Just when we thought this holiday season, finally, would be the back-to-normal one, some infectious disease experts are warning that a so-called “tripledemic” – influenza, COVID-19, and RSV – may be in the forecast.

The warning isn’t without basis. 

The flu season has gotten an early start. As of Oct. 21, early increases in seasonal flu activity have been reported in most of the country, the Centers for Disease Control and Prevention said, with the southeast and south-central areas having the highest activity levels. 

Children’s hospitals and EDs are seeing a surge in children with RSV.

COVID-19 cases are trending down, according to the CDC, but epidemiologists – scientists who study disease outbreaks – always have their eyes on emerging variants. 

Predicting exactly when cases will peak is difficult, said Justin Lessler, PhD, a professor of epidemiology at the University of North Carolina at Chapel Hill. Dr. Lessler is on the coordinating team for the COVID-19 Scenario Modeling Hub, which aims to predict the course COVID-19, and the Flu Scenario Modeling Hub, which does the same for influenza.

For COVID-19, some models are predicting some spikes before Christmas, he said, and others see a new wave in 2023. For the flu, the model is predicting an earlier-than-usual start, as the CDC has reported.  

While flu activity is relatively low, the CDC said, the season is off to an early start. For the week ending Oct. 21, 1,674 patients were hospitalized for flu, higher than in the summer months but fewer than the 2,675 hospitalizations for the week of May 15, 2022. 

As of Oct. 20, COVID-19 cases have declined 12% over the last 2 weeks, nationwide. But hospitalizations are up 10% in much of the Northeast, The New York Times reports, and the improvement in cases and deaths has been slowing down. 

As of Oct. 15, 15% of RSV tests reported nationwide were positive, compared with about 11% at that time in 2021, the CDC said. The surveillance collects information from 75 counties in 12 states. 

Experts point out that the viruses – all three are respiratory viruses – are simply playing catchup. 

“They spread the same way and along with lots of other viruses, and you tend to see an increase in them during the cold months,” said Timothy Brewer, MD, professor of medicine and epidemiology at UCLA.

The increase in all three viruses “is almost predictable at this point in the pandemic,” said Dean Blumberg, MD, a professor and chief of pediatric infectious diseases at the University of California Davis Health. “All the respiratory viruses are out of whack.” 

Last year, RSV cases were up, too, and began to appear very early, he said, in the summer instead of in the cooler months. Flu also appeared early in 2021, as it has in 2022. 

That contrasts with the flu season of 2020-2021, when COVID precautions were nearly universal, and cases were down. At UC Davis, “we didn’t have one pediatric admission due to influenza in the 2020-2021 [flu] season,” Dr. Blumberg said. 

The number of pediatric flu deaths usually range from 37 to 199 per year, according to CDC records. But in the 2020-2021 season, the CDC recorded one pediatric flu death in the U.S.

Both children and adults have had less contact with others the past two seasons, Dr. Blumberg said, “and they don’t get the immunity they got with those infections [previously]. That’s why we are seeing out-of-season, early season [viruses].” 

Eventually, he said, the cases of flu and RSV will return to previous levels. “It could be as soon as next year,” Dr. Blumberg said. And COVID-19, hopefully, will become like influenza, he said.

“RSV has always come around in the fall and winter,” said Elizabeth Murray, DO, a pediatric emergency medicine doctor at the University of Rochester (N.Y.) Medical Center and a spokesperson for the American Academy of Pediatrics. In 2022, children are back in school and for the most part not masking. “It’s a perfect storm for all the germs to spread now. They’ve just been waiting for their opportunity to come back.”
 

Self-care vs. not

RSV can pose a risk for anyone, but most at risk are children under age 5, especially infants under age 1, and adults over age 65. There is no vaccine for it. Symptoms include a runny nose, decreased appetite, coughing, sneezing, fever, and wheezing. But in young infants, there may only be decreased activity, crankiness, and breathing issues, the CDC said.

Keep an eye on the breathing if RSV is suspected, Dr. Murray tells parents. If your child can’t breathe easily, is unable to lie down comfortably, can’t speak clearly, or is sucking in the chest muscles to breathe, get medical help. Most kids with RSV can stay home and recover, she said, but often will need to be checked by a medical professional.

She advises against getting an oximeter to measure oxygen levels for home use. “They are often not accurate,” she said. If in doubt about how serious your child’s symptoms are, “don’t wait it out,” and don’t hesitate to call 911.

Symptoms of flu, COVID, and RSV can overlap. But each can involve breathing problems, which can be an emergency. 

“It’s important to seek medical attention for any concerning symptoms, but especially severe shortness of breath or difficulty breathing, as these could signal the need for supplemental oxygen or other emergency interventions,” said Mandy De Vries, a respiratory therapist and director of education at the American Association for Respiratory Care. Inhalation treatment or mechanical ventilation may be needed for severe respiratory issues.
 

Precautions

To avoid the tripledemic – or any single infection – Timothy Brewer, MD, a professor of medicine and epidemiology at the University of California, Los Angeles, suggests some familiar measures: “Stay home if you’re feeling sick. Make sure you are up to date on your vaccinations. Wear a mask indoors.”

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

Just when we thought this holiday season, finally, would be the back-to-normal one, some infectious disease experts are warning that a so-called “tripledemic” – influenza, COVID-19, and RSV – may be in the forecast.

The warning isn’t without basis. 

The flu season has gotten an early start. As of Oct. 21, early increases in seasonal flu activity have been reported in most of the country, the Centers for Disease Control and Prevention said, with the southeast and south-central areas having the highest activity levels. 

Children’s hospitals and EDs are seeing a surge in children with RSV.

COVID-19 cases are trending down, according to the CDC, but epidemiologists – scientists who study disease outbreaks – always have their eyes on emerging variants. 

Predicting exactly when cases will peak is difficult, said Justin Lessler, PhD, a professor of epidemiology at the University of North Carolina at Chapel Hill. Dr. Lessler is on the coordinating team for the COVID-19 Scenario Modeling Hub, which aims to predict the course COVID-19, and the Flu Scenario Modeling Hub, which does the same for influenza.

For COVID-19, some models are predicting some spikes before Christmas, he said, and others see a new wave in 2023. For the flu, the model is predicting an earlier-than-usual start, as the CDC has reported.  

While flu activity is relatively low, the CDC said, the season is off to an early start. For the week ending Oct. 21, 1,674 patients were hospitalized for flu, higher than in the summer months but fewer than the 2,675 hospitalizations for the week of May 15, 2022. 

As of Oct. 20, COVID-19 cases have declined 12% over the last 2 weeks, nationwide. But hospitalizations are up 10% in much of the Northeast, The New York Times reports, and the improvement in cases and deaths has been slowing down. 

As of Oct. 15, 15% of RSV tests reported nationwide were positive, compared with about 11% at that time in 2021, the CDC said. The surveillance collects information from 75 counties in 12 states. 

Experts point out that the viruses – all three are respiratory viruses – are simply playing catchup. 

“They spread the same way and along with lots of other viruses, and you tend to see an increase in them during the cold months,” said Timothy Brewer, MD, professor of medicine and epidemiology at UCLA.

The increase in all three viruses “is almost predictable at this point in the pandemic,” said Dean Blumberg, MD, a professor and chief of pediatric infectious diseases at the University of California Davis Health. “All the respiratory viruses are out of whack.” 

Last year, RSV cases were up, too, and began to appear very early, he said, in the summer instead of in the cooler months. Flu also appeared early in 2021, as it has in 2022. 

That contrasts with the flu season of 2020-2021, when COVID precautions were nearly universal, and cases were down. At UC Davis, “we didn’t have one pediatric admission due to influenza in the 2020-2021 [flu] season,” Dr. Blumberg said. 

The number of pediatric flu deaths usually range from 37 to 199 per year, according to CDC records. But in the 2020-2021 season, the CDC recorded one pediatric flu death in the U.S.

Both children and adults have had less contact with others the past two seasons, Dr. Blumberg said, “and they don’t get the immunity they got with those infections [previously]. That’s why we are seeing out-of-season, early season [viruses].” 

Eventually, he said, the cases of flu and RSV will return to previous levels. “It could be as soon as next year,” Dr. Blumberg said. And COVID-19, hopefully, will become like influenza, he said.

“RSV has always come around in the fall and winter,” said Elizabeth Murray, DO, a pediatric emergency medicine doctor at the University of Rochester (N.Y.) Medical Center and a spokesperson for the American Academy of Pediatrics. In 2022, children are back in school and for the most part not masking. “It’s a perfect storm for all the germs to spread now. They’ve just been waiting for their opportunity to come back.”
 

Self-care vs. not

RSV can pose a risk for anyone, but most at risk are children under age 5, especially infants under age 1, and adults over age 65. There is no vaccine for it. Symptoms include a runny nose, decreased appetite, coughing, sneezing, fever, and wheezing. But in young infants, there may only be decreased activity, crankiness, and breathing issues, the CDC said.

Keep an eye on the breathing if RSV is suspected, Dr. Murray tells parents. If your child can’t breathe easily, is unable to lie down comfortably, can’t speak clearly, or is sucking in the chest muscles to breathe, get medical help. Most kids with RSV can stay home and recover, she said, but often will need to be checked by a medical professional.

She advises against getting an oximeter to measure oxygen levels for home use. “They are often not accurate,” she said. If in doubt about how serious your child’s symptoms are, “don’t wait it out,” and don’t hesitate to call 911.

Symptoms of flu, COVID, and RSV can overlap. But each can involve breathing problems, which can be an emergency. 

“It’s important to seek medical attention for any concerning symptoms, but especially severe shortness of breath or difficulty breathing, as these could signal the need for supplemental oxygen or other emergency interventions,” said Mandy De Vries, a respiratory therapist and director of education at the American Association for Respiratory Care. Inhalation treatment or mechanical ventilation may be needed for severe respiratory issues.
 

Precautions

To avoid the tripledemic – or any single infection – Timothy Brewer, MD, a professor of medicine and epidemiology at the University of California, Los Angeles, suggests some familiar measures: “Stay home if you’re feeling sick. Make sure you are up to date on your vaccinations. Wear a mask indoors.”

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

Just when we thought this holiday season, finally, would be the back-to-normal one, some infectious disease experts are warning that a so-called “tripledemic” – influenza, COVID-19, and RSV – may be in the forecast.

The warning isn’t without basis. 

The flu season has gotten an early start. As of Oct. 21, early increases in seasonal flu activity have been reported in most of the country, the Centers for Disease Control and Prevention said, with the southeast and south-central areas having the highest activity levels. 

Children’s hospitals and EDs are seeing a surge in children with RSV.

COVID-19 cases are trending down, according to the CDC, but epidemiologists – scientists who study disease outbreaks – always have their eyes on emerging variants. 

Predicting exactly when cases will peak is difficult, said Justin Lessler, PhD, a professor of epidemiology at the University of North Carolina at Chapel Hill. Dr. Lessler is on the coordinating team for the COVID-19 Scenario Modeling Hub, which aims to predict the course COVID-19, and the Flu Scenario Modeling Hub, which does the same for influenza.

For COVID-19, some models are predicting some spikes before Christmas, he said, and others see a new wave in 2023. For the flu, the model is predicting an earlier-than-usual start, as the CDC has reported.  

While flu activity is relatively low, the CDC said, the season is off to an early start. For the week ending Oct. 21, 1,674 patients were hospitalized for flu, higher than in the summer months but fewer than the 2,675 hospitalizations for the week of May 15, 2022. 

As of Oct. 20, COVID-19 cases have declined 12% over the last 2 weeks, nationwide. But hospitalizations are up 10% in much of the Northeast, The New York Times reports, and the improvement in cases and deaths has been slowing down. 

As of Oct. 15, 15% of RSV tests reported nationwide were positive, compared with about 11% at that time in 2021, the CDC said. The surveillance collects information from 75 counties in 12 states. 

Experts point out that the viruses – all three are respiratory viruses – are simply playing catchup. 

“They spread the same way and along with lots of other viruses, and you tend to see an increase in them during the cold months,” said Timothy Brewer, MD, professor of medicine and epidemiology at UCLA.

The increase in all three viruses “is almost predictable at this point in the pandemic,” said Dean Blumberg, MD, a professor and chief of pediatric infectious diseases at the University of California Davis Health. “All the respiratory viruses are out of whack.” 

Last year, RSV cases were up, too, and began to appear very early, he said, in the summer instead of in the cooler months. Flu also appeared early in 2021, as it has in 2022. 

That contrasts with the flu season of 2020-2021, when COVID precautions were nearly universal, and cases were down. At UC Davis, “we didn’t have one pediatric admission due to influenza in the 2020-2021 [flu] season,” Dr. Blumberg said. 

The number of pediatric flu deaths usually range from 37 to 199 per year, according to CDC records. But in the 2020-2021 season, the CDC recorded one pediatric flu death in the U.S.

Both children and adults have had less contact with others the past two seasons, Dr. Blumberg said, “and they don’t get the immunity they got with those infections [previously]. That’s why we are seeing out-of-season, early season [viruses].” 

Eventually, he said, the cases of flu and RSV will return to previous levels. “It could be as soon as next year,” Dr. Blumberg said. And COVID-19, hopefully, will become like influenza, he said.

“RSV has always come around in the fall and winter,” said Elizabeth Murray, DO, a pediatric emergency medicine doctor at the University of Rochester (N.Y.) Medical Center and a spokesperson for the American Academy of Pediatrics. In 2022, children are back in school and for the most part not masking. “It’s a perfect storm for all the germs to spread now. They’ve just been waiting for their opportunity to come back.”
 

Self-care vs. not

RSV can pose a risk for anyone, but most at risk are children under age 5, especially infants under age 1, and adults over age 65. There is no vaccine for it. Symptoms include a runny nose, decreased appetite, coughing, sneezing, fever, and wheezing. But in young infants, there may only be decreased activity, crankiness, and breathing issues, the CDC said.

Keep an eye on the breathing if RSV is suspected, Dr. Murray tells parents. If your child can’t breathe easily, is unable to lie down comfortably, can’t speak clearly, or is sucking in the chest muscles to breathe, get medical help. Most kids with RSV can stay home and recover, she said, but often will need to be checked by a medical professional.

She advises against getting an oximeter to measure oxygen levels for home use. “They are often not accurate,” she said. If in doubt about how serious your child’s symptoms are, “don’t wait it out,” and don’t hesitate to call 911.

Symptoms of flu, COVID, and RSV can overlap. But each can involve breathing problems, which can be an emergency. 

“It’s important to seek medical attention for any concerning symptoms, but especially severe shortness of breath or difficulty breathing, as these could signal the need for supplemental oxygen or other emergency interventions,” said Mandy De Vries, a respiratory therapist and director of education at the American Association for Respiratory Care. Inhalation treatment or mechanical ventilation may be needed for severe respiratory issues.
 

Precautions

To avoid the tripledemic – or any single infection – Timothy Brewer, MD, a professor of medicine and epidemiology at the University of California, Los Angeles, suggests some familiar measures: “Stay home if you’re feeling sick. Make sure you are up to date on your vaccinations. Wear a mask indoors.”

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

CHARLOTTE, N.C. – People with moderate to severe ulcerative colitis benefit from stronger treatment from the start – a combination of monoclonal antibodies – compared with induction with either agent alone, a phase 2a study demonstrates.

Researchers compared the combination therapy of guselkumab and golimumab (both from Janssen) for 12 weeks, followed by guselkumab monotherapy up to week 38, versus either agent as monotherapy for the full 38 weeks.

Guselkumab is an interleukin-23p19 subunit antagonist being studied to treat inflammatory bowel disease (IBD). Golimumab is a TNF-alpha antagonist being evaluated for ulcerative colitis.

University of Western Ontario, London

The combination induction strategy “achieved higher rates of clinical remission, endoscopic improvement, composite endpoint of histologic remission, and endoscopic improvement,” said Brian G. Feagan, MD, senior scientific director at the contract research organization Alimentiv and a gastroenterologist at Western University in London, Ont.

The findings were presented at the annual meeting of the American College of Gastroenterology.
 

Study design

The current research builds on previous week 12 VEGA study results. The earlier findings indicated that blocking interleukin-23p19 by guselkumab and TNF-alpha with golimumab was superior on multiple measures, compared with monotherapy.

The new findings are from a randomized, double-blind, proof-of-concept study that included 214 adults with moderately to severely active ulcerative colitis. Participants were naive to TNF-alpha antagonists and refractory or intolerant to conventional therapy.

Of the participants, 71 were randomly assigned to receive guselkumab, 200 mg intravenous (IV) at baseline and at weeks 4 and 8, plus 100 mg subcutaneous (SC) every 8 weeks.

Another 72 participants received golimumab, 200 mg SC at baseline, and 100 mg SC at weeks 2, 6, and 10, and every 4 weeks thereafter.

The combination group of 71 participants received guselkumab 200 mg IV and golimumab 200 mg SC at baseline, followed by golimumab 100 mg SC at weeks 2, 6, and 10, and guselkumab 200 mg IV at weeks 4 and 8. At week 12, this group switched to monotherapy with guselkumab, 100 mg SC every 8 weeks.

Overall, 13% of patients discontinued treatment prior to week 34, the time of final dose of study intervention.

Dr. Feagan noted that they did not see differences between any adverse event, serious adverse event, or adverse event leading to discontinuation among the treatment groups.
 

Key findings through week 38

The rate of clinical remission in the combination group was 44%. The rate was lower with guselkumab monotherapy at 31% and golimumab monotherapy at 22% at week 38. These percentages were based on a full Mayo Score of 2 or less and no individual subscore greater than 1.

At the same time, the rates of clinical remission by modified Mayo score also favored the combination group at 48%, followed by 31% in the guselkumab group and 21% in the golimumab cohort.

Endoscopic improvement, endoscopic normalization, histologic remission, and composite histologic-endoscopic endpoints were also greater in the combination group than in the monotherapy groups.

“Quite striking differences were maintained up to week 38,” Dr. Feagan said. “This combination treatment warrants further investigation, and phase 3 trials are underway.”

He added that, while they were concerned about serious infection, they did not see any differences, with only two serious infections in each of the three groups.

Opportunistic infections were reported for two patients in the combination group: extrapulmonary tuberculosis and cytomegalovirus colitis. No opportunistic infections occurred in the monotherapy groups.
 

Valuable data

“The early study results, such as the VEGA study, appear promising for combination biologics with a good safety profile,” Jean-Paul Achkar, MD, staff physician in the Center for Inflammatory Bowel Disease at Cleveland Clinic and the Kenneth Rainin Endowed Chair for IBD Research, said when asked to comment.

“These data are particularly valuable as we have seemingly reached a therapeutic response ceiling for single-biologic therapy, and we need to determine the added benefit and safety profile of a combination of two biologics or the combination of a biologic and a small molecule,” added Dr. Achkar, who served as the session comoderator.

A meeting attendee asked about the likelihood of regulatory approval for this combination based on evidence like this study.

“I think they have to,” Dr. Feagan said. “We’ve probably seen our best results yet in Crohn’s disease, and we’re still at 50% [response rate for monotherapy]. If we’re ever going to come to terms with IBD, I don’t think it’s monotherapy.”

Dr. Feagan added that with combination therapy, “physicians will often worry about economics, but I think that’s a surrogate for their concerns about infection.”

However, he noted that “the better the agents we have, the better the incremental cost effectiveness. So, I don’t think economics is the issue; the issue is safety.”

Another meeting attendee asked if the results might apply to other biologic combinations.

“This model was picked to show the additive effect of the anti-p19 and the TNF antagonist,” Dr. Feagan said.

Similar results could be expected with a combination of treatments from the same classes, he said, but the treatment potential of other drug-class combination is unclear.

The study was funded by Janssen Research and Development. Dr. Feagan reports being a consultant for Janssen. Dr. Achkar reports no relevant financial relationships.

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

CHARLOTTE, N.C. – People with moderate to severe ulcerative colitis benefit from stronger treatment from the start – a combination of monoclonal antibodies – compared with induction with either agent alone, a phase 2a study demonstrates.

Researchers compared the combination therapy of guselkumab and golimumab (both from Janssen) for 12 weeks, followed by guselkumab monotherapy up to week 38, versus either agent as monotherapy for the full 38 weeks.

Guselkumab is an interleukin-23p19 subunit antagonist being studied to treat inflammatory bowel disease (IBD). Golimumab is a TNF-alpha antagonist being evaluated for ulcerative colitis.

University of Western Ontario, London

The combination induction strategy “achieved higher rates of clinical remission, endoscopic improvement, composite endpoint of histologic remission, and endoscopic improvement,” said Brian G. Feagan, MD, senior scientific director at the contract research organization Alimentiv and a gastroenterologist at Western University in London, Ont.

The findings were presented at the annual meeting of the American College of Gastroenterology.
 

Study design

The current research builds on previous week 12 VEGA study results. The earlier findings indicated that blocking interleukin-23p19 by guselkumab and TNF-alpha with golimumab was superior on multiple measures, compared with monotherapy.

The new findings are from a randomized, double-blind, proof-of-concept study that included 214 adults with moderately to severely active ulcerative colitis. Participants were naive to TNF-alpha antagonists and refractory or intolerant to conventional therapy.

Of the participants, 71 were randomly assigned to receive guselkumab, 200 mg intravenous (IV) at baseline and at weeks 4 and 8, plus 100 mg subcutaneous (SC) every 8 weeks.

Another 72 participants received golimumab, 200 mg SC at baseline, and 100 mg SC at weeks 2, 6, and 10, and every 4 weeks thereafter.

The combination group of 71 participants received guselkumab 200 mg IV and golimumab 200 mg SC at baseline, followed by golimumab 100 mg SC at weeks 2, 6, and 10, and guselkumab 200 mg IV at weeks 4 and 8. At week 12, this group switched to monotherapy with guselkumab, 100 mg SC every 8 weeks.

Overall, 13% of patients discontinued treatment prior to week 34, the time of final dose of study intervention.

Dr. Feagan noted that they did not see differences between any adverse event, serious adverse event, or adverse event leading to discontinuation among the treatment groups.
 

Key findings through week 38

The rate of clinical remission in the combination group was 44%. The rate was lower with guselkumab monotherapy at 31% and golimumab monotherapy at 22% at week 38. These percentages were based on a full Mayo Score of 2 or less and no individual subscore greater than 1.

At the same time, the rates of clinical remission by modified Mayo score also favored the combination group at 48%, followed by 31% in the guselkumab group and 21% in the golimumab cohort.

Endoscopic improvement, endoscopic normalization, histologic remission, and composite histologic-endoscopic endpoints were also greater in the combination group than in the monotherapy groups.

“Quite striking differences were maintained up to week 38,” Dr. Feagan said. “This combination treatment warrants further investigation, and phase 3 trials are underway.”

He added that, while they were concerned about serious infection, they did not see any differences, with only two serious infections in each of the three groups.

Opportunistic infections were reported for two patients in the combination group: extrapulmonary tuberculosis and cytomegalovirus colitis. No opportunistic infections occurred in the monotherapy groups.
 

Valuable data

“The early study results, such as the VEGA study, appear promising for combination biologics with a good safety profile,” Jean-Paul Achkar, MD, staff physician in the Center for Inflammatory Bowel Disease at Cleveland Clinic and the Kenneth Rainin Endowed Chair for IBD Research, said when asked to comment.

“These data are particularly valuable as we have seemingly reached a therapeutic response ceiling for single-biologic therapy, and we need to determine the added benefit and safety profile of a combination of two biologics or the combination of a biologic and a small molecule,” added Dr. Achkar, who served as the session comoderator.

A meeting attendee asked about the likelihood of regulatory approval for this combination based on evidence like this study.

“I think they have to,” Dr. Feagan said. “We’ve probably seen our best results yet in Crohn’s disease, and we’re still at 50% [response rate for monotherapy]. If we’re ever going to come to terms with IBD, I don’t think it’s monotherapy.”

Dr. Feagan added that with combination therapy, “physicians will often worry about economics, but I think that’s a surrogate for their concerns about infection.”

However, he noted that “the better the agents we have, the better the incremental cost effectiveness. So, I don’t think economics is the issue; the issue is safety.”

Another meeting attendee asked if the results might apply to other biologic combinations.

“This model was picked to show the additive effect of the anti-p19 and the TNF antagonist,” Dr. Feagan said.

Similar results could be expected with a combination of treatments from the same classes, he said, but the treatment potential of other drug-class combination is unclear.

The study was funded by Janssen Research and Development. Dr. Feagan reports being a consultant for Janssen. Dr. Achkar reports no relevant financial relationships.

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

CHARLOTTE, N.C. – People with moderate to severe ulcerative colitis benefit from stronger treatment from the start – a combination of monoclonal antibodies – compared with induction with either agent alone, a phase 2a study demonstrates.

Researchers compared the combination therapy of guselkumab and golimumab (both from Janssen) for 12 weeks, followed by guselkumab monotherapy up to week 38, versus either agent as monotherapy for the full 38 weeks.

Guselkumab is an interleukin-23p19 subunit antagonist being studied to treat inflammatory bowel disease (IBD). Golimumab is a TNF-alpha antagonist being evaluated for ulcerative colitis.

University of Western Ontario, London

The combination induction strategy “achieved higher rates of clinical remission, endoscopic improvement, composite endpoint of histologic remission, and endoscopic improvement,” said Brian G. Feagan, MD, senior scientific director at the contract research organization Alimentiv and a gastroenterologist at Western University in London, Ont.

The findings were presented at the annual meeting of the American College of Gastroenterology.
 

Study design

The current research builds on previous week 12 VEGA study results. The earlier findings indicated that blocking interleukin-23p19 by guselkumab and TNF-alpha with golimumab was superior on multiple measures, compared with monotherapy.

The new findings are from a randomized, double-blind, proof-of-concept study that included 214 adults with moderately to severely active ulcerative colitis. Participants were naive to TNF-alpha antagonists and refractory or intolerant to conventional therapy.

Of the participants, 71 were randomly assigned to receive guselkumab, 200 mg intravenous (IV) at baseline and at weeks 4 and 8, plus 100 mg subcutaneous (SC) every 8 weeks.

Another 72 participants received golimumab, 200 mg SC at baseline, and 100 mg SC at weeks 2, 6, and 10, and every 4 weeks thereafter.

The combination group of 71 participants received guselkumab 200 mg IV and golimumab 200 mg SC at baseline, followed by golimumab 100 mg SC at weeks 2, 6, and 10, and guselkumab 200 mg IV at weeks 4 and 8. At week 12, this group switched to monotherapy with guselkumab, 100 mg SC every 8 weeks.

Overall, 13% of patients discontinued treatment prior to week 34, the time of final dose of study intervention.

Dr. Feagan noted that they did not see differences between any adverse event, serious adverse event, or adverse event leading to discontinuation among the treatment groups.
 

Key findings through week 38

The rate of clinical remission in the combination group was 44%. The rate was lower with guselkumab monotherapy at 31% and golimumab monotherapy at 22% at week 38. These percentages were based on a full Mayo Score of 2 or less and no individual subscore greater than 1.

At the same time, the rates of clinical remission by modified Mayo score also favored the combination group at 48%, followed by 31% in the guselkumab group and 21% in the golimumab cohort.

Endoscopic improvement, endoscopic normalization, histologic remission, and composite histologic-endoscopic endpoints were also greater in the combination group than in the monotherapy groups.

“Quite striking differences were maintained up to week 38,” Dr. Feagan said. “This combination treatment warrants further investigation, and phase 3 trials are underway.”

He added that, while they were concerned about serious infection, they did not see any differences, with only two serious infections in each of the three groups.

Opportunistic infections were reported for two patients in the combination group: extrapulmonary tuberculosis and cytomegalovirus colitis. No opportunistic infections occurred in the monotherapy groups.
 

Valuable data

“The early study results, such as the VEGA study, appear promising for combination biologics with a good safety profile,” Jean-Paul Achkar, MD, staff physician in the Center for Inflammatory Bowel Disease at Cleveland Clinic and the Kenneth Rainin Endowed Chair for IBD Research, said when asked to comment.

“These data are particularly valuable as we have seemingly reached a therapeutic response ceiling for single-biologic therapy, and we need to determine the added benefit and safety profile of a combination of two biologics or the combination of a biologic and a small molecule,” added Dr. Achkar, who served as the session comoderator.

A meeting attendee asked about the likelihood of regulatory approval for this combination based on evidence like this study.

“I think they have to,” Dr. Feagan said. “We’ve probably seen our best results yet in Crohn’s disease, and we’re still at 50% [response rate for monotherapy]. If we’re ever going to come to terms with IBD, I don’t think it’s monotherapy.”

Dr. Feagan added that with combination therapy, “physicians will often worry about economics, but I think that’s a surrogate for their concerns about infection.”

However, he noted that “the better the agents we have, the better the incremental cost effectiveness. So, I don’t think economics is the issue; the issue is safety.”

Another meeting attendee asked if the results might apply to other biologic combinations.

“This model was picked to show the additive effect of the anti-p19 and the TNF antagonist,” Dr. Feagan said.

Similar results could be expected with a combination of treatments from the same classes, he said, but the treatment potential of other drug-class combination is unclear.

The study was funded by Janssen Research and Development. Dr. Feagan reports being a consultant for Janssen. Dr. Achkar reports no relevant financial relationships.

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

A new study provides more evidence that HPV infection doesn’t raise the risk of poor outcomes in women who undergo fertility treatment via in vitro fertilization with fresh embryos. In fact, HPV-positive women were somewhat more likely than HPV-negative women to become pregnant (relative risk, 1.20; 95% confidence interval, 1.03-1.39) and have live births (RR, 1.39; 95% CI, 1.13-1.70), researchers reported Oct. 24 at the American Society for Reproductive Medicine’s 2022 meeting .

“This evidence should reassure women that being HPV positive will not affect live birth rates after a fresh embryo transfer cycle,” said study coauthor and ob.gyn. Nina Vyas, MD, a clinical fellow at Weill Cornell Medicine, New York, in an interview.

According to Dr. Vyas, previous studies have offered conflicting results about whether HPV affects pregnancy outcomes. In 2006, for example, her group performed a pilot study (Fertil Steril. Jun 16. doi: 10.1016/j.fertnstert.2006.01.051) that linked lower pregnancy rates to HPV-positive tests on the day of egg retrieval.

“We sought to reevaluate this finding in a retrospective manner,” Dr. Vyas said. “You’re taking eggs out of their home, injecting with sperm, and putting them back. There’s so much that we don’t know, and we want to make sure there’s no extra risk.”

Also, she added, “prior studies had a relatively low sample size. We sought to use our patient volume to address this question on a larger scale. Our current study benefits from a large sample size and using the clinically meaningful endpoint of live birth as our primary outcome.”

For the new study, researchers retrospectively analyzed 1,333 patients (of 2,209 screened) who received first fresh embryo transfers from 2017 to 2019. All had cytology or HPV status documented per cervical cancer screening guidelines within 6 months before embryos were transferred.

The researchers looked at only fresh embryo transfers “so we could account for pregnancy outcomes closest to the documented HPV status at the time of egg retrieval,” Dr. Vyas said.

Ten percent (133) of patients were HPV positive. Of those, 60.1% became pregnant, and 43.6% of them had live births. Of the HPV-negative women (90% of subjects, n = 1,200), 52.2% became pregnant and 33.5% had live births. The researchers didn’t calculate P values, but Dr. Vyas said an analysis determined that the differences between HPV-positive and HPV-negative women were statistically significant.

The study size doesn’t allow researchers to determine whether HPV actually has a protective effect on pregnancy/live birth rates in IVF, Dr. Vyas said. Even if it did, the virus is dangerous.

What else could explain the discrepancy? “Some elements driving this could the smaller sample size of the HPV-positive group, differences in HPV prevalence between the general population and our population,” she said, “or other confounding factors we were not able to appreciate due to the limitations of the retrospective study.”

Researchers also reported that they found “no significant difference in biochemical or spontaneous abortion rates” between HPV-positive and HPV-negative women.

What is the message of the study? “Women with HPV can rest assured that they won’t have worse outcomes than their non-HPV [infected] counterparts after a fresh embryo transfer cycle,” Dr. Vyas said.

In an interview, McGill University, Montreal, epidemiologist Helen Trottier, PhD, MSc, noted that she recently coauthored a study that linked persistent HPV infection in pregnancy to premature births. The findings appear convincing, she said: “I think we can say that HPV is associated with preterm birth.”

She praised the new study but noted “the relative risks that are reported need to be adjusted for race and possibly other factors.”

Dr. Vyas said that kind of adjustment will occur in a future study that’s in progress. “We are now prospectively enrolling patients and collecting cytology data to understand whether there might be a difference for women with higher malignancy potential/different types of HPV genotypes.”

The study authors have no disclosures. Disclosure information for Dr. Trottier was unavailable.

A new study provides more evidence that HPV infection doesn’t raise the risk of poor outcomes in women who undergo fertility treatment via in vitro fertilization with fresh embryos. In fact, HPV-positive women were somewhat more likely than HPV-negative women to become pregnant (relative risk, 1.20; 95% confidence interval, 1.03-1.39) and have live births (RR, 1.39; 95% CI, 1.13-1.70), researchers reported Oct. 24 at the American Society for Reproductive Medicine’s 2022 meeting .

“This evidence should reassure women that being HPV positive will not affect live birth rates after a fresh embryo transfer cycle,” said study coauthor and ob.gyn. Nina Vyas, MD, a clinical fellow at Weill Cornell Medicine, New York, in an interview.

According to Dr. Vyas, previous studies have offered conflicting results about whether HPV affects pregnancy outcomes. In 2006, for example, her group performed a pilot study (Fertil Steril. Jun 16. doi: 10.1016/j.fertnstert.2006.01.051) that linked lower pregnancy rates to HPV-positive tests on the day of egg retrieval.

“We sought to reevaluate this finding in a retrospective manner,” Dr. Vyas said. “You’re taking eggs out of their home, injecting with sperm, and putting them back. There’s so much that we don’t know, and we want to make sure there’s no extra risk.”

Also, she added, “prior studies had a relatively low sample size. We sought to use our patient volume to address this question on a larger scale. Our current study benefits from a large sample size and using the clinically meaningful endpoint of live birth as our primary outcome.”

For the new study, researchers retrospectively analyzed 1,333 patients (of 2,209 screened) who received first fresh embryo transfers from 2017 to 2019. All had cytology or HPV status documented per cervical cancer screening guidelines within 6 months before embryos were transferred.

The researchers looked at only fresh embryo transfers “so we could account for pregnancy outcomes closest to the documented HPV status at the time of egg retrieval,” Dr. Vyas said.

Ten percent (133) of patients were HPV positive. Of those, 60.1% became pregnant, and 43.6% of them had live births. Of the HPV-negative women (90% of subjects, n = 1,200), 52.2% became pregnant and 33.5% had live births. The researchers didn’t calculate P values, but Dr. Vyas said an analysis determined that the differences between HPV-positive and HPV-negative women were statistically significant.

The study size doesn’t allow researchers to determine whether HPV actually has a protective effect on pregnancy/live birth rates in IVF, Dr. Vyas said. Even if it did, the virus is dangerous.

What else could explain the discrepancy? “Some elements driving this could the smaller sample size of the HPV-positive group, differences in HPV prevalence between the general population and our population,” she said, “or other confounding factors we were not able to appreciate due to the limitations of the retrospective study.”

Researchers also reported that they found “no significant difference in biochemical or spontaneous abortion rates” between HPV-positive and HPV-negative women.

What is the message of the study? “Women with HPV can rest assured that they won’t have worse outcomes than their non-HPV [infected] counterparts after a fresh embryo transfer cycle,” Dr. Vyas said.

In an interview, McGill University, Montreal, epidemiologist Helen Trottier, PhD, MSc, noted that she recently coauthored a study that linked persistent HPV infection in pregnancy to premature births. The findings appear convincing, she said: “I think we can say that HPV is associated with preterm birth.”

She praised the new study but noted “the relative risks that are reported need to be adjusted for race and possibly other factors.”

Dr. Vyas said that kind of adjustment will occur in a future study that’s in progress. “We are now prospectively enrolling patients and collecting cytology data to understand whether there might be a difference for women with higher malignancy potential/different types of HPV genotypes.”

The study authors have no disclosures. Disclosure information for Dr. Trottier was unavailable.

A new study provides more evidence that HPV infection doesn’t raise the risk of poor outcomes in women who undergo fertility treatment via in vitro fertilization with fresh embryos. In fact, HPV-positive women were somewhat more likely than HPV-negative women to become pregnant (relative risk, 1.20; 95% confidence interval, 1.03-1.39) and have live births (RR, 1.39; 95% CI, 1.13-1.70), researchers reported Oct. 24 at the American Society for Reproductive Medicine’s 2022 meeting .

“This evidence should reassure women that being HPV positive will not affect live birth rates after a fresh embryo transfer cycle,” said study coauthor and ob.gyn. Nina Vyas, MD, a clinical fellow at Weill Cornell Medicine, New York, in an interview.

According to Dr. Vyas, previous studies have offered conflicting results about whether HPV affects pregnancy outcomes. In 2006, for example, her group performed a pilot study (Fertil Steril. Jun 16. doi: 10.1016/j.fertnstert.2006.01.051) that linked lower pregnancy rates to HPV-positive tests on the day of egg retrieval.

“We sought to reevaluate this finding in a retrospective manner,” Dr. Vyas said. “You’re taking eggs out of their home, injecting with sperm, and putting them back. There’s so much that we don’t know, and we want to make sure there’s no extra risk.”

Also, she added, “prior studies had a relatively low sample size. We sought to use our patient volume to address this question on a larger scale. Our current study benefits from a large sample size and using the clinically meaningful endpoint of live birth as our primary outcome.”

For the new study, researchers retrospectively analyzed 1,333 patients (of 2,209 screened) who received first fresh embryo transfers from 2017 to 2019. All had cytology or HPV status documented per cervical cancer screening guidelines within 6 months before embryos were transferred.

The researchers looked at only fresh embryo transfers “so we could account for pregnancy outcomes closest to the documented HPV status at the time of egg retrieval,” Dr. Vyas said.

Ten percent (133) of patients were HPV positive. Of those, 60.1% became pregnant, and 43.6% of them had live births. Of the HPV-negative women (90% of subjects, n = 1,200), 52.2% became pregnant and 33.5% had live births. The researchers didn’t calculate P values, but Dr. Vyas said an analysis determined that the differences between HPV-positive and HPV-negative women were statistically significant.

The study size doesn’t allow researchers to determine whether HPV actually has a protective effect on pregnancy/live birth rates in IVF, Dr. Vyas said. Even if it did, the virus is dangerous.

What else could explain the discrepancy? “Some elements driving this could the smaller sample size of the HPV-positive group, differences in HPV prevalence between the general population and our population,” she said, “or other confounding factors we were not able to appreciate due to the limitations of the retrospective study.”

Researchers also reported that they found “no significant difference in biochemical or spontaneous abortion rates” between HPV-positive and HPV-negative women.

What is the message of the study? “Women with HPV can rest assured that they won’t have worse outcomes than their non-HPV [infected] counterparts after a fresh embryo transfer cycle,” Dr. Vyas said.

In an interview, McGill University, Montreal, epidemiologist Helen Trottier, PhD, MSc, noted that she recently coauthored a study that linked persistent HPV infection in pregnancy to premature births. The findings appear convincing, she said: “I think we can say that HPV is associated with preterm birth.”

She praised the new study but noted “the relative risks that are reported need to be adjusted for race and possibly other factors.”

Dr. Vyas said that kind of adjustment will occur in a future study that’s in progress. “We are now prospectively enrolling patients and collecting cytology data to understand whether there might be a difference for women with higher malignancy potential/different types of HPV genotypes.”

The study authors have no disclosures. Disclosure information for Dr. Trottier was unavailable.

High-efficacy therapies for multiple sclerosis (MS) have improved disease outcomes for many patients, but physicians are uncertain when to use them. Despite better long-term disease outcomes, there are concerns over long-term safety, and some physicians and patients remain wary of these medications.

High-efficacy therapies were the subject of a session at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Key topics included patient selection, timing of escalation to high-efficacy therapies, and initial use of high-efficacy therapies. The session produced a compelling message, according to moderator Patricia Coyle, MD. “I think [the speakers provided] accumulating data that this is a smart thing to do: Use high-efficacy therapies early to get the maximum bang for the buck,” Dr. Coyle said in an interview. She is professor of neurology and director of the MS Comprehensive Care Center at Stony Brook (N.Y.) University.
 

Consider baseline characteristics

In the first talk, Xavier Montalban, MD, PhD, noted that a statement from the ECTRIMS/EAN (European Academy of Neurology) guideline update in 2021 said that a high-efficacy disease-modifying therapy (DMT) should be considered early in the disease course. A key question is whether any baseline characteristics can be used to select patients, and studies have shown worse prognosis with older age, male sex, low levels of vitamin D, and smoking status, among various other factors.

He presented subgroup analyses from trials of fingolimod and ozanimod, which showed that the drugs did not work as well in patients with poor prognostic factors such as an Expanded Disability Status Scale (EDSS) score of 4 or above and age over 40 years. Lower doses also tend to have less efficacy in males. “If you have [a patient with] bad baseline prognostic factors, you need high-efficacy medication at the right dose, because a lower dose will not work well. It is the same phenomenon for age,” Dr. Montalban said in his talk. On the other hand, he showed the results of a study of ofatumumab and ocrelizumab, both of which showed high efficacy even in patients with poor prognostic factors.

Among patients with secondary progressive MS, clinical or MRI evidence of inflammatory activity is the only poor prognostic factor that appears to be a good predictor of treatment response.

Dr. Montalban also addressed the timing of intervention with DMTs. A study from his group prospectively followed 1,015 patients treated with DMTs. “Interestingly, what we observed is that patients who were treated with DMTs just after the first attack did better than those who were treated after the second attack, and you have to take into consideration that we treat those patients after the first attack, those who had the worst prognostic factors, so treatment was very effective in that sense,” said Dr. Montalban, director of the Multiple Sclerosis Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona.
 

Switching DMTs

In the second presentation, Dalia Rotstein, MD, discussed how to incorporate prognostic factors when switching a patient to high-efficacy therapies as a result of new disease activity while on another therapy.

Patients with favorable prognostic factors at baseline may be started out on immunomodulatory therapy. “Essentially, we want to match the intensity of the therapy to the intensity of the disease of the patient in front of us,” Dr. Rotstein said in her talk. Nevertheless, the course of MS is unpredictable, and the first year or two of immunomodulatory therapy can give physicians clues about the longer-term course of the disease. “We need to observe closely for disease activity in the first year, but even up to 2 years on therapy to determine a need for early escalation,” said Dr. Rotstein, assistant professor of medicine at University of Toronto.

For switching to high-efficacy therapies, any relapse, disability progression, or an EDSS change of 1 point or more could be a consideration. MRI indicators are more controversial, but one to three new T2 lesions also could prompt a switch.

Serum neural filament light chain (sNFL) is a useful biomarker for monitoring disease activity as it correlates well with new disease activity within the next year. It can be monitored every 3-4 months and adjusted for clinical factors and monitored for changing levels. A concerning finding can be followed up with an MRI or in-person visit.

When switching to a high-efficacy therapy, it’s important to administer any vaccines well in advance to ensure a good immune response.

When it comes to a washout period, physicians need to consider both the risk of immunosuppression and breakthrough disease activity. “But in general, we’ve observed that we can minimize the duration of the washout when stopping initial immunomodulator therapy to reduce the risk of breakthrough disease activity. We need to pay particular attention to the risk of rebound activity with longer washouts after stopping sphingosine-1 phosphate (S1P) receptor modulators because the rebound activity can be devastating,” said Dr. Rotstein.

A study of timing of relapses after fingolimod washout, carried out by Dr. Rotstein’s group, found a stark signal. “We observed that when the washout after fingolimod discontinuation was 30 days or more, there is a very high risk of early relapse,” she said.
 

The case for induction therapy

In the third talk, Gavin Giovannoni, MBBCh, PhD, discussed “flipping the pyramid” – that is, starting patients off immediately with high-efficacy therapies rather than waiting until they progress on other therapies. He likened such a decision to a gambler, because MS patients on less-effective therapy can suffer irreversible, long-term physical consequences, as well as social consequences such as unemployment due to cognitive effects.

“We always tend to put up a graph about the risks and benefits of a specific treatment, and we forget about the risks of untreated or undertreated MS. Keep that in mind when making decisions about high-efficacy therapies,” said Dr. Giovannoni, professor of neurology at Queen Mary University of London.

About 80% of patients on tier 1, or low-efficacy therapies, will have breakthrough activity on MRI within 4 years. Moving up a tier gets to about a 60% rate of breakthrough activity. High-efficacy therapies attain an efficacy of about 80% at 6 months. “If you have MS, you’ve got to realize that if you had to roll the dice, which tier would you want to be in? By putting all of them [on high-efficacy therapies], you’re going to get the majority responding and a few of them will break through,” said Dr. Giovannoni.

He presented some real-world evidence to back up the argument: A study comparing outcomes in Sweden and Denmark, which have similar demographics. In Denmark, 7.6% of patients with MS received high-efficacy therapies initially, while in Sweden the proportion was 34.5%. Patients with MS treated in Sweden had a 29% lower probability of progressing to disability (P = .004) and there were 22% fewer discontinuations of DMTs (P < .001). Since that study, the proportion of patients receiving high-efficacy therapies to begin with is closer to 70%. “This is compelling evidence that you want to be on a [high-efficacy therapy] early. If I had MS, I would want to live in Sweden,” said Dr. Giovannoni.

Historical treatments focused on reducing relapses, and more recently on eliminating evidence of inflammatory disease. He said that physicians are prioritizing brain volume loss to improve long-term outcomes in MS, and some are studying long-term disability. “We know that brain volume loss in MS is a prognostic sign both at baseline and at follow-up. It predicts poor outcome, poor cognition and employment, poor quality of life, et cetera,” said Dr. Giovannoni.

He cited data from studies of alemtuzumab that showed a significant reduction in brain volume loss. “The rate is about 0.2% per annum, which is kind of getting into the normal range for age-matched controls. Those people who were started off on interferons in the study lost a lot of brain volume in those first 2 years, and that’s irreversible,” said Dr. Giovannoni.

He pointed out that studies of hematopoietic stem cell therapy showed similar brain-volume outcomes. “So flipping the pyramid with the two most highly effective therapies almost normalizes brain volume loss in people with MS,” said Dr. Giovannoni.

There is also evidence in other autoimmune diseases that early use of high-efficacy therapies improves outcomes. More aggressive therapy in rheumatoid arthritis has reduced joint replacements by 90%.

“I think you really, really need to give your patients the opportunity of flipping the pyramid. You shouldn’t decide that for them,” said Dr. Giovannoni.

Dr. Coyle has consulted for nearly all pharmaceutical companies developing drugs in the MS space. Dr. Montalban has financial relationships with Biogen Idec, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva, Roche, Celgene, Actelion, Mylan, BMS, and Sandoz. Dr. Rotstein has financial ties with Roche Canada, Alexion, Biogen, EMD Serono, Novartis, Roche, and Sanofi Aventis. Dr. Giovannoni has financial ties with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, GW Pharma, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co., Merck KGaA/EMD Serono, Moderna, Novartis, Sanofi, Roche/Genentech, and Teva.

High-efficacy therapies for multiple sclerosis (MS) have improved disease outcomes for many patients, but physicians are uncertain when to use them. Despite better long-term disease outcomes, there are concerns over long-term safety, and some physicians and patients remain wary of these medications.

High-efficacy therapies were the subject of a session at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Key topics included patient selection, timing of escalation to high-efficacy therapies, and initial use of high-efficacy therapies. The session produced a compelling message, according to moderator Patricia Coyle, MD. “I think [the speakers provided] accumulating data that this is a smart thing to do: Use high-efficacy therapies early to get the maximum bang for the buck,” Dr. Coyle said in an interview. She is professor of neurology and director of the MS Comprehensive Care Center at Stony Brook (N.Y.) University.
 

Consider baseline characteristics

In the first talk, Xavier Montalban, MD, PhD, noted that a statement from the ECTRIMS/EAN (European Academy of Neurology) guideline update in 2021 said that a high-efficacy disease-modifying therapy (DMT) should be considered early in the disease course. A key question is whether any baseline characteristics can be used to select patients, and studies have shown worse prognosis with older age, male sex, low levels of vitamin D, and smoking status, among various other factors.

He presented subgroup analyses from trials of fingolimod and ozanimod, which showed that the drugs did not work as well in patients with poor prognostic factors such as an Expanded Disability Status Scale (EDSS) score of 4 or above and age over 40 years. Lower doses also tend to have less efficacy in males. “If you have [a patient with] bad baseline prognostic factors, you need high-efficacy medication at the right dose, because a lower dose will not work well. It is the same phenomenon for age,” Dr. Montalban said in his talk. On the other hand, he showed the results of a study of ofatumumab and ocrelizumab, both of which showed high efficacy even in patients with poor prognostic factors.

Among patients with secondary progressive MS, clinical or MRI evidence of inflammatory activity is the only poor prognostic factor that appears to be a good predictor of treatment response.

Dr. Montalban also addressed the timing of intervention with DMTs. A study from his group prospectively followed 1,015 patients treated with DMTs. “Interestingly, what we observed is that patients who were treated with DMTs just after the first attack did better than those who were treated after the second attack, and you have to take into consideration that we treat those patients after the first attack, those who had the worst prognostic factors, so treatment was very effective in that sense,” said Dr. Montalban, director of the Multiple Sclerosis Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona.
 

Switching DMTs

In the second presentation, Dalia Rotstein, MD, discussed how to incorporate prognostic factors when switching a patient to high-efficacy therapies as a result of new disease activity while on another therapy.

Patients with favorable prognostic factors at baseline may be started out on immunomodulatory therapy. “Essentially, we want to match the intensity of the therapy to the intensity of the disease of the patient in front of us,” Dr. Rotstein said in her talk. Nevertheless, the course of MS is unpredictable, and the first year or two of immunomodulatory therapy can give physicians clues about the longer-term course of the disease. “We need to observe closely for disease activity in the first year, but even up to 2 years on therapy to determine a need for early escalation,” said Dr. Rotstein, assistant professor of medicine at University of Toronto.

For switching to high-efficacy therapies, any relapse, disability progression, or an EDSS change of 1 point or more could be a consideration. MRI indicators are more controversial, but one to three new T2 lesions also could prompt a switch.

Serum neural filament light chain (sNFL) is a useful biomarker for monitoring disease activity as it correlates well with new disease activity within the next year. It can be monitored every 3-4 months and adjusted for clinical factors and monitored for changing levels. A concerning finding can be followed up with an MRI or in-person visit.

When switching to a high-efficacy therapy, it’s important to administer any vaccines well in advance to ensure a good immune response.

When it comes to a washout period, physicians need to consider both the risk of immunosuppression and breakthrough disease activity. “But in general, we’ve observed that we can minimize the duration of the washout when stopping initial immunomodulator therapy to reduce the risk of breakthrough disease activity. We need to pay particular attention to the risk of rebound activity with longer washouts after stopping sphingosine-1 phosphate (S1P) receptor modulators because the rebound activity can be devastating,” said Dr. Rotstein.

A study of timing of relapses after fingolimod washout, carried out by Dr. Rotstein’s group, found a stark signal. “We observed that when the washout after fingolimod discontinuation was 30 days or more, there is a very high risk of early relapse,” she said.
 

The case for induction therapy

In the third talk, Gavin Giovannoni, MBBCh, PhD, discussed “flipping the pyramid” – that is, starting patients off immediately with high-efficacy therapies rather than waiting until they progress on other therapies. He likened such a decision to a gambler, because MS patients on less-effective therapy can suffer irreversible, long-term physical consequences, as well as social consequences such as unemployment due to cognitive effects.

“We always tend to put up a graph about the risks and benefits of a specific treatment, and we forget about the risks of untreated or undertreated MS. Keep that in mind when making decisions about high-efficacy therapies,” said Dr. Giovannoni, professor of neurology at Queen Mary University of London.

About 80% of patients on tier 1, or low-efficacy therapies, will have breakthrough activity on MRI within 4 years. Moving up a tier gets to about a 60% rate of breakthrough activity. High-efficacy therapies attain an efficacy of about 80% at 6 months. “If you have MS, you’ve got to realize that if you had to roll the dice, which tier would you want to be in? By putting all of them [on high-efficacy therapies], you’re going to get the majority responding and a few of them will break through,” said Dr. Giovannoni.

He presented some real-world evidence to back up the argument: A study comparing outcomes in Sweden and Denmark, which have similar demographics. In Denmark, 7.6% of patients with MS received high-efficacy therapies initially, while in Sweden the proportion was 34.5%. Patients with MS treated in Sweden had a 29% lower probability of progressing to disability (P = .004) and there were 22% fewer discontinuations of DMTs (P < .001). Since that study, the proportion of patients receiving high-efficacy therapies to begin with is closer to 70%. “This is compelling evidence that you want to be on a [high-efficacy therapy] early. If I had MS, I would want to live in Sweden,” said Dr. Giovannoni.

Historical treatments focused on reducing relapses, and more recently on eliminating evidence of inflammatory disease. He said that physicians are prioritizing brain volume loss to improve long-term outcomes in MS, and some are studying long-term disability. “We know that brain volume loss in MS is a prognostic sign both at baseline and at follow-up. It predicts poor outcome, poor cognition and employment, poor quality of life, et cetera,” said Dr. Giovannoni.

He cited data from studies of alemtuzumab that showed a significant reduction in brain volume loss. “The rate is about 0.2% per annum, which is kind of getting into the normal range for age-matched controls. Those people who were started off on interferons in the study lost a lot of brain volume in those first 2 years, and that’s irreversible,” said Dr. Giovannoni.

He pointed out that studies of hematopoietic stem cell therapy showed similar brain-volume outcomes. “So flipping the pyramid with the two most highly effective therapies almost normalizes brain volume loss in people with MS,” said Dr. Giovannoni.

There is also evidence in other autoimmune diseases that early use of high-efficacy therapies improves outcomes. More aggressive therapy in rheumatoid arthritis has reduced joint replacements by 90%.

“I think you really, really need to give your patients the opportunity of flipping the pyramid. You shouldn’t decide that for them,” said Dr. Giovannoni.

Dr. Coyle has consulted for nearly all pharmaceutical companies developing drugs in the MS space. Dr. Montalban has financial relationships with Biogen Idec, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva, Roche, Celgene, Actelion, Mylan, BMS, and Sandoz. Dr. Rotstein has financial ties with Roche Canada, Alexion, Biogen, EMD Serono, Novartis, Roche, and Sanofi Aventis. Dr. Giovannoni has financial ties with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, GW Pharma, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co., Merck KGaA/EMD Serono, Moderna, Novartis, Sanofi, Roche/Genentech, and Teva.

High-efficacy therapies for multiple sclerosis (MS) have improved disease outcomes for many patients, but physicians are uncertain when to use them. Despite better long-term disease outcomes, there are concerns over long-term safety, and some physicians and patients remain wary of these medications.

High-efficacy therapies were the subject of a session at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Key topics included patient selection, timing of escalation to high-efficacy therapies, and initial use of high-efficacy therapies. The session produced a compelling message, according to moderator Patricia Coyle, MD. “I think [the speakers provided] accumulating data that this is a smart thing to do: Use high-efficacy therapies early to get the maximum bang for the buck,” Dr. Coyle said in an interview. She is professor of neurology and director of the MS Comprehensive Care Center at Stony Brook (N.Y.) University.
 

Consider baseline characteristics

In the first talk, Xavier Montalban, MD, PhD, noted that a statement from the ECTRIMS/EAN (European Academy of Neurology) guideline update in 2021 said that a high-efficacy disease-modifying therapy (DMT) should be considered early in the disease course. A key question is whether any baseline characteristics can be used to select patients, and studies have shown worse prognosis with older age, male sex, low levels of vitamin D, and smoking status, among various other factors.

He presented subgroup analyses from trials of fingolimod and ozanimod, which showed that the drugs did not work as well in patients with poor prognostic factors such as an Expanded Disability Status Scale (EDSS) score of 4 or above and age over 40 years. Lower doses also tend to have less efficacy in males. “If you have [a patient with] bad baseline prognostic factors, you need high-efficacy medication at the right dose, because a lower dose will not work well. It is the same phenomenon for age,” Dr. Montalban said in his talk. On the other hand, he showed the results of a study of ofatumumab and ocrelizumab, both of which showed high efficacy even in patients with poor prognostic factors.

Among patients with secondary progressive MS, clinical or MRI evidence of inflammatory activity is the only poor prognostic factor that appears to be a good predictor of treatment response.

Dr. Montalban also addressed the timing of intervention with DMTs. A study from his group prospectively followed 1,015 patients treated with DMTs. “Interestingly, what we observed is that patients who were treated with DMTs just after the first attack did better than those who were treated after the second attack, and you have to take into consideration that we treat those patients after the first attack, those who had the worst prognostic factors, so treatment was very effective in that sense,” said Dr. Montalban, director of the Multiple Sclerosis Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona.
 

Switching DMTs

In the second presentation, Dalia Rotstein, MD, discussed how to incorporate prognostic factors when switching a patient to high-efficacy therapies as a result of new disease activity while on another therapy.

Patients with favorable prognostic factors at baseline may be started out on immunomodulatory therapy. “Essentially, we want to match the intensity of the therapy to the intensity of the disease of the patient in front of us,” Dr. Rotstein said in her talk. Nevertheless, the course of MS is unpredictable, and the first year or two of immunomodulatory therapy can give physicians clues about the longer-term course of the disease. “We need to observe closely for disease activity in the first year, but even up to 2 years on therapy to determine a need for early escalation,” said Dr. Rotstein, assistant professor of medicine at University of Toronto.

For switching to high-efficacy therapies, any relapse, disability progression, or an EDSS change of 1 point or more could be a consideration. MRI indicators are more controversial, but one to three new T2 lesions also could prompt a switch.

Serum neural filament light chain (sNFL) is a useful biomarker for monitoring disease activity as it correlates well with new disease activity within the next year. It can be monitored every 3-4 months and adjusted for clinical factors and monitored for changing levels. A concerning finding can be followed up with an MRI or in-person visit.

When switching to a high-efficacy therapy, it’s important to administer any vaccines well in advance to ensure a good immune response.

When it comes to a washout period, physicians need to consider both the risk of immunosuppression and breakthrough disease activity. “But in general, we’ve observed that we can minimize the duration of the washout when stopping initial immunomodulator therapy to reduce the risk of breakthrough disease activity. We need to pay particular attention to the risk of rebound activity with longer washouts after stopping sphingosine-1 phosphate (S1P) receptor modulators because the rebound activity can be devastating,” said Dr. Rotstein.

A study of timing of relapses after fingolimod washout, carried out by Dr. Rotstein’s group, found a stark signal. “We observed that when the washout after fingolimod discontinuation was 30 days or more, there is a very high risk of early relapse,” she said.
 

The case for induction therapy

In the third talk, Gavin Giovannoni, MBBCh, PhD, discussed “flipping the pyramid” – that is, starting patients off immediately with high-efficacy therapies rather than waiting until they progress on other therapies. He likened such a decision to a gambler, because MS patients on less-effective therapy can suffer irreversible, long-term physical consequences, as well as social consequences such as unemployment due to cognitive effects.

“We always tend to put up a graph about the risks and benefits of a specific treatment, and we forget about the risks of untreated or undertreated MS. Keep that in mind when making decisions about high-efficacy therapies,” said Dr. Giovannoni, professor of neurology at Queen Mary University of London.

About 80% of patients on tier 1, or low-efficacy therapies, will have breakthrough activity on MRI within 4 years. Moving up a tier gets to about a 60% rate of breakthrough activity. High-efficacy therapies attain an efficacy of about 80% at 6 months. “If you have MS, you’ve got to realize that if you had to roll the dice, which tier would you want to be in? By putting all of them [on high-efficacy therapies], you’re going to get the majority responding and a few of them will break through,” said Dr. Giovannoni.

He presented some real-world evidence to back up the argument: A study comparing outcomes in Sweden and Denmark, which have similar demographics. In Denmark, 7.6% of patients with MS received high-efficacy therapies initially, while in Sweden the proportion was 34.5%. Patients with MS treated in Sweden had a 29% lower probability of progressing to disability (P = .004) and there were 22% fewer discontinuations of DMTs (P < .001). Since that study, the proportion of patients receiving high-efficacy therapies to begin with is closer to 70%. “This is compelling evidence that you want to be on a [high-efficacy therapy] early. If I had MS, I would want to live in Sweden,” said Dr. Giovannoni.

Historical treatments focused on reducing relapses, and more recently on eliminating evidence of inflammatory disease. He said that physicians are prioritizing brain volume loss to improve long-term outcomes in MS, and some are studying long-term disability. “We know that brain volume loss in MS is a prognostic sign both at baseline and at follow-up. It predicts poor outcome, poor cognition and employment, poor quality of life, et cetera,” said Dr. Giovannoni.

He cited data from studies of alemtuzumab that showed a significant reduction in brain volume loss. “The rate is about 0.2% per annum, which is kind of getting into the normal range for age-matched controls. Those people who were started off on interferons in the study lost a lot of brain volume in those first 2 years, and that’s irreversible,” said Dr. Giovannoni.

He pointed out that studies of hematopoietic stem cell therapy showed similar brain-volume outcomes. “So flipping the pyramid with the two most highly effective therapies almost normalizes brain volume loss in people with MS,” said Dr. Giovannoni.

There is also evidence in other autoimmune diseases that early use of high-efficacy therapies improves outcomes. More aggressive therapy in rheumatoid arthritis has reduced joint replacements by 90%.

“I think you really, really need to give your patients the opportunity of flipping the pyramid. You shouldn’t decide that for them,” said Dr. Giovannoni.

Dr. Coyle has consulted for nearly all pharmaceutical companies developing drugs in the MS space. Dr. Montalban has financial relationships with Biogen Idec, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva, Roche, Celgene, Actelion, Mylan, BMS, and Sandoz. Dr. Rotstein has financial ties with Roche Canada, Alexion, Biogen, EMD Serono, Novartis, Roche, and Sanofi Aventis. Dr. Giovannoni has financial ties with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, GW Pharma, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co., Merck KGaA/EMD Serono, Moderna, Novartis, Sanofi, Roche/Genentech, and Teva.

CINCINNATI – Sickle cell disease is well known for its associated anemia, but patients experience a range of other complications as well. These include vision and kidney problems, delayed growth, susceptibility to infection, and pain.

Another issue, not always as well recognized, is a considerably heightened risk for childhood stroke. “Children with sickle cell disease have 100 times the risk of stroke as other children without sickle cell disease, and there’s also an elevated risk of five times the general population in adults with sickle cell disease,” said Lori Jordan, MD, PhD, in an interview.

At the 2022 annual meeting of the Child Neurology Society, Dr. Jordan spoke about stroke as a complication of sickle cell disease, and the role that neurologists can play in preventing primary or secondary strokes. “At least in children, studies have shown that if we screen and identify patients who are at highest risk of stroke, there are primary prevention therapies – usually implemented by hematologists, but that neurologists often are involved with – both monitoring for cognitive effects of silent cerebral infarct and also with treating patients who unfortunately still have an acute stroke,” said Dr. Jordan, who is an associate professor of pediatrics, neurology, and radiology at Vanderbilt University Medical Center, Nashville, Tenn. She also is director of the pediatric stroke program at Vanderbilt.
 

Time is of the essence

“In general, stroke in children is rare, but it’s more common in sickle cell disease, so it’s really important for providers to know that stroke risk is higher in those patients, particularly in those children, and then identify it and treat it earlier. Time is of the essence, and if we can give them the same therapeutics that we give the general stroke population, then time really becomes a factor, so it’s important that people know that it’s an issue for this population,” said Eboni Lance, MD, PhD, who coordinated the session where Dr. Jordan spoke.

Sickle cell disease is caused by a double mutation in the gene encoding the hemoglobin gene, producing the altered sickle hemoglobin (hemoglobin S). The change causes the hemoglobin proteins to tend to stick to one another, which can lead red blood cells to adopt a sickle-like shape. The sickle-shaped blood cells in turn have a tendency to aggregate and can block blood flow or lead to endothelial injury. Symptoms of stroke in children can include hemiparesis, aphasia, and seizure, but they can also be silent.

If no preventive is employed, one in nine with sickle cell disease will experience a stroke by the age of 19. Cerebrovascular symptoms are the most frequent debilitating complication of the condition. Nearly 40% of patients with sickle cell disease will have a silent cerebral infarct by age 18, as will 50% by age 30. Silent strokes have been associated with worse educational attainment and a greater need for educational special services.

Factors contributing to stroke in children with sickle cell disease include anemia and a low blood oxygen count, reduced oxygen affinity of hemoglobin variant, and cerebral vasculopathy. An estimated 10%-15% of young adults with sickle cell disease have severe intracranial stenosis.
 

Primary and secondary stroke prevention strategies

The dire consequences of stroke in this patient population underline the importance of primary stroke prevention, which requires the use of transcranial Doppler (TCD) ultrasound. It has been validated as a tool to screen for initial stroke risk in children with no history of stroke. High velocity measured on TCD indicates a narrowed blood vessel or elevated blood that is compensating for anemia. It adds up to a “struggling brain,” said Dr. Jordan, during her talk. If the TCD ultrasound velocity is greater than 200 cm/sec (or 170 cm/sec, depending on nonimaging versus imaging TCD), the TWiTCH trial showed that seven monthly transfusions is the number needed to treat to prevent one stroke. After 1 year, patients can be switched from transfusions to hydroxyurea if the patient has no significant intracranial stenosis. Hydroxyurea boosts both fetal and total hemoglobin, and also counters inflammation.

Following an acute stroke or transient ischemic attack, patients should receive a transfusion within 2 hours of presenting in the health care setting. American Society of Hematology guidelines recommend exchange transfusion rather than a simple transfusion. A simple transfusion can be initiated if an exchange transfusion is not available within 2 hours and hemoglobin values are less than 8.5 g/dL, to be followed by performance of exchange transfusion when available.

For chronic secondary stroke prevention, transfusions should be performed approximately monthly with the goal of maintaining hemoglobin above 9 g/dL at all times, as well as suppressing hemoglobin S levels to 30% or less of total hemoglobin.

Sudden, severe headache is a potential harbinger of complications like aneurysm, which occurs 10-fold more often among patients with sickle cell disease than the general population. It could also indicate increased intracranial pressure or cerebral venous sinus thrombosis.

Treatment of acute headache in sickle cell disease should avoid use of triptans, since vasoconstriction can counter the increased cerebral blood flow that compensates for anemia. Gabapentin and amitriptyline are good treatment choices.

New-onset seizures are a potential sign of stroke or posterior reversible leukoencephalopathy (PRES) in patients with sickle cell disease. Urgent MRI should be considered for all new-onset seizures. If blood pressure is high, PRES may be present. Seizures may also be an indicator of a previous brain injury.

Dr. Jordan has no relevant financial disclosures. Dr. Lance has served on an advisory board for Novartis.
 

CINCINNATI – Sickle cell disease is well known for its associated anemia, but patients experience a range of other complications as well. These include vision and kidney problems, delayed growth, susceptibility to infection, and pain.

Another issue, not always as well recognized, is a considerably heightened risk for childhood stroke. “Children with sickle cell disease have 100 times the risk of stroke as other children without sickle cell disease, and there’s also an elevated risk of five times the general population in adults with sickle cell disease,” said Lori Jordan, MD, PhD, in an interview.

At the 2022 annual meeting of the Child Neurology Society, Dr. Jordan spoke about stroke as a complication of sickle cell disease, and the role that neurologists can play in preventing primary or secondary strokes. “At least in children, studies have shown that if we screen and identify patients who are at highest risk of stroke, there are primary prevention therapies – usually implemented by hematologists, but that neurologists often are involved with – both monitoring for cognitive effects of silent cerebral infarct and also with treating patients who unfortunately still have an acute stroke,” said Dr. Jordan, who is an associate professor of pediatrics, neurology, and radiology at Vanderbilt University Medical Center, Nashville, Tenn. She also is director of the pediatric stroke program at Vanderbilt.
 

Time is of the essence

“In general, stroke in children is rare, but it’s more common in sickle cell disease, so it’s really important for providers to know that stroke risk is higher in those patients, particularly in those children, and then identify it and treat it earlier. Time is of the essence, and if we can give them the same therapeutics that we give the general stroke population, then time really becomes a factor, so it’s important that people know that it’s an issue for this population,” said Eboni Lance, MD, PhD, who coordinated the session where Dr. Jordan spoke.

Sickle cell disease is caused by a double mutation in the gene encoding the hemoglobin gene, producing the altered sickle hemoglobin (hemoglobin S). The change causes the hemoglobin proteins to tend to stick to one another, which can lead red blood cells to adopt a sickle-like shape. The sickle-shaped blood cells in turn have a tendency to aggregate and can block blood flow or lead to endothelial injury. Symptoms of stroke in children can include hemiparesis, aphasia, and seizure, but they can also be silent.

If no preventive is employed, one in nine with sickle cell disease will experience a stroke by the age of 19. Cerebrovascular symptoms are the most frequent debilitating complication of the condition. Nearly 40% of patients with sickle cell disease will have a silent cerebral infarct by age 18, as will 50% by age 30. Silent strokes have been associated with worse educational attainment and a greater need for educational special services.

Factors contributing to stroke in children with sickle cell disease include anemia and a low blood oxygen count, reduced oxygen affinity of hemoglobin variant, and cerebral vasculopathy. An estimated 10%-15% of young adults with sickle cell disease have severe intracranial stenosis.
 

Primary and secondary stroke prevention strategies

The dire consequences of stroke in this patient population underline the importance of primary stroke prevention, which requires the use of transcranial Doppler (TCD) ultrasound. It has been validated as a tool to screen for initial stroke risk in children with no history of stroke. High velocity measured on TCD indicates a narrowed blood vessel or elevated blood that is compensating for anemia. It adds up to a “struggling brain,” said Dr. Jordan, during her talk. If the TCD ultrasound velocity is greater than 200 cm/sec (or 170 cm/sec, depending on nonimaging versus imaging TCD), the TWiTCH trial showed that seven monthly transfusions is the number needed to treat to prevent one stroke. After 1 year, patients can be switched from transfusions to hydroxyurea if the patient has no significant intracranial stenosis. Hydroxyurea boosts both fetal and total hemoglobin, and also counters inflammation.

Following an acute stroke or transient ischemic attack, patients should receive a transfusion within 2 hours of presenting in the health care setting. American Society of Hematology guidelines recommend exchange transfusion rather than a simple transfusion. A simple transfusion can be initiated if an exchange transfusion is not available within 2 hours and hemoglobin values are less than 8.5 g/dL, to be followed by performance of exchange transfusion when available.

For chronic secondary stroke prevention, transfusions should be performed approximately monthly with the goal of maintaining hemoglobin above 9 g/dL at all times, as well as suppressing hemoglobin S levels to 30% or less of total hemoglobin.

Sudden, severe headache is a potential harbinger of complications like aneurysm, which occurs 10-fold more often among patients with sickle cell disease than the general population. It could also indicate increased intracranial pressure or cerebral venous sinus thrombosis.

Treatment of acute headache in sickle cell disease should avoid use of triptans, since vasoconstriction can counter the increased cerebral blood flow that compensates for anemia. Gabapentin and amitriptyline are good treatment choices.

New-onset seizures are a potential sign of stroke or posterior reversible leukoencephalopathy (PRES) in patients with sickle cell disease. Urgent MRI should be considered for all new-onset seizures. If blood pressure is high, PRES may be present. Seizures may also be an indicator of a previous brain injury.

Dr. Jordan has no relevant financial disclosures. Dr. Lance has served on an advisory board for Novartis.
 

CINCINNATI – Sickle cell disease is well known for its associated anemia, but patients experience a range of other complications as well. These include vision and kidney problems, delayed growth, susceptibility to infection, and pain.

Another issue, not always as well recognized, is a considerably heightened risk for childhood stroke. “Children with sickle cell disease have 100 times the risk of stroke as other children without sickle cell disease, and there’s also an elevated risk of five times the general population in adults with sickle cell disease,” said Lori Jordan, MD, PhD, in an interview.

At the 2022 annual meeting of the Child Neurology Society, Dr. Jordan spoke about stroke as a complication of sickle cell disease, and the role that neurologists can play in preventing primary or secondary strokes. “At least in children, studies have shown that if we screen and identify patients who are at highest risk of stroke, there are primary prevention therapies – usually implemented by hematologists, but that neurologists often are involved with – both monitoring for cognitive effects of silent cerebral infarct and also with treating patients who unfortunately still have an acute stroke,” said Dr. Jordan, who is an associate professor of pediatrics, neurology, and radiology at Vanderbilt University Medical Center, Nashville, Tenn. She also is director of the pediatric stroke program at Vanderbilt.
 

Time is of the essence

“In general, stroke in children is rare, but it’s more common in sickle cell disease, so it’s really important for providers to know that stroke risk is higher in those patients, particularly in those children, and then identify it and treat it earlier. Time is of the essence, and if we can give them the same therapeutics that we give the general stroke population, then time really becomes a factor, so it’s important that people know that it’s an issue for this population,” said Eboni Lance, MD, PhD, who coordinated the session where Dr. Jordan spoke.

Sickle cell disease is caused by a double mutation in the gene encoding the hemoglobin gene, producing the altered sickle hemoglobin (hemoglobin S). The change causes the hemoglobin proteins to tend to stick to one another, which can lead red blood cells to adopt a sickle-like shape. The sickle-shaped blood cells in turn have a tendency to aggregate and can block blood flow or lead to endothelial injury. Symptoms of stroke in children can include hemiparesis, aphasia, and seizure, but they can also be silent.

If no preventive is employed, one in nine with sickle cell disease will experience a stroke by the age of 19. Cerebrovascular symptoms are the most frequent debilitating complication of the condition. Nearly 40% of patients with sickle cell disease will have a silent cerebral infarct by age 18, as will 50% by age 30. Silent strokes have been associated with worse educational attainment and a greater need for educational special services.

Factors contributing to stroke in children with sickle cell disease include anemia and a low blood oxygen count, reduced oxygen affinity of hemoglobin variant, and cerebral vasculopathy. An estimated 10%-15% of young adults with sickle cell disease have severe intracranial stenosis.
 

Primary and secondary stroke prevention strategies

The dire consequences of stroke in this patient population underline the importance of primary stroke prevention, which requires the use of transcranial Doppler (TCD) ultrasound. It has been validated as a tool to screen for initial stroke risk in children with no history of stroke. High velocity measured on TCD indicates a narrowed blood vessel or elevated blood that is compensating for anemia. It adds up to a “struggling brain,” said Dr. Jordan, during her talk. If the TCD ultrasound velocity is greater than 200 cm/sec (or 170 cm/sec, depending on nonimaging versus imaging TCD), the TWiTCH trial showed that seven monthly transfusions is the number needed to treat to prevent one stroke. After 1 year, patients can be switched from transfusions to hydroxyurea if the patient has no significant intracranial stenosis. Hydroxyurea boosts both fetal and total hemoglobin, and also counters inflammation.

Following an acute stroke or transient ischemic attack, patients should receive a transfusion within 2 hours of presenting in the health care setting. American Society of Hematology guidelines recommend exchange transfusion rather than a simple transfusion. A simple transfusion can be initiated if an exchange transfusion is not available within 2 hours and hemoglobin values are less than 8.5 g/dL, to be followed by performance of exchange transfusion when available.

For chronic secondary stroke prevention, transfusions should be performed approximately monthly with the goal of maintaining hemoglobin above 9 g/dL at all times, as well as suppressing hemoglobin S levels to 30% or less of total hemoglobin.

Sudden, severe headache is a potential harbinger of complications like aneurysm, which occurs 10-fold more often among patients with sickle cell disease than the general population. It could also indicate increased intracranial pressure or cerebral venous sinus thrombosis.

Treatment of acute headache in sickle cell disease should avoid use of triptans, since vasoconstriction can counter the increased cerebral blood flow that compensates for anemia. Gabapentin and amitriptyline are good treatment choices.

New-onset seizures are a potential sign of stroke or posterior reversible leukoencephalopathy (PRES) in patients with sickle cell disease. Urgent MRI should be considered for all new-onset seizures. If blood pressure is high, PRES may be present. Seizures may also be an indicator of a previous brain injury.

Dr. Jordan has no relevant financial disclosures. Dr. Lance has served on an advisory board for Novartis.
 

Vedolizumab (Entyvio) and ustekinumab (Stelara) appear to be equally effective for extraintestinal manifestation (EIM) of inflammatory bowel disease (IBD), according to results of a retrospective study published online in Digestive and Liver Disease.

Between 25% and 40% of patients with IBD experience EIM, which reduces quality of life, according to the Crohn’s & Colitis Foundation. EIM commonly involves the joints, skin, bones, eyes, kidney, and liver. Anemia is another extraintestinal complication.

Until now, it’s been unclear whether vedolizumab and ustekinumab are equally effective for treating EIM.

Vedolizumab specifically targets the gastrointestinal tract, a potential disadvantage in reducing EIM, while ustekinumab is thought to have a systemic effect, a potential treatment advantage, Moran Livne-Margolin, MD, and colleagues, Chaim Sheba Medical Center, Ramat Gan, Israel, point out.

To investigate, they included 111 adults with IBD who were treated at the medical center between 2015 and 2021 – 53 with vedolizumab and 58 with ustekinumab. Before starting treatment, all of them had active EIM, most commonly arthralgia (84%).

After 6 weeks of treatment, 66% of patients in both groups had a clinical response to their intestinal disease.

After 14 and 26 weeks of treatment, clinical response rates were 59% and 50%, respectively, with vedolizumab, and 48% and 41%, respectively, with ustekinumab.

Over 52 weeks, both biologics were equally effective against the intestinal disease, with clinical response rates of 42% with vedolizumab and 44% with ustekinumab.

A similar pattern emerged when looking at improvement in EIM.

At week 6, 44% of patients taking vedolizumab and 35% taking ustekinumab had improvement in EIM, with no significant difference between the two biologics (P = .4).

At week 14, rates of improvement in EIM were 43% for vedolizumab and 33% for ustekinumab (P = .39); at 26 weeks, rates were 39% and 33%, respectively (P = .6); and at 52 weeks, rates were 34% and 36% (P = .9).

Researchers also found a significant positive correlation between improvement of the intestinal disease and clinical improvement of EIM at each time point.

Ustekinumab is usually preferred in patients with EIM, Dr. Livne-Margolin and colleagues note. But their findings “may raise some questions whether ustekinumab is, in fact, a better choice in those specific patients.”

Limitations of the study include its retrospective design and small cohort size.

Additionally, vedolizumab is given intravenously in the clinic and mandates patients to have a routine checkup every 1-2 months, whereas ustekinumab can be given at home. As a result, data were missing on some of the patients treated with ustekinumab during the follow-up.

Another limitation is that most of the patients had articular complaints with a small presentation of other EIM.

Also, most of the patients had Crohn’s disease, with only one patient with ulcerative colitis in the ustekinumab group, compared with 12 in the vedolizumab group.

Finally, patients treated with ustekinumab had more experience with anti-TNF treatment, compared with the vedolizumab group, which might have influenced the results with a negative bias toward ustekinumab.

The study had no specific funding. Three authors have disclosed relationships with Janssen, which makes ustekinumab.

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

Vedolizumab (Entyvio) and ustekinumab (Stelara) appear to be equally effective for extraintestinal manifestation (EIM) of inflammatory bowel disease (IBD), according to results of a retrospective study published online in Digestive and Liver Disease.

Between 25% and 40% of patients with IBD experience EIM, which reduces quality of life, according to the Crohn’s & Colitis Foundation. EIM commonly involves the joints, skin, bones, eyes, kidney, and liver. Anemia is another extraintestinal complication.

Until now, it’s been unclear whether vedolizumab and ustekinumab are equally effective for treating EIM.

Vedolizumab specifically targets the gastrointestinal tract, a potential disadvantage in reducing EIM, while ustekinumab is thought to have a systemic effect, a potential treatment advantage, Moran Livne-Margolin, MD, and colleagues, Chaim Sheba Medical Center, Ramat Gan, Israel, point out.

To investigate, they included 111 adults with IBD who were treated at the medical center between 2015 and 2021 – 53 with vedolizumab and 58 with ustekinumab. Before starting treatment, all of them had active EIM, most commonly arthralgia (84%).

After 6 weeks of treatment, 66% of patients in both groups had a clinical response to their intestinal disease.

After 14 and 26 weeks of treatment, clinical response rates were 59% and 50%, respectively, with vedolizumab, and 48% and 41%, respectively, with ustekinumab.

Over 52 weeks, both biologics were equally effective against the intestinal disease, with clinical response rates of 42% with vedolizumab and 44% with ustekinumab.

A similar pattern emerged when looking at improvement in EIM.

At week 6, 44% of patients taking vedolizumab and 35% taking ustekinumab had improvement in EIM, with no significant difference between the two biologics (P = .4).

At week 14, rates of improvement in EIM were 43% for vedolizumab and 33% for ustekinumab (P = .39); at 26 weeks, rates were 39% and 33%, respectively (P = .6); and at 52 weeks, rates were 34% and 36% (P = .9).

Researchers also found a significant positive correlation between improvement of the intestinal disease and clinical improvement of EIM at each time point.

Ustekinumab is usually preferred in patients with EIM, Dr. Livne-Margolin and colleagues note. But their findings “may raise some questions whether ustekinumab is, in fact, a better choice in those specific patients.”

Limitations of the study include its retrospective design and small cohort size.

Additionally, vedolizumab is given intravenously in the clinic and mandates patients to have a routine checkup every 1-2 months, whereas ustekinumab can be given at home. As a result, data were missing on some of the patients treated with ustekinumab during the follow-up.

Another limitation is that most of the patients had articular complaints with a small presentation of other EIM.

Also, most of the patients had Crohn’s disease, with only one patient with ulcerative colitis in the ustekinumab group, compared with 12 in the vedolizumab group.

Finally, patients treated with ustekinumab had more experience with anti-TNF treatment, compared with the vedolizumab group, which might have influenced the results with a negative bias toward ustekinumab.

The study had no specific funding. Three authors have disclosed relationships with Janssen, which makes ustekinumab.

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

Vedolizumab (Entyvio) and ustekinumab (Stelara) appear to be equally effective for extraintestinal manifestation (EIM) of inflammatory bowel disease (IBD), according to results of a retrospective study published online in Digestive and Liver Disease.

Between 25% and 40% of patients with IBD experience EIM, which reduces quality of life, according to the Crohn’s & Colitis Foundation. EIM commonly involves the joints, skin, bones, eyes, kidney, and liver. Anemia is another extraintestinal complication.

Until now, it’s been unclear whether vedolizumab and ustekinumab are equally effective for treating EIM.

Vedolizumab specifically targets the gastrointestinal tract, a potential disadvantage in reducing EIM, while ustekinumab is thought to have a systemic effect, a potential treatment advantage, Moran Livne-Margolin, MD, and colleagues, Chaim Sheba Medical Center, Ramat Gan, Israel, point out.

To investigate, they included 111 adults with IBD who were treated at the medical center between 2015 and 2021 – 53 with vedolizumab and 58 with ustekinumab. Before starting treatment, all of them had active EIM, most commonly arthralgia (84%).

After 6 weeks of treatment, 66% of patients in both groups had a clinical response to their intestinal disease.

After 14 and 26 weeks of treatment, clinical response rates were 59% and 50%, respectively, with vedolizumab, and 48% and 41%, respectively, with ustekinumab.

Over 52 weeks, both biologics were equally effective against the intestinal disease, with clinical response rates of 42% with vedolizumab and 44% with ustekinumab.

A similar pattern emerged when looking at improvement in EIM.

At week 6, 44% of patients taking vedolizumab and 35% taking ustekinumab had improvement in EIM, with no significant difference between the two biologics (P = .4).

At week 14, rates of improvement in EIM were 43% for vedolizumab and 33% for ustekinumab (P = .39); at 26 weeks, rates were 39% and 33%, respectively (P = .6); and at 52 weeks, rates were 34% and 36% (P = .9).

Researchers also found a significant positive correlation between improvement of the intestinal disease and clinical improvement of EIM at each time point.

Ustekinumab is usually preferred in patients with EIM, Dr. Livne-Margolin and colleagues note. But their findings “may raise some questions whether ustekinumab is, in fact, a better choice in those specific patients.”

Limitations of the study include its retrospective design and small cohort size.

Additionally, vedolizumab is given intravenously in the clinic and mandates patients to have a routine checkup every 1-2 months, whereas ustekinumab can be given at home. As a result, data were missing on some of the patients treated with ustekinumab during the follow-up.

Another limitation is that most of the patients had articular complaints with a small presentation of other EIM.

Also, most of the patients had Crohn’s disease, with only one patient with ulcerative colitis in the ustekinumab group, compared with 12 in the vedolizumab group.

Finally, patients treated with ustekinumab had more experience with anti-TNF treatment, compared with the vedolizumab group, which might have influenced the results with a negative bias toward ustekinumab.

The study had no specific funding. Three authors have disclosed relationships with Janssen, which makes ustekinumab.

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

DENVER – Use of subcutaneous ropivacaine for Mohs surgery in highly vascularized anatomical regions such as the nose results in significantly shorter duration of anesthesia compared with less vascularized regions such as the shin, results from a single-center study showed.

Ropivacaine is a long-acting anesthetic that may be used as a substitute for the more commonly local anesthetics such as lidocaine or bupivacaine in dermatologic surgery, lead study author Kira Minkis, MD, PhD, told this news organization following the annual meeting of the American Society for Dermatologic Surgery, where the study results were presented during an oral abstract session. By comparison, ropivacaine has been reported to have a faster onset, similar duration in the range of 6-14 hours, less pain upon injection, and inherent vasoconstrictive properties.

“With tumescent anesthesia, studies have previously shown that the rate and absorption of anesthetics is influenced by the site of administration,” said Dr. Minkis, director of Mohs and dermatologic surgery at Weill Cornell Medicine, New York. “In studies comparing absorption of local anesthetics in tumescent anesthesia by regions that differ in vascularity, peak serum concentrations are greater and rise more rapidly after use in the head and neck compared to the trunk and extremities. However, no studies to date have compared the duration of ropivacaine in highly vascularized tissue or compared duration between regions that differ in vascularity.” The aim of the study, she noted, was to characterize the difference in duration of ropivacaine’s effects between anatomic regions of rich and comparably poor vascularity, such as the face and extremities, respectively.

Dr. Minkis and her colleagues recruited 17 women and 12 men with a mean age of 72 years who underwent Mohs surgery on the nose or the shin at Weill Cornell Medicine. Patients were anesthetized at each site with a subcutaneous injection of 0.5 mL of ropivacaine, 0.2%. Sensation was determined by pinprick prior to injection, at baseline, and every 15 minutes until sensation returned or surgery concluded. The primary endpoint was time to return of pinprick sensation.

The researchers found that the duration of ropivacaine was significantly shorter on the nose (a median of 60 minutes) than on the shin (a median of 210 minutes). In fact, the upper limit of the range of duration at the shin was not determinable because 22 of the 29 (76%) of participants did not regain sensation on the shin prior to leaving the surgical suite and concluding the study. The proportion of study participants who regained sensation within 1 hour was 76% among those who were treated on the nose vs. 3% of those who were treated on the shin (P < .0001).

“With durations of up to 6-14 hours reported, our results indicate a strikingly shorter duration of local anesthesia in highly vascularized tissue,” Dr. Minkis said. “The brevity of local anesthesia is even more surprising given the intrinsic vasoconstrictive properties of ropivacaine. Often, we co-administer epinephrine to achieve vasoconstriction and reduce local blood flow, thus prolonging local concentrations of the anesthetic with the added benefit of reducing bleeding during surgery. The short duration we’ve observed in our study is emphasized in using a potent, long-acting local anesthetic with vasoconstrictive properties that otherwise should attenuate the effects of high local vascularity.”

In other findings, patients with history of hypertension were more likely to regain sensation on the nose by 60 minutes but this did not reach statistical significance (P = .079). Other comorbidities including underlying anxiety/depression, diabetes, and kidney disease did not significantly impact duration of ropivacaine action on the nose. The same held true for patients who were treated on the shin.

“We highlight an inconsistency between the reported duration of a long-lasting local anesthetic and the short-lived anesthesia experienced by our patients in a highly vascularized region,” Dr. Minkis said. “In practice, adjunctive use of a long-acting anesthetic to prolong anesthesia is common, which may provide relief from multiple injections of shorter-acting lidocaine. However, the duration of Mohs surgery can be unpredictable. Extended wait times between stages may exceed the duration we’ve observed in this study.”

In addition, she continued, “pain is frequently reported on postoperative days 0 to 3, leading some to recommend the use of long-acting local anesthetics to prevent overprescription or a gap in pain coverage. This emphasizes a gap in effective pain control, but also an opportunity to improve our patients’ surgical and recovery experiences.”

 

Impact on practice

Keith L. Duffy, MD, associate professor of dermatology at the University of Utah, Salt Lake City, who was asked to comment on the study, said that in light of current local anesthetic shortages and back orders, “we dermatologic surgeons have been experimenting with different anesthetics and concentrations that we can use in our patients. Ropivacaine may become the anesthetic of choice for many of our practices given its inherent properties.”

The duration of anesthetic effects by anatomic location in this study is “actually more impressive than I would have suspected as a practicing Mohs surgeon. The results of this study will immediately impact my Mohs surgery clinic,” he said, adding that he hoped that Dr. Minkis and others “will expand on this study to include more patients, different anesthetics, and more anatomic locations.”

Dr. Minkis acknowledged certain limitations of the study, including its single-center design and the fact that there were too few observations of medical and clinical characteristics for subgroup analysis.

She and Dr. Duffy reported having no financial disclosures.

DENVER – Use of subcutaneous ropivacaine for Mohs surgery in highly vascularized anatomical regions such as the nose results in significantly shorter duration of anesthesia compared with less vascularized regions such as the shin, results from a single-center study showed.

Ropivacaine is a long-acting anesthetic that may be used as a substitute for the more commonly local anesthetics such as lidocaine or bupivacaine in dermatologic surgery, lead study author Kira Minkis, MD, PhD, told this news organization following the annual meeting of the American Society for Dermatologic Surgery, where the study results were presented during an oral abstract session. By comparison, ropivacaine has been reported to have a faster onset, similar duration in the range of 6-14 hours, less pain upon injection, and inherent vasoconstrictive properties.

“With tumescent anesthesia, studies have previously shown that the rate and absorption of anesthetics is influenced by the site of administration,” said Dr. Minkis, director of Mohs and dermatologic surgery at Weill Cornell Medicine, New York. “In studies comparing absorption of local anesthetics in tumescent anesthesia by regions that differ in vascularity, peak serum concentrations are greater and rise more rapidly after use in the head and neck compared to the trunk and extremities. However, no studies to date have compared the duration of ropivacaine in highly vascularized tissue or compared duration between regions that differ in vascularity.” The aim of the study, she noted, was to characterize the difference in duration of ropivacaine’s effects between anatomic regions of rich and comparably poor vascularity, such as the face and extremities, respectively.

Dr. Minkis and her colleagues recruited 17 women and 12 men with a mean age of 72 years who underwent Mohs surgery on the nose or the shin at Weill Cornell Medicine. Patients were anesthetized at each site with a subcutaneous injection of 0.5 mL of ropivacaine, 0.2%. Sensation was determined by pinprick prior to injection, at baseline, and every 15 minutes until sensation returned or surgery concluded. The primary endpoint was time to return of pinprick sensation.

The researchers found that the duration of ropivacaine was significantly shorter on the nose (a median of 60 minutes) than on the shin (a median of 210 minutes). In fact, the upper limit of the range of duration at the shin was not determinable because 22 of the 29 (76%) of participants did not regain sensation on the shin prior to leaving the surgical suite and concluding the study. The proportion of study participants who regained sensation within 1 hour was 76% among those who were treated on the nose vs. 3% of those who were treated on the shin (P < .0001).

“With durations of up to 6-14 hours reported, our results indicate a strikingly shorter duration of local anesthesia in highly vascularized tissue,” Dr. Minkis said. “The brevity of local anesthesia is even more surprising given the intrinsic vasoconstrictive properties of ropivacaine. Often, we co-administer epinephrine to achieve vasoconstriction and reduce local blood flow, thus prolonging local concentrations of the anesthetic with the added benefit of reducing bleeding during surgery. The short duration we’ve observed in our study is emphasized in using a potent, long-acting local anesthetic with vasoconstrictive properties that otherwise should attenuate the effects of high local vascularity.”

In other findings, patients with history of hypertension were more likely to regain sensation on the nose by 60 minutes but this did not reach statistical significance (P = .079). Other comorbidities including underlying anxiety/depression, diabetes, and kidney disease did not significantly impact duration of ropivacaine action on the nose. The same held true for patients who were treated on the shin.

“We highlight an inconsistency between the reported duration of a long-lasting local anesthetic and the short-lived anesthesia experienced by our patients in a highly vascularized region,” Dr. Minkis said. “In practice, adjunctive use of a long-acting anesthetic to prolong anesthesia is common, which may provide relief from multiple injections of shorter-acting lidocaine. However, the duration of Mohs surgery can be unpredictable. Extended wait times between stages may exceed the duration we’ve observed in this study.”

In addition, she continued, “pain is frequently reported on postoperative days 0 to 3, leading some to recommend the use of long-acting local anesthetics to prevent overprescription or a gap in pain coverage. This emphasizes a gap in effective pain control, but also an opportunity to improve our patients’ surgical and recovery experiences.”

 

Impact on practice

Keith L. Duffy, MD, associate professor of dermatology at the University of Utah, Salt Lake City, who was asked to comment on the study, said that in light of current local anesthetic shortages and back orders, “we dermatologic surgeons have been experimenting with different anesthetics and concentrations that we can use in our patients. Ropivacaine may become the anesthetic of choice for many of our practices given its inherent properties.”

The duration of anesthetic effects by anatomic location in this study is “actually more impressive than I would have suspected as a practicing Mohs surgeon. The results of this study will immediately impact my Mohs surgery clinic,” he said, adding that he hoped that Dr. Minkis and others “will expand on this study to include more patients, different anesthetics, and more anatomic locations.”

Dr. Minkis acknowledged certain limitations of the study, including its single-center design and the fact that there were too few observations of medical and clinical characteristics for subgroup analysis.

She and Dr. Duffy reported having no financial disclosures.

DENVER – Use of subcutaneous ropivacaine for Mohs surgery in highly vascularized anatomical regions such as the nose results in significantly shorter duration of anesthesia compared with less vascularized regions such as the shin, results from a single-center study showed.

Ropivacaine is a long-acting anesthetic that may be used as a substitute for the more commonly local anesthetics such as lidocaine or bupivacaine in dermatologic surgery, lead study author Kira Minkis, MD, PhD, told this news organization following the annual meeting of the American Society for Dermatologic Surgery, where the study results were presented during an oral abstract session. By comparison, ropivacaine has been reported to have a faster onset, similar duration in the range of 6-14 hours, less pain upon injection, and inherent vasoconstrictive properties.

“With tumescent anesthesia, studies have previously shown that the rate and absorption of anesthetics is influenced by the site of administration,” said Dr. Minkis, director of Mohs and dermatologic surgery at Weill Cornell Medicine, New York. “In studies comparing absorption of local anesthetics in tumescent anesthesia by regions that differ in vascularity, peak serum concentrations are greater and rise more rapidly after use in the head and neck compared to the trunk and extremities. However, no studies to date have compared the duration of ropivacaine in highly vascularized tissue or compared duration between regions that differ in vascularity.” The aim of the study, she noted, was to characterize the difference in duration of ropivacaine’s effects between anatomic regions of rich and comparably poor vascularity, such as the face and extremities, respectively.

Dr. Minkis and her colleagues recruited 17 women and 12 men with a mean age of 72 years who underwent Mohs surgery on the nose or the shin at Weill Cornell Medicine. Patients were anesthetized at each site with a subcutaneous injection of 0.5 mL of ropivacaine, 0.2%. Sensation was determined by pinprick prior to injection, at baseline, and every 15 minutes until sensation returned or surgery concluded. The primary endpoint was time to return of pinprick sensation.

The researchers found that the duration of ropivacaine was significantly shorter on the nose (a median of 60 minutes) than on the shin (a median of 210 minutes). In fact, the upper limit of the range of duration at the shin was not determinable because 22 of the 29 (76%) of participants did not regain sensation on the shin prior to leaving the surgical suite and concluding the study. The proportion of study participants who regained sensation within 1 hour was 76% among those who were treated on the nose vs. 3% of those who were treated on the shin (P < .0001).

“With durations of up to 6-14 hours reported, our results indicate a strikingly shorter duration of local anesthesia in highly vascularized tissue,” Dr. Minkis said. “The brevity of local anesthesia is even more surprising given the intrinsic vasoconstrictive properties of ropivacaine. Often, we co-administer epinephrine to achieve vasoconstriction and reduce local blood flow, thus prolonging local concentrations of the anesthetic with the added benefit of reducing bleeding during surgery. The short duration we’ve observed in our study is emphasized in using a potent, long-acting local anesthetic with vasoconstrictive properties that otherwise should attenuate the effects of high local vascularity.”

In other findings, patients with history of hypertension were more likely to regain sensation on the nose by 60 minutes but this did not reach statistical significance (P = .079). Other comorbidities including underlying anxiety/depression, diabetes, and kidney disease did not significantly impact duration of ropivacaine action on the nose. The same held true for patients who were treated on the shin.

“We highlight an inconsistency between the reported duration of a long-lasting local anesthetic and the short-lived anesthesia experienced by our patients in a highly vascularized region,” Dr. Minkis said. “In practice, adjunctive use of a long-acting anesthetic to prolong anesthesia is common, which may provide relief from multiple injections of shorter-acting lidocaine. However, the duration of Mohs surgery can be unpredictable. Extended wait times between stages may exceed the duration we’ve observed in this study.”

In addition, she continued, “pain is frequently reported on postoperative days 0 to 3, leading some to recommend the use of long-acting local anesthetics to prevent overprescription or a gap in pain coverage. This emphasizes a gap in effective pain control, but also an opportunity to improve our patients’ surgical and recovery experiences.”

 

Impact on practice

Keith L. Duffy, MD, associate professor of dermatology at the University of Utah, Salt Lake City, who was asked to comment on the study, said that in light of current local anesthetic shortages and back orders, “we dermatologic surgeons have been experimenting with different anesthetics and concentrations that we can use in our patients. Ropivacaine may become the anesthetic of choice for many of our practices given its inherent properties.”

The duration of anesthetic effects by anatomic location in this study is “actually more impressive than I would have suspected as a practicing Mohs surgeon. The results of this study will immediately impact my Mohs surgery clinic,” he said, adding that he hoped that Dr. Minkis and others “will expand on this study to include more patients, different anesthetics, and more anatomic locations.”

Dr. Minkis acknowledged certain limitations of the study, including its single-center design and the fact that there were too few observations of medical and clinical characteristics for subgroup analysis.

She and Dr. Duffy reported having no financial disclosures.

Before the introduction of insulin, there were few reported cases of pregnancy complicated by diabetes because women with the disease too often did not live to childbearing age, and when they did, they were often counseled to terminate their pregnancies. Perinatal and maternal mortality in the limited number of reported pregnancies were 70% and 40%, respectively,¹ making the risks of continuing the pregnancy quite high.

After insulin became available, maternal mortality dropped dramatically, down to a few percent. Perinatal mortality also declined, but it took several decades to achieve a similar magnitude of reduction.² Today, with insulin therapy and tight glucose control as well as improved perinatal care, almost all women with diabetes can contemplate pregnancy with greater hope for normal outcomes.

Problems persist, however. Maternal diabetes continues to cause a variety of adverse outcomes, including infants large for gestational age, prematurity, and structural birth defects. Birth defects and prematurity, in fact, are the top causes of the unacceptably high infant mortality rate in the United States – a rate that is about 70% higher than the average in comparable developed countries.³

Infant mortality is considered an indicator of population health and of the development of a country; to reduce its rate, we must address these two areas.

Women with type 1 and type 2 diabetes are five times more likely to have a child with birth defects than are nondiabetic women.⁴ Up to 10% of women with preexisting diabetes will have fetuses with a major congenital malformation.⁵

Over the years we have been striving in our Center for Birth Defects Research to understand the pathomechanisms and the molecular and epigenetic alterations behind the high rates of birth defects in the offspring of women with preexisting diabetes. We have focused on heart defects and neural tube defects (particularly the latter), which together cause significant mortality, morbidity, disability, and human suffering.

Using animal models that mimic human diabetic pregnancy, we have made significant strides in our understanding of the mechanisms, uncovering molecular pathways involving oxidative stress, senescence/premature cellular aging, and epigenetic modifications (Figure 1). Understanding these pathways is providing us, in turn, with potential therapeutic targets and approaches that may be used in the future to prevent birth defects in women who enter pregnancy with type 1 or type 2 diabetes.

Unraveling the role of oxidative stress

Our mouse models accurately reflect the human conditions of diabetes in pregnancy and diabetic embryopathy. Offspring of mice with type 1 and type 2 diabetes have a similarly higher rate of neural tube defects and congenital heart disease, compared to mice without diabetes. We observe a similar incidence of anencephaly and spina bifida, and of cardiac septation defects in the mouse embryo hearts, for instance.

A primary mechanism and causal event of diabetic embryopathy is hyperglycemia-induced apoptosis in embryonic cells. Excessive cell death in the neural epithelium or in the developing heart leads to abnormal organogenesis and dysfunctional developmental events that cause birth defects. We have identified pathways leading to apoptosis, and have found that many of these pathways crosstalk with each other.

Hyperglycemia induces oxidative stress – one of these pathways – by causing sustained generation of reactive oxygen species. The cells’ mitochondrial function is significantly impaired by the hyperglycemia response, and this diabetes-induced mitochondrial dysfunction further increases the production of reactive oxygen species and a weakening of the endogenous cellular antioxidant systems, both of which then exacerbate oxidative stress.

Our research has detailed what happens downstream. We’ve learned that oxidative stress in embryos exposed to maternal diabetes activates a cascade of proapoptotic kinase signaling molecules – for example, protein kinase C isoforms such as PKCalpha; apoptosis signal-regulating kinase 1; and c-Jun-N-terminal kinases – that ultimately lead to abnormal cell death in the neuroepithelium before neural tube closure (Figure 2).⁵

Hyperglycemia also alters membrane biochemistry in the developing embryo, suppressing lipids including arachidonic acid and myoinositol, and induces the elevation of other molecules that cause newly synthesized proteins to be misfolded. A build-up of misfolded/unfolded proteins triggers or exacerbates endoplasmic reticulum stress, which, like oxidative stress, plays a role in the activation of proapoptotic kinase signaling and apoptosis.⁶

When we’ve deleted genes for some of the proapoptotic kinase–signaling intermediates, or otherwise inhibited oxidative and endoplasmic reticulum stresses, we’ve been able to ameliorate neural cell apoptosis and the formation of neural tube defects. Studying the processes both forward and backward gives us confidence that the pathways are real and important, and that altering the pathways can alter the outcomes.

 

Reduced autophagy and induction of cellular senescence

Just as mitochondria are negatively affected by hyperglycemic conditions, so are autophagosomes – organelles that play a key role in removing abnormal or damaged stem cells and cellular components (including unfolded protein aggregates) and in maintaining cellular homeostasis. A high level of autophagy is essential for neural tube closure as well as cardiac morphogenesis.

In our models, maternal diabetes significantly suppressed the process of autophagy in neuroepithelial cells. We have identified responsible molecular intermediates and a key regulating gene for autophagy impairment and have found that deletion of the gene restores autophagy and reduces the development of neural tube defects.⁴ Administration of a naturally occurring compound, trehalose, which reactivates autophagy, had a similar effect.⁷Exposure to hyperglycemia not only causes cell death and suppresses autophagy, it also impairs other aspects of cellular function. More recently, we have shown that cells in the neuroepithelium become quiescent and cease proliferating. The quiescent cells, those cells with premature aging markers, also produce cytokines that influence the functioning and development of neighboring cells, causing additional cell death.

All told, premature senescence in the neuroepithelium adversely affects the neurulation process, leading to neural tube defects. In our mouse model, the senomorphic agent rapamycin suppressed cellular senescence, reduced the number of apoptotic neuroepithelial cells, and reduced the formation of neural tube defects.⁸

The role of epigenetics, future interventions

Epigenetics – the process by which gene expression and function can be modified by environmental conditions without modification of the DNA sequence – has become an additional area of focus in diabetic embryopathy. Our lab has studied the overexpression of both DNA methyltransferases (DNMTs) that cause DNA hypermethylation, and of microRNAs (miRNAs) that can suppress gene expression at the posttranscriptional level. Both are considered to be primary epigenetic mechanisms involved in human diseases and it appears that they are influential in the incidence of birth defects in diabetic mothers.

In our mouse models, maternal diabetes induces DNA hypermethylation via the increase of DNMTs, leading to the silencing of genes essential for neural tube closure and formation of the developing heart. MiRNAs also play a role; in addition to finding altered DNMT activity in the neural epithelium and other tissues of diabetes-exposed embryos, we also found altered miRNA expression. By deleting miRNA genes or by inhibiting DNMT activity through treatment with antioxidants, we saw significant reductions in birth defects.

In one study of the green tea polyphenol epigallocatechin gallate (EGCG), we demonstrated inhibition of diabetes-elevated DNMT expression and activity and suppression of DNA hypermethylation. The expression of genes essential for neural tube closure was restored, with a subsequent reduction in neural tube defects from 29.5% to 2% in embryos treated with EGCG.⁹

Our interventions to reverse or alter the mechanisms and pathways leading to birth defects have not only helped prove causation, but have given us hope for the future. Antioxidants are among the compounds that could be used as dietary supplements during pregnancy to prevent structural birth defects (Figure 3). Other compounds could activate the process of autophagy (for example, trehalose) and antisenescence compounds similar to rapamycin could be used to reduce numbers of senescent cells in the neuroepithelium or the developing heart.

Dr. Reece and Dr. Yang reported no relevant disclosures.

Dr. Reece, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president, endowed professor and director of CARTI, and codirector of the Center for Birth Defects.
Dr. Yang is professor of obstetrics, gynecology, and reproductive sciences and director, Center for the Study of Birth Defects at the University of Maryland School of Medicine, both in Baltimore.

*This story was updated on Nov. 3, 2022

References

1. Z Zhiyong and Reece EA. Clin Lab Med. 2013;33(2)207-33.

2. Reece EA and Coustan DR. Diabetes and obesity in women. Wolters Kluwer: 2019. 4th ed. (https://www.amazon.com/Diabetes-Obesity-Women-Albert-Reece/dp/1496390547).

3. The Peterson-KFF Health System Tracker. www.healthsystemtracker.org.

4. Wang F et al. Nat. Commun. 2017;8:15182.

5. Yang P et al. Am J Obstet Gynecol. 2015;212(5):569-79.

6. Li X et al. Diabetes. 2013 Feb;62(2):599-608.

7. Xu C et al. Am J Physiol Endocrinol Metab. 2013 Sep 1;305(5):E667-78.

8. Xu C et al. Sci Adv. 2021;7(27):eabf5089.

9. Zhong J et al. Am J Obstet Gynecol. 2016 Sep;215(3):368.e1-10.

Before the introduction of insulin, there were few reported cases of pregnancy complicated by diabetes because women with the disease too often did not live to childbearing age, and when they did, they were often counseled to terminate their pregnancies. Perinatal and maternal mortality in the limited number of reported pregnancies were 70% and 40%, respectively,¹ making the risks of continuing the pregnancy quite high.

After insulin became available, maternal mortality dropped dramatically, down to a few percent. Perinatal mortality also declined, but it took several decades to achieve a similar magnitude of reduction.² Today, with insulin therapy and tight glucose control as well as improved perinatal care, almost all women with diabetes can contemplate pregnancy with greater hope for normal outcomes.

Problems persist, however. Maternal diabetes continues to cause a variety of adverse outcomes, including infants large for gestational age, prematurity, and structural birth defects. Birth defects and prematurity, in fact, are the top causes of the unacceptably high infant mortality rate in the United States – a rate that is about 70% higher than the average in comparable developed countries.³

Infant mortality is considered an indicator of population health and of the development of a country; to reduce its rate, we must address these two areas.

Women with type 1 and type 2 diabetes are five times more likely to have a child with birth defects than are nondiabetic women.⁴ Up to 10% of women with preexisting diabetes will have fetuses with a major congenital malformation.⁵

Over the years we have been striving in our Center for Birth Defects Research to understand the pathomechanisms and the molecular and epigenetic alterations behind the high rates of birth defects in the offspring of women with preexisting diabetes. We have focused on heart defects and neural tube defects (particularly the latter), which together cause significant mortality, morbidity, disability, and human suffering.

Using animal models that mimic human diabetic pregnancy, we have made significant strides in our understanding of the mechanisms, uncovering molecular pathways involving oxidative stress, senescence/premature cellular aging, and epigenetic modifications (Figure 1). Understanding these pathways is providing us, in turn, with potential therapeutic targets and approaches that may be used in the future to prevent birth defects in women who enter pregnancy with type 1 or type 2 diabetes.

Unraveling the role of oxidative stress

Our mouse models accurately reflect the human conditions of diabetes in pregnancy and diabetic embryopathy. Offspring of mice with type 1 and type 2 diabetes have a similarly higher rate of neural tube defects and congenital heart disease, compared to mice without diabetes. We observe a similar incidence of anencephaly and spina bifida, and of cardiac septation defects in the mouse embryo hearts, for instance.

A primary mechanism and causal event of diabetic embryopathy is hyperglycemia-induced apoptosis in embryonic cells. Excessive cell death in the neural epithelium or in the developing heart leads to abnormal organogenesis and dysfunctional developmental events that cause birth defects. We have identified pathways leading to apoptosis, and have found that many of these pathways crosstalk with each other.

Hyperglycemia induces oxidative stress – one of these pathways – by causing sustained generation of reactive oxygen species. The cells’ mitochondrial function is significantly impaired by the hyperglycemia response, and this diabetes-induced mitochondrial dysfunction further increases the production of reactive oxygen species and a weakening of the endogenous cellular antioxidant systems, both of which then exacerbate oxidative stress.

Our research has detailed what happens downstream. We’ve learned that oxidative stress in embryos exposed to maternal diabetes activates a cascade of proapoptotic kinase signaling molecules – for example, protein kinase C isoforms such as PKCalpha; apoptosis signal-regulating kinase 1; and c-Jun-N-terminal kinases – that ultimately lead to abnormal cell death in the neuroepithelium before neural tube closure (Figure 2).⁵

Hyperglycemia also alters membrane biochemistry in the developing embryo, suppressing lipids including arachidonic acid and myoinositol, and induces the elevation of other molecules that cause newly synthesized proteins to be misfolded. A build-up of misfolded/unfolded proteins triggers or exacerbates endoplasmic reticulum stress, which, like oxidative stress, plays a role in the activation of proapoptotic kinase signaling and apoptosis.⁶

When we’ve deleted genes for some of the proapoptotic kinase–signaling intermediates, or otherwise inhibited oxidative and endoplasmic reticulum stresses, we’ve been able to ameliorate neural cell apoptosis and the formation of neural tube defects. Studying the processes both forward and backward gives us confidence that the pathways are real and important, and that altering the pathways can alter the outcomes.

 

Reduced autophagy and induction of cellular senescence

Just as mitochondria are negatively affected by hyperglycemic conditions, so are autophagosomes – organelles that play a key role in removing abnormal or damaged stem cells and cellular components (including unfolded protein aggregates) and in maintaining cellular homeostasis. A high level of autophagy is essential for neural tube closure as well as cardiac morphogenesis.

In our models, maternal diabetes significantly suppressed the process of autophagy in neuroepithelial cells. We have identified responsible molecular intermediates and a key regulating gene for autophagy impairment and have found that deletion of the gene restores autophagy and reduces the development of neural tube defects.⁴ Administration of a naturally occurring compound, trehalose, which reactivates autophagy, had a similar effect.⁷Exposure to hyperglycemia not only causes cell death and suppresses autophagy, it also impairs other aspects of cellular function. More recently, we have shown that cells in the neuroepithelium become quiescent and cease proliferating. The quiescent cells, those cells with premature aging markers, also produce cytokines that influence the functioning and development of neighboring cells, causing additional cell death.

All told, premature senescence in the neuroepithelium adversely affects the neurulation process, leading to neural tube defects. In our mouse model, the senomorphic agent rapamycin suppressed cellular senescence, reduced the number of apoptotic neuroepithelial cells, and reduced the formation of neural tube defects.⁸

The role of epigenetics, future interventions

Epigenetics – the process by which gene expression and function can be modified by environmental conditions without modification of the DNA sequence – has become an additional area of focus in diabetic embryopathy. Our lab has studied the overexpression of both DNA methyltransferases (DNMTs) that cause DNA hypermethylation, and of microRNAs (miRNAs) that can suppress gene expression at the posttranscriptional level. Both are considered to be primary epigenetic mechanisms involved in human diseases and it appears that they are influential in the incidence of birth defects in diabetic mothers.

In our mouse models, maternal diabetes induces DNA hypermethylation via the increase of DNMTs, leading to the silencing of genes essential for neural tube closure and formation of the developing heart. MiRNAs also play a role; in addition to finding altered DNMT activity in the neural epithelium and other tissues of diabetes-exposed embryos, we also found altered miRNA expression. By deleting miRNA genes or by inhibiting DNMT activity through treatment with antioxidants, we saw significant reductions in birth defects.

In one study of the green tea polyphenol epigallocatechin gallate (EGCG), we demonstrated inhibition of diabetes-elevated DNMT expression and activity and suppression of DNA hypermethylation. The expression of genes essential for neural tube closure was restored, with a subsequent reduction in neural tube defects from 29.5% to 2% in embryos treated with EGCG.⁹

Our interventions to reverse or alter the mechanisms and pathways leading to birth defects have not only helped prove causation, but have given us hope for the future. Antioxidants are among the compounds that could be used as dietary supplements during pregnancy to prevent structural birth defects (Figure 3). Other compounds could activate the process of autophagy (for example, trehalose) and antisenescence compounds similar to rapamycin could be used to reduce numbers of senescent cells in the neuroepithelium or the developing heart.

Dr. Reece and Dr. Yang reported no relevant disclosures.

Dr. Reece, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president, endowed professor and director of CARTI, and codirector of the Center for Birth Defects.
Dr. Yang is professor of obstetrics, gynecology, and reproductive sciences and director, Center for the Study of Birth Defects at the University of Maryland School of Medicine, both in Baltimore.

*This story was updated on Nov. 3, 2022

References

1. Z Zhiyong and Reece EA. Clin Lab Med. 2013;33(2)207-33.

2. Reece EA and Coustan DR. Diabetes and obesity in women. Wolters Kluwer: 2019. 4th ed. (https://www.amazon.com/Diabetes-Obesity-Women-Albert-Reece/dp/1496390547).

3. The Peterson-KFF Health System Tracker. www.healthsystemtracker.org.

4. Wang F et al. Nat. Commun. 2017;8:15182.

5. Yang P et al. Am J Obstet Gynecol. 2015;212(5):569-79.

6. Li X et al. Diabetes. 2013 Feb;62(2):599-608.

7. Xu C et al. Am J Physiol Endocrinol Metab. 2013 Sep 1;305(5):E667-78.

8. Xu C et al. Sci Adv. 2021;7(27):eabf5089.

9. Zhong J et al. Am J Obstet Gynecol. 2016 Sep;215(3):368.e1-10.

Before the introduction of insulin, there were few reported cases of pregnancy complicated by diabetes because women with the disease too often did not live to childbearing age, and when they did, they were often counseled to terminate their pregnancies. Perinatal and maternal mortality in the limited number of reported pregnancies were 70% and 40%, respectively,¹ making the risks of continuing the pregnancy quite high.

After insulin became available, maternal mortality dropped dramatically, down to a few percent. Perinatal mortality also declined, but it took several decades to achieve a similar magnitude of reduction.² Today, with insulin therapy and tight glucose control as well as improved perinatal care, almost all women with diabetes can contemplate pregnancy with greater hope for normal outcomes.

Problems persist, however. Maternal diabetes continues to cause a variety of adverse outcomes, including infants large for gestational age, prematurity, and structural birth defects. Birth defects and prematurity, in fact, are the top causes of the unacceptably high infant mortality rate in the United States – a rate that is about 70% higher than the average in comparable developed countries.³

Infant mortality is considered an indicator of population health and of the development of a country; to reduce its rate, we must address these two areas.

Women with type 1 and type 2 diabetes are five times more likely to have a child with birth defects than are nondiabetic women.⁴ Up to 10% of women with preexisting diabetes will have fetuses with a major congenital malformation.⁵

Over the years we have been striving in our Center for Birth Defects Research to understand the pathomechanisms and the molecular and epigenetic alterations behind the high rates of birth defects in the offspring of women with preexisting diabetes. We have focused on heart defects and neural tube defects (particularly the latter), which together cause significant mortality, morbidity, disability, and human suffering.

Using animal models that mimic human diabetic pregnancy, we have made significant strides in our understanding of the mechanisms, uncovering molecular pathways involving oxidative stress, senescence/premature cellular aging, and epigenetic modifications (Figure 1). Understanding these pathways is providing us, in turn, with potential therapeutic targets and approaches that may be used in the future to prevent birth defects in women who enter pregnancy with type 1 or type 2 diabetes.

Unraveling the role of oxidative stress

Our mouse models accurately reflect the human conditions of diabetes in pregnancy and diabetic embryopathy. Offspring of mice with type 1 and type 2 diabetes have a similarly higher rate of neural tube defects and congenital heart disease, compared to mice without diabetes. We observe a similar incidence of anencephaly and spina bifida, and of cardiac septation defects in the mouse embryo hearts, for instance.

A primary mechanism and causal event of diabetic embryopathy is hyperglycemia-induced apoptosis in embryonic cells. Excessive cell death in the neural epithelium or in the developing heart leads to abnormal organogenesis and dysfunctional developmental events that cause birth defects. We have identified pathways leading to apoptosis, and have found that many of these pathways crosstalk with each other.

Hyperglycemia induces oxidative stress – one of these pathways – by causing sustained generation of reactive oxygen species. The cells’ mitochondrial function is significantly impaired by the hyperglycemia response, and this diabetes-induced mitochondrial dysfunction further increases the production of reactive oxygen species and a weakening of the endogenous cellular antioxidant systems, both of which then exacerbate oxidative stress.

Our research has detailed what happens downstream. We’ve learned that oxidative stress in embryos exposed to maternal diabetes activates a cascade of proapoptotic kinase signaling molecules – for example, protein kinase C isoforms such as PKCalpha; apoptosis signal-regulating kinase 1; and c-Jun-N-terminal kinases – that ultimately lead to abnormal cell death in the neuroepithelium before neural tube closure (Figure 2).⁵

Hyperglycemia also alters membrane biochemistry in the developing embryo, suppressing lipids including arachidonic acid and myoinositol, and induces the elevation of other molecules that cause newly synthesized proteins to be misfolded. A build-up of misfolded/unfolded proteins triggers or exacerbates endoplasmic reticulum stress, which, like oxidative stress, plays a role in the activation of proapoptotic kinase signaling and apoptosis.⁶

When we’ve deleted genes for some of the proapoptotic kinase–signaling intermediates, or otherwise inhibited oxidative and endoplasmic reticulum stresses, we’ve been able to ameliorate neural cell apoptosis and the formation of neural tube defects. Studying the processes both forward and backward gives us confidence that the pathways are real and important, and that altering the pathways can alter the outcomes.

 

Reduced autophagy and induction of cellular senescence

Just as mitochondria are negatively affected by hyperglycemic conditions, so are autophagosomes – organelles that play a key role in removing abnormal or damaged stem cells and cellular components (including unfolded protein aggregates) and in maintaining cellular homeostasis. A high level of autophagy is essential for neural tube closure as well as cardiac morphogenesis.

In our models, maternal diabetes significantly suppressed the process of autophagy in neuroepithelial cells. We have identified responsible molecular intermediates and a key regulating gene for autophagy impairment and have found that deletion of the gene restores autophagy and reduces the development of neural tube defects.⁴ Administration of a naturally occurring compound, trehalose, which reactivates autophagy, had a similar effect.⁷Exposure to hyperglycemia not only causes cell death and suppresses autophagy, it also impairs other aspects of cellular function. More recently, we have shown that cells in the neuroepithelium become quiescent and cease proliferating. The quiescent cells, those cells with premature aging markers, also produce cytokines that influence the functioning and development of neighboring cells, causing additional cell death.

All told, premature senescence in the neuroepithelium adversely affects the neurulation process, leading to neural tube defects. In our mouse model, the senomorphic agent rapamycin suppressed cellular senescence, reduced the number of apoptotic neuroepithelial cells, and reduced the formation of neural tube defects.⁸

The role of epigenetics, future interventions

Epigenetics – the process by which gene expression and function can be modified by environmental conditions without modification of the DNA sequence – has become an additional area of focus in diabetic embryopathy. Our lab has studied the overexpression of both DNA methyltransferases (DNMTs) that cause DNA hypermethylation, and of microRNAs (miRNAs) that can suppress gene expression at the posttranscriptional level. Both are considered to be primary epigenetic mechanisms involved in human diseases and it appears that they are influential in the incidence of birth defects in diabetic mothers.

In our mouse models, maternal diabetes induces DNA hypermethylation via the increase of DNMTs, leading to the silencing of genes essential for neural tube closure and formation of the developing heart. MiRNAs also play a role; in addition to finding altered DNMT activity in the neural epithelium and other tissues of diabetes-exposed embryos, we also found altered miRNA expression. By deleting miRNA genes or by inhibiting DNMT activity through treatment with antioxidants, we saw significant reductions in birth defects.

In one study of the green tea polyphenol epigallocatechin gallate (EGCG), we demonstrated inhibition of diabetes-elevated DNMT expression and activity and suppression of DNA hypermethylation. The expression of genes essential for neural tube closure was restored, with a subsequent reduction in neural tube defects from 29.5% to 2% in embryos treated with EGCG.⁹

Our interventions to reverse or alter the mechanisms and pathways leading to birth defects have not only helped prove causation, but have given us hope for the future. Antioxidants are among the compounds that could be used as dietary supplements during pregnancy to prevent structural birth defects (Figure 3). Other compounds could activate the process of autophagy (for example, trehalose) and antisenescence compounds similar to rapamycin could be used to reduce numbers of senescent cells in the neuroepithelium or the developing heart.

Dr. Reece and Dr. Yang reported no relevant disclosures.

Dr. Reece, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president, endowed professor and director of CARTI, and codirector of the Center for Birth Defects.
Dr. Yang is professor of obstetrics, gynecology, and reproductive sciences and director, Center for the Study of Birth Defects at the University of Maryland School of Medicine, both in Baltimore.

*This story was updated on Nov. 3, 2022

References

1. Z Zhiyong and Reece EA. Clin Lab Med. 2013;33(2)207-33.

2. Reece EA and Coustan DR. Diabetes and obesity in women. Wolters Kluwer: 2019. 4th ed. (https://www.amazon.com/Diabetes-Obesity-Women-Albert-Reece/dp/1496390547).

3. The Peterson-KFF Health System Tracker. www.healthsystemtracker.org.

4. Wang F et al. Nat. Commun. 2017;8:15182.

5. Yang P et al. Am J Obstet Gynecol. 2015;212(5):569-79.

6. Li X et al. Diabetes. 2013 Feb;62(2):599-608.

7. Xu C et al. Am J Physiol Endocrinol Metab. 2013 Sep 1;305(5):E667-78.

8. Xu C et al. Sci Adv. 2021;7(27):eabf5089.

9. Zhong J et al. Am J Obstet Gynecol. 2016 Sep;215(3):368.e1-10.

Many issues surrounding pregnancy care of women with preexisting diabetes remain challenging, especially in light of the relentless increase in maternal morbidity and mortality in the United States and globally. Rising rates of death and severe morbidity in diabetic women have continued despite significant advances in insulin pharmacology and administration technology.

However, despite these advances in glucose monitoring and insulin administration, fetal mortality and childhood morbidity rates continue to climb. This is because critical fetal structural anomalies arise from developmental errors occurring in the embryonic period – between 2 and 13 weeks of gestation – a time when most women with preexisting diabetes are just entering into prenatal care, often with suboptimal glycemic control.

Thus, significant future progress in reducing fetal mortality and childhood disability in infants of diabetic mothers will depend upon effective interventions in the first trimester while embryogenesis and critical organ formation are underway.

Dr. Moore is professor emeritus of maternal-fetal medicine and chair emeritus in the department of obstetrics, gynecology, and reproductive sciences at UC San Diego Health. He reported no disclosures.

*This story was updated on Nov. 3, 2022.

Many issues surrounding pregnancy care of women with preexisting diabetes remain challenging, especially in light of the relentless increase in maternal morbidity and mortality in the United States and globally. Rising rates of death and severe morbidity in diabetic women have continued despite significant advances in insulin pharmacology and administration technology.

However, despite these advances in glucose monitoring and insulin administration, fetal mortality and childhood morbidity rates continue to climb. This is because critical fetal structural anomalies arise from developmental errors occurring in the embryonic period – between 2 and 13 weeks of gestation – a time when most women with preexisting diabetes are just entering into prenatal care, often with suboptimal glycemic control.

Thus, significant future progress in reducing fetal mortality and childhood disability in infants of diabetic mothers will depend upon effective interventions in the first trimester while embryogenesis and critical organ formation are underway.

Dr. Moore is professor emeritus of maternal-fetal medicine and chair emeritus in the department of obstetrics, gynecology, and reproductive sciences at UC San Diego Health. He reported no disclosures.

*This story was updated on Nov. 3, 2022.

Many issues surrounding pregnancy care of women with preexisting diabetes remain challenging, especially in light of the relentless increase in maternal morbidity and mortality in the United States and globally. Rising rates of death and severe morbidity in diabetic women have continued despite significant advances in insulin pharmacology and administration technology.

However, despite these advances in glucose monitoring and insulin administration, fetal mortality and childhood morbidity rates continue to climb. This is because critical fetal structural anomalies arise from developmental errors occurring in the embryonic period – between 2 and 13 weeks of gestation – a time when most women with preexisting diabetes are just entering into prenatal care, often with suboptimal glycemic control.

Thus, significant future progress in reducing fetal mortality and childhood disability in infants of diabetic mothers will depend upon effective interventions in the first trimester while embryogenesis and critical organ formation are underway.

Dr. Moore is professor emeritus of maternal-fetal medicine and chair emeritus in the department of obstetrics, gynecology, and reproductive sciences at UC San Diego Health. He reported no disclosures.

*This story was updated on Nov. 3, 2022.

DENVER – One expert’s clinical experience suggests that Ellacor, a dermal microcoring device that became available in the United States in October 2022, is an effective treatment for facial wrinkles and tightening.

“It’s early yet, but I have treated dozens of patients with this device, and they have been happy with the results,” Mathew M. Avram, MD, JD, said at the annual meeting of the American Society for Dermatologic Surgery. “This is a new technique that offers the ability to remove a significant amount of damaged, lax skin without concern for scarring,” he said.

A brainchild of dermatologists and plastic surgeons at Massachusetts General Hospital, Boston, the first-in-class device is cleared by the Food and Drug Administration for the treatment of moderate and severe wrinkles in the mid and lower face in adults aged 22 years or older with Fitzpatrick skin types I-IV. It features a proprietary needle design that makes a series of high throughput microexcisions in epidermal and dermal tissue, with minimal downtime and without using thermal energy.

“It doesn’t do anything equivalent to a facelift, but the concept is a facelift by thousands of micro-punch excisions,” said Dr. Avram, director of laser, cosmetics, and dermatologic surgery at Massachusetts General Hospital. “Rather than pulling up the skin and lifting it and cutting the excess skin like we do with a facelift, we are creating thousands of smaller-scale tissue removals with immediate closures to do the same thing. The micro-cores are about the size of a 22-gauge needle and there is no scarring due to the small size of these tissue extractions.”

The device features needle cartridges capable of excising up to 24,000 cores per treatment. According to data from Cytrellis, the manufacturer, the equivalent of about 2 inches of skin can be removed during the procedure, which typically takes fewer than 30 minutes to perform. “There is no heat whatsoever,” Dr. Avram said. “In my experience, it especially helps with jawline definition, the lower medial cheek excess skin, and accordion lines in that area.”

In a pivotal trial of the device, 51 patients with mid to lower face wrinkles (moderately deep or deep wrinkles with well-defined edges) were treated 2-3 times with 7%-8% skin removal and up to a 5-mm needle coring depth). The investigators found that 40% of study participants achieved an improvement of 2 grades on the Lemperle Wrinkle Severity Scale and that the rate of overall satisfaction (slightly, somewhat, and extremely satisfied) was 86%.

In addition, 90% showed improvement of treated sites on the Global Aesthetic Improvement Scale, and 70% were comfortable enough to go out in public or return to work 3 days after treatment. Common side effects that can occur immediately post treatment include redness, swelling, and pinpoint bleeding, which typically clear in a few days.

Dr. Avram, immediate past president of the ASDS, has posted videos to his Instagram feed that show him treating patients with the Ellacor device and he admits that the procedure looks painful. “There are all these tear emojis and people cursing me out,” he said, referring to responses from his Instagram followers.

Proper local anesthesia prior to treatment is key. “I perform nerve blocks and infiltrate the skin,” he said. “You have to cover the whole treatment area. If you don’t, then it’s going to hurt. The average pain score is 1.9 out of 10. The highest pain score I’ve gotten from a patient is a 3 out of 10.”

Dr. Avram disclosed that he has received consulting fees from Allergan, Merz, Sciton, and Soliton, and has ownership and/or shareholder interest in Cytrellis.

DENVER – One expert’s clinical experience suggests that Ellacor, a dermal microcoring device that became available in the United States in October 2022, is an effective treatment for facial wrinkles and tightening.

“It’s early yet, but I have treated dozens of patients with this device, and they have been happy with the results,” Mathew M. Avram, MD, JD, said at the annual meeting of the American Society for Dermatologic Surgery. “This is a new technique that offers the ability to remove a significant amount of damaged, lax skin without concern for scarring,” he said.

A brainchild of dermatologists and plastic surgeons at Massachusetts General Hospital, Boston, the first-in-class device is cleared by the Food and Drug Administration for the treatment of moderate and severe wrinkles in the mid and lower face in adults aged 22 years or older with Fitzpatrick skin types I-IV. It features a proprietary needle design that makes a series of high throughput microexcisions in epidermal and dermal tissue, with minimal downtime and without using thermal energy.

“It doesn’t do anything equivalent to a facelift, but the concept is a facelift by thousands of micro-punch excisions,” said Dr. Avram, director of laser, cosmetics, and dermatologic surgery at Massachusetts General Hospital. “Rather than pulling up the skin and lifting it and cutting the excess skin like we do with a facelift, we are creating thousands of smaller-scale tissue removals with immediate closures to do the same thing. The micro-cores are about the size of a 22-gauge needle and there is no scarring due to the small size of these tissue extractions.”

The device features needle cartridges capable of excising up to 24,000 cores per treatment. According to data from Cytrellis, the manufacturer, the equivalent of about 2 inches of skin can be removed during the procedure, which typically takes fewer than 30 minutes to perform. “There is no heat whatsoever,” Dr. Avram said. “In my experience, it especially helps with jawline definition, the lower medial cheek excess skin, and accordion lines in that area.”

In a pivotal trial of the device, 51 patients with mid to lower face wrinkles (moderately deep or deep wrinkles with well-defined edges) were treated 2-3 times with 7%-8% skin removal and up to a 5-mm needle coring depth). The investigators found that 40% of study participants achieved an improvement of 2 grades on the Lemperle Wrinkle Severity Scale and that the rate of overall satisfaction (slightly, somewhat, and extremely satisfied) was 86%.

In addition, 90% showed improvement of treated sites on the Global Aesthetic Improvement Scale, and 70% were comfortable enough to go out in public or return to work 3 days after treatment. Common side effects that can occur immediately post treatment include redness, swelling, and pinpoint bleeding, which typically clear in a few days.

Dr. Avram, immediate past president of the ASDS, has posted videos to his Instagram feed that show him treating patients with the Ellacor device and he admits that the procedure looks painful. “There are all these tear emojis and people cursing me out,” he said, referring to responses from his Instagram followers.

Proper local anesthesia prior to treatment is key. “I perform nerve blocks and infiltrate the skin,” he said. “You have to cover the whole treatment area. If you don’t, then it’s going to hurt. The average pain score is 1.9 out of 10. The highest pain score I’ve gotten from a patient is a 3 out of 10.”

Dr. Avram disclosed that he has received consulting fees from Allergan, Merz, Sciton, and Soliton, and has ownership and/or shareholder interest in Cytrellis.

DENVER – One expert’s clinical experience suggests that Ellacor, a dermal microcoring device that became available in the United States in October 2022, is an effective treatment for facial wrinkles and tightening.

“It’s early yet, but I have treated dozens of patients with this device, and they have been happy with the results,” Mathew M. Avram, MD, JD, said at the annual meeting of the American Society for Dermatologic Surgery. “This is a new technique that offers the ability to remove a significant amount of damaged, lax skin without concern for scarring,” he said.

A brainchild of dermatologists and plastic surgeons at Massachusetts General Hospital, Boston, the first-in-class device is cleared by the Food and Drug Administration for the treatment of moderate and severe wrinkles in the mid and lower face in adults aged 22 years or older with Fitzpatrick skin types I-IV. It features a proprietary needle design that makes a series of high throughput microexcisions in epidermal and dermal tissue, with minimal downtime and without using thermal energy.

“It doesn’t do anything equivalent to a facelift, but the concept is a facelift by thousands of micro-punch excisions,” said Dr. Avram, director of laser, cosmetics, and dermatologic surgery at Massachusetts General Hospital. “Rather than pulling up the skin and lifting it and cutting the excess skin like we do with a facelift, we are creating thousands of smaller-scale tissue removals with immediate closures to do the same thing. The micro-cores are about the size of a 22-gauge needle and there is no scarring due to the small size of these tissue extractions.”

The device features needle cartridges capable of excising up to 24,000 cores per treatment. According to data from Cytrellis, the manufacturer, the equivalent of about 2 inches of skin can be removed during the procedure, which typically takes fewer than 30 minutes to perform. “There is no heat whatsoever,” Dr. Avram said. “In my experience, it especially helps with jawline definition, the lower medial cheek excess skin, and accordion lines in that area.”

In a pivotal trial of the device, 51 patients with mid to lower face wrinkles (moderately deep or deep wrinkles with well-defined edges) were treated 2-3 times with 7%-8% skin removal and up to a 5-mm needle coring depth). The investigators found that 40% of study participants achieved an improvement of 2 grades on the Lemperle Wrinkle Severity Scale and that the rate of overall satisfaction (slightly, somewhat, and extremely satisfied) was 86%.

In addition, 90% showed improvement of treated sites on the Global Aesthetic Improvement Scale, and 70% were comfortable enough to go out in public or return to work 3 days after treatment. Common side effects that can occur immediately post treatment include redness, swelling, and pinpoint bleeding, which typically clear in a few days.

Dr. Avram, immediate past president of the ASDS, has posted videos to his Instagram feed that show him treating patients with the Ellacor device and he admits that the procedure looks painful. “There are all these tear emojis and people cursing me out,” he said, referring to responses from his Instagram followers.

Proper local anesthesia prior to treatment is key. “I perform nerve blocks and infiltrate the skin,” he said. “You have to cover the whole treatment area. If you don’t, then it’s going to hurt. The average pain score is 1.9 out of 10. The highest pain score I’ve gotten from a patient is a 3 out of 10.”

Dr. Avram disclosed that he has received consulting fees from Allergan, Merz, Sciton, and Soliton, and has ownership and/or shareholder interest in Cytrellis.