39 new drug applications (NDAs) (only one was an innovator product, known as a new molecular entity) for chronic pain were approved with an “enriched enrollment randomized withdrawal” (EERW) trial design. Such a design, in this case, allowed manufacturers to exclude 32%-43% of the initially enrolled patients from the double-blind treatment phase.

“The question for regulators, policy makers, and others is: How did we get to a point where these approvals took place based on trials that were by design unlikely to yield some of the most important information about safety and efficacy that patients and clinicians would care about?” study investigator G. Caleb Alexander, MD, Johns Hopkins University, Baltimore, said in an interview.

The study was published online Sept. 29 in the Annals of Internal Medicine.
 

‘Cooking the books’

Little is known about the evidence required by the FDA for new approvals of opioid analgesics.

To characterize the quality of safety and efficacy data in NDAs for opioid analgesics approved by the FDA between 1997 and 2018, the investigators conducted the cross-sectional analysis using data from ClinicalTrials.gov, FDA reviews, and peer-reviewed publications regarding phase 3 pivotal trials.

The investigators examined the key characteristics of each NDA, including the number, size, and duration of pivotal trials, trial control groups, use of EERW, and systematically measured safety outcomes.

Results showed that most of the 48 NDAs evaluated were for new dosage forms (52.1%) or new formulations (18.8%). Only one (2.1%) was for a new molecular entity.

Of 39 NDAs approved for the treatment of chronic pain, only 21 products were supported by at least one pivotal trial. The mean duration of these 28 trials was 84 days, and they enrolled a median of 299 patients.

Results showed that, for 17 of the 39 opioids approved for chronic pain, pivotal trials had an EERW design. For the latest period – 2012-2018 – trials of all eight of the approved opioids used the EERW method.

This EERW design allows the manufacturer to assess efficacy “among a subset of patients most likely to respond and least likely to have adverse effects, reducing generalizability to real-world settings,” the investigators noted.

They called on the FDA to stop relying on this type of trial to assess opioid efficacy.

In an August 2020 article, Andrew Kolodny, MD, pointed out the pitfalls of the EERW approach. In such a study, all participants are made physiologically dependent on the opioid in a 4- to 6-week open-label phase. Only those who tolerate the drug and find it helpful are included in the randomized study. Dr. Kolodny is codirector of opioid policy research at Brandeis University, Waltham, Mass.

“Critics of EERW have correctly described this methodology as ‘cooking the books,’ ” Dr. Kolodny writes.

He noted that the agency’s decision to rely on EERW trials for opioids was “based on discussions at private meetings between FDA officials and pharmaceutical company executives hosted by an organization called Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials.” The 2013 meetings were reported in an article published in the Washington Post.

Little sign of change

Among NDAs for chronic pain, the investigators found that eight (20.5%) included pooled safety reviews that reported systematic assessment of diversion. Seven (17.9%) reported systematic measurement of nonmedical use, and 15 (38.5%) assessed incident tolerance.

The study revealed that eight of nine products that were approved for acute pain were supported by at least one pivotal trial. The median duration of these 19 trials was 1 day, and they enrolled a median of 329 patients.

The investigators noted that the findings “underscore the evidence gaps that have limited clinicians’ and patients’ understanding and appreciation of the inherent risks of prescription opioid analgesics.”

Dr. Alexander, who has been an FDA advisory committee chairman and currently serves as a consultant to plaintiffs who are suing opioid manufacturers in federal multidistrict litigation, said the study “is a story about missed opportunities to improve the safety and to improve the regulatory review of these products.”

Coinvestigator Peter Lurie, MD, who was an official at the FDA from 2009 to 2017, said that “there’s not a lot of signs that things are changing” at the agency.

The study shows that the FDA has “accepted what the companies have been presenting,” said Dr. Lurie, who is president of the Center for Science in the Public Interest.

The FDA “absolutely has the authority” to require manufacturers to undertake more rigorous trials, but agency culture keeps it from making such demands, especially if doing so means a new applicant might have to conduct trials that weren’t previously required, Dr. Lurie said in an interview.

“FDA is pretty rigorous about trying to establish a level playing field. That’s a virtuous thing, but it becomes problematic when that prevents change,” said Dr. Lurie.

The most recent FDA guidance to manufacturers, issued in 2019, does not provide advice on criteria for endpoints, study duration, or which populations are most likely to benefit from opioid treatment. The agency also does not require drug manufacturers to formally collect data on safety, tolerance, overdose symptoms, or constipation.

The guidance does suggest that the agency would likely take into account public health considerations when evaluating opioids, such as the risk to the overall population for overdose and diversion.
 

‘Overwhelming evidence’

Dr. Kolodny said that, as far as he is aware, “this is the first scientific publication in a peer-reviewed journal demonstrating clearly the problems with FDA’s opioid approval process.”

The article offers “overwhelming evidence that they are improperly approving the most dangerous medications – medications that killed more people than any other medication on the market,” added Dr. Kolodny, who is also president of Physicians for Responsible Opioid Prescribing.

Asked to respond to the study findings, FDA spokesperson Charles Kohler said the agency “does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

A version of this article originally appeared on Medscape.com.

Despite the ongoing epidemic of misuse, overuse, and diversion of opioids, the Food and Drug Administration has set a low bar for approval of these medications over the past 20 years, new research suggests.

Results of a cross-sectional study reveal that between 1997 and 2018, the majority of approvals of opioids for the treatment of chronic pain were based on pivotal trials that lacked critical safety and efficacy data.

The study results also show that the FDA did not require manufacturers to collect safety data on tolerance, withdrawal, overdose, misuse, and diversion in any rigorous fashion.

In addition, during the study period, 17 of the 39 new drug applications (NDAs) (only one was an innovator product, known as a new molecular entity) for chronic pain were approved with an “enriched enrollment randomized withdrawal” (EERW) trial design. Such a design, in this case, allowed manufacturers to exclude 32%-43% of the initially enrolled patients from the double-blind treatment phase.

“The question for regulators, policy makers, and others is: How did we get to a point where these approvals took place based on trials that were by design unlikely to yield some of the most important information about safety and efficacy that patients and clinicians would care about?” study investigator G. Caleb Alexander, MD, Johns Hopkins University, Baltimore, said in an interview.

The study was published online Sept. 29 in the Annals of Internal Medicine.
 

‘Cooking the books’

Little is known about the evidence required by the FDA for new approvals of opioid analgesics.

To characterize the quality of safety and efficacy data in NDAs for opioid analgesics approved by the FDA between 1997 and 2018, the investigators conducted the cross-sectional analysis using data from ClinicalTrials.gov, FDA reviews, and peer-reviewed publications regarding phase 3 pivotal trials.

The investigators examined the key characteristics of each NDA, including the number, size, and duration of pivotal trials, trial control groups, use of EERW, and systematically measured safety outcomes.

Results showed that most of the 48 NDAs evaluated were for new dosage forms (52.1%) or new formulations (18.8%). Only one (2.1%) was for a new molecular entity.

Of 39 NDAs approved for the treatment of chronic pain, only 21 products were supported by at least one pivotal trial. The mean duration of these 28 trials was 84 days, and they enrolled a median of 299 patients.

Results showed that, for 17 of the 39 opioids approved for chronic pain, pivotal trials had an EERW design. For the latest period – 2012-2018 – trials of all eight of the approved opioids used the EERW method.

This EERW design allows the manufacturer to assess efficacy “among a subset of patients most likely to respond and least likely to have adverse effects, reducing generalizability to real-world settings,” the investigators noted.

They called on the FDA to stop relying on this type of trial to assess opioid efficacy.

In an August 2020 article, Andrew Kolodny, MD, pointed out the pitfalls of the EERW approach. In such a study, all participants are made physiologically dependent on the opioid in a 4- to 6-week open-label phase. Only those who tolerate the drug and find it helpful are included in the randomized study. Dr. Kolodny is codirector of opioid policy research at Brandeis University, Waltham, Mass.

“Critics of EERW have correctly described this methodology as ‘cooking the books,’ ” Dr. Kolodny writes.

He noted that the agency’s decision to rely on EERW trials for opioids was “based on discussions at private meetings between FDA officials and pharmaceutical company executives hosted by an organization called Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials.” The 2013 meetings were reported in an article published in the Washington Post.

Little sign of change

Among NDAs for chronic pain, the investigators found that eight (20.5%) included pooled safety reviews that reported systematic assessment of diversion. Seven (17.9%) reported systematic measurement of nonmedical use, and 15 (38.5%) assessed incident tolerance.

The study revealed that eight of nine products that were approved for acute pain were supported by at least one pivotal trial. The median duration of these 19 trials was 1 day, and they enrolled a median of 329 patients.

The investigators noted that the findings “underscore the evidence gaps that have limited clinicians’ and patients’ understanding and appreciation of the inherent risks of prescription opioid analgesics.”

Dr. Alexander, who has been an FDA advisory committee chairman and currently serves as a consultant to plaintiffs who are suing opioid manufacturers in federal multidistrict litigation, said the study “is a story about missed opportunities to improve the safety and to improve the regulatory review of these products.”

Coinvestigator Peter Lurie, MD, who was an official at the FDA from 2009 to 2017, said that “there’s not a lot of signs that things are changing” at the agency.

The study shows that the FDA has “accepted what the companies have been presenting,” said Dr. Lurie, who is president of the Center for Science in the Public Interest.

The FDA “absolutely has the authority” to require manufacturers to undertake more rigorous trials, but agency culture keeps it from making such demands, especially if doing so means a new applicant might have to conduct trials that weren’t previously required, Dr. Lurie said in an interview.

“FDA is pretty rigorous about trying to establish a level playing field. That’s a virtuous thing, but it becomes problematic when that prevents change,” said Dr. Lurie.

The most recent FDA guidance to manufacturers, issued in 2019, does not provide advice on criteria for endpoints, study duration, or which populations are most likely to benefit from opioid treatment. The agency also does not require drug manufacturers to formally collect data on safety, tolerance, overdose symptoms, or constipation.

The guidance does suggest that the agency would likely take into account public health considerations when evaluating opioids, such as the risk to the overall population for overdose and diversion.
 

‘Overwhelming evidence’

Dr. Kolodny said that, as far as he is aware, “this is the first scientific publication in a peer-reviewed journal demonstrating clearly the problems with FDA’s opioid approval process.”

The article offers “overwhelming evidence that they are improperly approving the most dangerous medications – medications that killed more people than any other medication on the market,” added Dr. Kolodny, who is also president of Physicians for Responsible Opioid Prescribing.

Asked to respond to the study findings, FDA spokesperson Charles Kohler said the agency “does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

A version of this article originally appeared on Medscape.com.

Despite the ongoing epidemic of misuse, overuse, and diversion of opioids, the Food and Drug Administration has set a low bar for approval of these medications over the past 20 years, new research suggests.

Results of a cross-sectional study reveal that between 1997 and 2018, the majority of approvals of opioids for the treatment of chronic pain were based on pivotal trials that lacked critical safety and efficacy data.

The study results also show that the FDA did not require manufacturers to collect safety data on tolerance, withdrawal, overdose, misuse, and diversion in any rigorous fashion.

In addition, during the study period, 17 of the 39 new drug applications (NDAs) (only one was an innovator product, known as a new molecular entity) for chronic pain were approved with an “enriched enrollment randomized withdrawal” (EERW) trial design. Such a design, in this case, allowed manufacturers to exclude 32%-43% of the initially enrolled patients from the double-blind treatment phase.

“The question for regulators, policy makers, and others is: How did we get to a point where these approvals took place based on trials that were by design unlikely to yield some of the most important information about safety and efficacy that patients and clinicians would care about?” study investigator G. Caleb Alexander, MD, Johns Hopkins University, Baltimore, said in an interview.

The study was published online Sept. 29 in the Annals of Internal Medicine.
 

‘Cooking the books’

Little is known about the evidence required by the FDA for new approvals of opioid analgesics.

To characterize the quality of safety and efficacy data in NDAs for opioid analgesics approved by the FDA between 1997 and 2018, the investigators conducted the cross-sectional analysis using data from ClinicalTrials.gov, FDA reviews, and peer-reviewed publications regarding phase 3 pivotal trials.

The investigators examined the key characteristics of each NDA, including the number, size, and duration of pivotal trials, trial control groups, use of EERW, and systematically measured safety outcomes.

Results showed that most of the 48 NDAs evaluated were for new dosage forms (52.1%) or new formulations (18.8%). Only one (2.1%) was for a new molecular entity.

Of 39 NDAs approved for the treatment of chronic pain, only 21 products were supported by at least one pivotal trial. The mean duration of these 28 trials was 84 days, and they enrolled a median of 299 patients.

Results showed that, for 17 of the 39 opioids approved for chronic pain, pivotal trials had an EERW design. For the latest period – 2012-2018 – trials of all eight of the approved opioids used the EERW method.

This EERW design allows the manufacturer to assess efficacy “among a subset of patients most likely to respond and least likely to have adverse effects, reducing generalizability to real-world settings,” the investigators noted.

They called on the FDA to stop relying on this type of trial to assess opioid efficacy.

In an August 2020 article, Andrew Kolodny, MD, pointed out the pitfalls of the EERW approach. In such a study, all participants are made physiologically dependent on the opioid in a 4- to 6-week open-label phase. Only those who tolerate the drug and find it helpful are included in the randomized study. Dr. Kolodny is codirector of opioid policy research at Brandeis University, Waltham, Mass.

“Critics of EERW have correctly described this methodology as ‘cooking the books,’ ” Dr. Kolodny writes.

He noted that the agency’s decision to rely on EERW trials for opioids was “based on discussions at private meetings between FDA officials and pharmaceutical company executives hosted by an organization called Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials.” The 2013 meetings were reported in an article published in the Washington Post.

Little sign of change

Among NDAs for chronic pain, the investigators found that eight (20.5%) included pooled safety reviews that reported systematic assessment of diversion. Seven (17.9%) reported systematic measurement of nonmedical use, and 15 (38.5%) assessed incident tolerance.

The study revealed that eight of nine products that were approved for acute pain were supported by at least one pivotal trial. The median duration of these 19 trials was 1 day, and they enrolled a median of 329 patients.

The investigators noted that the findings “underscore the evidence gaps that have limited clinicians’ and patients’ understanding and appreciation of the inherent risks of prescription opioid analgesics.”

Dr. Alexander, who has been an FDA advisory committee chairman and currently serves as a consultant to plaintiffs who are suing opioid manufacturers in federal multidistrict litigation, said the study “is a story about missed opportunities to improve the safety and to improve the regulatory review of these products.”

Coinvestigator Peter Lurie, MD, who was an official at the FDA from 2009 to 2017, said that “there’s not a lot of signs that things are changing” at the agency.

The study shows that the FDA has “accepted what the companies have been presenting,” said Dr. Lurie, who is president of the Center for Science in the Public Interest.

The FDA “absolutely has the authority” to require manufacturers to undertake more rigorous trials, but agency culture keeps it from making such demands, especially if doing so means a new applicant might have to conduct trials that weren’t previously required, Dr. Lurie said in an interview.

“FDA is pretty rigorous about trying to establish a level playing field. That’s a virtuous thing, but it becomes problematic when that prevents change,” said Dr. Lurie.

The most recent FDA guidance to manufacturers, issued in 2019, does not provide advice on criteria for endpoints, study duration, or which populations are most likely to benefit from opioid treatment. The agency also does not require drug manufacturers to formally collect data on safety, tolerance, overdose symptoms, or constipation.

The guidance does suggest that the agency would likely take into account public health considerations when evaluating opioids, such as the risk to the overall population for overdose and diversion.
 

‘Overwhelming evidence’

Dr. Kolodny said that, as far as he is aware, “this is the first scientific publication in a peer-reviewed journal demonstrating clearly the problems with FDA’s opioid approval process.”

The article offers “overwhelming evidence that they are improperly approving the most dangerous medications – medications that killed more people than any other medication on the market,” added Dr. Kolodny, who is also president of Physicians for Responsible Opioid Prescribing.

Asked to respond to the study findings, FDA spokesperson Charles Kohler said the agency “does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

A version of this article originally appeared on Medscape.com.

Listening to Mozart’s piano music improves epilepsy, according to a meta-analysis presented at the virtual congress of the European College of Neuropsychopharmacology.

The results of the meta-analysis of 12 published studies of the so-called Mozart Effect that met rigorous Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines demonstrate that listening to Mozart results in significant reductions in both epileptic seizure frequency and interictal epileptiform discharges (IED), compared with baseline.

The benefits were apparent during and after even a single listening session, although the effect was greater with regular daily listening sessions, according to Gianluca Sesso, MD, a resident in child and adolescent psychiatry at the University of Pisa (Italy.)

“Obviously other music may have similar effects, but it may be that Mozart’s sonatas have distinctive rhythmic structures which are particularly suited to working on epilepsy,” he speculated, adding that the mechanism involved in the Mozart Effect on brain systems remains unclear.

“The highly consistent results of our meta-analysis strongly suggest that music-based neurostimulation may improve the clinical outcome in epilepsy by reducing seizures and IED, and thus deserves to be included in the set of nonpharmacologic complementary approaches for treating epilepsy,” Dr. Sesso added.

Four studies examined the effects of listening to Mozart’s Sonata for Two Pianos in D, K.448, the most-studied piece of music as a treatment for epilepsy. The data documented a 31% reduction in seizure frequency and 28% decrease in IED during a single listen, and a 79% reduction in IED after long-term Mozart music therapy. Similarly, studies demonstrated that listening to a set of Mozart’s compositions resulted in a 36% reduction in IED during and 38% decrease after a single listen, while regular listening in a prolonged treatment period resulted in a 66% reduction in seizure frequency from baseline.

Several studies compared the benefits of listening to K. 488 with those accrued through listening to Piano Sonata No. 16 in C major, K. 545. There was no significant difference between the two, according to Dr. Sesso.

He reported having no financial conflicts regarding his meta-analysis, carried out free of commercial support.

The full details of the meta-analysis were recently published in Clinical Neurophysiology.

bjancin@mdedge.com

Listening to Mozart’s piano music improves epilepsy, according to a meta-analysis presented at the virtual congress of the European College of Neuropsychopharmacology.

The results of the meta-analysis of 12 published studies of the so-called Mozart Effect that met rigorous Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines demonstrate that listening to Mozart results in significant reductions in both epileptic seizure frequency and interictal epileptiform discharges (IED), compared with baseline.

The benefits were apparent during and after even a single listening session, although the effect was greater with regular daily listening sessions, according to Gianluca Sesso, MD, a resident in child and adolescent psychiatry at the University of Pisa (Italy.)

“Obviously other music may have similar effects, but it may be that Mozart’s sonatas have distinctive rhythmic structures which are particularly suited to working on epilepsy,” he speculated, adding that the mechanism involved in the Mozart Effect on brain systems remains unclear.

“The highly consistent results of our meta-analysis strongly suggest that music-based neurostimulation may improve the clinical outcome in epilepsy by reducing seizures and IED, and thus deserves to be included in the set of nonpharmacologic complementary approaches for treating epilepsy,” Dr. Sesso added.

Four studies examined the effects of listening to Mozart’s Sonata for Two Pianos in D, K.448, the most-studied piece of music as a treatment for epilepsy. The data documented a 31% reduction in seizure frequency and 28% decrease in IED during a single listen, and a 79% reduction in IED after long-term Mozart music therapy. Similarly, studies demonstrated that listening to a set of Mozart’s compositions resulted in a 36% reduction in IED during and 38% decrease after a single listen, while regular listening in a prolonged treatment period resulted in a 66% reduction in seizure frequency from baseline.

Several studies compared the benefits of listening to K. 488 with those accrued through listening to Piano Sonata No. 16 in C major, K. 545. There was no significant difference between the two, according to Dr. Sesso.

He reported having no financial conflicts regarding his meta-analysis, carried out free of commercial support.

The full details of the meta-analysis were recently published in Clinical Neurophysiology.

bjancin@mdedge.com

Listening to Mozart’s piano music improves epilepsy, according to a meta-analysis presented at the virtual congress of the European College of Neuropsychopharmacology.

The results of the meta-analysis of 12 published studies of the so-called Mozart Effect that met rigorous Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines demonstrate that listening to Mozart results in significant reductions in both epileptic seizure frequency and interictal epileptiform discharges (IED), compared with baseline.

The benefits were apparent during and after even a single listening session, although the effect was greater with regular daily listening sessions, according to Gianluca Sesso, MD, a resident in child and adolescent psychiatry at the University of Pisa (Italy.)

“Obviously other music may have similar effects, but it may be that Mozart’s sonatas have distinctive rhythmic structures which are particularly suited to working on epilepsy,” he speculated, adding that the mechanism involved in the Mozart Effect on brain systems remains unclear.

“The highly consistent results of our meta-analysis strongly suggest that music-based neurostimulation may improve the clinical outcome in epilepsy by reducing seizures and IED, and thus deserves to be included in the set of nonpharmacologic complementary approaches for treating epilepsy,” Dr. Sesso added.

Four studies examined the effects of listening to Mozart’s Sonata for Two Pianos in D, K.448, the most-studied piece of music as a treatment for epilepsy. The data documented a 31% reduction in seizure frequency and 28% decrease in IED during a single listen, and a 79% reduction in IED after long-term Mozart music therapy. Similarly, studies demonstrated that listening to a set of Mozart’s compositions resulted in a 36% reduction in IED during and 38% decrease after a single listen, while regular listening in a prolonged treatment period resulted in a 66% reduction in seizure frequency from baseline.

Several studies compared the benefits of listening to K. 488 with those accrued through listening to Piano Sonata No. 16 in C major, K. 545. There was no significant difference between the two, according to Dr. Sesso.

He reported having no financial conflicts regarding his meta-analysis, carried out free of commercial support.

The full details of the meta-analysis were recently published in Clinical Neurophysiology.

bjancin@mdedge.com

Among women with multiple sclerosis (MS), levels of serum neurofilament light (sNfL) are higher during pregnancy and the postpartum period. The increase in sNfL is independent of relapses, which suggests that patients have increased subclinical disease activity during this period, according to the researchers.

When the investigators controlled their data for exposure to disease-modifying therapy (DMT), the effect of pregnancy on sNfL was no longer evident. These data were presented said at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

The results suggest that “sNfL may qualify as a sensitive and minimally invasive measure of disease activity in pregnancy,” said Özgür Yaldizli, MD, consultant neurologist at University Hospital Basel (Switzerland). “Strategies allowing the continuation of DMT during pregnancy may be warranted.”

MS preferentially affects women in their reproductive years, said Dr. Yaldizli. Almost one-third of women with MS become pregnant after they receive their diagnosis. A decrease in disease activity is typical in the third trimester, as is an increase in relapse frequency post partum.

DMTs reduce the risk of relapse, but have potential side effects for the woman and the fetus. Some DMTs are immunosuppressants, and they increase the risk of infection during pregnancy. Other DMTs may harm the development of the fetus, particularly if administered early during pregnancy.

“There is an urgent need to identify patients with high disease activity during pregnancy,” said Dr. Yaldizli. Increased levels of NfL, a specific biomarker of neuroaxonal injury, are associated with relapses, MRI activity, and disability worsening among patients with MS. Response to DMT is associated with decreased NfL levels. But few data about sNfL during pregnancy or post partum are available.
 

Relapses were associated with increased sNfL

Dr. Yaldizli and colleagues examined data from the Swiss MS Cohort Study to describe DMT use before, during, and after pregnancy. They also sought to assess sNfL as a marker of disease activity during and after pregnancy and to evaluate whether interrupting DMT because of pregnancy leads to increased sNfL levels.

Eligible participants had prospectively documented pregnancies, and Dr. Yaldizli’s group excluded pregnancies with early termination from their analysis. Serum samples were collected every 6 or 12 months and analyzed using the Simoa NF-light assay. The investigators used univariable and multivariable mixed-effects models to investigate associations between clinical characteristics and longitudinal sNfL levels in women before pregnancy, during pregnancy, and post partum.

Dr. Yaldizli and colleagues included 72 pregnancies in 63 patients with relapsing MS in their analysis. Nine patients had two pregnancies during follow-up. The population’s median age was 31.4 years, and median disease duration was 7.1 years. Median Expanded Disability Status Scale (EDSS) score at last visit before birth was 1.5. Median follow-up time was 6 years.

Most patients were treated with DMT before or during pregnancy. For most patients (39), fingolimod or natalizumab was the last DMT given before birth. Four patients did not use DMT before, during, or after pregnancy. In 14 pregnancies, the patient continued DMT for more than 6 months.

The univariable analysis showed that sNfL levels were 22% higher during pregnancy, compared with outside the pregnancy and postpartum period. The investigators recorded 29 relapses during the pregnancy and postpartum period. Relapses were more likely to occur during the first trimester and the first 3 months post partum. In the multivariable analysis, relapses that occurred within 120 days before serum sampling were associated with 98% higher levels of sNfL. In addition, sNfL was 7% higher for each step increase in EDSS and 13% higher during the pregnancy and postpartum period, compared with outside of that period.

When the investigators included DMT exposure at sampling time in the model, however, the pregnancy and postpartum period no longer had an effect on sNfL. The sNfL levels were 12% lower among patients exposed to DMT, compared with patients without DMT exposure.

Some DMTs, such as interferon-beta, are relatively safe during pregnancy, but the greater the medication’s efficacy, the more problematic it can be, said Dr. Yaldizi. “There are medications that are given, for example, every 6 months, like ocrelizumab. There are other medications that have to be taken daily. Probably the safest medications are those that are not given so often during pregnancy.”

Future research should examine the escalation therapies (i.e., the newer and more effective DMTs) during pregnancy in patients with MS, he added. “Not only in pregnancy, but also in general, we have to look for ways to measure disease activity in patients who switch therapy, who deescalate therapy.”
 

Pregnancy may not forestall disease activity

“The results of this study demonstrate that DMT withdrawal in the context of pregnancy can lead to subclinical disease re-emergence, as evidenced by increased sNfL levels in the DMT-free period,” said Vilija G. Jokubaitis, PhD, senior research fellow in the department of neuroscience at Monash University, Melbourne. Dr. Jokubaitis was not involved in the study.

“Interestingly, the median EDSS score in this cohort was quite low, demonstrating that, even in women with mild disease, pregnancy may not be sufficient to protect against ongoing MS activity.” Nevertheless, 28 of the 63 women were exposed to monoclonal antibody therapy, so it is unclear whether these women have mild disease or well-managed disease on DMT, she added.

“This study provides further evidence that pregnancy planning requires advanced planning, and that therapy continuation into pregnancy should be considered, particularly in women with moderate disease activity, to protect against disease reactivation,” said Dr. Jokubaitis.

The strengths of the study include its prospective design, the investigators’ ability to describe the various DMT exposures before and during pregnancy, and the multivariable mixed-effects modeling, she added. On the other hand, the results are at the group level, individual trajectories in sNfL level are not described, and the small sample size prevented the investigators from differentiating between the effects of various DMTs on sNfL outcomes. In addition, Dr. Yaldizli and colleagues did not take time off DMT into account in the models; they considered DMT exposure as a dichotomous variable.

“More work is needed to determine the therapeutic strategies that will give women with MS the greatest protection against disease reactivation in pregnancy and post partum, whilst also protecting fetal and neonatal outcomes,” said Dr. Jokubaitis. Group studies will enable researchers to identify trends, but neurologists ultimately need to provide individualized advice to their patients. “There is a need to look at [the effect of] DMT identity, timing, and duration of DMT withdrawal on fluctuation of sNfL levels, and how these relate to baseline disease severity,” Dr. Jokubaitis added. Furthermore, researchers must compare sNfL changes in pregnancy between patients with MS and healthy women in large cohorts.

The analysis by Dr. Yaldizli and colleagues was conducted without outside funding. The Swiss MS Cohort receives funding from the Swiss MS society, Biogen, Celgene, Sanofi, Merck, Novartis, Roche, and research associations such as the International Progressive MS Alliance and the Swiss National Science Foundation. Dr. Yaldizli received grants from ECTRIMS/MAGNIMS, the University of Basel, Pro Patient Stiftung, University Hospital Basel, Free Academy Basel, and the Swiss MS Society. He has received advisory board fees from Sanofi Genzyme, Biogen, Almirall, and Novartis. Dr. Jokubaitis has received conference travel support from Merck and Roche and speakers honoraria from Biogen and Roche. These relationships are not related to the current study. Dr. Jokubaitis receives research support from the Australian National Health and Medical Research Grant and MS Research Australia.

egreb@mdedge.com

Among women with multiple sclerosis (MS), levels of serum neurofilament light (sNfL) are higher during pregnancy and the postpartum period. The increase in sNfL is independent of relapses, which suggests that patients have increased subclinical disease activity during this period, according to the researchers.

When the investigators controlled their data for exposure to disease-modifying therapy (DMT), the effect of pregnancy on sNfL was no longer evident. These data were presented said at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

The results suggest that “sNfL may qualify as a sensitive and minimally invasive measure of disease activity in pregnancy,” said Özgür Yaldizli, MD, consultant neurologist at University Hospital Basel (Switzerland). “Strategies allowing the continuation of DMT during pregnancy may be warranted.”

MS preferentially affects women in their reproductive years, said Dr. Yaldizli. Almost one-third of women with MS become pregnant after they receive their diagnosis. A decrease in disease activity is typical in the third trimester, as is an increase in relapse frequency post partum.

DMTs reduce the risk of relapse, but have potential side effects for the woman and the fetus. Some DMTs are immunosuppressants, and they increase the risk of infection during pregnancy. Other DMTs may harm the development of the fetus, particularly if administered early during pregnancy.

“There is an urgent need to identify patients with high disease activity during pregnancy,” said Dr. Yaldizli. Increased levels of NfL, a specific biomarker of neuroaxonal injury, are associated with relapses, MRI activity, and disability worsening among patients with MS. Response to DMT is associated with decreased NfL levels. But few data about sNfL during pregnancy or post partum are available.
 

Relapses were associated with increased sNfL

Dr. Yaldizli and colleagues examined data from the Swiss MS Cohort Study to describe DMT use before, during, and after pregnancy. They also sought to assess sNfL as a marker of disease activity during and after pregnancy and to evaluate whether interrupting DMT because of pregnancy leads to increased sNfL levels.

Eligible participants had prospectively documented pregnancies, and Dr. Yaldizli’s group excluded pregnancies with early termination from their analysis. Serum samples were collected every 6 or 12 months and analyzed using the Simoa NF-light assay. The investigators used univariable and multivariable mixed-effects models to investigate associations between clinical characteristics and longitudinal sNfL levels in women before pregnancy, during pregnancy, and post partum.

Dr. Yaldizli and colleagues included 72 pregnancies in 63 patients with relapsing MS in their analysis. Nine patients had two pregnancies during follow-up. The population’s median age was 31.4 years, and median disease duration was 7.1 years. Median Expanded Disability Status Scale (EDSS) score at last visit before birth was 1.5. Median follow-up time was 6 years.

Most patients were treated with DMT before or during pregnancy. For most patients (39), fingolimod or natalizumab was the last DMT given before birth. Four patients did not use DMT before, during, or after pregnancy. In 14 pregnancies, the patient continued DMT for more than 6 months.

The univariable analysis showed that sNfL levels were 22% higher during pregnancy, compared with outside the pregnancy and postpartum period. The investigators recorded 29 relapses during the pregnancy and postpartum period. Relapses were more likely to occur during the first trimester and the first 3 months post partum. In the multivariable analysis, relapses that occurred within 120 days before serum sampling were associated with 98% higher levels of sNfL. In addition, sNfL was 7% higher for each step increase in EDSS and 13% higher during the pregnancy and postpartum period, compared with outside of that period.

When the investigators included DMT exposure at sampling time in the model, however, the pregnancy and postpartum period no longer had an effect on sNfL. The sNfL levels were 12% lower among patients exposed to DMT, compared with patients without DMT exposure.

Some DMTs, such as interferon-beta, are relatively safe during pregnancy, but the greater the medication’s efficacy, the more problematic it can be, said Dr. Yaldizi. “There are medications that are given, for example, every 6 months, like ocrelizumab. There are other medications that have to be taken daily. Probably the safest medications are those that are not given so often during pregnancy.”

Future research should examine the escalation therapies (i.e., the newer and more effective DMTs) during pregnancy in patients with MS, he added. “Not only in pregnancy, but also in general, we have to look for ways to measure disease activity in patients who switch therapy, who deescalate therapy.”
 

Pregnancy may not forestall disease activity

“The results of this study demonstrate that DMT withdrawal in the context of pregnancy can lead to subclinical disease re-emergence, as evidenced by increased sNfL levels in the DMT-free period,” said Vilija G. Jokubaitis, PhD, senior research fellow in the department of neuroscience at Monash University, Melbourne. Dr. Jokubaitis was not involved in the study.

“Interestingly, the median EDSS score in this cohort was quite low, demonstrating that, even in women with mild disease, pregnancy may not be sufficient to protect against ongoing MS activity.” Nevertheless, 28 of the 63 women were exposed to monoclonal antibody therapy, so it is unclear whether these women have mild disease or well-managed disease on DMT, she added.

“This study provides further evidence that pregnancy planning requires advanced planning, and that therapy continuation into pregnancy should be considered, particularly in women with moderate disease activity, to protect against disease reactivation,” said Dr. Jokubaitis.

The strengths of the study include its prospective design, the investigators’ ability to describe the various DMT exposures before and during pregnancy, and the multivariable mixed-effects modeling, she added. On the other hand, the results are at the group level, individual trajectories in sNfL level are not described, and the small sample size prevented the investigators from differentiating between the effects of various DMTs on sNfL outcomes. In addition, Dr. Yaldizli and colleagues did not take time off DMT into account in the models; they considered DMT exposure as a dichotomous variable.

“More work is needed to determine the therapeutic strategies that will give women with MS the greatest protection against disease reactivation in pregnancy and post partum, whilst also protecting fetal and neonatal outcomes,” said Dr. Jokubaitis. Group studies will enable researchers to identify trends, but neurologists ultimately need to provide individualized advice to their patients. “There is a need to look at [the effect of] DMT identity, timing, and duration of DMT withdrawal on fluctuation of sNfL levels, and how these relate to baseline disease severity,” Dr. Jokubaitis added. Furthermore, researchers must compare sNfL changes in pregnancy between patients with MS and healthy women in large cohorts.

The analysis by Dr. Yaldizli and colleagues was conducted without outside funding. The Swiss MS Cohort receives funding from the Swiss MS society, Biogen, Celgene, Sanofi, Merck, Novartis, Roche, and research associations such as the International Progressive MS Alliance and the Swiss National Science Foundation. Dr. Yaldizli received grants from ECTRIMS/MAGNIMS, the University of Basel, Pro Patient Stiftung, University Hospital Basel, Free Academy Basel, and the Swiss MS Society. He has received advisory board fees from Sanofi Genzyme, Biogen, Almirall, and Novartis. Dr. Jokubaitis has received conference travel support from Merck and Roche and speakers honoraria from Biogen and Roche. These relationships are not related to the current study. Dr. Jokubaitis receives research support from the Australian National Health and Medical Research Grant and MS Research Australia.

egreb@mdedge.com

Among women with multiple sclerosis (MS), levels of serum neurofilament light (sNfL) are higher during pregnancy and the postpartum period. The increase in sNfL is independent of relapses, which suggests that patients have increased subclinical disease activity during this period, according to the researchers.

When the investigators controlled their data for exposure to disease-modifying therapy (DMT), the effect of pregnancy on sNfL was no longer evident. These data were presented said at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

The results suggest that “sNfL may qualify as a sensitive and minimally invasive measure of disease activity in pregnancy,” said Özgür Yaldizli, MD, consultant neurologist at University Hospital Basel (Switzerland). “Strategies allowing the continuation of DMT during pregnancy may be warranted.”

MS preferentially affects women in their reproductive years, said Dr. Yaldizli. Almost one-third of women with MS become pregnant after they receive their diagnosis. A decrease in disease activity is typical in the third trimester, as is an increase in relapse frequency post partum.

DMTs reduce the risk of relapse, but have potential side effects for the woman and the fetus. Some DMTs are immunosuppressants, and they increase the risk of infection during pregnancy. Other DMTs may harm the development of the fetus, particularly if administered early during pregnancy.

“There is an urgent need to identify patients with high disease activity during pregnancy,” said Dr. Yaldizli. Increased levels of NfL, a specific biomarker of neuroaxonal injury, are associated with relapses, MRI activity, and disability worsening among patients with MS. Response to DMT is associated with decreased NfL levels. But few data about sNfL during pregnancy or post partum are available.
 

Relapses were associated with increased sNfL

Dr. Yaldizli and colleagues examined data from the Swiss MS Cohort Study to describe DMT use before, during, and after pregnancy. They also sought to assess sNfL as a marker of disease activity during and after pregnancy and to evaluate whether interrupting DMT because of pregnancy leads to increased sNfL levels.

Eligible participants had prospectively documented pregnancies, and Dr. Yaldizli’s group excluded pregnancies with early termination from their analysis. Serum samples were collected every 6 or 12 months and analyzed using the Simoa NF-light assay. The investigators used univariable and multivariable mixed-effects models to investigate associations between clinical characteristics and longitudinal sNfL levels in women before pregnancy, during pregnancy, and post partum.

Dr. Yaldizli and colleagues included 72 pregnancies in 63 patients with relapsing MS in their analysis. Nine patients had two pregnancies during follow-up. The population’s median age was 31.4 years, and median disease duration was 7.1 years. Median Expanded Disability Status Scale (EDSS) score at last visit before birth was 1.5. Median follow-up time was 6 years.

Most patients were treated with DMT before or during pregnancy. For most patients (39), fingolimod or natalizumab was the last DMT given before birth. Four patients did not use DMT before, during, or after pregnancy. In 14 pregnancies, the patient continued DMT for more than 6 months.

The univariable analysis showed that sNfL levels were 22% higher during pregnancy, compared with outside the pregnancy and postpartum period. The investigators recorded 29 relapses during the pregnancy and postpartum period. Relapses were more likely to occur during the first trimester and the first 3 months post partum. In the multivariable analysis, relapses that occurred within 120 days before serum sampling were associated with 98% higher levels of sNfL. In addition, sNfL was 7% higher for each step increase in EDSS and 13% higher during the pregnancy and postpartum period, compared with outside of that period.

When the investigators included DMT exposure at sampling time in the model, however, the pregnancy and postpartum period no longer had an effect on sNfL. The sNfL levels were 12% lower among patients exposed to DMT, compared with patients without DMT exposure.

Some DMTs, such as interferon-beta, are relatively safe during pregnancy, but the greater the medication’s efficacy, the more problematic it can be, said Dr. Yaldizi. “There are medications that are given, for example, every 6 months, like ocrelizumab. There are other medications that have to be taken daily. Probably the safest medications are those that are not given so often during pregnancy.”

Future research should examine the escalation therapies (i.e., the newer and more effective DMTs) during pregnancy in patients with MS, he added. “Not only in pregnancy, but also in general, we have to look for ways to measure disease activity in patients who switch therapy, who deescalate therapy.”
 

Pregnancy may not forestall disease activity

“The results of this study demonstrate that DMT withdrawal in the context of pregnancy can lead to subclinical disease re-emergence, as evidenced by increased sNfL levels in the DMT-free period,” said Vilija G. Jokubaitis, PhD, senior research fellow in the department of neuroscience at Monash University, Melbourne. Dr. Jokubaitis was not involved in the study.

“Interestingly, the median EDSS score in this cohort was quite low, demonstrating that, even in women with mild disease, pregnancy may not be sufficient to protect against ongoing MS activity.” Nevertheless, 28 of the 63 women were exposed to monoclonal antibody therapy, so it is unclear whether these women have mild disease or well-managed disease on DMT, she added.

“This study provides further evidence that pregnancy planning requires advanced planning, and that therapy continuation into pregnancy should be considered, particularly in women with moderate disease activity, to protect against disease reactivation,” said Dr. Jokubaitis.

The strengths of the study include its prospective design, the investigators’ ability to describe the various DMT exposures before and during pregnancy, and the multivariable mixed-effects modeling, she added. On the other hand, the results are at the group level, individual trajectories in sNfL level are not described, and the small sample size prevented the investigators from differentiating between the effects of various DMTs on sNfL outcomes. In addition, Dr. Yaldizli and colleagues did not take time off DMT into account in the models; they considered DMT exposure as a dichotomous variable.

“More work is needed to determine the therapeutic strategies that will give women with MS the greatest protection against disease reactivation in pregnancy and post partum, whilst also protecting fetal and neonatal outcomes,” said Dr. Jokubaitis. Group studies will enable researchers to identify trends, but neurologists ultimately need to provide individualized advice to their patients. “There is a need to look at [the effect of] DMT identity, timing, and duration of DMT withdrawal on fluctuation of sNfL levels, and how these relate to baseline disease severity,” Dr. Jokubaitis added. Furthermore, researchers must compare sNfL changes in pregnancy between patients with MS and healthy women in large cohorts.

The analysis by Dr. Yaldizli and colleagues was conducted without outside funding. The Swiss MS Cohort receives funding from the Swiss MS society, Biogen, Celgene, Sanofi, Merck, Novartis, Roche, and research associations such as the International Progressive MS Alliance and the Swiss National Science Foundation. Dr. Yaldizli received grants from ECTRIMS/MAGNIMS, the University of Basel, Pro Patient Stiftung, University Hospital Basel, Free Academy Basel, and the Swiss MS Society. He has received advisory board fees from Sanofi Genzyme, Biogen, Almirall, and Novartis. Dr. Jokubaitis has received conference travel support from Merck and Roche and speakers honoraria from Biogen and Roche. These relationships are not related to the current study. Dr. Jokubaitis receives research support from the Australian National Health and Medical Research Grant and MS Research Australia.

egreb@mdedge.com

Over-the-counter (OTC) supplements advertised to improve memory and cognitive function may contain unapproved pharmaceutical drugs in potentially dangerous combinations and dosages, new research shows.

“Americans spend more than $600 million on over-the-counter smart pills every year, but we know very little about what is actually in these products,” said Pieter A. Cohen, MD, of the department of medicine at Harvard Medical School, Boston.

“Finding new combinations of drugs [that have] never been tested in humans in over-the-counter brain-boosting supplements is alarming,” said Dr. Cohen.

The study was published online Sept. 23 in Neurology Clinical Practice, a journal of the American Academy of Neurology.
 

Buyer beware

In a search of the National Institutes of Health Dietary Supplement Label Database and the Natural Medicines Database, Dr. Cohen and colleagues identified 10 supplements labeled as containing omberacetam, aniracetam, phenylpiracetam, or oxiracetam – four analogues of piracetam that are not approved for human use in the United States. Piracetam is also not approved in the United States.

In these 10 products, five unapproved drugs were discovered – omberacetam and aniracetam along with three others (phenibut, vinpocetine and picamilon).

By consuming the recommended serving size of these products, consumers could be exposed to pharmaceutical-level dosages of drugs including a maximum of 40.6 mg omberacetam (typical pharmacologic dose 10 mg), 502 mg of aniracetam (typical pharmacologic dose 200-750 mg), 15.4 mg of phenibut (typical dose 250-500 mg), 4.3 mg of vinpocetine (typical dose 5-40 mg), and 90.1 mg of picamilon (typical  dose 50-200 mg), the study team reported.

Several drugs detected in these “smart” pills were not declared on the label, and several declared drugs were not detected in the products. For those products with drug quantities provided on the labels, three-quarters of declared quantities were inaccurate.

Consumers who use these cognitive enhancers could be exposed to amounts of these unapproved drugs that are fourfold greater than pharmaceutical dosages and combinations never tested in humans, the study team says. One product combined three different unapproved drugs and another product contained four different drugs.

“We have previously shown that these products may contain individual foreign drugs, but in our new study we found complex combinations of foreign drugs, up to four different drugs in a single product,” Dr. Cohen said.

The presence of these unapproved drugs in supplements, including at supratherapeutic dosages, suggests “serious risks to consumers and weaknesses in the regulatory framework under which supplements are permitted to be introduced in the U.S.,” Dr. Cohen and colleagues wrote.

“We should counsel our patients to avoid over-the-counter ‘smart pills’ until we can be assured as to the safety and efficacy of these products,” said Dr. Cohen.
 

Concerning findings

Glen R. Finney, MD, director of the Geisinger Memory and Cognition Program at the Neuroscience Institute, Geisinger Health System, Wilkes-Barre, Penn., said in an interview that two findings are very concerning: the lack of listed ingredients and especially the presence of unlisted drugs at active levels. “What if a person has a sensitivity or allergy to one of the unlisted drugs? This is a safety issue and a consumer issue,” Dr. Finney said.

Despite being widely promoted on television, “over-the-counter supplements are not regulated, so there is no guarantee that they contain what they claim, and there is very little evidence that they help memory and thinking even when they do have the ingredients they claim in the supplement,” said Dr. Finney,

“The best way to stay safe and help memory and thinking is to speak with your health providers about proven treatments that have good safety regulation, so you know what you’re getting, and what you’re getting from it,” Dr. Finney advised.

The study had no targeted funding. Dr. Cohen has collaborated in research with NSF International, received compensation from UptoDate, and received research support from Consumers Union and PEW Charitable Trusts. Dr. Finney has no relevant disclosures.

A version of this article originally appeared on Medscape.com.

Over-the-counter (OTC) supplements advertised to improve memory and cognitive function may contain unapproved pharmaceutical drugs in potentially dangerous combinations and dosages, new research shows.

“Americans spend more than $600 million on over-the-counter smart pills every year, but we know very little about what is actually in these products,” said Pieter A. Cohen, MD, of the department of medicine at Harvard Medical School, Boston.

“Finding new combinations of drugs [that have] never been tested in humans in over-the-counter brain-boosting supplements is alarming,” said Dr. Cohen.

The study was published online Sept. 23 in Neurology Clinical Practice, a journal of the American Academy of Neurology.
 

Buyer beware

In a search of the National Institutes of Health Dietary Supplement Label Database and the Natural Medicines Database, Dr. Cohen and colleagues identified 10 supplements labeled as containing omberacetam, aniracetam, phenylpiracetam, or oxiracetam – four analogues of piracetam that are not approved for human use in the United States. Piracetam is also not approved in the United States.

In these 10 products, five unapproved drugs were discovered – omberacetam and aniracetam along with three others (phenibut, vinpocetine and picamilon).

By consuming the recommended serving size of these products, consumers could be exposed to pharmaceutical-level dosages of drugs including a maximum of 40.6 mg omberacetam (typical pharmacologic dose 10 mg), 502 mg of aniracetam (typical pharmacologic dose 200-750 mg), 15.4 mg of phenibut (typical dose 250-500 mg), 4.3 mg of vinpocetine (typical dose 5-40 mg), and 90.1 mg of picamilon (typical  dose 50-200 mg), the study team reported.

Several drugs detected in these “smart” pills were not declared on the label, and several declared drugs were not detected in the products. For those products with drug quantities provided on the labels, three-quarters of declared quantities were inaccurate.

Consumers who use these cognitive enhancers could be exposed to amounts of these unapproved drugs that are fourfold greater than pharmaceutical dosages and combinations never tested in humans, the study team says. One product combined three different unapproved drugs and another product contained four different drugs.

“We have previously shown that these products may contain individual foreign drugs, but in our new study we found complex combinations of foreign drugs, up to four different drugs in a single product,” Dr. Cohen said.

The presence of these unapproved drugs in supplements, including at supratherapeutic dosages, suggests “serious risks to consumers and weaknesses in the regulatory framework under which supplements are permitted to be introduced in the U.S.,” Dr. Cohen and colleagues wrote.

“We should counsel our patients to avoid over-the-counter ‘smart pills’ until we can be assured as to the safety and efficacy of these products,” said Dr. Cohen.
 

Concerning findings

Glen R. Finney, MD, director of the Geisinger Memory and Cognition Program at the Neuroscience Institute, Geisinger Health System, Wilkes-Barre, Penn., said in an interview that two findings are very concerning: the lack of listed ingredients and especially the presence of unlisted drugs at active levels. “What if a person has a sensitivity or allergy to one of the unlisted drugs? This is a safety issue and a consumer issue,” Dr. Finney said.

Despite being widely promoted on television, “over-the-counter supplements are not regulated, so there is no guarantee that they contain what they claim, and there is very little evidence that they help memory and thinking even when they do have the ingredients they claim in the supplement,” said Dr. Finney,

“The best way to stay safe and help memory and thinking is to speak with your health providers about proven treatments that have good safety regulation, so you know what you’re getting, and what you’re getting from it,” Dr. Finney advised.

The study had no targeted funding. Dr. Cohen has collaborated in research with NSF International, received compensation from UptoDate, and received research support from Consumers Union and PEW Charitable Trusts. Dr. Finney has no relevant disclosures.

A version of this article originally appeared on Medscape.com.

Over-the-counter (OTC) supplements advertised to improve memory and cognitive function may contain unapproved pharmaceutical drugs in potentially dangerous combinations and dosages, new research shows.

“Americans spend more than $600 million on over-the-counter smart pills every year, but we know very little about what is actually in these products,” said Pieter A. Cohen, MD, of the department of medicine at Harvard Medical School, Boston.

“Finding new combinations of drugs [that have] never been tested in humans in over-the-counter brain-boosting supplements is alarming,” said Dr. Cohen.

The study was published online Sept. 23 in Neurology Clinical Practice, a journal of the American Academy of Neurology.
 

Buyer beware

In a search of the National Institutes of Health Dietary Supplement Label Database and the Natural Medicines Database, Dr. Cohen and colleagues identified 10 supplements labeled as containing omberacetam, aniracetam, phenylpiracetam, or oxiracetam – four analogues of piracetam that are not approved for human use in the United States. Piracetam is also not approved in the United States.

In these 10 products, five unapproved drugs were discovered – omberacetam and aniracetam along with three others (phenibut, vinpocetine and picamilon).

By consuming the recommended serving size of these products, consumers could be exposed to pharmaceutical-level dosages of drugs including a maximum of 40.6 mg omberacetam (typical pharmacologic dose 10 mg), 502 mg of aniracetam (typical pharmacologic dose 200-750 mg), 15.4 mg of phenibut (typical dose 250-500 mg), 4.3 mg of vinpocetine (typical dose 5-40 mg), and 90.1 mg of picamilon (typical  dose 50-200 mg), the study team reported.

Several drugs detected in these “smart” pills were not declared on the label, and several declared drugs were not detected in the products. For those products with drug quantities provided on the labels, three-quarters of declared quantities were inaccurate.

Consumers who use these cognitive enhancers could be exposed to amounts of these unapproved drugs that are fourfold greater than pharmaceutical dosages and combinations never tested in humans, the study team says. One product combined three different unapproved drugs and another product contained four different drugs.

“We have previously shown that these products may contain individual foreign drugs, but in our new study we found complex combinations of foreign drugs, up to four different drugs in a single product,” Dr. Cohen said.

The presence of these unapproved drugs in supplements, including at supratherapeutic dosages, suggests “serious risks to consumers and weaknesses in the regulatory framework under which supplements are permitted to be introduced in the U.S.,” Dr. Cohen and colleagues wrote.

“We should counsel our patients to avoid over-the-counter ‘smart pills’ until we can be assured as to the safety and efficacy of these products,” said Dr. Cohen.
 

Concerning findings

Glen R. Finney, MD, director of the Geisinger Memory and Cognition Program at the Neuroscience Institute, Geisinger Health System, Wilkes-Barre, Penn., said in an interview that two findings are very concerning: the lack of listed ingredients and especially the presence of unlisted drugs at active levels. “What if a person has a sensitivity or allergy to one of the unlisted drugs? This is a safety issue and a consumer issue,” Dr. Finney said.

Despite being widely promoted on television, “over-the-counter supplements are not regulated, so there is no guarantee that they contain what they claim, and there is very little evidence that they help memory and thinking even when they do have the ingredients they claim in the supplement,” said Dr. Finney,

“The best way to stay safe and help memory and thinking is to speak with your health providers about proven treatments that have good safety regulation, so you know what you’re getting, and what you’re getting from it,” Dr. Finney advised.

The study had no targeted funding. Dr. Cohen has collaborated in research with NSF International, received compensation from UptoDate, and received research support from Consumers Union and PEW Charitable Trusts. Dr. Finney has no relevant disclosures.

A version of this article originally appeared on Medscape.com.

Recently I was in a minor car accident. No injuries, just some bent metal and scratched paint from a low-speed parking lot mishap.

The other driver and I got out of our cars, made sure we were both okay, and then I said “Let’s exchange insurance information.” We got our insurance cards out; I took a picture of her card, and she wrote down my info. Then we drove off and went on with our days. The whole thing took a few minutes.

Why am I writing about this?

Because it was all handled very politely. There were no angry words, name calling, or heated exchanges. We checked the damage, made sure the other was okay, and exchanged insurance cards ... without a single impolite phrase or gesture.

To me this is a good thing. In a world in which people yell (and sometimes brandish weapons) over imagined and minor offenses, in which political candidates exchange crude insults rather then debate policy, and in which an opposing viewpoint is treated as blasphemy rather than an honest difference of opinion, it was nice to have a polite, adult, exchange under unpleasant circumstances.

Perhaps it’s sad to find relief in such a minor event, but it’s also reassuring. In medicine (especially hospital work) we often see people at their very worst, and dealing with them can be a challenge. We live in a world of at-times seemingly endless rudeness, one-upping, and “problem-solving” with yelling, threats, and intimidation.

So I was glad the minor incident resulted in nothing more serious at the time than a brief, polite, conversation. It’s nice to know many people out there still subscribe to civil ideas and polite behavior, even when the circumstances are difficult.

Dr. Block has a solo neurology practice in Scottsdale, Arizona. He has nothing to disclose.

Recently I was in a minor car accident. No injuries, just some bent metal and scratched paint from a low-speed parking lot mishap.

The other driver and I got out of our cars, made sure we were both okay, and then I said “Let’s exchange insurance information.” We got our insurance cards out; I took a picture of her card, and she wrote down my info. Then we drove off and went on with our days. The whole thing took a few minutes.

Why am I writing about this?

Because it was all handled very politely. There were no angry words, name calling, or heated exchanges. We checked the damage, made sure the other was okay, and exchanged insurance cards ... without a single impolite phrase or gesture.

To me this is a good thing. In a world in which people yell (and sometimes brandish weapons) over imagined and minor offenses, in which political candidates exchange crude insults rather then debate policy, and in which an opposing viewpoint is treated as blasphemy rather than an honest difference of opinion, it was nice to have a polite, adult, exchange under unpleasant circumstances.

Perhaps it’s sad to find relief in such a minor event, but it’s also reassuring. In medicine (especially hospital work) we often see people at their very worst, and dealing with them can be a challenge. We live in a world of at-times seemingly endless rudeness, one-upping, and “problem-solving” with yelling, threats, and intimidation.

So I was glad the minor incident resulted in nothing more serious at the time than a brief, polite, conversation. It’s nice to know many people out there still subscribe to civil ideas and polite behavior, even when the circumstances are difficult.

Dr. Block has a solo neurology practice in Scottsdale, Arizona. He has nothing to disclose.

Recently I was in a minor car accident. No injuries, just some bent metal and scratched paint from a low-speed parking lot mishap.

The other driver and I got out of our cars, made sure we were both okay, and then I said “Let’s exchange insurance information.” We got our insurance cards out; I took a picture of her card, and she wrote down my info. Then we drove off and went on with our days. The whole thing took a few minutes.

Why am I writing about this?

Because it was all handled very politely. There were no angry words, name calling, or heated exchanges. We checked the damage, made sure the other was okay, and exchanged insurance cards ... without a single impolite phrase or gesture.

To me this is a good thing. In a world in which people yell (and sometimes brandish weapons) over imagined and minor offenses, in which political candidates exchange crude insults rather then debate policy, and in which an opposing viewpoint is treated as blasphemy rather than an honest difference of opinion, it was nice to have a polite, adult, exchange under unpleasant circumstances.

Perhaps it’s sad to find relief in such a minor event, but it’s also reassuring. In medicine (especially hospital work) we often see people at their very worst, and dealing with them can be a challenge. We live in a world of at-times seemingly endless rudeness, one-upping, and “problem-solving” with yelling, threats, and intimidation.

So I was glad the minor incident resulted in nothing more serious at the time than a brief, polite, conversation. It’s nice to know many people out there still subscribe to civil ideas and polite behavior, even when the circumstances are difficult.

Dr. Block has a solo neurology practice in Scottsdale, Arizona. He has nothing to disclose.

The cumulative percentage of COVID-19 cases reported in children continues to climb, but “the history behind that cumulative number shows substantial change,” according to a new analysis of state health department data.

As of Sept. 10, the 549,432 cases in children represented 10.0% of all reported COVID-19 cases in the United States following a substantial rise over the course of the pandemic – the figure was 7.7% on July 16 and 3.2% on May 7, Blake Sisk, PhD, of the American Academy of Pediatrics and associates reported Sept. 29 in Pediatrics.

Unlike the cumulative number, the weekly proportion of cases in children fell early in the summer but then started climbing again in late July. “In the last 8 weeks, children represented between 12%-15.9% of new weekly reported cases,” Dr. Sisk and associates wrote.

Despite the increase, however, the proportion of pediatric COVID-19 cases is still well below children’s share of the overall population (22.6%). Also, “it is unclear how much of the increase in child cases is due to increased testing capacity, although CDC data from public and commercial laboratories show the share of all tests administered to children ages 0-17 has remained stable at 5%-7% since late April,” they said.

Data for the current report were drawn from 49 state health department websites (New York state does not report ages for COVID-19 cases), along with New York City, the District of Columbia, Puerto Rico, and Guam. Alabama changed its definition of a child case in August and was not included in the trend analysis (see graph), the investigators explained.

Those data show “substantial variation in case growth by region: in April, a preponderance of cases was in the Northeast. In June, cases surged in the South and West, followed by mid-July increases in the Midwest,” Dr. Sisk and associates said.

The increase among children in Midwest states is ongoing with the number of new cases reaching its highest level yet during the week ending Sept. 10, they reported.

rfranki@mdedge.com

SOURCE: Sisk B et al. Pediatrics. 2020 Sep 29. doi: 10.1542/peds.2020-027425.

The cumulative percentage of COVID-19 cases reported in children continues to climb, but “the history behind that cumulative number shows substantial change,” according to a new analysis of state health department data.

As of Sept. 10, the 549,432 cases in children represented 10.0% of all reported COVID-19 cases in the United States following a substantial rise over the course of the pandemic – the figure was 7.7% on July 16 and 3.2% on May 7, Blake Sisk, PhD, of the American Academy of Pediatrics and associates reported Sept. 29 in Pediatrics.

Unlike the cumulative number, the weekly proportion of cases in children fell early in the summer but then started climbing again in late July. “In the last 8 weeks, children represented between 12%-15.9% of new weekly reported cases,” Dr. Sisk and associates wrote.

Despite the increase, however, the proportion of pediatric COVID-19 cases is still well below children’s share of the overall population (22.6%). Also, “it is unclear how much of the increase in child cases is due to increased testing capacity, although CDC data from public and commercial laboratories show the share of all tests administered to children ages 0-17 has remained stable at 5%-7% since late April,” they said.

Data for the current report were drawn from 49 state health department websites (New York state does not report ages for COVID-19 cases), along with New York City, the District of Columbia, Puerto Rico, and Guam. Alabama changed its definition of a child case in August and was not included in the trend analysis (see graph), the investigators explained.

Those data show “substantial variation in case growth by region: in April, a preponderance of cases was in the Northeast. In June, cases surged in the South and West, followed by mid-July increases in the Midwest,” Dr. Sisk and associates said.

The increase among children in Midwest states is ongoing with the number of new cases reaching its highest level yet during the week ending Sept. 10, they reported.

rfranki@mdedge.com

SOURCE: Sisk B et al. Pediatrics. 2020 Sep 29. doi: 10.1542/peds.2020-027425.

The cumulative percentage of COVID-19 cases reported in children continues to climb, but “the history behind that cumulative number shows substantial change,” according to a new analysis of state health department data.

As of Sept. 10, the 549,432 cases in children represented 10.0% of all reported COVID-19 cases in the United States following a substantial rise over the course of the pandemic – the figure was 7.7% on July 16 and 3.2% on May 7, Blake Sisk, PhD, of the American Academy of Pediatrics and associates reported Sept. 29 in Pediatrics.

Unlike the cumulative number, the weekly proportion of cases in children fell early in the summer but then started climbing again in late July. “In the last 8 weeks, children represented between 12%-15.9% of new weekly reported cases,” Dr. Sisk and associates wrote.

Despite the increase, however, the proportion of pediatric COVID-19 cases is still well below children’s share of the overall population (22.6%). Also, “it is unclear how much of the increase in child cases is due to increased testing capacity, although CDC data from public and commercial laboratories show the share of all tests administered to children ages 0-17 has remained stable at 5%-7% since late April,” they said.

Data for the current report were drawn from 49 state health department websites (New York state does not report ages for COVID-19 cases), along with New York City, the District of Columbia, Puerto Rico, and Guam. Alabama changed its definition of a child case in August and was not included in the trend analysis (see graph), the investigators explained.

Those data show “substantial variation in case growth by region: in April, a preponderance of cases was in the Northeast. In June, cases surged in the South and West, followed by mid-July increases in the Midwest,” Dr. Sisk and associates said.

The increase among children in Midwest states is ongoing with the number of new cases reaching its highest level yet during the week ending Sept. 10, they reported.

rfranki@mdedge.com

SOURCE: Sisk B et al. Pediatrics. 2020 Sep 29. doi: 10.1542/peds.2020-027425.

Rural primary care doctors are facing a new set of obstacles to practicing in the COVID-19 pandemic. These include struggling with seeing patients virtually and treating patients who have politicized the virus. Additionally, the pandemic has exposed rural practices to greater financial difficulties.

Courtesy Dr. Jacqueline W. Fincher

Before the pandemic some rurally based primary care physicians were already working through big challenges, such as having few local medical colleagues to consult and working in small practices with lean budgets. In fact, data gathered by the National Rural Health Association showed that there are only 40 primary care physicians per 100,000 patients in rural regions, compared with 53 in urban areas – and the number of physicians overall is 13 per 10,000 in rural areas, compared with 31 in cities.

In the prepandemic world, for some doctors, the challenges were balanced by the benefits of practicing in these sparsely populated communities with scenic, low-traffic roads. Some perks of practicing in rural areas touted by doctors included having a fast commute, being able to swim in a lake near the office before work, having a low cost of living, and feeling like they are making a difference in their communities as they treat generations of the families they see around town.

But today, new hurdles to practicing medicine in rural America created by the COVID-19 pandemic have caused the hardships to feel heavier than the joys at times for some physicians interviewed by MDedge.

Many independent rural practices in need of assistance were not able to get much from the federal Provider Relief Funds, said John M. Westfall, MD, who is director of the Robert Graham Center for Policy Studies in Family Medicine and Primary Care, in an interview.

“Rural primary care doctors function independently or in smaller critical access hospitals and community health centers,” said Dr. Westfall, who previously practiced family medicine in a small town in Colorado. “Many of these have much less financial reserves so are at risk of cutbacks and closure.”

Jacqueline W. Fincher, MD, an internist based in a tiny Georgia community along the highway between Atlanta and Augusta, said her small practice works on really thin margins and doesn’t have much cushion. At the beginning of the pandemic, all visits were down, and her practice operated at a loss. To help, Dr. Fincher and her colleagues applied for funding from the Small Business Administration’s Paycheck Protection Program (PPP) through the CARES Act.

“COVID-19 has had a tremendous impact especially on primary care practices. We live and die by volume. … Our volume in mid-March to mid-May really dropped dramatically,” explained Dr. Fincher, who is also president of the American College of Physicians. “The PPP sustained us for 2 months, enabling us to pay our staff and to remain open and get us up and running on telehealth.”
 

Starting up telemedicine

Experiencing spotty or no access to broadband Internet is nothing new to rural physicians, but having this problem interfere with their ability to provide care to patients is.

As much of the American health system rapidly embraced telehealth during the pandemic, obtaining access to high-speed Internet has been a major challenge for rural patients, noted Dr. Westfall.

“Some practices were able to quickly adopt some telehealth capacity with phone and video. Changes in payment for telehealth helped. But in some rural communities there was not adequate Internet bandwidth for quality video connections. And some patients did not have the means for high-speed video connections,” Dr. Westfall said.

Indeed, according to a 2019 Pew Research Center survey, 63% of rural Americans say they can access the Internet through a broadband connection at home, compared with 75% and 79% in suburban and urban areas, respectively.

G&P Productions

In the Appalachian town of Zanesville, Ohio, for example, family physician Shelly L. Dunmyer, MD, and her colleagues discovered that many patients don’t have Internet access at home. Dr. Fincher has to go to the office to conduct telehealth visits because her own Internet access at home is unpredictable. As for patients, it may take 15 minutes for them to work out technical glitches and find good Internet reception, said Dr. Fincher. For internist Y. Ki Shin, MD, who practices in the coastal town of Montesano in Washington state, about 25% of his practice’s telehealth visits must be conducted by phone because of limitations on video, such as lack of high-speed access.

But telephone visits are often insufficient replacements for appointments via video, according to several rural physicians interviewed for this piece.

“Telehealth can be frustrating at times due to connectivity issues which can be difficult at times in the rural areas,” said Dr. Fincher. “In order for telehealth to be reasonably helpful to patients and physicians to care for people with chronic problems, the patients must have things like blood pressure monitors, glucometers, and scales to address problems like hypertension, diabetes myelitis, and congestive heart failure.”

“If you have the audio and video and the data from these devices, you’re good. If you don’t have these data, and/or don’t have the video you just can’t provide good care,” she explained.

G&P Productions

Dr. Dunmyer and her colleagues at Medical Home Primary Care Center in Zanesville, Ohio, found a way to get around the problem of patients not being able to access Internet to participate in video visits from their homes. This involved having her patients drive into her practice’s parking lot to participate in modified telehealth visits. Staffers gave iPads to patients in their cars, and Dr. Dunmyer conducted visits from her office, about 50 yards away.

“We were even doing Medicare wellness visits: Instead of asking them to get up and move around the room, we would sit at the window and wave at them, ask them to get out, walk around the car. We were able to check mobility and all kinds of things that we’d normally do in the office,” Dr. Dunmyer explained in an interview.

The family physician noted that her practice is now conducting fewer parking lot visits since her office is allowing in-person appointments, but that they’re still an option for her patients.
 

Treating political adversaries

Some rural physicians have experienced strained relationships with patients for reasons other than technology – stark differences in opinion over the pandemic itself. Certain patients are following President Trump’s lead and questioning everything from the pandemic death toll to preventive measures recommended by scientists and medical experts, physicians interviewed by MDedge said.

Patients everywhere share these viewpoints, of course, but research and election results confirm that rural areas are more receptive to conservative viewpoints. In 2018, a Pew Research Center survey reported that rural and urban areas are “becoming more polarized politically,” and “rural areas tend to have a higher concentration of Republicans and Republican-leaning independents.” For example, 40% of rural respondents reported “very warm” or “somewhat warm” feelings toward Donald Trump, compared with just 19% in urban areas.

Dr. Shin has struggled to cope with patients who want to argue about pandemic safety precautions like wearing masks and seem to question whether systemic racism exists.

“We are seeing a lot more people who feel that this pandemic is not real, that it’s a political and not-true infection,” he said in an interview. “We’ve had patients who were angry at us because we made them wear masks, and some were demanding hydroxychloroquine and wanted to have an argument because we’re not going to prescribe it for them.”

In one situation, which he found especially disturbing, Dr. Shin had to leave the exam room because a patient wouldn’t stop challenging him regarding the pandemic. Things have gotten so bad that Dr. Shin has even questioned whether he wants to continue his long career in his small town because of local political attitudes such as opposition to mask-wearing and social distancing.

“Mr. Trump’s misinformation on this pandemic made my job much more difficult. As a minority, I feel less safe in my community than ever,” said Dr. Shin, who described himself as Asian American.

Despite these new stressors, Dr. Shin has experienced some joyful moments while practicing medicine in the pandemic.

Courtesy Dr. Clara Shin

He said a recent home visit to a patient who had been hospitalized for over 3 months and nearly died helped him put political disputes with his patients into perspective.

“He was discharged home but is bedbound. He had gangrene on his toes, and I could not fully examine him using video,” Dr. Shin recalled. “It was tricky to find the house, but a very large Trump sign was very helpful in locating it. It was a good visit: He was happy to see me, and I was happy to see that he was doing okay at home.”

“I need to remind myself that supporting Mr. Trump does not always mean that my patient supports Mr. Trump’s view on the pandemic and the race issues in our country,” Dr. Shin added.

The Washington-based internist said he also tells himself that, even if his patients refuse to follow his strong advice regarding pandemic precautions, it does not mean he has failed as a doctor.

“I need to continue to educate patients about the dangers of COVID infection but cannot be angry if they don’t choose to follow my recommendations,” he noted.

Dr. Fincher says her close connection with patients has allowed her to smooth over politically charged claims about the pandemic in the town of Thomson, Georgia, with a population 6,800.

“I have a sense that, even though we may differ in our understanding of some basic facts, they appreciate what I say since we have a long-term relationship built on trust,” she said. This kind of trust, Dr. Fincher suggested, may be more common than in urban areas where there’s a larger supply of physicians, and patients don’t see the same doctors for long periods of time.

“It’s more meaningful when it comes from me, rather than doctors who are [new to patients] every year when their employer changes their insurance,” she noted.

Rural primary care doctors are facing a new set of obstacles to practicing in the COVID-19 pandemic. These include struggling with seeing patients virtually and treating patients who have politicized the virus. Additionally, the pandemic has exposed rural practices to greater financial difficulties.

Courtesy Dr. Jacqueline W. Fincher

Before the pandemic some rurally based primary care physicians were already working through big challenges, such as having few local medical colleagues to consult and working in small practices with lean budgets. In fact, data gathered by the National Rural Health Association showed that there are only 40 primary care physicians per 100,000 patients in rural regions, compared with 53 in urban areas – and the number of physicians overall is 13 per 10,000 in rural areas, compared with 31 in cities.

In the prepandemic world, for some doctors, the challenges were balanced by the benefits of practicing in these sparsely populated communities with scenic, low-traffic roads. Some perks of practicing in rural areas touted by doctors included having a fast commute, being able to swim in a lake near the office before work, having a low cost of living, and feeling like they are making a difference in their communities as they treat generations of the families they see around town.

But today, new hurdles to practicing medicine in rural America created by the COVID-19 pandemic have caused the hardships to feel heavier than the joys at times for some physicians interviewed by MDedge.

Many independent rural practices in need of assistance were not able to get much from the federal Provider Relief Funds, said John M. Westfall, MD, who is director of the Robert Graham Center for Policy Studies in Family Medicine and Primary Care, in an interview.

“Rural primary care doctors function independently or in smaller critical access hospitals and community health centers,” said Dr. Westfall, who previously practiced family medicine in a small town in Colorado. “Many of these have much less financial reserves so are at risk of cutbacks and closure.”

Jacqueline W. Fincher, MD, an internist based in a tiny Georgia community along the highway between Atlanta and Augusta, said her small practice works on really thin margins and doesn’t have much cushion. At the beginning of the pandemic, all visits were down, and her practice operated at a loss. To help, Dr. Fincher and her colleagues applied for funding from the Small Business Administration’s Paycheck Protection Program (PPP) through the CARES Act.

“COVID-19 has had a tremendous impact especially on primary care practices. We live and die by volume. … Our volume in mid-March to mid-May really dropped dramatically,” explained Dr. Fincher, who is also president of the American College of Physicians. “The PPP sustained us for 2 months, enabling us to pay our staff and to remain open and get us up and running on telehealth.”
 

Starting up telemedicine

Experiencing spotty or no access to broadband Internet is nothing new to rural physicians, but having this problem interfere with their ability to provide care to patients is.

As much of the American health system rapidly embraced telehealth during the pandemic, obtaining access to high-speed Internet has been a major challenge for rural patients, noted Dr. Westfall.

“Some practices were able to quickly adopt some telehealth capacity with phone and video. Changes in payment for telehealth helped. But in some rural communities there was not adequate Internet bandwidth for quality video connections. And some patients did not have the means for high-speed video connections,” Dr. Westfall said.

Indeed, according to a 2019 Pew Research Center survey, 63% of rural Americans say they can access the Internet through a broadband connection at home, compared with 75% and 79% in suburban and urban areas, respectively.

G&P Productions

In the Appalachian town of Zanesville, Ohio, for example, family physician Shelly L. Dunmyer, MD, and her colleagues discovered that many patients don’t have Internet access at home. Dr. Fincher has to go to the office to conduct telehealth visits because her own Internet access at home is unpredictable. As for patients, it may take 15 minutes for them to work out technical glitches and find good Internet reception, said Dr. Fincher. For internist Y. Ki Shin, MD, who practices in the coastal town of Montesano in Washington state, about 25% of his practice’s telehealth visits must be conducted by phone because of limitations on video, such as lack of high-speed access.

But telephone visits are often insufficient replacements for appointments via video, according to several rural physicians interviewed for this piece.

“Telehealth can be frustrating at times due to connectivity issues which can be difficult at times in the rural areas,” said Dr. Fincher. “In order for telehealth to be reasonably helpful to patients and physicians to care for people with chronic problems, the patients must have things like blood pressure monitors, glucometers, and scales to address problems like hypertension, diabetes myelitis, and congestive heart failure.”

“If you have the audio and video and the data from these devices, you’re good. If you don’t have these data, and/or don’t have the video you just can’t provide good care,” she explained.

G&P Productions

Dr. Dunmyer and her colleagues at Medical Home Primary Care Center in Zanesville, Ohio, found a way to get around the problem of patients not being able to access Internet to participate in video visits from their homes. This involved having her patients drive into her practice’s parking lot to participate in modified telehealth visits. Staffers gave iPads to patients in their cars, and Dr. Dunmyer conducted visits from her office, about 50 yards away.

“We were even doing Medicare wellness visits: Instead of asking them to get up and move around the room, we would sit at the window and wave at them, ask them to get out, walk around the car. We were able to check mobility and all kinds of things that we’d normally do in the office,” Dr. Dunmyer explained in an interview.

The family physician noted that her practice is now conducting fewer parking lot visits since her office is allowing in-person appointments, but that they’re still an option for her patients.
 

Treating political adversaries

Some rural physicians have experienced strained relationships with patients for reasons other than technology – stark differences in opinion over the pandemic itself. Certain patients are following President Trump’s lead and questioning everything from the pandemic death toll to preventive measures recommended by scientists and medical experts, physicians interviewed by MDedge said.

Patients everywhere share these viewpoints, of course, but research and election results confirm that rural areas are more receptive to conservative viewpoints. In 2018, a Pew Research Center survey reported that rural and urban areas are “becoming more polarized politically,” and “rural areas tend to have a higher concentration of Republicans and Republican-leaning independents.” For example, 40% of rural respondents reported “very warm” or “somewhat warm” feelings toward Donald Trump, compared with just 19% in urban areas.

Dr. Shin has struggled to cope with patients who want to argue about pandemic safety precautions like wearing masks and seem to question whether systemic racism exists.

“We are seeing a lot more people who feel that this pandemic is not real, that it’s a political and not-true infection,” he said in an interview. “We’ve had patients who were angry at us because we made them wear masks, and some were demanding hydroxychloroquine and wanted to have an argument because we’re not going to prescribe it for them.”

In one situation, which he found especially disturbing, Dr. Shin had to leave the exam room because a patient wouldn’t stop challenging him regarding the pandemic. Things have gotten so bad that Dr. Shin has even questioned whether he wants to continue his long career in his small town because of local political attitudes such as opposition to mask-wearing and social distancing.

“Mr. Trump’s misinformation on this pandemic made my job much more difficult. As a minority, I feel less safe in my community than ever,” said Dr. Shin, who described himself as Asian American.

Despite these new stressors, Dr. Shin has experienced some joyful moments while practicing medicine in the pandemic.

Courtesy Dr. Clara Shin

He said a recent home visit to a patient who had been hospitalized for over 3 months and nearly died helped him put political disputes with his patients into perspective.

“He was discharged home but is bedbound. He had gangrene on his toes, and I could not fully examine him using video,” Dr. Shin recalled. “It was tricky to find the house, but a very large Trump sign was very helpful in locating it. It was a good visit: He was happy to see me, and I was happy to see that he was doing okay at home.”

“I need to remind myself that supporting Mr. Trump does not always mean that my patient supports Mr. Trump’s view on the pandemic and the race issues in our country,” Dr. Shin added.

The Washington-based internist said he also tells himself that, even if his patients refuse to follow his strong advice regarding pandemic precautions, it does not mean he has failed as a doctor.

“I need to continue to educate patients about the dangers of COVID infection but cannot be angry if they don’t choose to follow my recommendations,” he noted.

Dr. Fincher says her close connection with patients has allowed her to smooth over politically charged claims about the pandemic in the town of Thomson, Georgia, with a population 6,800.

“I have a sense that, even though we may differ in our understanding of some basic facts, they appreciate what I say since we have a long-term relationship built on trust,” she said. This kind of trust, Dr. Fincher suggested, may be more common than in urban areas where there’s a larger supply of physicians, and patients don’t see the same doctors for long periods of time.

“It’s more meaningful when it comes from me, rather than doctors who are [new to patients] every year when their employer changes their insurance,” she noted.

Rural primary care doctors are facing a new set of obstacles to practicing in the COVID-19 pandemic. These include struggling with seeing patients virtually and treating patients who have politicized the virus. Additionally, the pandemic has exposed rural practices to greater financial difficulties.

Courtesy Dr. Jacqueline W. Fincher

Before the pandemic some rurally based primary care physicians were already working through big challenges, such as having few local medical colleagues to consult and working in small practices with lean budgets. In fact, data gathered by the National Rural Health Association showed that there are only 40 primary care physicians per 100,000 patients in rural regions, compared with 53 in urban areas – and the number of physicians overall is 13 per 10,000 in rural areas, compared with 31 in cities.

In the prepandemic world, for some doctors, the challenges were balanced by the benefits of practicing in these sparsely populated communities with scenic, low-traffic roads. Some perks of practicing in rural areas touted by doctors included having a fast commute, being able to swim in a lake near the office before work, having a low cost of living, and feeling like they are making a difference in their communities as they treat generations of the families they see around town.

But today, new hurdles to practicing medicine in rural America created by the COVID-19 pandemic have caused the hardships to feel heavier than the joys at times for some physicians interviewed by MDedge.

Many independent rural practices in need of assistance were not able to get much from the federal Provider Relief Funds, said John M. Westfall, MD, who is director of the Robert Graham Center for Policy Studies in Family Medicine and Primary Care, in an interview.

“Rural primary care doctors function independently or in smaller critical access hospitals and community health centers,” said Dr. Westfall, who previously practiced family medicine in a small town in Colorado. “Many of these have much less financial reserves so are at risk of cutbacks and closure.”

Jacqueline W. Fincher, MD, an internist based in a tiny Georgia community along the highway between Atlanta and Augusta, said her small practice works on really thin margins and doesn’t have much cushion. At the beginning of the pandemic, all visits were down, and her practice operated at a loss. To help, Dr. Fincher and her colleagues applied for funding from the Small Business Administration’s Paycheck Protection Program (PPP) through the CARES Act.

“COVID-19 has had a tremendous impact especially on primary care practices. We live and die by volume. … Our volume in mid-March to mid-May really dropped dramatically,” explained Dr. Fincher, who is also president of the American College of Physicians. “The PPP sustained us for 2 months, enabling us to pay our staff and to remain open and get us up and running on telehealth.”
 

Starting up telemedicine

Experiencing spotty or no access to broadband Internet is nothing new to rural physicians, but having this problem interfere with their ability to provide care to patients is.

As much of the American health system rapidly embraced telehealth during the pandemic, obtaining access to high-speed Internet has been a major challenge for rural patients, noted Dr. Westfall.

“Some practices were able to quickly adopt some telehealth capacity with phone and video. Changes in payment for telehealth helped. But in some rural communities there was not adequate Internet bandwidth for quality video connections. And some patients did not have the means for high-speed video connections,” Dr. Westfall said.

Indeed, according to a 2019 Pew Research Center survey, 63% of rural Americans say they can access the Internet through a broadband connection at home, compared with 75% and 79% in suburban and urban areas, respectively.

G&P Productions

In the Appalachian town of Zanesville, Ohio, for example, family physician Shelly L. Dunmyer, MD, and her colleagues discovered that many patients don’t have Internet access at home. Dr. Fincher has to go to the office to conduct telehealth visits because her own Internet access at home is unpredictable. As for patients, it may take 15 minutes for them to work out technical glitches and find good Internet reception, said Dr. Fincher. For internist Y. Ki Shin, MD, who practices in the coastal town of Montesano in Washington state, about 25% of his practice’s telehealth visits must be conducted by phone because of limitations on video, such as lack of high-speed access.

But telephone visits are often insufficient replacements for appointments via video, according to several rural physicians interviewed for this piece.

“Telehealth can be frustrating at times due to connectivity issues which can be difficult at times in the rural areas,” said Dr. Fincher. “In order for telehealth to be reasonably helpful to patients and physicians to care for people with chronic problems, the patients must have things like blood pressure monitors, glucometers, and scales to address problems like hypertension, diabetes myelitis, and congestive heart failure.”

“If you have the audio and video and the data from these devices, you’re good. If you don’t have these data, and/or don’t have the video you just can’t provide good care,” she explained.

G&P Productions

Dr. Dunmyer and her colleagues at Medical Home Primary Care Center in Zanesville, Ohio, found a way to get around the problem of patients not being able to access Internet to participate in video visits from their homes. This involved having her patients drive into her practice’s parking lot to participate in modified telehealth visits. Staffers gave iPads to patients in their cars, and Dr. Dunmyer conducted visits from her office, about 50 yards away.

“We were even doing Medicare wellness visits: Instead of asking them to get up and move around the room, we would sit at the window and wave at them, ask them to get out, walk around the car. We were able to check mobility and all kinds of things that we’d normally do in the office,” Dr. Dunmyer explained in an interview.

The family physician noted that her practice is now conducting fewer parking lot visits since her office is allowing in-person appointments, but that they’re still an option for her patients.
 

Treating political adversaries

Some rural physicians have experienced strained relationships with patients for reasons other than technology – stark differences in opinion over the pandemic itself. Certain patients are following President Trump’s lead and questioning everything from the pandemic death toll to preventive measures recommended by scientists and medical experts, physicians interviewed by MDedge said.

Patients everywhere share these viewpoints, of course, but research and election results confirm that rural areas are more receptive to conservative viewpoints. In 2018, a Pew Research Center survey reported that rural and urban areas are “becoming more polarized politically,” and “rural areas tend to have a higher concentration of Republicans and Republican-leaning independents.” For example, 40% of rural respondents reported “very warm” or “somewhat warm” feelings toward Donald Trump, compared with just 19% in urban areas.

Dr. Shin has struggled to cope with patients who want to argue about pandemic safety precautions like wearing masks and seem to question whether systemic racism exists.

“We are seeing a lot more people who feel that this pandemic is not real, that it’s a political and not-true infection,” he said in an interview. “We’ve had patients who were angry at us because we made them wear masks, and some were demanding hydroxychloroquine and wanted to have an argument because we’re not going to prescribe it for them.”

In one situation, which he found especially disturbing, Dr. Shin had to leave the exam room because a patient wouldn’t stop challenging him regarding the pandemic. Things have gotten so bad that Dr. Shin has even questioned whether he wants to continue his long career in his small town because of local political attitudes such as opposition to mask-wearing and social distancing.

“Mr. Trump’s misinformation on this pandemic made my job much more difficult. As a minority, I feel less safe in my community than ever,” said Dr. Shin, who described himself as Asian American.

Despite these new stressors, Dr. Shin has experienced some joyful moments while practicing medicine in the pandemic.

Courtesy Dr. Clara Shin

He said a recent home visit to a patient who had been hospitalized for over 3 months and nearly died helped him put political disputes with his patients into perspective.

“He was discharged home but is bedbound. He had gangrene on his toes, and I could not fully examine him using video,” Dr. Shin recalled. “It was tricky to find the house, but a very large Trump sign was very helpful in locating it. It was a good visit: He was happy to see me, and I was happy to see that he was doing okay at home.”

“I need to remind myself that supporting Mr. Trump does not always mean that my patient supports Mr. Trump’s view on the pandemic and the race issues in our country,” Dr. Shin added.

The Washington-based internist said he also tells himself that, even if his patients refuse to follow his strong advice regarding pandemic precautions, it does not mean he has failed as a doctor.

“I need to continue to educate patients about the dangers of COVID infection but cannot be angry if they don’t choose to follow my recommendations,” he noted.

Dr. Fincher says her close connection with patients has allowed her to smooth over politically charged claims about the pandemic in the town of Thomson, Georgia, with a population 6,800.

“I have a sense that, even though we may differ in our understanding of some basic facts, they appreciate what I say since we have a long-term relationship built on trust,” she said. This kind of trust, Dr. Fincher suggested, may be more common than in urban areas where there’s a larger supply of physicians, and patients don’t see the same doctors for long periods of time.

“It’s more meaningful when it comes from me, rather than doctors who are [new to patients] every year when their employer changes their insurance,” she noted.

Further data suggesting that a lower dose of rituximab seems to offer similar effectiveness with a better safety profile than higher doses commonly used in multiple sclerosis (MS), according to a new observational study. “We showed similar numbers of relapses, MRI new/active lesions, and effects on disability with a higher and lower dose of rituximab over a median follow of 16 months,” said lead author, Luciana Midaglia, MD, Multiple Sclerosis Centre of Catalonia (Cemcat) at Vall d’Hebron University Hospital, Barcelona. “But adverse effects – particularly frequency of infection – were increased in the high-dose group.”

Dr. Midaglia presented the findings at the recent Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

“There haven’t been large studies of rituximab in MS as the company [Genentech/Roche] prioritized development of ocrelizumab over rituximab,” she explained. Rituximab has, therefore, never been approved for this indication. But it is available for several other conditions, and it is often used off label for MS.

“Although we now have a lot of experience with rituximab in MS, a dosage regimen has not been standardized,” Dr. Midaglia noted.

The current study was conducted to compare the efficacy and safety of two different dosage regimens of rituximab used at two different Catalan MS centers.

In the Barcelona center, 249 patients received a regimen of 2 g IV for the first three 6-month cycles followed by 1 g every 6 months thereafter (higher-dose group). In the Girona center, 54 patients received just one loading dose of 2 g followed by 500 mg every 6 months thereafter (lower-dose group).

Patients were followed up clinically every 6 months, and MRI brain scans were performed at baseline and yearly thereafter. Blood samples for safety and B cell/immunoglobulin monitoring were drawn at 3 months after rituximab infusions.

Results showed that the annualized relapse rate reduced by 87% (from 0.4 to 0.05; P < .001) in the higher-dose cohort, and by 90% (from 0.31 to 0.03; P = .018) in the lower-dose cohort.

The Expanded Disability Status Scale score remained stable or improved in 83% of the higher-dose group versus 72% of the lower-dose group (P = .09).

Contrast-enhancing lesions were reduced by 92% by 12 months and by 100% by 36 months in the higher-dose group and by 81% and 100%, respectively, in the lower-dose group.

New T2 lesions were present in 19% of patients at 12 months and in 12% at 36 months in the higher-dose group and in 16% and 0%, respectively, in the lower-dose group.

Reductions in B cell levels were similar with both doses. However, a reduced rate of adverse effects, mainly infections, was seen in the lower-dose group.

Infections were reported in 7.2% of the higher-dose group and 3.7% of the lower-dose group at 1 year, in 9.7% versus 0% in the second year, and in 9.7% versus 0% in the third year. Urinary tract infections, followed by respiratory infections, were the most prevalent.

A randomized phase 3 study is now underway testing an even lower dose of rituximab. The trial, known as RIDOSE-MS, is comparing maintenance doses of 500 mg every 6 months and 500 mg every 12 months.

Dr. Midaglia said that most centers are using higher doses of rituximab – similar to the Barcelona cohort in this study.

“After this study, we will we now start a new protocol and use the lower dose for all MS patients,” she said.

She reported that her hospital has been using rituximab extensively in MS.

“There were delays to ocrelizumab being introduced in Spain, and while we were waiting, we started using rituximab,” she said. “We believe it is similarly effective to ocrelizumab. It has exactly the same mechanism of action. The only difference is that rituximab is a chimeric antibody while ocrelizumab is fully humanized.”

While rituximab has not had the validation of a full phase 3 trial, she added, “there are data available from several smaller studies and we feel we have learned how to use it in the real world, but we don’t have an approved dosage schedule. We started off using the dose approved for use in rheumatological and hematological conditions.”

Now that ocrelizumab is approved, Dr. Midaglia said they are using that drug for the patients who meet the approved criteria, but there are many patients who don’t qualify.

“For example, in progressive MS, ocrelizumab has quite a narrow indication – it is not reimbursed for patients without any inflammatory activity. So for these patients, we tend to use rituximab,” she noted.

“While there is no good data on its efficacy in these patients, we believe it has some effect and there is no other option at present. Rituximab is an inexpensive drug and has a long safety record in other conditions, so we feel it’s worth a try,” Dr. Midaglia concluded. “And now we have better data on the optimal dosage.”

Commenting on the study, Daniel Ontaneda, MD, comoderator of the session at which the study was presented, said: “Rituximab is not an [Food and Drug Administration]–approved medication for MS, but it has been used in clinical practice quite extensively in the U.S. and also in Europe. The study is of interest as it showed that the lower dose of rituximab achieved good control of disease activity.”

Dr. Ontaneda, a neurologist at the Mellen Center for MS at the Cleveland Clinic, Ohio, added: “Many centers have been using lower doses or less frequent infusions and this study supports this practice. Some degree of residual confounding in the study in the differences in side effects may be related to the two different sites, but overall I think these results add to the real-world observational data now available for anti-CD20 therapies.”

Dr. Midaglia reported receiving travel funding from Genzyme, Roche, Biogen Idec, and Novartis, and personal fees for lectures from Roche.
 

A version of this article originally appeared on Medscape.com.

Further data suggesting that a lower dose of rituximab seems to offer similar effectiveness with a better safety profile than higher doses commonly used in multiple sclerosis (MS), according to a new observational study. “We showed similar numbers of relapses, MRI new/active lesions, and effects on disability with a higher and lower dose of rituximab over a median follow of 16 months,” said lead author, Luciana Midaglia, MD, Multiple Sclerosis Centre of Catalonia (Cemcat) at Vall d’Hebron University Hospital, Barcelona. “But adverse effects – particularly frequency of infection – were increased in the high-dose group.”

Dr. Midaglia presented the findings at the recent Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

“There haven’t been large studies of rituximab in MS as the company [Genentech/Roche] prioritized development of ocrelizumab over rituximab,” she explained. Rituximab has, therefore, never been approved for this indication. But it is available for several other conditions, and it is often used off label for MS.

“Although we now have a lot of experience with rituximab in MS, a dosage regimen has not been standardized,” Dr. Midaglia noted.

The current study was conducted to compare the efficacy and safety of two different dosage regimens of rituximab used at two different Catalan MS centers.

In the Barcelona center, 249 patients received a regimen of 2 g IV for the first three 6-month cycles followed by 1 g every 6 months thereafter (higher-dose group). In the Girona center, 54 patients received just one loading dose of 2 g followed by 500 mg every 6 months thereafter (lower-dose group).

Patients were followed up clinically every 6 months, and MRI brain scans were performed at baseline and yearly thereafter. Blood samples for safety and B cell/immunoglobulin monitoring were drawn at 3 months after rituximab infusions.

Results showed that the annualized relapse rate reduced by 87% (from 0.4 to 0.05; P < .001) in the higher-dose cohort, and by 90% (from 0.31 to 0.03; P = .018) in the lower-dose cohort.

The Expanded Disability Status Scale score remained stable or improved in 83% of the higher-dose group versus 72% of the lower-dose group (P = .09).

Contrast-enhancing lesions were reduced by 92% by 12 months and by 100% by 36 months in the higher-dose group and by 81% and 100%, respectively, in the lower-dose group.

New T2 lesions were present in 19% of patients at 12 months and in 12% at 36 months in the higher-dose group and in 16% and 0%, respectively, in the lower-dose group.

Reductions in B cell levels were similar with both doses. However, a reduced rate of adverse effects, mainly infections, was seen in the lower-dose group.

Infections were reported in 7.2% of the higher-dose group and 3.7% of the lower-dose group at 1 year, in 9.7% versus 0% in the second year, and in 9.7% versus 0% in the third year. Urinary tract infections, followed by respiratory infections, were the most prevalent.

A randomized phase 3 study is now underway testing an even lower dose of rituximab. The trial, known as RIDOSE-MS, is comparing maintenance doses of 500 mg every 6 months and 500 mg every 12 months.

Dr. Midaglia said that most centers are using higher doses of rituximab – similar to the Barcelona cohort in this study.

“After this study, we will we now start a new protocol and use the lower dose for all MS patients,” she said.

She reported that her hospital has been using rituximab extensively in MS.

“There were delays to ocrelizumab being introduced in Spain, and while we were waiting, we started using rituximab,” she said. “We believe it is similarly effective to ocrelizumab. It has exactly the same mechanism of action. The only difference is that rituximab is a chimeric antibody while ocrelizumab is fully humanized.”

While rituximab has not had the validation of a full phase 3 trial, she added, “there are data available from several smaller studies and we feel we have learned how to use it in the real world, but we don’t have an approved dosage schedule. We started off using the dose approved for use in rheumatological and hematological conditions.”

Now that ocrelizumab is approved, Dr. Midaglia said they are using that drug for the patients who meet the approved criteria, but there are many patients who don’t qualify.

“For example, in progressive MS, ocrelizumab has quite a narrow indication – it is not reimbursed for patients without any inflammatory activity. So for these patients, we tend to use rituximab,” she noted.

“While there is no good data on its efficacy in these patients, we believe it has some effect and there is no other option at present. Rituximab is an inexpensive drug and has a long safety record in other conditions, so we feel it’s worth a try,” Dr. Midaglia concluded. “And now we have better data on the optimal dosage.”

Commenting on the study, Daniel Ontaneda, MD, comoderator of the session at which the study was presented, said: “Rituximab is not an [Food and Drug Administration]–approved medication for MS, but it has been used in clinical practice quite extensively in the U.S. and also in Europe. The study is of interest as it showed that the lower dose of rituximab achieved good control of disease activity.”

Dr. Ontaneda, a neurologist at the Mellen Center for MS at the Cleveland Clinic, Ohio, added: “Many centers have been using lower doses or less frequent infusions and this study supports this practice. Some degree of residual confounding in the study in the differences in side effects may be related to the two different sites, but overall I think these results add to the real-world observational data now available for anti-CD20 therapies.”

Dr. Midaglia reported receiving travel funding from Genzyme, Roche, Biogen Idec, and Novartis, and personal fees for lectures from Roche.
 

A version of this article originally appeared on Medscape.com.

Further data suggesting that a lower dose of rituximab seems to offer similar effectiveness with a better safety profile than higher doses commonly used in multiple sclerosis (MS), according to a new observational study. “We showed similar numbers of relapses, MRI new/active lesions, and effects on disability with a higher and lower dose of rituximab over a median follow of 16 months,” said lead author, Luciana Midaglia, MD, Multiple Sclerosis Centre of Catalonia (Cemcat) at Vall d’Hebron University Hospital, Barcelona. “But adverse effects – particularly frequency of infection – were increased in the high-dose group.”

Dr. Midaglia presented the findings at the recent Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

“There haven’t been large studies of rituximab in MS as the company [Genentech/Roche] prioritized development of ocrelizumab over rituximab,” she explained. Rituximab has, therefore, never been approved for this indication. But it is available for several other conditions, and it is often used off label for MS.

“Although we now have a lot of experience with rituximab in MS, a dosage regimen has not been standardized,” Dr. Midaglia noted.

The current study was conducted to compare the efficacy and safety of two different dosage regimens of rituximab used at two different Catalan MS centers.

In the Barcelona center, 249 patients received a regimen of 2 g IV for the first three 6-month cycles followed by 1 g every 6 months thereafter (higher-dose group). In the Girona center, 54 patients received just one loading dose of 2 g followed by 500 mg every 6 months thereafter (lower-dose group).

Patients were followed up clinically every 6 months, and MRI brain scans were performed at baseline and yearly thereafter. Blood samples for safety and B cell/immunoglobulin monitoring were drawn at 3 months after rituximab infusions.

Results showed that the annualized relapse rate reduced by 87% (from 0.4 to 0.05; P < .001) in the higher-dose cohort, and by 90% (from 0.31 to 0.03; P = .018) in the lower-dose cohort.

The Expanded Disability Status Scale score remained stable or improved in 83% of the higher-dose group versus 72% of the lower-dose group (P = .09).

Contrast-enhancing lesions were reduced by 92% by 12 months and by 100% by 36 months in the higher-dose group and by 81% and 100%, respectively, in the lower-dose group.

New T2 lesions were present in 19% of patients at 12 months and in 12% at 36 months in the higher-dose group and in 16% and 0%, respectively, in the lower-dose group.

Reductions in B cell levels were similar with both doses. However, a reduced rate of adverse effects, mainly infections, was seen in the lower-dose group.

Infections were reported in 7.2% of the higher-dose group and 3.7% of the lower-dose group at 1 year, in 9.7% versus 0% in the second year, and in 9.7% versus 0% in the third year. Urinary tract infections, followed by respiratory infections, were the most prevalent.

A randomized phase 3 study is now underway testing an even lower dose of rituximab. The trial, known as RIDOSE-MS, is comparing maintenance doses of 500 mg every 6 months and 500 mg every 12 months.

Dr. Midaglia said that most centers are using higher doses of rituximab – similar to the Barcelona cohort in this study.

“After this study, we will we now start a new protocol and use the lower dose for all MS patients,” she said.

She reported that her hospital has been using rituximab extensively in MS.

“There were delays to ocrelizumab being introduced in Spain, and while we were waiting, we started using rituximab,” she said. “We believe it is similarly effective to ocrelizumab. It has exactly the same mechanism of action. The only difference is that rituximab is a chimeric antibody while ocrelizumab is fully humanized.”

While rituximab has not had the validation of a full phase 3 trial, she added, “there are data available from several smaller studies and we feel we have learned how to use it in the real world, but we don’t have an approved dosage schedule. We started off using the dose approved for use in rheumatological and hematological conditions.”

Now that ocrelizumab is approved, Dr. Midaglia said they are using that drug for the patients who meet the approved criteria, but there are many patients who don’t qualify.

“For example, in progressive MS, ocrelizumab has quite a narrow indication – it is not reimbursed for patients without any inflammatory activity. So for these patients, we tend to use rituximab,” she noted.

“While there is no good data on its efficacy in these patients, we believe it has some effect and there is no other option at present. Rituximab is an inexpensive drug and has a long safety record in other conditions, so we feel it’s worth a try,” Dr. Midaglia concluded. “And now we have better data on the optimal dosage.”

Commenting on the study, Daniel Ontaneda, MD, comoderator of the session at which the study was presented, said: “Rituximab is not an [Food and Drug Administration]–approved medication for MS, but it has been used in clinical practice quite extensively in the U.S. and also in Europe. The study is of interest as it showed that the lower dose of rituximab achieved good control of disease activity.”

Dr. Ontaneda, a neurologist at the Mellen Center for MS at the Cleveland Clinic, Ohio, added: “Many centers have been using lower doses or less frequent infusions and this study supports this practice. Some degree of residual confounding in the study in the differences in side effects may be related to the two different sites, but overall I think these results add to the real-world observational data now available for anti-CD20 therapies.”

Dr. Midaglia reported receiving travel funding from Genzyme, Roche, Biogen Idec, and Novartis, and personal fees for lectures from Roche.
 

A version of this article originally appeared on Medscape.com.

There is no evidence to support the idea that previous autoimmunity before or after alemtuzumab treatment predicts subsequent rare but serious and possibly life-threatening autoimmune events that have recently been linked to the drug, a new study has shown.

These latest data were reported by Alasdair J. Coles, MD, University of Cambridge (England), at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Dr. Coles, who led the initial research to develop alemtuzumab in partnership with Genzyme, explained that autoimmune disease is a well-described and common adverse event with the drug, manifesting mainly as autoimmune thyroid events that can occur in up to 40% of patients.

But as postmarketing experience has grown, it has become clear that there is a low frequency of more serious autoimmune disease, he noted. In an effort to understand this better, regulators have suggested that the presence of non–multiple sclerosis (MS) autoimmune disease before alemtuzumab treatment and the emergence of autoimmune disease after alemtuzumab treatment may define a group that is at higher risk of one of the rare but serious autoimmune events for those on the drug.

To investigate if this was the case, Dr. Coles and colleagues analyzed data on 1,216 patients who received alemtuzumab in the clinical development program. Of these, 96 had preexisting non-MS autoimmunity.

Results showed that up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) versus without (35.3%) preexisting autoimmunity.

Similar percentages of patients with versus without preexisting autoimmunity had two or more new autoimmune events (5.2% vs. 8.2%, respectively). And most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab.

In addition, treatment-emergent thyroid autoimmunity after the first alemtuzumab course was not associated with subsequent nonthyroid autoimmunity after the second course. Similarly, thyroid autoimmunity after the second course did not predict non-thyroid autoimmunity after the third course.

In another analysis of the incidence of serious autoimmune events from postmarketing data on 25,292 patients treated with alemtuzumab, immune thrombocytopenic purpura was reported in 43 patients, newly identified autoimmune hepatitis in 11 patients, and hemophagocytic lymphohistiocytosis in 9 patients.

There was “no hint at all” that baseline thyroid disorders or postalemtuzumab thyroid disorders are associated with increased risk of these serious autoimmune adverse events, Dr. Coles said.

He calculated that the incidence of serious autoimmune diseases that could be life-threatening after alemtuzumab treatment was 10.7 per 10,000 patients treated for autoimmune hepatitis and 2.7 per 10,000 patients treated for hemophagocytic lymphohistiocytosis.

“From two separate data sources – phase 2/3 trials populations combined and postmarketing data – there is no evidence to support the hypothesis that preexisting non-MS autoimmunity predisposes to the serious but rare autoimmune events that have newly been described, nor does thyroid autoimmunity following the use of alemtuzumab,” Dr. Coles stated.

“In my opinion it is not appropriate to preclude the use of alemtuzumab to patients who have had previous autoimmune disease before treatment or who develop thyroid autoimmunity after alemtuzumab,” he said.

“It remains in my view a reasonable treatment option for patients with active MS to receive this highly effective therapy in the face of well-managed, well-understood thyroid autoimmunity and the very unlikely, rare, but serious autoimmune disease,” he concluded.
 

Risk stratification

Commenting on the presentation, Robert J. Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis, Cleveland Clinic, Ohio, explained that, whenever there is a serious risk of a complication, clinicians like to try to stratify that risk.

“We like to identify those at higher risk [and perhaps not use the therapy] and those at lower risk [and perhaps consider more likely the use of that therapy],” he said.

With regard to alemtuzumab, Dr. Fox noted: “We’d like to stratify the risk of autoimmune complications, which could help guide us regarding the patients in whom therapy may be safer. Unfortunately, these findings did not point to a risk stratification to help guide its use towards lower-risk patients.

“I view this as an unfortunate result, because it leaves me without a way to stratify the risks of alemtuzumab, which are quite significant and currently limit my use of that MS therapy only to those with no other treatment options,” he added.

On Dr. Coles’ view of alemtuzumab as a “reasonable” treatment option, Dr. Fox commented: “I guess it depends upon how that’s interpreted. Given the risks of serious, life-threatening immune and infectious complications, I only consider alemtuzumab when all other immune-modulating therapies have been tried or are not a reasonable treatment option. So, yes, I see it as ‘reasonable,’ but only when there are no other available treatment options.”

The current work was supported by Sanofi and Bayer HealthCare. Dr. Coles reported sitting on advisory boards for Genzyme (Sanofi). He is credited as an inventor on several patents related to the technology on which alemtuzumab is based. Dr. Fox has disclosed no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

There is no evidence to support the idea that previous autoimmunity before or after alemtuzumab treatment predicts subsequent rare but serious and possibly life-threatening autoimmune events that have recently been linked to the drug, a new study has shown.

These latest data were reported by Alasdair J. Coles, MD, University of Cambridge (England), at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Dr. Coles, who led the initial research to develop alemtuzumab in partnership with Genzyme, explained that autoimmune disease is a well-described and common adverse event with the drug, manifesting mainly as autoimmune thyroid events that can occur in up to 40% of patients.

But as postmarketing experience has grown, it has become clear that there is a low frequency of more serious autoimmune disease, he noted. In an effort to understand this better, regulators have suggested that the presence of non–multiple sclerosis (MS) autoimmune disease before alemtuzumab treatment and the emergence of autoimmune disease after alemtuzumab treatment may define a group that is at higher risk of one of the rare but serious autoimmune events for those on the drug.

To investigate if this was the case, Dr. Coles and colleagues analyzed data on 1,216 patients who received alemtuzumab in the clinical development program. Of these, 96 had preexisting non-MS autoimmunity.

Results showed that up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) versus without (35.3%) preexisting autoimmunity.

Similar percentages of patients with versus without preexisting autoimmunity had two or more new autoimmune events (5.2% vs. 8.2%, respectively). And most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab.

In addition, treatment-emergent thyroid autoimmunity after the first alemtuzumab course was not associated with subsequent nonthyroid autoimmunity after the second course. Similarly, thyroid autoimmunity after the second course did not predict non-thyroid autoimmunity after the third course.

In another analysis of the incidence of serious autoimmune events from postmarketing data on 25,292 patients treated with alemtuzumab, immune thrombocytopenic purpura was reported in 43 patients, newly identified autoimmune hepatitis in 11 patients, and hemophagocytic lymphohistiocytosis in 9 patients.

There was “no hint at all” that baseline thyroid disorders or postalemtuzumab thyroid disorders are associated with increased risk of these serious autoimmune adverse events, Dr. Coles said.

He calculated that the incidence of serious autoimmune diseases that could be life-threatening after alemtuzumab treatment was 10.7 per 10,000 patients treated for autoimmune hepatitis and 2.7 per 10,000 patients treated for hemophagocytic lymphohistiocytosis.

“From two separate data sources – phase 2/3 trials populations combined and postmarketing data – there is no evidence to support the hypothesis that preexisting non-MS autoimmunity predisposes to the serious but rare autoimmune events that have newly been described, nor does thyroid autoimmunity following the use of alemtuzumab,” Dr. Coles stated.

“In my opinion it is not appropriate to preclude the use of alemtuzumab to patients who have had previous autoimmune disease before treatment or who develop thyroid autoimmunity after alemtuzumab,” he said.

“It remains in my view a reasonable treatment option for patients with active MS to receive this highly effective therapy in the face of well-managed, well-understood thyroid autoimmunity and the very unlikely, rare, but serious autoimmune disease,” he concluded.
 

Risk stratification

Commenting on the presentation, Robert J. Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis, Cleveland Clinic, Ohio, explained that, whenever there is a serious risk of a complication, clinicians like to try to stratify that risk.

“We like to identify those at higher risk [and perhaps not use the therapy] and those at lower risk [and perhaps consider more likely the use of that therapy],” he said.

With regard to alemtuzumab, Dr. Fox noted: “We’d like to stratify the risk of autoimmune complications, which could help guide us regarding the patients in whom therapy may be safer. Unfortunately, these findings did not point to a risk stratification to help guide its use towards lower-risk patients.

“I view this as an unfortunate result, because it leaves me without a way to stratify the risks of alemtuzumab, which are quite significant and currently limit my use of that MS therapy only to those with no other treatment options,” he added.

On Dr. Coles’ view of alemtuzumab as a “reasonable” treatment option, Dr. Fox commented: “I guess it depends upon how that’s interpreted. Given the risks of serious, life-threatening immune and infectious complications, I only consider alemtuzumab when all other immune-modulating therapies have been tried or are not a reasonable treatment option. So, yes, I see it as ‘reasonable,’ but only when there are no other available treatment options.”

The current work was supported by Sanofi and Bayer HealthCare. Dr. Coles reported sitting on advisory boards for Genzyme (Sanofi). He is credited as an inventor on several patents related to the technology on which alemtuzumab is based. Dr. Fox has disclosed no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

There is no evidence to support the idea that previous autoimmunity before or after alemtuzumab treatment predicts subsequent rare but serious and possibly life-threatening autoimmune events that have recently been linked to the drug, a new study has shown.

These latest data were reported by Alasdair J. Coles, MD, University of Cambridge (England), at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Dr. Coles, who led the initial research to develop alemtuzumab in partnership with Genzyme, explained that autoimmune disease is a well-described and common adverse event with the drug, manifesting mainly as autoimmune thyroid events that can occur in up to 40% of patients.

But as postmarketing experience has grown, it has become clear that there is a low frequency of more serious autoimmune disease, he noted. In an effort to understand this better, regulators have suggested that the presence of non–multiple sclerosis (MS) autoimmune disease before alemtuzumab treatment and the emergence of autoimmune disease after alemtuzumab treatment may define a group that is at higher risk of one of the rare but serious autoimmune events for those on the drug.

To investigate if this was the case, Dr. Coles and colleagues analyzed data on 1,216 patients who received alemtuzumab in the clinical development program. Of these, 96 had preexisting non-MS autoimmunity.

Results showed that up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) versus without (35.3%) preexisting autoimmunity.

Similar percentages of patients with versus without preexisting autoimmunity had two or more new autoimmune events (5.2% vs. 8.2%, respectively). And most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab.

In addition, treatment-emergent thyroid autoimmunity after the first alemtuzumab course was not associated with subsequent nonthyroid autoimmunity after the second course. Similarly, thyroid autoimmunity after the second course did not predict non-thyroid autoimmunity after the third course.

In another analysis of the incidence of serious autoimmune events from postmarketing data on 25,292 patients treated with alemtuzumab, immune thrombocytopenic purpura was reported in 43 patients, newly identified autoimmune hepatitis in 11 patients, and hemophagocytic lymphohistiocytosis in 9 patients.

There was “no hint at all” that baseline thyroid disorders or postalemtuzumab thyroid disorders are associated with increased risk of these serious autoimmune adverse events, Dr. Coles said.

He calculated that the incidence of serious autoimmune diseases that could be life-threatening after alemtuzumab treatment was 10.7 per 10,000 patients treated for autoimmune hepatitis and 2.7 per 10,000 patients treated for hemophagocytic lymphohistiocytosis.

“From two separate data sources – phase 2/3 trials populations combined and postmarketing data – there is no evidence to support the hypothesis that preexisting non-MS autoimmunity predisposes to the serious but rare autoimmune events that have newly been described, nor does thyroid autoimmunity following the use of alemtuzumab,” Dr. Coles stated.

“In my opinion it is not appropriate to preclude the use of alemtuzumab to patients who have had previous autoimmune disease before treatment or who develop thyroid autoimmunity after alemtuzumab,” he said.

“It remains in my view a reasonable treatment option for patients with active MS to receive this highly effective therapy in the face of well-managed, well-understood thyroid autoimmunity and the very unlikely, rare, but serious autoimmune disease,” he concluded.
 

Risk stratification

Commenting on the presentation, Robert J. Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis, Cleveland Clinic, Ohio, explained that, whenever there is a serious risk of a complication, clinicians like to try to stratify that risk.

“We like to identify those at higher risk [and perhaps not use the therapy] and those at lower risk [and perhaps consider more likely the use of that therapy],” he said.

With regard to alemtuzumab, Dr. Fox noted: “We’d like to stratify the risk of autoimmune complications, which could help guide us regarding the patients in whom therapy may be safer. Unfortunately, these findings did not point to a risk stratification to help guide its use towards lower-risk patients.

“I view this as an unfortunate result, because it leaves me without a way to stratify the risks of alemtuzumab, which are quite significant and currently limit my use of that MS therapy only to those with no other treatment options,” he added.

On Dr. Coles’ view of alemtuzumab as a “reasonable” treatment option, Dr. Fox commented: “I guess it depends upon how that’s interpreted. Given the risks of serious, life-threatening immune and infectious complications, I only consider alemtuzumab when all other immune-modulating therapies have been tried or are not a reasonable treatment option. So, yes, I see it as ‘reasonable,’ but only when there are no other available treatment options.”

The current work was supported by Sanofi and Bayer HealthCare. Dr. Coles reported sitting on advisory boards for Genzyme (Sanofi). He is credited as an inventor on several patents related to the technology on which alemtuzumab is based. Dr. Fox has disclosed no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

A common adverse effect of the multiple sclerosis (MS) treatment alemtuzumab (Lemtrada) may be predicted by pretreatment levels of certain types of B cells, a new study suggests.

“Alemtuzumab has proven to be an effective treatment for patients with highly active remitting relapsing MS, but adverse events may limit the use of this drug, particularly autoimmune adverse events, which are the most prevalent, occurring in about 30% of patients. Reliable biomarkers to assess patient risk for developing this complication would be of great importance,” said lead author Paulette Walo, MD.

“Our results suggest that a higher percentage of total B cells, and in particular plasmablasts, could be a very predictive biomarker for autoimmunity after alemtuzumab treatment. This could help us in choosing the patients for this drug,” said Dr. Walo, an immunologist at Ramon y Cajal University Hospital, Madrid. She presented the findings at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

The objective of this study was to explore if patient blood lymphocyte profile before alemtuzumab treatment initiation can identify patients with an increased risk of developing later autoimmunity, Dr. Walo explained.

The study included 54 patients from five hospitals throughout Spain who had received treatment with alemtuzumab. Of these, the vast majority had received the normal two-dose cycle and two patients had received a third dose because of worsening MS activity.

Blood samples were collected before initiating treatment with alemtuzumab. Peripheral blood mononuclear cells were obtained and cryopreserved. Leukocyte populations were assessed by flow cytometry.

Autoimmune adverse events were defined as the development, at any point within 2 years of follow-up, of any autoimmune thyroid-associated event, immune thrombocytopenia, and/or autoimmune nephropathy.

Over the 2 years of follow-up, 14 patients (25.9%) experienced autoimmune adverse events, all of which were dysthyroidism. No immune thrombocytopenia or nephropathies were observed.

No statistical differences were found in clinical and demographic characteristics between patients who developed autoimmune adverse events and those who did not. Previous treatments did not influence B-cell percentages.

Analysis of blood lymphocyte profiles showed no difference in T-cell subsets between those who had an autoimmune event and those who did not.

Still, there were important differences in the B-cell profile, Dr. Walo said. “Total B cells were higher in patients who had an autoimmune event mainly due to naive B cells and plasmablasts.”

Patients who experienced autoimmune adverse events before treatment onset had a higher percentage of blood CD19+ B cells (P = .001), with a higher relative percentage of naive B cells and plasmablasts.

When individual types of cell numbers were explored, only plasmablast levels remained significant (P = .02).

The researchers calculated a CD19+ B-cell predictive value for autoimmunity of 7.6%. If patients had more than 7.6% B cells, they were at higher risk of an autoimmune adverse event after alemtuzumab treatment versus those with lower levels (odds ratio, 14.67; P ≤ .0001).

Similarly, the predictive value for plasmablasts was 0.13%. If patients had levels higher than 0.13% they had a higher risk of an autoimmune event after alemtuzumab treatment (P = .002). Plasmablasts are a category of B cells which are very differentiated and have the capacity to produce antibodies; they are a very active and aggressive subtype of B cells, Dr. Walo noted. 

She explained that, as was the case in this study, autoimmune events after alemtuzumab treatment normally manifests as the development of antibodies against the thyroid gland, with the development of either hyperthyroidism or hypothyroidism, necessitating long-term treatment to manage these conditions.

“Autoimmunity develops at variable timescales. It can appear in the first year after alemtuzumab treatment but it can also appear later on,” she said.

Dr. Walo’s group is hoping to validate their results in a larger study. “This is only a small study so we need to replicate these findings in a larger cohort. We are in the process of doing this, collaborating with other hospitals,” she commented. 

She said that, if the results are validated, then patients could undergo blood tests before alemtuzumab treatment to analyze their B-cell counts.

“For those with high levels of B cells – and particularly plasmablasts – alemtuzumab may not be the best treatment to choose,” Dr. Walo said.
 

Personalized strategy

During the postpresentation discussion, the suggestion was raised of giving an anti–B-cell drug before alemtuzumab to try and prevent autoimmunity. Dr. Walo responded that this is a possibility. “This is something that we are going to look into. If our larger study validates our initial results, then we would plan a study to give an anti–B-cell treatment such as rituximab before alemtuzumab and see whether this reduces the risk of autoimmunity.”

Commenting on the study, session comoderator Darin Okuda, MD, professor in the department of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center, Dallas, said: “This is an intriguing approach and suggests a more personalized strategy for sure if we can identify patients who are at higher risk of developing autoimmunity.”

Also commenting, ACTRIMS president Jeffrey Cohen, MD, said: “One of the main drawbacks of alemtuzumab is the risk of antibody-mediated autoimmune conditions, so the ability to predict who is at risk for autoimmune adverse events prior to initiating alemtuzumab would be useful. Not surprisingly, factors related to B-cell number and profile were predictive.”

Dr. Cohen, who is a director of experimental neurotherapeutics at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, added however that the suggestion of pretreating patients with an anti-CD20 monoclonal antibody “does not seem tenable to me,” because of the potential cost of such a strategy, and “no efficacy advantage for most patients over an anti-CD20 antibody alone.”

Commenting on this presentation, Alasdair J. Coles, MD, University of Cambridge (England), who was one of the co-inventors of alemtuzumab, said observations of an increased B-cell count before treatment as a risk predictor of thyroid autoimmunity after alemtuzumab had not been replicated in the clinical trial datasets of the drug. “So I fear we still do not have a reliable biomarker,” he added.

The study had no specific funding listed. Dr. Walo has disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

A common adverse effect of the multiple sclerosis (MS) treatment alemtuzumab (Lemtrada) may be predicted by pretreatment levels of certain types of B cells, a new study suggests.

“Alemtuzumab has proven to be an effective treatment for patients with highly active remitting relapsing MS, but adverse events may limit the use of this drug, particularly autoimmune adverse events, which are the most prevalent, occurring in about 30% of patients. Reliable biomarkers to assess patient risk for developing this complication would be of great importance,” said lead author Paulette Walo, MD.

“Our results suggest that a higher percentage of total B cells, and in particular plasmablasts, could be a very predictive biomarker for autoimmunity after alemtuzumab treatment. This could help us in choosing the patients for this drug,” said Dr. Walo, an immunologist at Ramon y Cajal University Hospital, Madrid. She presented the findings at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

The objective of this study was to explore if patient blood lymphocyte profile before alemtuzumab treatment initiation can identify patients with an increased risk of developing later autoimmunity, Dr. Walo explained.

The study included 54 patients from five hospitals throughout Spain who had received treatment with alemtuzumab. Of these, the vast majority had received the normal two-dose cycle and two patients had received a third dose because of worsening MS activity.

Blood samples were collected before initiating treatment with alemtuzumab. Peripheral blood mononuclear cells were obtained and cryopreserved. Leukocyte populations were assessed by flow cytometry.

Autoimmune adverse events were defined as the development, at any point within 2 years of follow-up, of any autoimmune thyroid-associated event, immune thrombocytopenia, and/or autoimmune nephropathy.

Over the 2 years of follow-up, 14 patients (25.9%) experienced autoimmune adverse events, all of which were dysthyroidism. No immune thrombocytopenia or nephropathies were observed.

No statistical differences were found in clinical and demographic characteristics between patients who developed autoimmune adverse events and those who did not. Previous treatments did not influence B-cell percentages.

Analysis of blood lymphocyte profiles showed no difference in T-cell subsets between those who had an autoimmune event and those who did not.

Still, there were important differences in the B-cell profile, Dr. Walo said. “Total B cells were higher in patients who had an autoimmune event mainly due to naive B cells and plasmablasts.”

Patients who experienced autoimmune adverse events before treatment onset had a higher percentage of blood CD19+ B cells (P = .001), with a higher relative percentage of naive B cells and plasmablasts.

When individual types of cell numbers were explored, only plasmablast levels remained significant (P = .02).

The researchers calculated a CD19+ B-cell predictive value for autoimmunity of 7.6%. If patients had more than 7.6% B cells, they were at higher risk of an autoimmune adverse event after alemtuzumab treatment versus those with lower levels (odds ratio, 14.67; P ≤ .0001).

Similarly, the predictive value for plasmablasts was 0.13%. If patients had levels higher than 0.13% they had a higher risk of an autoimmune event after alemtuzumab treatment (P = .002). Plasmablasts are a category of B cells which are very differentiated and have the capacity to produce antibodies; they are a very active and aggressive subtype of B cells, Dr. Walo noted. 

She explained that, as was the case in this study, autoimmune events after alemtuzumab treatment normally manifests as the development of antibodies against the thyroid gland, with the development of either hyperthyroidism or hypothyroidism, necessitating long-term treatment to manage these conditions.

“Autoimmunity develops at variable timescales. It can appear in the first year after alemtuzumab treatment but it can also appear later on,” she said.

Dr. Walo’s group is hoping to validate their results in a larger study. “This is only a small study so we need to replicate these findings in a larger cohort. We are in the process of doing this, collaborating with other hospitals,” she commented. 

She said that, if the results are validated, then patients could undergo blood tests before alemtuzumab treatment to analyze their B-cell counts.

“For those with high levels of B cells – and particularly plasmablasts – alemtuzumab may not be the best treatment to choose,” Dr. Walo said.
 

Personalized strategy

During the postpresentation discussion, the suggestion was raised of giving an anti–B-cell drug before alemtuzumab to try and prevent autoimmunity. Dr. Walo responded that this is a possibility. “This is something that we are going to look into. If our larger study validates our initial results, then we would plan a study to give an anti–B-cell treatment such as rituximab before alemtuzumab and see whether this reduces the risk of autoimmunity.”

Commenting on the study, session comoderator Darin Okuda, MD, professor in the department of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center, Dallas, said: “This is an intriguing approach and suggests a more personalized strategy for sure if we can identify patients who are at higher risk of developing autoimmunity.”

Also commenting, ACTRIMS president Jeffrey Cohen, MD, said: “One of the main drawbacks of alemtuzumab is the risk of antibody-mediated autoimmune conditions, so the ability to predict who is at risk for autoimmune adverse events prior to initiating alemtuzumab would be useful. Not surprisingly, factors related to B-cell number and profile were predictive.”

Dr. Cohen, who is a director of experimental neurotherapeutics at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, added however that the suggestion of pretreating patients with an anti-CD20 monoclonal antibody “does not seem tenable to me,” because of the potential cost of such a strategy, and “no efficacy advantage for most patients over an anti-CD20 antibody alone.”

Commenting on this presentation, Alasdair J. Coles, MD, University of Cambridge (England), who was one of the co-inventors of alemtuzumab, said observations of an increased B-cell count before treatment as a risk predictor of thyroid autoimmunity after alemtuzumab had not been replicated in the clinical trial datasets of the drug. “So I fear we still do not have a reliable biomarker,” he added.

The study had no specific funding listed. Dr. Walo has disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

A common adverse effect of the multiple sclerosis (MS) treatment alemtuzumab (Lemtrada) may be predicted by pretreatment levels of certain types of B cells, a new study suggests.

“Alemtuzumab has proven to be an effective treatment for patients with highly active remitting relapsing MS, but adverse events may limit the use of this drug, particularly autoimmune adverse events, which are the most prevalent, occurring in about 30% of patients. Reliable biomarkers to assess patient risk for developing this complication would be of great importance,” said lead author Paulette Walo, MD.

“Our results suggest that a higher percentage of total B cells, and in particular plasmablasts, could be a very predictive biomarker for autoimmunity after alemtuzumab treatment. This could help us in choosing the patients for this drug,” said Dr. Walo, an immunologist at Ramon y Cajal University Hospital, Madrid. She presented the findings at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

The objective of this study was to explore if patient blood lymphocyte profile before alemtuzumab treatment initiation can identify patients with an increased risk of developing later autoimmunity, Dr. Walo explained.

The study included 54 patients from five hospitals throughout Spain who had received treatment with alemtuzumab. Of these, the vast majority had received the normal two-dose cycle and two patients had received a third dose because of worsening MS activity.

Blood samples were collected before initiating treatment with alemtuzumab. Peripheral blood mononuclear cells were obtained and cryopreserved. Leukocyte populations were assessed by flow cytometry.

Autoimmune adverse events were defined as the development, at any point within 2 years of follow-up, of any autoimmune thyroid-associated event, immune thrombocytopenia, and/or autoimmune nephropathy.

Over the 2 years of follow-up, 14 patients (25.9%) experienced autoimmune adverse events, all of which were dysthyroidism. No immune thrombocytopenia or nephropathies were observed.

No statistical differences were found in clinical and demographic characteristics between patients who developed autoimmune adverse events and those who did not. Previous treatments did not influence B-cell percentages.

Analysis of blood lymphocyte profiles showed no difference in T-cell subsets between those who had an autoimmune event and those who did not.

Still, there were important differences in the B-cell profile, Dr. Walo said. “Total B cells were higher in patients who had an autoimmune event mainly due to naive B cells and plasmablasts.”

Patients who experienced autoimmune adverse events before treatment onset had a higher percentage of blood CD19+ B cells (P = .001), with a higher relative percentage of naive B cells and plasmablasts.

When individual types of cell numbers were explored, only plasmablast levels remained significant (P = .02).

The researchers calculated a CD19+ B-cell predictive value for autoimmunity of 7.6%. If patients had more than 7.6% B cells, they were at higher risk of an autoimmune adverse event after alemtuzumab treatment versus those with lower levels (odds ratio, 14.67; P ≤ .0001).

Similarly, the predictive value for plasmablasts was 0.13%. If patients had levels higher than 0.13% they had a higher risk of an autoimmune event after alemtuzumab treatment (P = .002). Plasmablasts are a category of B cells which are very differentiated and have the capacity to produce antibodies; they are a very active and aggressive subtype of B cells, Dr. Walo noted. 

She explained that, as was the case in this study, autoimmune events after alemtuzumab treatment normally manifests as the development of antibodies against the thyroid gland, with the development of either hyperthyroidism or hypothyroidism, necessitating long-term treatment to manage these conditions.

“Autoimmunity develops at variable timescales. It can appear in the first year after alemtuzumab treatment but it can also appear later on,” she said.

Dr. Walo’s group is hoping to validate their results in a larger study. “This is only a small study so we need to replicate these findings in a larger cohort. We are in the process of doing this, collaborating with other hospitals,” she commented. 

She said that, if the results are validated, then patients could undergo blood tests before alemtuzumab treatment to analyze their B-cell counts.

“For those with high levels of B cells – and particularly plasmablasts – alemtuzumab may not be the best treatment to choose,” Dr. Walo said.
 

Personalized strategy

During the postpresentation discussion, the suggestion was raised of giving an anti–B-cell drug before alemtuzumab to try and prevent autoimmunity. Dr. Walo responded that this is a possibility. “This is something that we are going to look into. If our larger study validates our initial results, then we would plan a study to give an anti–B-cell treatment such as rituximab before alemtuzumab and see whether this reduces the risk of autoimmunity.”

Commenting on the study, session comoderator Darin Okuda, MD, professor in the department of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center, Dallas, said: “This is an intriguing approach and suggests a more personalized strategy for sure if we can identify patients who are at higher risk of developing autoimmunity.”

Also commenting, ACTRIMS president Jeffrey Cohen, MD, said: “One of the main drawbacks of alemtuzumab is the risk of antibody-mediated autoimmune conditions, so the ability to predict who is at risk for autoimmune adverse events prior to initiating alemtuzumab would be useful. Not surprisingly, factors related to B-cell number and profile were predictive.”

Dr. Cohen, who is a director of experimental neurotherapeutics at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, added however that the suggestion of pretreating patients with an anti-CD20 monoclonal antibody “does not seem tenable to me,” because of the potential cost of such a strategy, and “no efficacy advantage for most patients over an anti-CD20 antibody alone.”

Commenting on this presentation, Alasdair J. Coles, MD, University of Cambridge (England), who was one of the co-inventors of alemtuzumab, said observations of an increased B-cell count before treatment as a risk predictor of thyroid autoimmunity after alemtuzumab had not been replicated in the clinical trial datasets of the drug. “So I fear we still do not have a reliable biomarker,” he added.

The study had no specific funding listed. Dr. Walo has disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.