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Can experiencing bigotry and racism lead to PTSD?
I have been studying, writing about, and treating posttraumatic stress disorder for many years. Over this time, I have seen PTSD expand to more and more areas of life, including my own view of a “subthreshold” version, which occurs in vulnerable people who experience a job loss, divorce, financial setbacks, or any number of painful life events.
As I noted in my recent book, “Find Freedom Fast,” for some people, PTSD can be triggered in the wake of events that are not life-threatening yet catastrophic for them and not tied to manmade or natural disasters, torture, assault, or war zone experiences.
The expansion of PTSD has led to the disorder being recognized in ICU patients during and after recovery (Crit Care Med. 2015 May;43[5]:1121-9), as well as in people diagnosed with cancer (Lancet Psychiatry. 2017 Apr;4[4]:330-8) and other illnesses that may cause emotional trauma – where one feels that one’s life is threatened. In some instances, the person’s life might indeed be in danger, not unlike what can happen in disasters, wars, torture, and even in some encounters with law enforcement.
This leads me to yet another circumstance that in some, may be tied to PTSD – and that is racial, religious, ethnic, and gender-related bigotry. In these cases, individuals feel threatened just for who they are in a society. Being on the receiving end of a circumstance that threatens a person’s very existence would seem to me to place a person as a potential survivor of PTSD, as well as any number of disorders, including anxiety, depression, or even paranoia.
Yes, discrimination and prejudice have been with us for a long time, and what concerns me is the psychological effect it has on children as well as adults. Friends of Irish descent remind me of hearing stories from parents and grandparents about employment signs reading, “Irish need not apply.” Certainly, those of Italian ancestry will easily recall the prejudice focused against them. And members of the Jewish community also can easily remember the bigotry and exclusion they have been subject to in certain neighborhoods and organizations, in addition to the horrors of the Holocaust during World War II, and the anti-Semitic chants in Charlottesville, Va., from just 3 years ago – with gun-carrying militants doing the chanting.
Obviously, in certain circles, we still have private clubs, plus neighborhoods and residential buildings that exclude people for a variety of reasons.
Coming from a medical family, years ago I heard stories that, if you were Roman Catholic, it would be hard to get into certain medical schools – which might explain the establishment of Catholic medical schools that often were open to people of other faiths. Then we had medical school discrimination toward Jewish students, which was followed by the establishment of medical schools focused on admitting more Jewish students. The African American community also responded to discrimination by establishing medical schools, such as the school at Howard University in Washington.
Furthermore, we cannot forget the discrimination that women faced in institutions of higher learning. My father had two women in his medical school class, I was told. In my era, I would say at least 30% were women, and today, in the United States, medical school classes are more equally balanced with men and women. Some schools have more women than men.
The question I ask, is: How did all those women feel for so many years knowing that, for reasons beyond their control, they were prevented from achieving their chosen goals? Some might have felt badly, and others might have internalized the rejection. Others might have developed PTSD based on feelings of rejection.
However, the question here mainly is: Can PTSD result when exclusion and prejudice induce fear and terror in those on the receiving end – especially innocent children? Children separated from their parents at the U.S.-Mexico border and those who witness their parents being shot immediately come to mind. This trauma can last well beyond childhood.
and make us realize the extent to which the African American community has been traumatized. Perhaps we should not be surprised by a study that found that the prevalence of PTSD among African Americans is 9.1%, compared with 6.8% for Whites (J Anxiety Dis. 2009 Jun;23[5]:573-90). Speaking with Black colleagues, friends, and patients, reading books such “The Warmth of Other Suns,” and watching films such as “Green Book,” give us a sense of how dangerous it was for Black families to travel in certain parts of the country in the recent past. I recall as a child hearing that, in Miami Beach, people of color could not stay overnight. (Even as a child I was surprised – having never heard anything like that. After all, I went to school with people of many religions and backgrounds. My parents thought those practices were terrible, and were appalled when they learned that some hotels were closed to Jews and others closed to Catholics.)
DSM-5, ICD-10 fall short
The DSM-5 describes trauma using a more or less one-dimensional set of guidelines as the focus. Those guidelines include exposure to direct violence, manmade or natural disasters, war, or torture, as well as exposure to a disaster or a life-threatening situation affecting a loved one. The ICD-10 is less restrictive about trauma but still has some limitations.
While considering potential PTSD, I try to use a less rigid diagnostic multidimensional approach, where I assess individual differences and experiences that play a role in those experiences as well as the patient’s vulnerability to the causation of PTSD – which also has to include any exposure to trauma (Curr Opin Psychol. 2017 Apr;14:29-34) before age 11 or 12. The data suggest that such early exposure leaves people more vulnerable to PTSD as adults (Soc Sci Med. 2018 Feb;199:230-40).
In my view, if individuals are frightened because of who they are – be it tied to their religion, race, sexual identity, or ethnicity – and what harm may come to them, and if they live in fear and avoidance of these potential traumatic situations that affect their mental stability and the way they live their lives, they might fit the PTSD model.
If we clinicians focus on what’s currently being brought vividly into the public eye today regarding the African American community, we would see that some of the ongoing fears of racism – whether tied to residential or workplace discrimination, unfair treatment by figures of authority, harassment, health inequities, or microaggressions – may give rise to PTSD. I know we can do better. We should broaden our definition and awareness of this very serious disorder – and be prepared to treat it.
Dr. London has been a practicing psychiatrist for 4 decades and a newspaper columnist for almost as long. He has a private practice in New York and is author of “Find Freedom Fast: Short-Term Therapy That Works” (New York: Kettlehole Publishing, 2019). Dr. London has no conflicts of interest.
I have been studying, writing about, and treating posttraumatic stress disorder for many years. Over this time, I have seen PTSD expand to more and more areas of life, including my own view of a “subthreshold” version, which occurs in vulnerable people who experience a job loss, divorce, financial setbacks, or any number of painful life events.
As I noted in my recent book, “Find Freedom Fast,” for some people, PTSD can be triggered in the wake of events that are not life-threatening yet catastrophic for them and not tied to manmade or natural disasters, torture, assault, or war zone experiences.
The expansion of PTSD has led to the disorder being recognized in ICU patients during and after recovery (Crit Care Med. 2015 May;43[5]:1121-9), as well as in people diagnosed with cancer (Lancet Psychiatry. 2017 Apr;4[4]:330-8) and other illnesses that may cause emotional trauma – where one feels that one’s life is threatened. In some instances, the person’s life might indeed be in danger, not unlike what can happen in disasters, wars, torture, and even in some encounters with law enforcement.
This leads me to yet another circumstance that in some, may be tied to PTSD – and that is racial, religious, ethnic, and gender-related bigotry. In these cases, individuals feel threatened just for who they are in a society. Being on the receiving end of a circumstance that threatens a person’s very existence would seem to me to place a person as a potential survivor of PTSD, as well as any number of disorders, including anxiety, depression, or even paranoia.
Yes, discrimination and prejudice have been with us for a long time, and what concerns me is the psychological effect it has on children as well as adults. Friends of Irish descent remind me of hearing stories from parents and grandparents about employment signs reading, “Irish need not apply.” Certainly, those of Italian ancestry will easily recall the prejudice focused against them. And members of the Jewish community also can easily remember the bigotry and exclusion they have been subject to in certain neighborhoods and organizations, in addition to the horrors of the Holocaust during World War II, and the anti-Semitic chants in Charlottesville, Va., from just 3 years ago – with gun-carrying militants doing the chanting.
Obviously, in certain circles, we still have private clubs, plus neighborhoods and residential buildings that exclude people for a variety of reasons.
Coming from a medical family, years ago I heard stories that, if you were Roman Catholic, it would be hard to get into certain medical schools – which might explain the establishment of Catholic medical schools that often were open to people of other faiths. Then we had medical school discrimination toward Jewish students, which was followed by the establishment of medical schools focused on admitting more Jewish students. The African American community also responded to discrimination by establishing medical schools, such as the school at Howard University in Washington.
Furthermore, we cannot forget the discrimination that women faced in institutions of higher learning. My father had two women in his medical school class, I was told. In my era, I would say at least 30% were women, and today, in the United States, medical school classes are more equally balanced with men and women. Some schools have more women than men.
The question I ask, is: How did all those women feel for so many years knowing that, for reasons beyond their control, they were prevented from achieving their chosen goals? Some might have felt badly, and others might have internalized the rejection. Others might have developed PTSD based on feelings of rejection.
However, the question here mainly is: Can PTSD result when exclusion and prejudice induce fear and terror in those on the receiving end – especially innocent children? Children separated from their parents at the U.S.-Mexico border and those who witness their parents being shot immediately come to mind. This trauma can last well beyond childhood.
and make us realize the extent to which the African American community has been traumatized. Perhaps we should not be surprised by a study that found that the prevalence of PTSD among African Americans is 9.1%, compared with 6.8% for Whites (J Anxiety Dis. 2009 Jun;23[5]:573-90). Speaking with Black colleagues, friends, and patients, reading books such “The Warmth of Other Suns,” and watching films such as “Green Book,” give us a sense of how dangerous it was for Black families to travel in certain parts of the country in the recent past. I recall as a child hearing that, in Miami Beach, people of color could not stay overnight. (Even as a child I was surprised – having never heard anything like that. After all, I went to school with people of many religions and backgrounds. My parents thought those practices were terrible, and were appalled when they learned that some hotels were closed to Jews and others closed to Catholics.)
DSM-5, ICD-10 fall short
The DSM-5 describes trauma using a more or less one-dimensional set of guidelines as the focus. Those guidelines include exposure to direct violence, manmade or natural disasters, war, or torture, as well as exposure to a disaster or a life-threatening situation affecting a loved one. The ICD-10 is less restrictive about trauma but still has some limitations.
While considering potential PTSD, I try to use a less rigid diagnostic multidimensional approach, where I assess individual differences and experiences that play a role in those experiences as well as the patient’s vulnerability to the causation of PTSD – which also has to include any exposure to trauma (Curr Opin Psychol. 2017 Apr;14:29-34) before age 11 or 12. The data suggest that such early exposure leaves people more vulnerable to PTSD as adults (Soc Sci Med. 2018 Feb;199:230-40).
In my view, if individuals are frightened because of who they are – be it tied to their religion, race, sexual identity, or ethnicity – and what harm may come to them, and if they live in fear and avoidance of these potential traumatic situations that affect their mental stability and the way they live their lives, they might fit the PTSD model.
If we clinicians focus on what’s currently being brought vividly into the public eye today regarding the African American community, we would see that some of the ongoing fears of racism – whether tied to residential or workplace discrimination, unfair treatment by figures of authority, harassment, health inequities, or microaggressions – may give rise to PTSD. I know we can do better. We should broaden our definition and awareness of this very serious disorder – and be prepared to treat it.
Dr. London has been a practicing psychiatrist for 4 decades and a newspaper columnist for almost as long. He has a private practice in New York and is author of “Find Freedom Fast: Short-Term Therapy That Works” (New York: Kettlehole Publishing, 2019). Dr. London has no conflicts of interest.
I have been studying, writing about, and treating posttraumatic stress disorder for many years. Over this time, I have seen PTSD expand to more and more areas of life, including my own view of a “subthreshold” version, which occurs in vulnerable people who experience a job loss, divorce, financial setbacks, or any number of painful life events.
As I noted in my recent book, “Find Freedom Fast,” for some people, PTSD can be triggered in the wake of events that are not life-threatening yet catastrophic for them and not tied to manmade or natural disasters, torture, assault, or war zone experiences.
The expansion of PTSD has led to the disorder being recognized in ICU patients during and after recovery (Crit Care Med. 2015 May;43[5]:1121-9), as well as in people diagnosed with cancer (Lancet Psychiatry. 2017 Apr;4[4]:330-8) and other illnesses that may cause emotional trauma – where one feels that one’s life is threatened. In some instances, the person’s life might indeed be in danger, not unlike what can happen in disasters, wars, torture, and even in some encounters with law enforcement.
This leads me to yet another circumstance that in some, may be tied to PTSD – and that is racial, religious, ethnic, and gender-related bigotry. In these cases, individuals feel threatened just for who they are in a society. Being on the receiving end of a circumstance that threatens a person’s very existence would seem to me to place a person as a potential survivor of PTSD, as well as any number of disorders, including anxiety, depression, or even paranoia.
Yes, discrimination and prejudice have been with us for a long time, and what concerns me is the psychological effect it has on children as well as adults. Friends of Irish descent remind me of hearing stories from parents and grandparents about employment signs reading, “Irish need not apply.” Certainly, those of Italian ancestry will easily recall the prejudice focused against them. And members of the Jewish community also can easily remember the bigotry and exclusion they have been subject to in certain neighborhoods and organizations, in addition to the horrors of the Holocaust during World War II, and the anti-Semitic chants in Charlottesville, Va., from just 3 years ago – with gun-carrying militants doing the chanting.
Obviously, in certain circles, we still have private clubs, plus neighborhoods and residential buildings that exclude people for a variety of reasons.
Coming from a medical family, years ago I heard stories that, if you were Roman Catholic, it would be hard to get into certain medical schools – which might explain the establishment of Catholic medical schools that often were open to people of other faiths. Then we had medical school discrimination toward Jewish students, which was followed by the establishment of medical schools focused on admitting more Jewish students. The African American community also responded to discrimination by establishing medical schools, such as the school at Howard University in Washington.
Furthermore, we cannot forget the discrimination that women faced in institutions of higher learning. My father had two women in his medical school class, I was told. In my era, I would say at least 30% were women, and today, in the United States, medical school classes are more equally balanced with men and women. Some schools have more women than men.
The question I ask, is: How did all those women feel for so many years knowing that, for reasons beyond their control, they were prevented from achieving their chosen goals? Some might have felt badly, and others might have internalized the rejection. Others might have developed PTSD based on feelings of rejection.
However, the question here mainly is: Can PTSD result when exclusion and prejudice induce fear and terror in those on the receiving end – especially innocent children? Children separated from their parents at the U.S.-Mexico border and those who witness their parents being shot immediately come to mind. This trauma can last well beyond childhood.
and make us realize the extent to which the African American community has been traumatized. Perhaps we should not be surprised by a study that found that the prevalence of PTSD among African Americans is 9.1%, compared with 6.8% for Whites (J Anxiety Dis. 2009 Jun;23[5]:573-90). Speaking with Black colleagues, friends, and patients, reading books such “The Warmth of Other Suns,” and watching films such as “Green Book,” give us a sense of how dangerous it was for Black families to travel in certain parts of the country in the recent past. I recall as a child hearing that, in Miami Beach, people of color could not stay overnight. (Even as a child I was surprised – having never heard anything like that. After all, I went to school with people of many religions and backgrounds. My parents thought those practices were terrible, and were appalled when they learned that some hotels were closed to Jews and others closed to Catholics.)
DSM-5, ICD-10 fall short
The DSM-5 describes trauma using a more or less one-dimensional set of guidelines as the focus. Those guidelines include exposure to direct violence, manmade or natural disasters, war, or torture, as well as exposure to a disaster or a life-threatening situation affecting a loved one. The ICD-10 is less restrictive about trauma but still has some limitations.
While considering potential PTSD, I try to use a less rigid diagnostic multidimensional approach, where I assess individual differences and experiences that play a role in those experiences as well as the patient’s vulnerability to the causation of PTSD – which also has to include any exposure to trauma (Curr Opin Psychol. 2017 Apr;14:29-34) before age 11 or 12. The data suggest that such early exposure leaves people more vulnerable to PTSD as adults (Soc Sci Med. 2018 Feb;199:230-40).
In my view, if individuals are frightened because of who they are – be it tied to their religion, race, sexual identity, or ethnicity – and what harm may come to them, and if they live in fear and avoidance of these potential traumatic situations that affect their mental stability and the way they live their lives, they might fit the PTSD model.
If we clinicians focus on what’s currently being brought vividly into the public eye today regarding the African American community, we would see that some of the ongoing fears of racism – whether tied to residential or workplace discrimination, unfair treatment by figures of authority, harassment, health inequities, or microaggressions – may give rise to PTSD. I know we can do better. We should broaden our definition and awareness of this very serious disorder – and be prepared to treat it.
Dr. London has been a practicing psychiatrist for 4 decades and a newspaper columnist for almost as long. He has a private practice in New York and is author of “Find Freedom Fast: Short-Term Therapy That Works” (New York: Kettlehole Publishing, 2019). Dr. London has no conflicts of interest.
GERD: Endoscopic therapies may offer alternative to PPIs
For patients with gastroesophageal reflux disease (GERD), endoscopic and minimally invasive surgical techniques may be viable alternatives to proton pump inhibitor (PPI) therapy, according to investigators.
Still, their exact role in the treatment process remains undetermined, reported Michael F. Vaezi, MD, PhD, of Vanderbilt University Medical Center in Nashville, Tenn., and colleagues.
“The frequent incomplete response to PPI therapy, in addition to recent studies suggesting chronic complications with PPI therapy, have fueled discussion of alternative strategies for treating patients with GERD,” the investigators wrote in Gastroenterology. “For a substantial number of patients and providers with the above concerns who are unwilling to pursue the traditional surgical gastric fundoplication, endoscopic or less invasive surgical strategies have gained some traction.”
Dr. Vaezi and colleagues noted that they conducted the scoping review with intentions of being more descriptive than prescriptive.
“Our goal is not to recommend the utility of any of the discussed techniques in specific clinical scenarios,” they wrote. “Rather, it is to summarize the currently available evidence and identify where more research may be helpful.”
Across 22 randomized, controlled trials and observational studies, objective and symptomatic improvement varied between modalities. Measured outcomes also varied; most studies reported symptoms, health-related quality of life, and PPI use; fewer studies (but still a majority) reported intraesophageal acid exposure and/or lower esophageal sphincter (LES) pressure. Conclusions drawn by Dr. Vaezi and colleagues are summarized below.
Magnetic sphincter augmentation of the LES
In multiple trials, magnetic sphincter augmentation demonstrated a “high degree of efficacy” in the short or midterm, and a favorable safety profile. Dr. Vaezi and colleagues highlighted significant improvements in disease-related quality of life, with “a substantial proportion” of patients achieving normalization or at least 50% improvement in acid exposure. While some patients required esophageal dilation after the procedure, this was not needed any more frequently than after surgical fundoplication.
Radiofrequency ablation
Across five trials, radiofrequency ablation, which involves delivery of energy to the LES and gastric cardia, improved GERD-related quality of life, and reduced, but did not normalize, acid exposure. The technique lessened short-term need for PPIs, but long-term relief was not observed. Compared with observational studies, efficacy signals were weaker in randomized, controlled trials. The procedure was generally safe.
Surgical implantation of LES pacemaker
Limited data were available for LES sphincter stimulation among patients with GERD, and the most recent study, involving a comparison of device placement with or without stimulation, was terminated early. Still, available data suggest that the technique is generally well tolerated, with reduced need for PPIs, improved symptoms, and lessened acid exposure. Dr. Vaezi and colleagues noted that the manufacturing company, EndoStim, is in receivership, putting U.S. availability in question.
Full-thickness fundoplication
Endoscopic full-thickness fundoplication was associated with improvement of symptoms and quality of life, and a favorable safety profile. Although the procedure generally reduced PPI use, most patients still needed PPIs long-term. Reflux improved after the procedure, but not to the same degree as laparoscopic plication.
Transoral incisionless fundoplication
Based on a number of studies, including five randomized, controlled trials, transoral incisionless fundoplication appears safe and effective, with reduced need for PPIs up to 5 years. According to Dr. Vaezi and colleagues, variable results across studies are likely explained by variations in the technique over time and heterogeneous patient populations. Recent studies in which the “TIF 2.0 technique” has been performed on patients with hiatal hernias less than 2 cm have met objective efficacy outcomes.
Incisionless fundoplication with magnetic ultrasonic surgical endostapler
The magnetic ultrasonic surgical endostapler, which allows for incisionless fundoplication, had more limited data. Only two studies have been conducted, and neither had sham-controlled nor comparative-trial data. Furthermore, multiple safety signals have been encountered, with “substantial” complication rates and serious adverse events that were “noticeable and concerning,” according to Dr. Vaezi and colleagues.
Concluding their discussion, the investigators suggested that some endoscopic and minimally invasive approaches to GERD are “promising” alternatives to PPI therapy.
“However, their place in the treatment algorithm for GERD will be better defined when important clinical parameters, especially the durability of their effect, are understood,” they wrote.
The investigators reported no conflicts of interest.
SOURCE: Vaezi MF et al. Gastroenterology. 2020 Jul 1. doi: 10.1053/j.gastro.2020.05.097.
For patients with gastroesophageal reflux disease (GERD), endoscopic and minimally invasive surgical techniques may be viable alternatives to proton pump inhibitor (PPI) therapy, according to investigators.
Still, their exact role in the treatment process remains undetermined, reported Michael F. Vaezi, MD, PhD, of Vanderbilt University Medical Center in Nashville, Tenn., and colleagues.
“The frequent incomplete response to PPI therapy, in addition to recent studies suggesting chronic complications with PPI therapy, have fueled discussion of alternative strategies for treating patients with GERD,” the investigators wrote in Gastroenterology. “For a substantial number of patients and providers with the above concerns who are unwilling to pursue the traditional surgical gastric fundoplication, endoscopic or less invasive surgical strategies have gained some traction.”
Dr. Vaezi and colleagues noted that they conducted the scoping review with intentions of being more descriptive than prescriptive.
“Our goal is not to recommend the utility of any of the discussed techniques in specific clinical scenarios,” they wrote. “Rather, it is to summarize the currently available evidence and identify where more research may be helpful.”
Across 22 randomized, controlled trials and observational studies, objective and symptomatic improvement varied between modalities. Measured outcomes also varied; most studies reported symptoms, health-related quality of life, and PPI use; fewer studies (but still a majority) reported intraesophageal acid exposure and/or lower esophageal sphincter (LES) pressure. Conclusions drawn by Dr. Vaezi and colleagues are summarized below.
Magnetic sphincter augmentation of the LES
In multiple trials, magnetic sphincter augmentation demonstrated a “high degree of efficacy” in the short or midterm, and a favorable safety profile. Dr. Vaezi and colleagues highlighted significant improvements in disease-related quality of life, with “a substantial proportion” of patients achieving normalization or at least 50% improvement in acid exposure. While some patients required esophageal dilation after the procedure, this was not needed any more frequently than after surgical fundoplication.
Radiofrequency ablation
Across five trials, radiofrequency ablation, which involves delivery of energy to the LES and gastric cardia, improved GERD-related quality of life, and reduced, but did not normalize, acid exposure. The technique lessened short-term need for PPIs, but long-term relief was not observed. Compared with observational studies, efficacy signals were weaker in randomized, controlled trials. The procedure was generally safe.
Surgical implantation of LES pacemaker
Limited data were available for LES sphincter stimulation among patients with GERD, and the most recent study, involving a comparison of device placement with or without stimulation, was terminated early. Still, available data suggest that the technique is generally well tolerated, with reduced need for PPIs, improved symptoms, and lessened acid exposure. Dr. Vaezi and colleagues noted that the manufacturing company, EndoStim, is in receivership, putting U.S. availability in question.
Full-thickness fundoplication
Endoscopic full-thickness fundoplication was associated with improvement of symptoms and quality of life, and a favorable safety profile. Although the procedure generally reduced PPI use, most patients still needed PPIs long-term. Reflux improved after the procedure, but not to the same degree as laparoscopic plication.
Transoral incisionless fundoplication
Based on a number of studies, including five randomized, controlled trials, transoral incisionless fundoplication appears safe and effective, with reduced need for PPIs up to 5 years. According to Dr. Vaezi and colleagues, variable results across studies are likely explained by variations in the technique over time and heterogeneous patient populations. Recent studies in which the “TIF 2.0 technique” has been performed on patients with hiatal hernias less than 2 cm have met objective efficacy outcomes.
Incisionless fundoplication with magnetic ultrasonic surgical endostapler
The magnetic ultrasonic surgical endostapler, which allows for incisionless fundoplication, had more limited data. Only two studies have been conducted, and neither had sham-controlled nor comparative-trial data. Furthermore, multiple safety signals have been encountered, with “substantial” complication rates and serious adverse events that were “noticeable and concerning,” according to Dr. Vaezi and colleagues.
Concluding their discussion, the investigators suggested that some endoscopic and minimally invasive approaches to GERD are “promising” alternatives to PPI therapy.
“However, their place in the treatment algorithm for GERD will be better defined when important clinical parameters, especially the durability of their effect, are understood,” they wrote.
The investigators reported no conflicts of interest.
SOURCE: Vaezi MF et al. Gastroenterology. 2020 Jul 1. doi: 10.1053/j.gastro.2020.05.097.
For patients with gastroesophageal reflux disease (GERD), endoscopic and minimally invasive surgical techniques may be viable alternatives to proton pump inhibitor (PPI) therapy, according to investigators.
Still, their exact role in the treatment process remains undetermined, reported Michael F. Vaezi, MD, PhD, of Vanderbilt University Medical Center in Nashville, Tenn., and colleagues.
“The frequent incomplete response to PPI therapy, in addition to recent studies suggesting chronic complications with PPI therapy, have fueled discussion of alternative strategies for treating patients with GERD,” the investigators wrote in Gastroenterology. “For a substantial number of patients and providers with the above concerns who are unwilling to pursue the traditional surgical gastric fundoplication, endoscopic or less invasive surgical strategies have gained some traction.”
Dr. Vaezi and colleagues noted that they conducted the scoping review with intentions of being more descriptive than prescriptive.
“Our goal is not to recommend the utility of any of the discussed techniques in specific clinical scenarios,” they wrote. “Rather, it is to summarize the currently available evidence and identify where more research may be helpful.”
Across 22 randomized, controlled trials and observational studies, objective and symptomatic improvement varied between modalities. Measured outcomes also varied; most studies reported symptoms, health-related quality of life, and PPI use; fewer studies (but still a majority) reported intraesophageal acid exposure and/or lower esophageal sphincter (LES) pressure. Conclusions drawn by Dr. Vaezi and colleagues are summarized below.
Magnetic sphincter augmentation of the LES
In multiple trials, magnetic sphincter augmentation demonstrated a “high degree of efficacy” in the short or midterm, and a favorable safety profile. Dr. Vaezi and colleagues highlighted significant improvements in disease-related quality of life, with “a substantial proportion” of patients achieving normalization or at least 50% improvement in acid exposure. While some patients required esophageal dilation after the procedure, this was not needed any more frequently than after surgical fundoplication.
Radiofrequency ablation
Across five trials, radiofrequency ablation, which involves delivery of energy to the LES and gastric cardia, improved GERD-related quality of life, and reduced, but did not normalize, acid exposure. The technique lessened short-term need for PPIs, but long-term relief was not observed. Compared with observational studies, efficacy signals were weaker in randomized, controlled trials. The procedure was generally safe.
Surgical implantation of LES pacemaker
Limited data were available for LES sphincter stimulation among patients with GERD, and the most recent study, involving a comparison of device placement with or without stimulation, was terminated early. Still, available data suggest that the technique is generally well tolerated, with reduced need for PPIs, improved symptoms, and lessened acid exposure. Dr. Vaezi and colleagues noted that the manufacturing company, EndoStim, is in receivership, putting U.S. availability in question.
Full-thickness fundoplication
Endoscopic full-thickness fundoplication was associated with improvement of symptoms and quality of life, and a favorable safety profile. Although the procedure generally reduced PPI use, most patients still needed PPIs long-term. Reflux improved after the procedure, but not to the same degree as laparoscopic plication.
Transoral incisionless fundoplication
Based on a number of studies, including five randomized, controlled trials, transoral incisionless fundoplication appears safe and effective, with reduced need for PPIs up to 5 years. According to Dr. Vaezi and colleagues, variable results across studies are likely explained by variations in the technique over time and heterogeneous patient populations. Recent studies in which the “TIF 2.0 technique” has been performed on patients with hiatal hernias less than 2 cm have met objective efficacy outcomes.
Incisionless fundoplication with magnetic ultrasonic surgical endostapler
The magnetic ultrasonic surgical endostapler, which allows for incisionless fundoplication, had more limited data. Only two studies have been conducted, and neither had sham-controlled nor comparative-trial data. Furthermore, multiple safety signals have been encountered, with “substantial” complication rates and serious adverse events that were “noticeable and concerning,” according to Dr. Vaezi and colleagues.
Concluding their discussion, the investigators suggested that some endoscopic and minimally invasive approaches to GERD are “promising” alternatives to PPI therapy.
“However, their place in the treatment algorithm for GERD will be better defined when important clinical parameters, especially the durability of their effect, are understood,” they wrote.
The investigators reported no conflicts of interest.
SOURCE: Vaezi MF et al. Gastroenterology. 2020 Jul 1. doi: 10.1053/j.gastro.2020.05.097.
FROM GASTROENTEROLOGY
In a time of two pandemics, a recommitment to work together
Overwhelmed. As if we weren’t already overwhelmed. For decades, hospitalists have been on the forefront of improving acute care amidst a rapidly changing environment. These last few decades have seen tremendous advances in medicine, technology, safety culture, innovations in payment models, transformation in business models, and a rising tide of health care policy. There was never a year we didn’t face major change … and adapt to it. Then 2020 came upon us.
This year, we adapt to more than a score and 4 years’ worth of change.
The two pandemics that have come upon us are like tsunamis. And many of us are drowning. We know of threats of pandemics: influenza, Ebola, and the like. But SARS-CoV-2 is new and like no other. We live in fear and isolation, each and every day learning new information and debunking others. We also know of racial injustice and racism, implicit or explicit in our nation, whether we live it or just read of it. George Floyd’s death in my hometown marked another tsunami, a great realization in our nation, and a great unmasking of our denial.
Yet our country is not united.
Hospital medicine is not immune to this disunity. At a time that we are all treading water, staying afloat in our own hospitals and communities, confronting these issues beyond our immediate spheres of influence is overwhelming. We are impacted by these pandemics, personally and professionally. And admittedly, we can be both victim and perpetrator.
In the face of a novel infectious agent, medicine responded quickly and pushed us beyond our limits. We have developed new infection prevention guidelines. We worked creatively to solve PPE shortages. We fashioned new work flows and new care models. We accelerated telehealth applications. We expanded the boundaries on home-based programs and reached out to vulnerable elderly in congregate living – an isolation no older person should have to endure. We cared for our colleagues, neighbors, and family members who fell ill, some who recovered, and sadly, some who fell. We developed best-practice guidelines, research protocols, created new order sets, note templates, and documentation standards. We flexed into EDs, ICUs, and field hospitals. Amidst the turmoil, we took pay cuts and saw colleagues go on furlough. And still, we mentored leaders in our schools, churches, synagogues, mosques, and civic communities.
And just when we thought we could endure no more, on May 25, we witnessed a black man in Minneapolis killed by a policeman’s knee. The same knee that divided Americans when black American athletes knelt to protest the injustice their people have endured for centuries. A knee that has been confused for insolence, when it was meant for justice ... yes, justice, for all. So, in early June, around the nation in support of black lives we also knelt, for almost 9 minutes.
This was the third time I cried during the pandemics.
For many of us, structural racism in America had finally been unmasked. The nation protested and rioted for weeks, and some communities have continued. Indeed, these two pandemics are still surging.
Side by side COVID-19 case conferences we lay transparent data demonstrating health disparities that we have tolerated for so long. We have vowed to resource equity work, and we opened dialogue, not only with patients and communities of color, but also with colleagues of color – some ready and some not yet ready to share and relive the traumas of their past and their present.
And still, we are not united.
While we physically mask to prevent the spread of COVID-19, we must make efforts to unmask the truths of SARS-CoV-2, the failings of our health system, the richness of our communities of color, and the injustice in the fabric of our society. More importantly, we must work together to create solutions. While we have diverse interests and priorities, at SHM, we can find common ground with kindred spirits, enhance the role of our specialty, and advance the health of our patients.
Let’s not be mistaken. These pandemics add to a growing list of interwoven issues in our society. In 2018, I wrote a piece on the role of hospitalists in addressing rural health disparities.1 According to the Sheps Center for Health Services Research, 129 rural hospitals have closed since 2010, closures that have accelerated with the COVID-19 pandemic.2 More than ever, we must stand above our inner and outer conflicts and be united to promote the health of our nation during these pandemics, because “all policy is health policy.”3
Most SHM presidents and president-elects come in with a platform, a priority for the specialty and for the society. This year, the platform has chosen us. For 20 years, I have witnessed SHM be a workshop for our members to address the pressing needs of our specialty and our patients. In 2020, we’ve continued to see SHM as a workshop for our members and a tour de force addressing these pandemics, from just in time publications of research and perspectives in the Journal of Hospital Medicine, to webinars and open access education in the Learning Portal, to advocacy on Capitol Hill. All of that work has been informed by you and for you. While there is still so much to do, we need not be overwhelmed when we do it together.
A score and 4 years ago, Robert Wachter, MD, and Lee Goldman, MD, dubbed us “hospitalists.” A year later, our shared workshop was born. Through one name change and now our first CEO transition from Larry Wellikson, MD, to Eric Howell, MD, SHM will continue to be where hospitalists both adapt and shape our nation through solutions that put an end to these pandemics. Let’s recommit to this work together.
Dr. Siy is division medical director, hospital specialties, in the departments of hospital medicine and community senior and palliative care, at HealthPartners in Bloomington, Minn. He is president-elect of SHM.
Sources
1. Hardeman RR et al. Stolen Breaths. N Engl J Med. 2020 Jul 16;383:197-9.
2. Siy JC. Reviving Rural Health Care. The Hospitalist. 2018 Sep 24.
3. The Cecil G. Sheps Center For Health Services Research. Rural Hospital Closures. 2014. https://www.shepscenter.unc.edu/programs-projects/rural-health/rural-hospital-closures/
Overwhelmed. As if we weren’t already overwhelmed. For decades, hospitalists have been on the forefront of improving acute care amidst a rapidly changing environment. These last few decades have seen tremendous advances in medicine, technology, safety culture, innovations in payment models, transformation in business models, and a rising tide of health care policy. There was never a year we didn’t face major change … and adapt to it. Then 2020 came upon us.
This year, we adapt to more than a score and 4 years’ worth of change.
The two pandemics that have come upon us are like tsunamis. And many of us are drowning. We know of threats of pandemics: influenza, Ebola, and the like. But SARS-CoV-2 is new and like no other. We live in fear and isolation, each and every day learning new information and debunking others. We also know of racial injustice and racism, implicit or explicit in our nation, whether we live it or just read of it. George Floyd’s death in my hometown marked another tsunami, a great realization in our nation, and a great unmasking of our denial.
Yet our country is not united.
Hospital medicine is not immune to this disunity. At a time that we are all treading water, staying afloat in our own hospitals and communities, confronting these issues beyond our immediate spheres of influence is overwhelming. We are impacted by these pandemics, personally and professionally. And admittedly, we can be both victim and perpetrator.
In the face of a novel infectious agent, medicine responded quickly and pushed us beyond our limits. We have developed new infection prevention guidelines. We worked creatively to solve PPE shortages. We fashioned new work flows and new care models. We accelerated telehealth applications. We expanded the boundaries on home-based programs and reached out to vulnerable elderly in congregate living – an isolation no older person should have to endure. We cared for our colleagues, neighbors, and family members who fell ill, some who recovered, and sadly, some who fell. We developed best-practice guidelines, research protocols, created new order sets, note templates, and documentation standards. We flexed into EDs, ICUs, and field hospitals. Amidst the turmoil, we took pay cuts and saw colleagues go on furlough. And still, we mentored leaders in our schools, churches, synagogues, mosques, and civic communities.
And just when we thought we could endure no more, on May 25, we witnessed a black man in Minneapolis killed by a policeman’s knee. The same knee that divided Americans when black American athletes knelt to protest the injustice their people have endured for centuries. A knee that has been confused for insolence, when it was meant for justice ... yes, justice, for all. So, in early June, around the nation in support of black lives we also knelt, for almost 9 minutes.
This was the third time I cried during the pandemics.
For many of us, structural racism in America had finally been unmasked. The nation protested and rioted for weeks, and some communities have continued. Indeed, these two pandemics are still surging.
Side by side COVID-19 case conferences we lay transparent data demonstrating health disparities that we have tolerated for so long. We have vowed to resource equity work, and we opened dialogue, not only with patients and communities of color, but also with colleagues of color – some ready and some not yet ready to share and relive the traumas of their past and their present.
And still, we are not united.
While we physically mask to prevent the spread of COVID-19, we must make efforts to unmask the truths of SARS-CoV-2, the failings of our health system, the richness of our communities of color, and the injustice in the fabric of our society. More importantly, we must work together to create solutions. While we have diverse interests and priorities, at SHM, we can find common ground with kindred spirits, enhance the role of our specialty, and advance the health of our patients.
Let’s not be mistaken. These pandemics add to a growing list of interwoven issues in our society. In 2018, I wrote a piece on the role of hospitalists in addressing rural health disparities.1 According to the Sheps Center for Health Services Research, 129 rural hospitals have closed since 2010, closures that have accelerated with the COVID-19 pandemic.2 More than ever, we must stand above our inner and outer conflicts and be united to promote the health of our nation during these pandemics, because “all policy is health policy.”3
Most SHM presidents and president-elects come in with a platform, a priority for the specialty and for the society. This year, the platform has chosen us. For 20 years, I have witnessed SHM be a workshop for our members to address the pressing needs of our specialty and our patients. In 2020, we’ve continued to see SHM as a workshop for our members and a tour de force addressing these pandemics, from just in time publications of research and perspectives in the Journal of Hospital Medicine, to webinars and open access education in the Learning Portal, to advocacy on Capitol Hill. All of that work has been informed by you and for you. While there is still so much to do, we need not be overwhelmed when we do it together.
A score and 4 years ago, Robert Wachter, MD, and Lee Goldman, MD, dubbed us “hospitalists.” A year later, our shared workshop was born. Through one name change and now our first CEO transition from Larry Wellikson, MD, to Eric Howell, MD, SHM will continue to be where hospitalists both adapt and shape our nation through solutions that put an end to these pandemics. Let’s recommit to this work together.
Dr. Siy is division medical director, hospital specialties, in the departments of hospital medicine and community senior and palliative care, at HealthPartners in Bloomington, Minn. He is president-elect of SHM.
Sources
1. Hardeman RR et al. Stolen Breaths. N Engl J Med. 2020 Jul 16;383:197-9.
2. Siy JC. Reviving Rural Health Care. The Hospitalist. 2018 Sep 24.
3. The Cecil G. Sheps Center For Health Services Research. Rural Hospital Closures. 2014. https://www.shepscenter.unc.edu/programs-projects/rural-health/rural-hospital-closures/
Overwhelmed. As if we weren’t already overwhelmed. For decades, hospitalists have been on the forefront of improving acute care amidst a rapidly changing environment. These last few decades have seen tremendous advances in medicine, technology, safety culture, innovations in payment models, transformation in business models, and a rising tide of health care policy. There was never a year we didn’t face major change … and adapt to it. Then 2020 came upon us.
This year, we adapt to more than a score and 4 years’ worth of change.
The two pandemics that have come upon us are like tsunamis. And many of us are drowning. We know of threats of pandemics: influenza, Ebola, and the like. But SARS-CoV-2 is new and like no other. We live in fear and isolation, each and every day learning new information and debunking others. We also know of racial injustice and racism, implicit or explicit in our nation, whether we live it or just read of it. George Floyd’s death in my hometown marked another tsunami, a great realization in our nation, and a great unmasking of our denial.
Yet our country is not united.
Hospital medicine is not immune to this disunity. At a time that we are all treading water, staying afloat in our own hospitals and communities, confronting these issues beyond our immediate spheres of influence is overwhelming. We are impacted by these pandemics, personally and professionally. And admittedly, we can be both victim and perpetrator.
In the face of a novel infectious agent, medicine responded quickly and pushed us beyond our limits. We have developed new infection prevention guidelines. We worked creatively to solve PPE shortages. We fashioned new work flows and new care models. We accelerated telehealth applications. We expanded the boundaries on home-based programs and reached out to vulnerable elderly in congregate living – an isolation no older person should have to endure. We cared for our colleagues, neighbors, and family members who fell ill, some who recovered, and sadly, some who fell. We developed best-practice guidelines, research protocols, created new order sets, note templates, and documentation standards. We flexed into EDs, ICUs, and field hospitals. Amidst the turmoil, we took pay cuts and saw colleagues go on furlough. And still, we mentored leaders in our schools, churches, synagogues, mosques, and civic communities.
And just when we thought we could endure no more, on May 25, we witnessed a black man in Minneapolis killed by a policeman’s knee. The same knee that divided Americans when black American athletes knelt to protest the injustice their people have endured for centuries. A knee that has been confused for insolence, when it was meant for justice ... yes, justice, for all. So, in early June, around the nation in support of black lives we also knelt, for almost 9 minutes.
This was the third time I cried during the pandemics.
For many of us, structural racism in America had finally been unmasked. The nation protested and rioted for weeks, and some communities have continued. Indeed, these two pandemics are still surging.
Side by side COVID-19 case conferences we lay transparent data demonstrating health disparities that we have tolerated for so long. We have vowed to resource equity work, and we opened dialogue, not only with patients and communities of color, but also with colleagues of color – some ready and some not yet ready to share and relive the traumas of their past and their present.
And still, we are not united.
While we physically mask to prevent the spread of COVID-19, we must make efforts to unmask the truths of SARS-CoV-2, the failings of our health system, the richness of our communities of color, and the injustice in the fabric of our society. More importantly, we must work together to create solutions. While we have diverse interests and priorities, at SHM, we can find common ground with kindred spirits, enhance the role of our specialty, and advance the health of our patients.
Let’s not be mistaken. These pandemics add to a growing list of interwoven issues in our society. In 2018, I wrote a piece on the role of hospitalists in addressing rural health disparities.1 According to the Sheps Center for Health Services Research, 129 rural hospitals have closed since 2010, closures that have accelerated with the COVID-19 pandemic.2 More than ever, we must stand above our inner and outer conflicts and be united to promote the health of our nation during these pandemics, because “all policy is health policy.”3
Most SHM presidents and president-elects come in with a platform, a priority for the specialty and for the society. This year, the platform has chosen us. For 20 years, I have witnessed SHM be a workshop for our members to address the pressing needs of our specialty and our patients. In 2020, we’ve continued to see SHM as a workshop for our members and a tour de force addressing these pandemics, from just in time publications of research and perspectives in the Journal of Hospital Medicine, to webinars and open access education in the Learning Portal, to advocacy on Capitol Hill. All of that work has been informed by you and for you. While there is still so much to do, we need not be overwhelmed when we do it together.
A score and 4 years ago, Robert Wachter, MD, and Lee Goldman, MD, dubbed us “hospitalists.” A year later, our shared workshop was born. Through one name change and now our first CEO transition from Larry Wellikson, MD, to Eric Howell, MD, SHM will continue to be where hospitalists both adapt and shape our nation through solutions that put an end to these pandemics. Let’s recommit to this work together.
Dr. Siy is division medical director, hospital specialties, in the departments of hospital medicine and community senior and palliative care, at HealthPartners in Bloomington, Minn. He is president-elect of SHM.
Sources
1. Hardeman RR et al. Stolen Breaths. N Engl J Med. 2020 Jul 16;383:197-9.
2. Siy JC. Reviving Rural Health Care. The Hospitalist. 2018 Sep 24.
3. The Cecil G. Sheps Center For Health Services Research. Rural Hospital Closures. 2014. https://www.shepscenter.unc.edu/programs-projects/rural-health/rural-hospital-closures/
Worry over family, friends the main driver of COVID-19 stress
Individuals are more worried about family members becoming ill with COVID-19 or about unknowingly transmitting the disease to family members than they are about contracting it themselves, results of a new survey show.
Investigators surveyed over 3,000 adults, using an online questionnaire. Of the respondents, about 20% were health care workers, and most were living in locations with active stay-at-home orders at the time of the survey.
Close to half of participants were worried about family members contracting the virus, one third were worried about unknowingly infecting others, and 20% were worried about contracting the virus themselves.
“We were a little surprised to see that people were more concerned about others than about themselves, specifically worrying about whether a family member would contract COVID-19 and whether they might unintentionally infect others,” lead author Ran Barzilay, MD, PhD, child and adolescent psychiatrist at the Children’s Hospital of Philadelphia (CHOP), told Medscape Medical News.
The study was published online August 20 in Translational Psychiatry.
Interactive platform
“The pandemic has provided a unique opportunity to study resilience in healthcare professionals and others,” said Barzilay, assistant professor at the Lifespan Brain Institute, a collaboration between CHOP and the University of Pennsylvania, under the directorship of Raquel Gur, MD, PhD.
“After the pandemic broke out in March, we launched a website in early April where we surveyed people for levels of resilience, mental health, and well-being during the outbreak,” he added.
Survey participants then shared it with their contacts.
“To date, over 7000 people have completed it – mostly from the US but also from Israel,” Barzilay said.
The survey was anonymous, but participants could choose to have follow-up contact. The survey included an interactive 21-item resilience questionnaire and an assessment of COVID-19-related items related to worries concerning the following: contracting, dying from, or currently having the illness; having a family member contract the illness; unknowingly infecting others; and experiencing significant financial burden.
A total of 1350 participants took a second survey on anxiety and depression that utilized the Generalized Anxiety Disorder–7 and the Patient Health Questionnaire–2.
“What makes the survey unique is that it’s not just a means of collecting data but also an interactive platform that gives participants immediate personalized feedback, based on their responses to the resilience and well-being surveys, with practical tips and recommendations for stress management and ways of boosting resilience,” Barzilay said.
Tend and befriend
Ten days into the survey, data were available on 3,042 participants (64% women, 54% with advanced education, 20.5% health care providers), who ranged in age from 18 to 70 years (mean [SD], 38.9 [11.9] years).
After accounting for covariates, the researchers found that participants reported more distress about family members contracting COVID-19 and about unknowingly infecting others than about getting COVID-19 themselves (48.5% and 36% vs. 19.9%, respectively; P < .0005).
Increased COVID-19-related worries were associated with 22% higher anxiety and 16.1% higher depression scores; women had higher scores than men on both.
Each 1-SD increase in the composite score of COVID-19 worries was associated with over twice the increased probability of generalized anxiety and depression (odds ratio, 2.23; 95% confidence interval, 1.88-2.65; and OR, 1.67; 95% CI, 1.41-1.98, respectively; for both, P < .001).
On the other hand, for every 1-SD increase in the resilience score, there was a 64.9% decrease in the possibility of screening positive for generalized anxiety disorder and a 69.3% decrease in the possibility of screening positive for depression (for both, P < .0001).
Compared to participants from Israel, US participants were “more stressed” about contracting, dying from, and currently having COVID-19 themselves. Overall, Israeli participants scored higher than US participants on the resilience scale.
Rates of anxiety and depression did not differ significantly between healthcare providers and others. Health care providers worried more about contracting COVID-19 themselves and worried less about finances after COVID-19.
The authors propose that survey participants were more worried about others than about themselves because of “prosocial behavior under stress” and “tend-and-befriend,” whereby, “in response to threat, humans tend to protect their close ones (tending) and seek out their social group for mutual defense (befriending).”
This type of altruistic behavior has been “described in acute situations throughout history” and has been “linked to mechanisms of resilience for overcoming adversity,” the authors indicate.
Demographic biases
Commenting on the findings for Medscape Medical News, Golnaz Tabibnia, PhD, a neuroscientist at the University of California, Irvine, who was not involved in the research, suggested that although higher resilience scores were associated with lower COVID-related worries, it is possible, “as the authors suggest, that having more resilience resources makes you less worried, but the causality could go the other direction as well, and less worry/rumination may lead to more resilience.”
Also commenting on the study for Medscape Medical News, Christiaan Vinkers, MD, PhD, a psychiatrist at the Amsterdam University Medical Center, Amsterdam, the Netherlands, said it was noteworthy that healthcare providers reported similar levels of mood and anxiety symptoms, compared to others.
“This is encouraging, as it suggests adequate resilience levels in professionals who work in the front lines of the COVID-19 pandemic,” he said.
Resilience occurs not only at the individual level but also at the community level, which may help explain the striking differences in COVID-19-related worries and anxiety between participants from the United States and Israel, Vinkers added.
E. Alison Holman, PhD, professor, Sue and Bill Gross School of Nursing, University of California, Irvine, noted that respondents were predominantly white, female, and had relatively high incomes, “suggesting strong demographic biases in those who chose to participate.”
Holman, who was not involved with the study, told Medscape Medical News that the “findings do not address the real impact of COVID-19 on the hardest-hit communities in America – poor, Black, and Latinx communities, where a large proportion of essential workers live.”
Barzilay acknowledged that, “unfortunately, because of the way the study was circulated, it did not reach minorities, which is one of the things we want to improve.”
The study is ongoing and has been translated into Spanish, French, and Hebrew. The team plans to collect data on diverse populations.
The study was supported by grants from the National Institute of Mental Health, the Lifespan Brain Institute of Children’s Hospital of Philadelphia, Penn Medicine, the University of Pennsylvania, and in part by the Zuckerman STEM Leadership Program. Barzilay serves on the scientific board and reports stock ownership in Taliaz Health. The other authors, Golnaz, Vinkers, and Holman have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Individuals are more worried about family members becoming ill with COVID-19 or about unknowingly transmitting the disease to family members than they are about contracting it themselves, results of a new survey show.
Investigators surveyed over 3,000 adults, using an online questionnaire. Of the respondents, about 20% were health care workers, and most were living in locations with active stay-at-home orders at the time of the survey.
Close to half of participants were worried about family members contracting the virus, one third were worried about unknowingly infecting others, and 20% were worried about contracting the virus themselves.
“We were a little surprised to see that people were more concerned about others than about themselves, specifically worrying about whether a family member would contract COVID-19 and whether they might unintentionally infect others,” lead author Ran Barzilay, MD, PhD, child and adolescent psychiatrist at the Children’s Hospital of Philadelphia (CHOP), told Medscape Medical News.
The study was published online August 20 in Translational Psychiatry.
Interactive platform
“The pandemic has provided a unique opportunity to study resilience in healthcare professionals and others,” said Barzilay, assistant professor at the Lifespan Brain Institute, a collaboration between CHOP and the University of Pennsylvania, under the directorship of Raquel Gur, MD, PhD.
“After the pandemic broke out in March, we launched a website in early April where we surveyed people for levels of resilience, mental health, and well-being during the outbreak,” he added.
Survey participants then shared it with their contacts.
“To date, over 7000 people have completed it – mostly from the US but also from Israel,” Barzilay said.
The survey was anonymous, but participants could choose to have follow-up contact. The survey included an interactive 21-item resilience questionnaire and an assessment of COVID-19-related items related to worries concerning the following: contracting, dying from, or currently having the illness; having a family member contract the illness; unknowingly infecting others; and experiencing significant financial burden.
A total of 1350 participants took a second survey on anxiety and depression that utilized the Generalized Anxiety Disorder–7 and the Patient Health Questionnaire–2.
“What makes the survey unique is that it’s not just a means of collecting data but also an interactive platform that gives participants immediate personalized feedback, based on their responses to the resilience and well-being surveys, with practical tips and recommendations for stress management and ways of boosting resilience,” Barzilay said.
Tend and befriend
Ten days into the survey, data were available on 3,042 participants (64% women, 54% with advanced education, 20.5% health care providers), who ranged in age from 18 to 70 years (mean [SD], 38.9 [11.9] years).
After accounting for covariates, the researchers found that participants reported more distress about family members contracting COVID-19 and about unknowingly infecting others than about getting COVID-19 themselves (48.5% and 36% vs. 19.9%, respectively; P < .0005).
Increased COVID-19-related worries were associated with 22% higher anxiety and 16.1% higher depression scores; women had higher scores than men on both.
Each 1-SD increase in the composite score of COVID-19 worries was associated with over twice the increased probability of generalized anxiety and depression (odds ratio, 2.23; 95% confidence interval, 1.88-2.65; and OR, 1.67; 95% CI, 1.41-1.98, respectively; for both, P < .001).
On the other hand, for every 1-SD increase in the resilience score, there was a 64.9% decrease in the possibility of screening positive for generalized anxiety disorder and a 69.3% decrease in the possibility of screening positive for depression (for both, P < .0001).
Compared to participants from Israel, US participants were “more stressed” about contracting, dying from, and currently having COVID-19 themselves. Overall, Israeli participants scored higher than US participants on the resilience scale.
Rates of anxiety and depression did not differ significantly between healthcare providers and others. Health care providers worried more about contracting COVID-19 themselves and worried less about finances after COVID-19.
The authors propose that survey participants were more worried about others than about themselves because of “prosocial behavior under stress” and “tend-and-befriend,” whereby, “in response to threat, humans tend to protect their close ones (tending) and seek out their social group for mutual defense (befriending).”
This type of altruistic behavior has been “described in acute situations throughout history” and has been “linked to mechanisms of resilience for overcoming adversity,” the authors indicate.
Demographic biases
Commenting on the findings for Medscape Medical News, Golnaz Tabibnia, PhD, a neuroscientist at the University of California, Irvine, who was not involved in the research, suggested that although higher resilience scores were associated with lower COVID-related worries, it is possible, “as the authors suggest, that having more resilience resources makes you less worried, but the causality could go the other direction as well, and less worry/rumination may lead to more resilience.”
Also commenting on the study for Medscape Medical News, Christiaan Vinkers, MD, PhD, a psychiatrist at the Amsterdam University Medical Center, Amsterdam, the Netherlands, said it was noteworthy that healthcare providers reported similar levels of mood and anxiety symptoms, compared to others.
“This is encouraging, as it suggests adequate resilience levels in professionals who work in the front lines of the COVID-19 pandemic,” he said.
Resilience occurs not only at the individual level but also at the community level, which may help explain the striking differences in COVID-19-related worries and anxiety between participants from the United States and Israel, Vinkers added.
E. Alison Holman, PhD, professor, Sue and Bill Gross School of Nursing, University of California, Irvine, noted that respondents were predominantly white, female, and had relatively high incomes, “suggesting strong demographic biases in those who chose to participate.”
Holman, who was not involved with the study, told Medscape Medical News that the “findings do not address the real impact of COVID-19 on the hardest-hit communities in America – poor, Black, and Latinx communities, where a large proportion of essential workers live.”
Barzilay acknowledged that, “unfortunately, because of the way the study was circulated, it did not reach minorities, which is one of the things we want to improve.”
The study is ongoing and has been translated into Spanish, French, and Hebrew. The team plans to collect data on diverse populations.
The study was supported by grants from the National Institute of Mental Health, the Lifespan Brain Institute of Children’s Hospital of Philadelphia, Penn Medicine, the University of Pennsylvania, and in part by the Zuckerman STEM Leadership Program. Barzilay serves on the scientific board and reports stock ownership in Taliaz Health. The other authors, Golnaz, Vinkers, and Holman have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Individuals are more worried about family members becoming ill with COVID-19 or about unknowingly transmitting the disease to family members than they are about contracting it themselves, results of a new survey show.
Investigators surveyed over 3,000 adults, using an online questionnaire. Of the respondents, about 20% were health care workers, and most were living in locations with active stay-at-home orders at the time of the survey.
Close to half of participants were worried about family members contracting the virus, one third were worried about unknowingly infecting others, and 20% were worried about contracting the virus themselves.
“We were a little surprised to see that people were more concerned about others than about themselves, specifically worrying about whether a family member would contract COVID-19 and whether they might unintentionally infect others,” lead author Ran Barzilay, MD, PhD, child and adolescent psychiatrist at the Children’s Hospital of Philadelphia (CHOP), told Medscape Medical News.
The study was published online August 20 in Translational Psychiatry.
Interactive platform
“The pandemic has provided a unique opportunity to study resilience in healthcare professionals and others,” said Barzilay, assistant professor at the Lifespan Brain Institute, a collaboration between CHOP and the University of Pennsylvania, under the directorship of Raquel Gur, MD, PhD.
“After the pandemic broke out in March, we launched a website in early April where we surveyed people for levels of resilience, mental health, and well-being during the outbreak,” he added.
Survey participants then shared it with their contacts.
“To date, over 7000 people have completed it – mostly from the US but also from Israel,” Barzilay said.
The survey was anonymous, but participants could choose to have follow-up contact. The survey included an interactive 21-item resilience questionnaire and an assessment of COVID-19-related items related to worries concerning the following: contracting, dying from, or currently having the illness; having a family member contract the illness; unknowingly infecting others; and experiencing significant financial burden.
A total of 1350 participants took a second survey on anxiety and depression that utilized the Generalized Anxiety Disorder–7 and the Patient Health Questionnaire–2.
“What makes the survey unique is that it’s not just a means of collecting data but also an interactive platform that gives participants immediate personalized feedback, based on their responses to the resilience and well-being surveys, with practical tips and recommendations for stress management and ways of boosting resilience,” Barzilay said.
Tend and befriend
Ten days into the survey, data were available on 3,042 participants (64% women, 54% with advanced education, 20.5% health care providers), who ranged in age from 18 to 70 years (mean [SD], 38.9 [11.9] years).
After accounting for covariates, the researchers found that participants reported more distress about family members contracting COVID-19 and about unknowingly infecting others than about getting COVID-19 themselves (48.5% and 36% vs. 19.9%, respectively; P < .0005).
Increased COVID-19-related worries were associated with 22% higher anxiety and 16.1% higher depression scores; women had higher scores than men on both.
Each 1-SD increase in the composite score of COVID-19 worries was associated with over twice the increased probability of generalized anxiety and depression (odds ratio, 2.23; 95% confidence interval, 1.88-2.65; and OR, 1.67; 95% CI, 1.41-1.98, respectively; for both, P < .001).
On the other hand, for every 1-SD increase in the resilience score, there was a 64.9% decrease in the possibility of screening positive for generalized anxiety disorder and a 69.3% decrease in the possibility of screening positive for depression (for both, P < .0001).
Compared to participants from Israel, US participants were “more stressed” about contracting, dying from, and currently having COVID-19 themselves. Overall, Israeli participants scored higher than US participants on the resilience scale.
Rates of anxiety and depression did not differ significantly between healthcare providers and others. Health care providers worried more about contracting COVID-19 themselves and worried less about finances after COVID-19.
The authors propose that survey participants were more worried about others than about themselves because of “prosocial behavior under stress” and “tend-and-befriend,” whereby, “in response to threat, humans tend to protect their close ones (tending) and seek out their social group for mutual defense (befriending).”
This type of altruistic behavior has been “described in acute situations throughout history” and has been “linked to mechanisms of resilience for overcoming adversity,” the authors indicate.
Demographic biases
Commenting on the findings for Medscape Medical News, Golnaz Tabibnia, PhD, a neuroscientist at the University of California, Irvine, who was not involved in the research, suggested that although higher resilience scores were associated with lower COVID-related worries, it is possible, “as the authors suggest, that having more resilience resources makes you less worried, but the causality could go the other direction as well, and less worry/rumination may lead to more resilience.”
Also commenting on the study for Medscape Medical News, Christiaan Vinkers, MD, PhD, a psychiatrist at the Amsterdam University Medical Center, Amsterdam, the Netherlands, said it was noteworthy that healthcare providers reported similar levels of mood and anxiety symptoms, compared to others.
“This is encouraging, as it suggests adequate resilience levels in professionals who work in the front lines of the COVID-19 pandemic,” he said.
Resilience occurs not only at the individual level but also at the community level, which may help explain the striking differences in COVID-19-related worries and anxiety between participants from the United States and Israel, Vinkers added.
E. Alison Holman, PhD, professor, Sue and Bill Gross School of Nursing, University of California, Irvine, noted that respondents were predominantly white, female, and had relatively high incomes, “suggesting strong demographic biases in those who chose to participate.”
Holman, who was not involved with the study, told Medscape Medical News that the “findings do not address the real impact of COVID-19 on the hardest-hit communities in America – poor, Black, and Latinx communities, where a large proportion of essential workers live.”
Barzilay acknowledged that, “unfortunately, because of the way the study was circulated, it did not reach minorities, which is one of the things we want to improve.”
The study is ongoing and has been translated into Spanish, French, and Hebrew. The team plans to collect data on diverse populations.
The study was supported by grants from the National Institute of Mental Health, the Lifespan Brain Institute of Children’s Hospital of Philadelphia, Penn Medicine, the University of Pennsylvania, and in part by the Zuckerman STEM Leadership Program. Barzilay serves on the scientific board and reports stock ownership in Taliaz Health. The other authors, Golnaz, Vinkers, and Holman have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
The earlier the better for colchicine post-MI: COLCOT
The earlier the anti-inflammatory drug colchicine is initiated after a myocardial infarction (MI) the greater the benefit, a new COLCOT analysis suggests.
The parent trial was conducted in patients with a recent MI because of the intense inflammation present at that time, and added colchicine 0.5 mg daily to standard care within 30 days following MI.
As previously reported, colchicine significantly reduced the risk of the primary end point – a composite of cardiovascular (CV) death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring revascularization – by 23% compared with placebo.
This new analysis shows the risk was reduced by 48% in patients receiving colchicine within 3 days of an MI (4.3% vs. 8.3%; adjusted hazard ratio, 0.52; 95% confidence interval, 0.32-0.84, P = .007).
Risk of a secondary efficacy end point – CV death, resuscitated cardiac arrest, MI, or stroke – was reduced by 45% over an average follow up of 22.7 months (3.3% vs 6.1%; adjusted HR, 0.55; 95% CI, 0.32-0.95, P = .031).
“We believe that our results support an early, in-hospital initiation of adjunctive colchicine for post-MI prevention,” Nadia Bouabdallaoui, MD, Montreal Heart Institute, Quebec, Canada, said during an online session devoted to colchicine at the European Society of Cardiology Congress 2020.
Session moderator Massimo Imazio, MD, professor of cardiology at the University of Turin, Italy, said the improved outcomes suggest that earlier treatment is better – a finding that parallels his own experience using colchicine in patients with pericarditis.
“This substudy is very important because this is probably also the year in cardiovascular applications [that] early use of the drug could improve outcomes,” he said.
Positive data have been accumulating for colchicine from COLCOT, LoDoCo, and, most recently, the LoDoCo2 trial, even as another anti-inflammatory drug, methotrexate, flamed out as secondary prevention in the CIRT trial.
The new COLCOT substudy included 4,661 of the 4,745 original patients and examined treatment initiation using three strata: within 0-3 days (n = 1,193), 4-7 days (n = 720), and 8-30 days (n = 2,748). Patients who received treatment within 3 days were slightly younger, more likely to be smokers, and to have a shorter time from MI to randomization (2.1 days vs 5.1 days vs. 20.8 days, respectively).
In the subset receiving treatment within 3 days, those assigned to colchicine had the same number of cardiac deaths as those given placebo (2 vs. 2) but fewer resuscitated cardiac arrests (1 vs. 3), MIs (17 vs. 29), strokes (1 vs. 5), and urgent hospitalizations for angina requiring revascularization (6 vs. 17).
“A larger trial might have allowed for a better assessment of individual endpoints and subgroups,” observed Bouabdallaoui.
Although there is growing support for colchicine, experts caution that the drug many not be for everyone. In COLCOT, 1 in 10 patients were unable to tolerate the drug, largely because of gastrointestinal (GI) issues.
Pharmacogenomics substudy
A second COLCOT substudy aimed to identify genetic markers predictive of colchicine response and to gain insights into the mechanisms behind this response. It included 767 patients treated with colchicine and another 755 treated with placebo – or about one-third the patients in the original trial.
A genome-wide association study did not find a significant association for the primary CV endpoint, although a prespecified subgroup analysis in men identified an interesting region on chromosome 9 (variant: rs10811106), which just missed reaching genomewide significance, said Marie-Pierre Dubé, PhD, director of the Université de Montréal Beaulieu-Saucier Pharmacogenomics Centre at the Montreal Heart Institute.
In addition, the genomewide analysis found two significant regions for GI events: one on chromosome 6 (variant: rs6916345) and one on chromosome 10 (variant: rs74795203).
For each of the identified regions, the researchers then tested the effect of the allele in the placebo group and the interaction between the genetic variant and treatment with colchicine. For the chromosome 9 region in males, there was no effect in the placebo group and a significant interaction in the colchicine group.
For the significant GI event findings, there was a small effect for the chromosome 6 region in the placebo group and a very significant interaction with colchicine, Dubé said. Similarly, there was no effect for the chromosome 10 region in the placebo group and a significant interaction with colchicine.
Additional analyses in stratified patient populations showed that males with the protective allele (CC) for the chromosome 9 region represented 83% of the population. The primary CV endpoint occurred in 3.2% of these men treated with colchicine and 6.3% treated with placebo (HR, 0.46; 95% CI, 0.24 - 0.86).
For the gastrointestinal events, 25% of patients carried the risk allele (AA) for the chromosome 6 region and 36.9% of these had GI events when treated with colchicine versus 18.6% when treated with placebo (HR, 2.42; 95% CI, 1.57-3.72).
Similarly, 13% of individuals carried one or two copies of the risk allele (AG+GG) for the chromosome 10 region and the risk of GI events in these was nearly four times higher with colchicine (47.1% vs. 18.9%; HR, 3.98; 95% CI 2.24-7.07).
Functional genomic analyses of the identified regions were also performed and showed that the chromosome 9 locus overlaps with the SAXO1 gene, a stabilizer of axonemal microtubules 1.
“The leading variant at this locus (rs10811106 C allele) correlated with the expression of the HAUS6 gene, which is involved in microtubule generation from existing microtubules, and may interact with the effect of colchicine, which is known to inhibit microtubule formation,” observed Dubé.
Also, the chromosome 6 locus associated with gastrointestinal events was colocalizing with the Crohn’s disease locus, adding further support for this region.
“The results support potential personalized approaches to inflammation reduction for cardiovascular prevention,” Dubé said.
This is a post hoc subgroup analysis, however, and replication is necessary, ideally in prospective randomized trials, she noted.
The substudy is important because it provides further insights into the link between colchicine and microtubule polymerization, affecting the activation of the inflammasome, session moderator Imazio said.
“Second, it is important because pharmacogenomics can help us to better understand the optimal responder to colchicine and colchicine resistance,” he said. “So it can be useful for personalized medicine, leading to the proper use of the drug for the proper patient.”
COLCOT was supported by the government of Quebec, the Canadian Institutes of Health Research, and philanthropic foundations. Bouabdallaoui has disclosed no relevant financial relationships. Dubé reported grants from the government of Quebec; personal fees from DalCor and GlaxoSmithKline; research support from AstraZeneca, Pfizer, Servier, Sanofi; and minor equity interest in DalCor. Dubé is also coauthor of patents on pharmacogenomics-guided CETP inhibition, and pharmacogenomics markers of response to colchicine.
This article first appeared on Medscape.com.
The earlier the anti-inflammatory drug colchicine is initiated after a myocardial infarction (MI) the greater the benefit, a new COLCOT analysis suggests.
The parent trial was conducted in patients with a recent MI because of the intense inflammation present at that time, and added colchicine 0.5 mg daily to standard care within 30 days following MI.
As previously reported, colchicine significantly reduced the risk of the primary end point – a composite of cardiovascular (CV) death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring revascularization – by 23% compared with placebo.
This new analysis shows the risk was reduced by 48% in patients receiving colchicine within 3 days of an MI (4.3% vs. 8.3%; adjusted hazard ratio, 0.52; 95% confidence interval, 0.32-0.84, P = .007).
Risk of a secondary efficacy end point – CV death, resuscitated cardiac arrest, MI, or stroke – was reduced by 45% over an average follow up of 22.7 months (3.3% vs 6.1%; adjusted HR, 0.55; 95% CI, 0.32-0.95, P = .031).
“We believe that our results support an early, in-hospital initiation of adjunctive colchicine for post-MI prevention,” Nadia Bouabdallaoui, MD, Montreal Heart Institute, Quebec, Canada, said during an online session devoted to colchicine at the European Society of Cardiology Congress 2020.
Session moderator Massimo Imazio, MD, professor of cardiology at the University of Turin, Italy, said the improved outcomes suggest that earlier treatment is better – a finding that parallels his own experience using colchicine in patients with pericarditis.
“This substudy is very important because this is probably also the year in cardiovascular applications [that] early use of the drug could improve outcomes,” he said.
Positive data have been accumulating for colchicine from COLCOT, LoDoCo, and, most recently, the LoDoCo2 trial, even as another anti-inflammatory drug, methotrexate, flamed out as secondary prevention in the CIRT trial.
The new COLCOT substudy included 4,661 of the 4,745 original patients and examined treatment initiation using three strata: within 0-3 days (n = 1,193), 4-7 days (n = 720), and 8-30 days (n = 2,748). Patients who received treatment within 3 days were slightly younger, more likely to be smokers, and to have a shorter time from MI to randomization (2.1 days vs 5.1 days vs. 20.8 days, respectively).
In the subset receiving treatment within 3 days, those assigned to colchicine had the same number of cardiac deaths as those given placebo (2 vs. 2) but fewer resuscitated cardiac arrests (1 vs. 3), MIs (17 vs. 29), strokes (1 vs. 5), and urgent hospitalizations for angina requiring revascularization (6 vs. 17).
“A larger trial might have allowed for a better assessment of individual endpoints and subgroups,” observed Bouabdallaoui.
Although there is growing support for colchicine, experts caution that the drug many not be for everyone. In COLCOT, 1 in 10 patients were unable to tolerate the drug, largely because of gastrointestinal (GI) issues.
Pharmacogenomics substudy
A second COLCOT substudy aimed to identify genetic markers predictive of colchicine response and to gain insights into the mechanisms behind this response. It included 767 patients treated with colchicine and another 755 treated with placebo – or about one-third the patients in the original trial.
A genome-wide association study did not find a significant association for the primary CV endpoint, although a prespecified subgroup analysis in men identified an interesting region on chromosome 9 (variant: rs10811106), which just missed reaching genomewide significance, said Marie-Pierre Dubé, PhD, director of the Université de Montréal Beaulieu-Saucier Pharmacogenomics Centre at the Montreal Heart Institute.
In addition, the genomewide analysis found two significant regions for GI events: one on chromosome 6 (variant: rs6916345) and one on chromosome 10 (variant: rs74795203).
For each of the identified regions, the researchers then tested the effect of the allele in the placebo group and the interaction between the genetic variant and treatment with colchicine. For the chromosome 9 region in males, there was no effect in the placebo group and a significant interaction in the colchicine group.
For the significant GI event findings, there was a small effect for the chromosome 6 region in the placebo group and a very significant interaction with colchicine, Dubé said. Similarly, there was no effect for the chromosome 10 region in the placebo group and a significant interaction with colchicine.
Additional analyses in stratified patient populations showed that males with the protective allele (CC) for the chromosome 9 region represented 83% of the population. The primary CV endpoint occurred in 3.2% of these men treated with colchicine and 6.3% treated with placebo (HR, 0.46; 95% CI, 0.24 - 0.86).
For the gastrointestinal events, 25% of patients carried the risk allele (AA) for the chromosome 6 region and 36.9% of these had GI events when treated with colchicine versus 18.6% when treated with placebo (HR, 2.42; 95% CI, 1.57-3.72).
Similarly, 13% of individuals carried one or two copies of the risk allele (AG+GG) for the chromosome 10 region and the risk of GI events in these was nearly four times higher with colchicine (47.1% vs. 18.9%; HR, 3.98; 95% CI 2.24-7.07).
Functional genomic analyses of the identified regions were also performed and showed that the chromosome 9 locus overlaps with the SAXO1 gene, a stabilizer of axonemal microtubules 1.
“The leading variant at this locus (rs10811106 C allele) correlated with the expression of the HAUS6 gene, which is involved in microtubule generation from existing microtubules, and may interact with the effect of colchicine, which is known to inhibit microtubule formation,” observed Dubé.
Also, the chromosome 6 locus associated with gastrointestinal events was colocalizing with the Crohn’s disease locus, adding further support for this region.
“The results support potential personalized approaches to inflammation reduction for cardiovascular prevention,” Dubé said.
This is a post hoc subgroup analysis, however, and replication is necessary, ideally in prospective randomized trials, she noted.
The substudy is important because it provides further insights into the link between colchicine and microtubule polymerization, affecting the activation of the inflammasome, session moderator Imazio said.
“Second, it is important because pharmacogenomics can help us to better understand the optimal responder to colchicine and colchicine resistance,” he said. “So it can be useful for personalized medicine, leading to the proper use of the drug for the proper patient.”
COLCOT was supported by the government of Quebec, the Canadian Institutes of Health Research, and philanthropic foundations. Bouabdallaoui has disclosed no relevant financial relationships. Dubé reported grants from the government of Quebec; personal fees from DalCor and GlaxoSmithKline; research support from AstraZeneca, Pfizer, Servier, Sanofi; and minor equity interest in DalCor. Dubé is also coauthor of patents on pharmacogenomics-guided CETP inhibition, and pharmacogenomics markers of response to colchicine.
This article first appeared on Medscape.com.
The earlier the anti-inflammatory drug colchicine is initiated after a myocardial infarction (MI) the greater the benefit, a new COLCOT analysis suggests.
The parent trial was conducted in patients with a recent MI because of the intense inflammation present at that time, and added colchicine 0.5 mg daily to standard care within 30 days following MI.
As previously reported, colchicine significantly reduced the risk of the primary end point – a composite of cardiovascular (CV) death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring revascularization – by 23% compared with placebo.
This new analysis shows the risk was reduced by 48% in patients receiving colchicine within 3 days of an MI (4.3% vs. 8.3%; adjusted hazard ratio, 0.52; 95% confidence interval, 0.32-0.84, P = .007).
Risk of a secondary efficacy end point – CV death, resuscitated cardiac arrest, MI, or stroke – was reduced by 45% over an average follow up of 22.7 months (3.3% vs 6.1%; adjusted HR, 0.55; 95% CI, 0.32-0.95, P = .031).
“We believe that our results support an early, in-hospital initiation of adjunctive colchicine for post-MI prevention,” Nadia Bouabdallaoui, MD, Montreal Heart Institute, Quebec, Canada, said during an online session devoted to colchicine at the European Society of Cardiology Congress 2020.
Session moderator Massimo Imazio, MD, professor of cardiology at the University of Turin, Italy, said the improved outcomes suggest that earlier treatment is better – a finding that parallels his own experience using colchicine in patients with pericarditis.
“This substudy is very important because this is probably also the year in cardiovascular applications [that] early use of the drug could improve outcomes,” he said.
Positive data have been accumulating for colchicine from COLCOT, LoDoCo, and, most recently, the LoDoCo2 trial, even as another anti-inflammatory drug, methotrexate, flamed out as secondary prevention in the CIRT trial.
The new COLCOT substudy included 4,661 of the 4,745 original patients and examined treatment initiation using three strata: within 0-3 days (n = 1,193), 4-7 days (n = 720), and 8-30 days (n = 2,748). Patients who received treatment within 3 days were slightly younger, more likely to be smokers, and to have a shorter time from MI to randomization (2.1 days vs 5.1 days vs. 20.8 days, respectively).
In the subset receiving treatment within 3 days, those assigned to colchicine had the same number of cardiac deaths as those given placebo (2 vs. 2) but fewer resuscitated cardiac arrests (1 vs. 3), MIs (17 vs. 29), strokes (1 vs. 5), and urgent hospitalizations for angina requiring revascularization (6 vs. 17).
“A larger trial might have allowed for a better assessment of individual endpoints and subgroups,” observed Bouabdallaoui.
Although there is growing support for colchicine, experts caution that the drug many not be for everyone. In COLCOT, 1 in 10 patients were unable to tolerate the drug, largely because of gastrointestinal (GI) issues.
Pharmacogenomics substudy
A second COLCOT substudy aimed to identify genetic markers predictive of colchicine response and to gain insights into the mechanisms behind this response. It included 767 patients treated with colchicine and another 755 treated with placebo – or about one-third the patients in the original trial.
A genome-wide association study did not find a significant association for the primary CV endpoint, although a prespecified subgroup analysis in men identified an interesting region on chromosome 9 (variant: rs10811106), which just missed reaching genomewide significance, said Marie-Pierre Dubé, PhD, director of the Université de Montréal Beaulieu-Saucier Pharmacogenomics Centre at the Montreal Heart Institute.
In addition, the genomewide analysis found two significant regions for GI events: one on chromosome 6 (variant: rs6916345) and one on chromosome 10 (variant: rs74795203).
For each of the identified regions, the researchers then tested the effect of the allele in the placebo group and the interaction between the genetic variant and treatment with colchicine. For the chromosome 9 region in males, there was no effect in the placebo group and a significant interaction in the colchicine group.
For the significant GI event findings, there was a small effect for the chromosome 6 region in the placebo group and a very significant interaction with colchicine, Dubé said. Similarly, there was no effect for the chromosome 10 region in the placebo group and a significant interaction with colchicine.
Additional analyses in stratified patient populations showed that males with the protective allele (CC) for the chromosome 9 region represented 83% of the population. The primary CV endpoint occurred in 3.2% of these men treated with colchicine and 6.3% treated with placebo (HR, 0.46; 95% CI, 0.24 - 0.86).
For the gastrointestinal events, 25% of patients carried the risk allele (AA) for the chromosome 6 region and 36.9% of these had GI events when treated with colchicine versus 18.6% when treated with placebo (HR, 2.42; 95% CI, 1.57-3.72).
Similarly, 13% of individuals carried one or two copies of the risk allele (AG+GG) for the chromosome 10 region and the risk of GI events in these was nearly four times higher with colchicine (47.1% vs. 18.9%; HR, 3.98; 95% CI 2.24-7.07).
Functional genomic analyses of the identified regions were also performed and showed that the chromosome 9 locus overlaps with the SAXO1 gene, a stabilizer of axonemal microtubules 1.
“The leading variant at this locus (rs10811106 C allele) correlated with the expression of the HAUS6 gene, which is involved in microtubule generation from existing microtubules, and may interact with the effect of colchicine, which is known to inhibit microtubule formation,” observed Dubé.
Also, the chromosome 6 locus associated with gastrointestinal events was colocalizing with the Crohn’s disease locus, adding further support for this region.
“The results support potential personalized approaches to inflammation reduction for cardiovascular prevention,” Dubé said.
This is a post hoc subgroup analysis, however, and replication is necessary, ideally in prospective randomized trials, she noted.
The substudy is important because it provides further insights into the link between colchicine and microtubule polymerization, affecting the activation of the inflammasome, session moderator Imazio said.
“Second, it is important because pharmacogenomics can help us to better understand the optimal responder to colchicine and colchicine resistance,” he said. “So it can be useful for personalized medicine, leading to the proper use of the drug for the proper patient.”
COLCOT was supported by the government of Quebec, the Canadian Institutes of Health Research, and philanthropic foundations. Bouabdallaoui has disclosed no relevant financial relationships. Dubé reported grants from the government of Quebec; personal fees from DalCor and GlaxoSmithKline; research support from AstraZeneca, Pfizer, Servier, Sanofi; and minor equity interest in DalCor. Dubé is also coauthor of patents on pharmacogenomics-guided CETP inhibition, and pharmacogenomics markers of response to colchicine.
This article first appeared on Medscape.com.
Masitinib impresses in nonactive progressive MS
“This is the first time that we have seen significant activity in slowing disability in a population of nonactive primary progressive and secondary progressive MS,” lead investigator, Patrick Vermersch, MD, commented. “There are no drugs available for these patients, which make up the vast majority of progressive MS patients, so these results are impressive. They are definitely a big deal.”
Dr. Vermersch, who is professor of neurology at the University of Lille, France, presented the study at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
“Masitinib – a first-in-class tyrosine kinase inhibitor targeting the innate immune system via inhibition of mast cell and microglia/macrophage activity – may provide a new treatment option for primary progressive and nonactive secondary progressive MS,” he concluded.
This study, known as AB07002, demonstrated a sustained and significant benefit for masitinib at a dose of 4.5 mg/kg per day in Expanded Disability Status Scale (EDSS) score change over 2 years versus placebo, with a 37% reduction in 3-month confirmed disability progression. This change “is relevant from a medical standpoint,” Dr. Vermersch reported.
However, a second dosing schedule, in which the drug was titrated up to 6 mg/kg per day, did not show significant benefit. Dr. Vermersch said this was because of an unexpected improvement in EDSS score in the placebo group.
In the 4.5-mg/kg group, the benefit was demonstrated across a broad population, with no difference with regard to age, duration of disease, or baseline disability. The benefits were similar in both primary and secondary MS phenotypes and were present irrespective of baseline active inflammation status.
Masitinib showed a safety profile “suitable for long-term administration in this population,” Dr. Vermersch said. “Masitinib addresses the huge unmet need in progressive MS,” he said. “The drugs currently used in MS target B cells and T cells. They are immunomodulating drugs and are used for relapsing/remitting MS. But in progressive forms of the disease, there is a strong involvement of innate immunity, so to be effective we need drugs that target this part of the immune system.”
Innate immunity is a major part of the immune system in primates; it is related to the immune cells inside tissues and the CNS and is separate from adaptive peripheral immunity, he explained.
Masitinib is a novel drug for MS in that it inhibits tyrosine kinase and blocks the activity of immune cells involved in the innate immune system – mainly microglia and mast cells. “Both of these types of cells are very involved in progressive MS. Masitinib has no action against T or B cells. It is a small molecule and penetrates the CNS,” Dr. Vermersch noted.
“This has opened up a whole new area of opportunity to develop treatments for progressive MS,” he added.
“We showed a positive significant result in slowing disability in patients with nonactive progressive MS,” he said. “The term ‘nonactive’ is important. Some other drugs [ocrelizumab and siponimod] have shown some modest activity in slowing progressive forms of MS, but this is driven by patients with some degree of inflammatory activity at baseline. Our study excluded such patients.”
The trial tested two different dosing schedules independently, each with its own placebo group. There were two subsets, each with 300 patients. The first subset was randomly assigned in a 2:1 ratio to daily masitinib at 4.5 mg/kg orally or placebo. The second subset was randomly assigned in a 2:1 ratio to daily masitinib titrated to 6 mg/kg or placebo.
The inclusion criteria were patients with primary progressive or secondary progressive MS without relapse (as measured by EDSS progression) within the previous 2 years. “No patients were enrolled who had superimposed relapses during the previous 2 years,” Dr. Vermersch stressed.
Baseline EDSS score was 5.0, and patients had an average disease duration of 15 years. Mean age was 50 years.
The primary endpoint was change from baseline in absolute EDSS value, which was measured every 12 weeks throughout the study, averaged over the 2-year study period (mean change in EDSS score).
Results in the 4.5-mg/kg group showed a mean increase in EDSS score in the masitinib recipients of 0.001 versus 0.098 in the placebo group, giving a mean difference of –0.097 for masitinib (P = 0.025). The results were similar in patients with primary or secondary progressive MS. Sensitivity analysis based on ordinal EDSS change showed a significant 39% increased probability of having more improvements in EDSS or fewer worsening EDSS scores with masitinib (odds ratio, 0.61; P = 0.044). Other results showed that masitinib reduced the risk for first disability progression by 42% (hazard ratio, 0.58; P = 0.034) and the risk for confirmed (3-month) disability progression by 37% (hazard ratio, 0.63; P = 0.15).
Masitinib also showed a 98% reduction in the risk of reaching an EDSS score of 7, corresponding to disability severe enough that the patient is restricted to a wheelchair (hazard ratio, 0.02; P = 0.009). No patients in the masitinib group reached the endpoint of confirmed (3-month) EDSS score of 7, compared with four patients in the placebo group.
In terms of safety in the 4.5-mg/kg group, the most common adverse events were rash (1,5%) gastrointestinal (GI) disturbances (1%), neutropenia (1%), and edema (1%). “We had a couple of patients with skin reactions and neutropenia, but all adverse events were mild to moderate and very manageable,” Dr. Vermersch commented.
He showed just one slide on the subset who were titrated up 6 mg/kg. “Numerically the change in EDSS was comparable in the 6-mg/kg–titrated group as it was in the 4.5-mg/kg group; however, the placebo arm of the 6-mg/kg subset unusually showed an improvement relative to baseline after 96 weeks. The placebo group of the 4.5-mg/kg cohort was consistent with the literature and expected worsening in EDSS score over 96 weeks,” Dr. Vermersch reported.
No new safety signal was observed in the 6-mg/kg cohort. Only the 4.5-mg/kg cohort will be pursued in further trials in MS.
Dr. Vermersch noted that masitinib is also being investigated in other indications and “there are thousands of patient-years of experience which show reassuring safety data.”
“There is some GI disturbances and skin reactions, but a very small percentage of patients discontinue treatment. If the drug is titrated slowly there are fewer adverse effects,” he said. “We will do that in the next study.”
A second confirmatory study is now being planned. The trial will enroll around 700 patients and is expected to recruit quickly because there is such a big unmet need, Dr. Vermersch added.
Commenting on the findings, ACTRIMS president Jeffrey Cohen, MD, of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, Ohio, said this is “an interesting study from several perspectives.”
“Masitinib is a new drug for MS with a completely novel mechanism of action targeting the innate immune system”, he said. “The study had several innovative features in that it combined primary and secondary progressive MS patients and measured disability in a different way to what we are used to.”
“It did show a slowing of disability, which is great news as we do not have any drugs for these patients at the moment, so this is a very hopeful result,” Dr. Cohen said.
The study was supported by AB Science. Dr. Vermersch reports sitting on advisory boards for Biogen, Sanofi-Genzyme, Teva, Roche, Novartis, Celgene, and Merck KGaA.
A version of this article originally appeared on Medscape.com.
“This is the first time that we have seen significant activity in slowing disability in a population of nonactive primary progressive and secondary progressive MS,” lead investigator, Patrick Vermersch, MD, commented. “There are no drugs available for these patients, which make up the vast majority of progressive MS patients, so these results are impressive. They are definitely a big deal.”
Dr. Vermersch, who is professor of neurology at the University of Lille, France, presented the study at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
“Masitinib – a first-in-class tyrosine kinase inhibitor targeting the innate immune system via inhibition of mast cell and microglia/macrophage activity – may provide a new treatment option for primary progressive and nonactive secondary progressive MS,” he concluded.
This study, known as AB07002, demonstrated a sustained and significant benefit for masitinib at a dose of 4.5 mg/kg per day in Expanded Disability Status Scale (EDSS) score change over 2 years versus placebo, with a 37% reduction in 3-month confirmed disability progression. This change “is relevant from a medical standpoint,” Dr. Vermersch reported.
However, a second dosing schedule, in which the drug was titrated up to 6 mg/kg per day, did not show significant benefit. Dr. Vermersch said this was because of an unexpected improvement in EDSS score in the placebo group.
In the 4.5-mg/kg group, the benefit was demonstrated across a broad population, with no difference with regard to age, duration of disease, or baseline disability. The benefits were similar in both primary and secondary MS phenotypes and were present irrespective of baseline active inflammation status.
Masitinib showed a safety profile “suitable for long-term administration in this population,” Dr. Vermersch said. “Masitinib addresses the huge unmet need in progressive MS,” he said. “The drugs currently used in MS target B cells and T cells. They are immunomodulating drugs and are used for relapsing/remitting MS. But in progressive forms of the disease, there is a strong involvement of innate immunity, so to be effective we need drugs that target this part of the immune system.”
Innate immunity is a major part of the immune system in primates; it is related to the immune cells inside tissues and the CNS and is separate from adaptive peripheral immunity, he explained.
Masitinib is a novel drug for MS in that it inhibits tyrosine kinase and blocks the activity of immune cells involved in the innate immune system – mainly microglia and mast cells. “Both of these types of cells are very involved in progressive MS. Masitinib has no action against T or B cells. It is a small molecule and penetrates the CNS,” Dr. Vermersch noted.
“This has opened up a whole new area of opportunity to develop treatments for progressive MS,” he added.
“We showed a positive significant result in slowing disability in patients with nonactive progressive MS,” he said. “The term ‘nonactive’ is important. Some other drugs [ocrelizumab and siponimod] have shown some modest activity in slowing progressive forms of MS, but this is driven by patients with some degree of inflammatory activity at baseline. Our study excluded such patients.”
The trial tested two different dosing schedules independently, each with its own placebo group. There were two subsets, each with 300 patients. The first subset was randomly assigned in a 2:1 ratio to daily masitinib at 4.5 mg/kg orally or placebo. The second subset was randomly assigned in a 2:1 ratio to daily masitinib titrated to 6 mg/kg or placebo.
The inclusion criteria were patients with primary progressive or secondary progressive MS without relapse (as measured by EDSS progression) within the previous 2 years. “No patients were enrolled who had superimposed relapses during the previous 2 years,” Dr. Vermersch stressed.
Baseline EDSS score was 5.0, and patients had an average disease duration of 15 years. Mean age was 50 years.
The primary endpoint was change from baseline in absolute EDSS value, which was measured every 12 weeks throughout the study, averaged over the 2-year study period (mean change in EDSS score).
Results in the 4.5-mg/kg group showed a mean increase in EDSS score in the masitinib recipients of 0.001 versus 0.098 in the placebo group, giving a mean difference of –0.097 for masitinib (P = 0.025). The results were similar in patients with primary or secondary progressive MS. Sensitivity analysis based on ordinal EDSS change showed a significant 39% increased probability of having more improvements in EDSS or fewer worsening EDSS scores with masitinib (odds ratio, 0.61; P = 0.044). Other results showed that masitinib reduced the risk for first disability progression by 42% (hazard ratio, 0.58; P = 0.034) and the risk for confirmed (3-month) disability progression by 37% (hazard ratio, 0.63; P = 0.15).
Masitinib also showed a 98% reduction in the risk of reaching an EDSS score of 7, corresponding to disability severe enough that the patient is restricted to a wheelchair (hazard ratio, 0.02; P = 0.009). No patients in the masitinib group reached the endpoint of confirmed (3-month) EDSS score of 7, compared with four patients in the placebo group.
In terms of safety in the 4.5-mg/kg group, the most common adverse events were rash (1,5%) gastrointestinal (GI) disturbances (1%), neutropenia (1%), and edema (1%). “We had a couple of patients with skin reactions and neutropenia, but all adverse events were mild to moderate and very manageable,” Dr. Vermersch commented.
He showed just one slide on the subset who were titrated up 6 mg/kg. “Numerically the change in EDSS was comparable in the 6-mg/kg–titrated group as it was in the 4.5-mg/kg group; however, the placebo arm of the 6-mg/kg subset unusually showed an improvement relative to baseline after 96 weeks. The placebo group of the 4.5-mg/kg cohort was consistent with the literature and expected worsening in EDSS score over 96 weeks,” Dr. Vermersch reported.
No new safety signal was observed in the 6-mg/kg cohort. Only the 4.5-mg/kg cohort will be pursued in further trials in MS.
Dr. Vermersch noted that masitinib is also being investigated in other indications and “there are thousands of patient-years of experience which show reassuring safety data.”
“There is some GI disturbances and skin reactions, but a very small percentage of patients discontinue treatment. If the drug is titrated slowly there are fewer adverse effects,” he said. “We will do that in the next study.”
A second confirmatory study is now being planned. The trial will enroll around 700 patients and is expected to recruit quickly because there is such a big unmet need, Dr. Vermersch added.
Commenting on the findings, ACTRIMS president Jeffrey Cohen, MD, of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, Ohio, said this is “an interesting study from several perspectives.”
“Masitinib is a new drug for MS with a completely novel mechanism of action targeting the innate immune system”, he said. “The study had several innovative features in that it combined primary and secondary progressive MS patients and measured disability in a different way to what we are used to.”
“It did show a slowing of disability, which is great news as we do not have any drugs for these patients at the moment, so this is a very hopeful result,” Dr. Cohen said.
The study was supported by AB Science. Dr. Vermersch reports sitting on advisory boards for Biogen, Sanofi-Genzyme, Teva, Roche, Novartis, Celgene, and Merck KGaA.
A version of this article originally appeared on Medscape.com.
“This is the first time that we have seen significant activity in slowing disability in a population of nonactive primary progressive and secondary progressive MS,” lead investigator, Patrick Vermersch, MD, commented. “There are no drugs available for these patients, which make up the vast majority of progressive MS patients, so these results are impressive. They are definitely a big deal.”
Dr. Vermersch, who is professor of neurology at the University of Lille, France, presented the study at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
“Masitinib – a first-in-class tyrosine kinase inhibitor targeting the innate immune system via inhibition of mast cell and microglia/macrophage activity – may provide a new treatment option for primary progressive and nonactive secondary progressive MS,” he concluded.
This study, known as AB07002, demonstrated a sustained and significant benefit for masitinib at a dose of 4.5 mg/kg per day in Expanded Disability Status Scale (EDSS) score change over 2 years versus placebo, with a 37% reduction in 3-month confirmed disability progression. This change “is relevant from a medical standpoint,” Dr. Vermersch reported.
However, a second dosing schedule, in which the drug was titrated up to 6 mg/kg per day, did not show significant benefit. Dr. Vermersch said this was because of an unexpected improvement in EDSS score in the placebo group.
In the 4.5-mg/kg group, the benefit was demonstrated across a broad population, with no difference with regard to age, duration of disease, or baseline disability. The benefits were similar in both primary and secondary MS phenotypes and were present irrespective of baseline active inflammation status.
Masitinib showed a safety profile “suitable for long-term administration in this population,” Dr. Vermersch said. “Masitinib addresses the huge unmet need in progressive MS,” he said. “The drugs currently used in MS target B cells and T cells. They are immunomodulating drugs and are used for relapsing/remitting MS. But in progressive forms of the disease, there is a strong involvement of innate immunity, so to be effective we need drugs that target this part of the immune system.”
Innate immunity is a major part of the immune system in primates; it is related to the immune cells inside tissues and the CNS and is separate from adaptive peripheral immunity, he explained.
Masitinib is a novel drug for MS in that it inhibits tyrosine kinase and blocks the activity of immune cells involved in the innate immune system – mainly microglia and mast cells. “Both of these types of cells are very involved in progressive MS. Masitinib has no action against T or B cells. It is a small molecule and penetrates the CNS,” Dr. Vermersch noted.
“This has opened up a whole new area of opportunity to develop treatments for progressive MS,” he added.
“We showed a positive significant result in slowing disability in patients with nonactive progressive MS,” he said. “The term ‘nonactive’ is important. Some other drugs [ocrelizumab and siponimod] have shown some modest activity in slowing progressive forms of MS, but this is driven by patients with some degree of inflammatory activity at baseline. Our study excluded such patients.”
The trial tested two different dosing schedules independently, each with its own placebo group. There were two subsets, each with 300 patients. The first subset was randomly assigned in a 2:1 ratio to daily masitinib at 4.5 mg/kg orally or placebo. The second subset was randomly assigned in a 2:1 ratio to daily masitinib titrated to 6 mg/kg or placebo.
The inclusion criteria were patients with primary progressive or secondary progressive MS without relapse (as measured by EDSS progression) within the previous 2 years. “No patients were enrolled who had superimposed relapses during the previous 2 years,” Dr. Vermersch stressed.
Baseline EDSS score was 5.0, and patients had an average disease duration of 15 years. Mean age was 50 years.
The primary endpoint was change from baseline in absolute EDSS value, which was measured every 12 weeks throughout the study, averaged over the 2-year study period (mean change in EDSS score).
Results in the 4.5-mg/kg group showed a mean increase in EDSS score in the masitinib recipients of 0.001 versus 0.098 in the placebo group, giving a mean difference of –0.097 for masitinib (P = 0.025). The results were similar in patients with primary or secondary progressive MS. Sensitivity analysis based on ordinal EDSS change showed a significant 39% increased probability of having more improvements in EDSS or fewer worsening EDSS scores with masitinib (odds ratio, 0.61; P = 0.044). Other results showed that masitinib reduced the risk for first disability progression by 42% (hazard ratio, 0.58; P = 0.034) and the risk for confirmed (3-month) disability progression by 37% (hazard ratio, 0.63; P = 0.15).
Masitinib also showed a 98% reduction in the risk of reaching an EDSS score of 7, corresponding to disability severe enough that the patient is restricted to a wheelchair (hazard ratio, 0.02; P = 0.009). No patients in the masitinib group reached the endpoint of confirmed (3-month) EDSS score of 7, compared with four patients in the placebo group.
In terms of safety in the 4.5-mg/kg group, the most common adverse events were rash (1,5%) gastrointestinal (GI) disturbances (1%), neutropenia (1%), and edema (1%). “We had a couple of patients with skin reactions and neutropenia, but all adverse events were mild to moderate and very manageable,” Dr. Vermersch commented.
He showed just one slide on the subset who were titrated up 6 mg/kg. “Numerically the change in EDSS was comparable in the 6-mg/kg–titrated group as it was in the 4.5-mg/kg group; however, the placebo arm of the 6-mg/kg subset unusually showed an improvement relative to baseline after 96 weeks. The placebo group of the 4.5-mg/kg cohort was consistent with the literature and expected worsening in EDSS score over 96 weeks,” Dr. Vermersch reported.
No new safety signal was observed in the 6-mg/kg cohort. Only the 4.5-mg/kg cohort will be pursued in further trials in MS.
Dr. Vermersch noted that masitinib is also being investigated in other indications and “there are thousands of patient-years of experience which show reassuring safety data.”
“There is some GI disturbances and skin reactions, but a very small percentage of patients discontinue treatment. If the drug is titrated slowly there are fewer adverse effects,” he said. “We will do that in the next study.”
A second confirmatory study is now being planned. The trial will enroll around 700 patients and is expected to recruit quickly because there is such a big unmet need, Dr. Vermersch added.
Commenting on the findings, ACTRIMS president Jeffrey Cohen, MD, of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, Ohio, said this is “an interesting study from several perspectives.”
“Masitinib is a new drug for MS with a completely novel mechanism of action targeting the innate immune system”, he said. “The study had several innovative features in that it combined primary and secondary progressive MS patients and measured disability in a different way to what we are used to.”
“It did show a slowing of disability, which is great news as we do not have any drugs for these patients at the moment, so this is a very hopeful result,” Dr. Cohen said.
The study was supported by AB Science. Dr. Vermersch reports sitting on advisory boards for Biogen, Sanofi-Genzyme, Teva, Roche, Novartis, Celgene, and Merck KGaA.
A version of this article originally appeared on Medscape.com.
From MSVirtual2020
Multiple sclerosis prodrome holds promise of earlier diagnosis
“It is time that the prodromal phase of multiple sclerosis [MS] is formally recognized.” That was the conclusion of Helen Tremlett, PhD, delivering the opening plenary session lecture at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
There is a myriad of prodromal features but none that are specific to MS,” Dr. Tremlett said.
“These findings show that in future there could be an earlier window of opportunity to identify and manage MS,” she suggested.
In an interview, Dr. Tremlett, who is professor and Canada Research Chair in Neuroepidemiology and Multiple Sclerosis at the University of British Columbia, Vancouver, explained that for MS a prodrome is a relatively new concept. “Right up until the year 2000, MS leaders were specifically saying that a prodrome did not exist,” she said. “But things have changed. Studies started emerging in the last decade suggestive of a prodrome, and I think we can now say there is definitely proof that a prodrome does exist. If you ask MS patients, the vast majority of them will say they had an increase in health issues in the years before diagnosis.”
In her plenary talk, Dr. Tremlett summarized the available evidence showing that, in the years before the first demyelinating event, patients are more likely to be have multiple health issues and an increase in hospitalizations and physician visits.
In a 2018 study, her group analyzed data from four Canadian provinces, including 14,000 patients with MS and 75,000 matched controls, and found a 75% increase in the rate of hospitalization, a 88% higher rate of physician service use, and a 49% increase in prescription numbers in the 5 years before the first demyelinating event in the patients with MS, compared with controls.
This included a 50% increase in mental health visits to physicians and increased rates of fibromyalgia, pain, headache, migraine, sleep disturbances, urology, and dermatology referrals, as well as irritable bowel syndrome. In addition, there were fewer pregnancies and increased prescriptions for contraception in the female patients later diagnosed with MS.
“There is a huge range of nonspecific symptoms in the 5 years before MS diagnosis, and some of these are really intriguing and unanticipated,” Dr. Tremlett said. “We are not surprised by the findings that fatigue, mental health issues, and bladder and bowel symptoms are increased, but the finding that there are more visits to a dermatologist and an increase in prescriptions for skin conditions was completely unexpected.”
The researchers found that dermatology referrals increased in patients who went on to develop relapsing remitting but not primary progressive forms of MS, which correlates with the established knowledge that the relapsing form has an inflammatory component not seen in progressive MS.
In a large U.K. population study of 10,000 patients with MS and 39,000 matched controls sourced from primary care doctors’ records, there was an increase in gastrointestinal and urinary issues, pain, anxiety and depression, insomnia, and fatigue in the 10 years before the first diagnosis of MS or clinically isolated syndrome (CIS) in patients later diagnosed with those conditions, compared with controls, Dr. Tremlett reported.
Other data have suggested that sex and age may affect the prodrome. In a study published this year, anemia was increased in the year before the first demyelinating event and pain was increased for 5 years beforehand. But anemia was more common in male patients later diagnosed with MS/CIS (odds ratio compared with controls, 2.4) than in female patients (OR compared with controls, 1.2).
The increase in pain seemed to be greater with age, with ORs of 1.8 for those younger than 30 years, 2.1 for those age 30-49 years, and 2.4 for those older than 50 years compared with controls.
A Norwegian military study in men that included 900 patients with MS and 19,000 matched controls found that cognitive performance was reduced in the 2 years before MS symptoms developed and up to 20 years before symptoms in those who developed primary progressive MS. “This suggests that primary progressive MS could start decades before the first apparent symptoms become obvious,” Dr. Tremlett commented.
A study in pediatric MS found that the mothers of the patients had higher use of health care (rate ratio, 1.16) and mental health (rate ratio, 1.33) services in the 5 years before their children had their first demyelinating event.
A study in Bavaria, Germany, including 10,000 patients with MS and 73,000 controls, concluded that “many physician visits before MS diagnosis were, in hindsight, likely a demyelinating event,” with the implication that this is evidence of missed opportunity for earlier diagnosis, Dr. Tremlett noted.
In a 2019 study, psychiatric symptoms were more common before MS diagnosis across various different immune-mediated disease (MS, rheumatoid arthritis, inflammatory bowel disease), with an incidence rate ratio of 1.6. The rate was even increased 10 years before diagnosis (incidence rate ratio, 1.5).
“This is evidence for shared prodromal features across immune diseases, but there isn’t a single feature specific to MS,” Dr. Tremlett said. She also referred to evidence that the blood biomarker of neuronal damage, neurofilament light chain (NfL), is raised several years before MS diagnosis. In a U.S. military study that examined serum repository samples, NfL was increased for 6 years before disease onset in 30 patients with MS, compared with 30 matched controls.
What are the implications?
Dr. Tremlett said the immediate impact of these observations about the prodrome is focused on research, particularly investigation of risk factors for MS. “If we want to know what causes MS, we have to be very careful that we are not detecting prodromal symptoms and mistaking that for a causal MS risk factor. We need to make sure we look further back than just the last few years when looking for risk factors.”
She gave the example of the observation that women in the years before MS diagnosis are less likely to have a pregnancy and more likely to fill a prescription for contraception. “This has led to the idea that avoiding pregnancy and using contraceptives increases the risk of MS, but I interpret it as these women know that something odd is going on and make the lifestyle decision not to become pregnant.”
She believes the longer-term impact of the prodrome is going to require much thought. “There is no such diagnosis of prodromal MS at the moment, but there could be in future. But the idea that we can use this information to detect MS earlier is going to require collaboration from many international stakeholders and MS organizations. We can’t automatically suspect MS in people who have these symptoms because they are so nonspecific. I think to request an MRI in patients experiencing headaches/fatigue/bowel issues is jumping the gun at the present moment as these symptoms are very common.”
On the idea of measuring NfL in patients with some of these symptoms, she believes that may be a possibility in the future but much more data are required.“We do have some evidence suggesting that the NfL blood biomarker is raised before MS diagnosis, and this was from a very well-designed study, but it was small so I think it is too early to start looking at this in clinical practice,” she said. “But it does justify doing this as part of a research study. We definitely need more data on this. We must be cautious as NfL is not specific for MS – many other conditions are also associated with raised levels, but it is certainly an interesting marker if used carefully.”
Following in the footsteps of Parkinson disease
She suggested that the way forward will be to package up these symptoms with information on biomarkers, such as NfL and imaging information, to enhance the ability to identify prodromal MS. “We could create a risk score and when a certain level of confidence is reached that this could be prodromal MS, then these patients could be enrolled in an intervention research study.”
Dr. Tremlett pointed out that, in the Parkinson disease field, a set of validated criteria for a prodrome have already been identified. “This is not used in clinical practice yet, but it is being used to identify patients for enrollment into clinical trials. I’m hoping that MS will follow in their footsteps.”
Commenting on the presentation, ACTRIMS president, Jeffrey Cohen, MD, Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, said: “There is no doubt that the MS disease process begins prior to the first attack (in the case of relapsing MS) or the onset of overt disability progression (in the case of primary progressive MS).”
He explained that this is demonstrated by the presence of old lesions on MRI in most patients at the time of presentation, the existence of so-called radiologically isolated syndrome (patients without symptoms of MS who undergo MRI for another reason and are found to have lesions suggesting of MS, many of whom go on to develop MS at a later date), and the occurrence of a variety of symptoms 5-10 years before presentation to a neurologist.
“Those symptoms are ones that are common in MS, though not specific for MS,” Dr. Cohen noted. “The main implication is that the timeline for MS needs to be moved earlier – for diagnosis, categorization of disease course, prognostic studies, and treatment. The issue is that the symptoms of the prodrome are rather nonspecific and most people with those symptoms do not have MS.”
New incoming president of ECTRIMS, Maria Pia Amato, MD, professor of neurology at the University of Florence (Italy), added: “The million-dollar question is when does progression really begin? This plenary talk tells us the disease is there years and years before it manifests itself with first demyelinating event. This opens up an immense opportunity for research and to open the window to the possibility of earlier diagnosis and treatment.”
Dr. Tremlett reports an investment in Precision NanoSystems.
A version of this article originally appeared on Medscape.com.
“It is time that the prodromal phase of multiple sclerosis [MS] is formally recognized.” That was the conclusion of Helen Tremlett, PhD, delivering the opening plenary session lecture at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
There is a myriad of prodromal features but none that are specific to MS,” Dr. Tremlett said.
“These findings show that in future there could be an earlier window of opportunity to identify and manage MS,” she suggested.
In an interview, Dr. Tremlett, who is professor and Canada Research Chair in Neuroepidemiology and Multiple Sclerosis at the University of British Columbia, Vancouver, explained that for MS a prodrome is a relatively new concept. “Right up until the year 2000, MS leaders were specifically saying that a prodrome did not exist,” she said. “But things have changed. Studies started emerging in the last decade suggestive of a prodrome, and I think we can now say there is definitely proof that a prodrome does exist. If you ask MS patients, the vast majority of them will say they had an increase in health issues in the years before diagnosis.”
In her plenary talk, Dr. Tremlett summarized the available evidence showing that, in the years before the first demyelinating event, patients are more likely to be have multiple health issues and an increase in hospitalizations and physician visits.
In a 2018 study, her group analyzed data from four Canadian provinces, including 14,000 patients with MS and 75,000 matched controls, and found a 75% increase in the rate of hospitalization, a 88% higher rate of physician service use, and a 49% increase in prescription numbers in the 5 years before the first demyelinating event in the patients with MS, compared with controls.
This included a 50% increase in mental health visits to physicians and increased rates of fibromyalgia, pain, headache, migraine, sleep disturbances, urology, and dermatology referrals, as well as irritable bowel syndrome. In addition, there were fewer pregnancies and increased prescriptions for contraception in the female patients later diagnosed with MS.
“There is a huge range of nonspecific symptoms in the 5 years before MS diagnosis, and some of these are really intriguing and unanticipated,” Dr. Tremlett said. “We are not surprised by the findings that fatigue, mental health issues, and bladder and bowel symptoms are increased, but the finding that there are more visits to a dermatologist and an increase in prescriptions for skin conditions was completely unexpected.”
The researchers found that dermatology referrals increased in patients who went on to develop relapsing remitting but not primary progressive forms of MS, which correlates with the established knowledge that the relapsing form has an inflammatory component not seen in progressive MS.
In a large U.K. population study of 10,000 patients with MS and 39,000 matched controls sourced from primary care doctors’ records, there was an increase in gastrointestinal and urinary issues, pain, anxiety and depression, insomnia, and fatigue in the 10 years before the first diagnosis of MS or clinically isolated syndrome (CIS) in patients later diagnosed with those conditions, compared with controls, Dr. Tremlett reported.
Other data have suggested that sex and age may affect the prodrome. In a study published this year, anemia was increased in the year before the first demyelinating event and pain was increased for 5 years beforehand. But anemia was more common in male patients later diagnosed with MS/CIS (odds ratio compared with controls, 2.4) than in female patients (OR compared with controls, 1.2).
The increase in pain seemed to be greater with age, with ORs of 1.8 for those younger than 30 years, 2.1 for those age 30-49 years, and 2.4 for those older than 50 years compared with controls.
A Norwegian military study in men that included 900 patients with MS and 19,000 matched controls found that cognitive performance was reduced in the 2 years before MS symptoms developed and up to 20 years before symptoms in those who developed primary progressive MS. “This suggests that primary progressive MS could start decades before the first apparent symptoms become obvious,” Dr. Tremlett commented.
A study in pediatric MS found that the mothers of the patients had higher use of health care (rate ratio, 1.16) and mental health (rate ratio, 1.33) services in the 5 years before their children had their first demyelinating event.
A study in Bavaria, Germany, including 10,000 patients with MS and 73,000 controls, concluded that “many physician visits before MS diagnosis were, in hindsight, likely a demyelinating event,” with the implication that this is evidence of missed opportunity for earlier diagnosis, Dr. Tremlett noted.
In a 2019 study, psychiatric symptoms were more common before MS diagnosis across various different immune-mediated disease (MS, rheumatoid arthritis, inflammatory bowel disease), with an incidence rate ratio of 1.6. The rate was even increased 10 years before diagnosis (incidence rate ratio, 1.5).
“This is evidence for shared prodromal features across immune diseases, but there isn’t a single feature specific to MS,” Dr. Tremlett said. She also referred to evidence that the blood biomarker of neuronal damage, neurofilament light chain (NfL), is raised several years before MS diagnosis. In a U.S. military study that examined serum repository samples, NfL was increased for 6 years before disease onset in 30 patients with MS, compared with 30 matched controls.
What are the implications?
Dr. Tremlett said the immediate impact of these observations about the prodrome is focused on research, particularly investigation of risk factors for MS. “If we want to know what causes MS, we have to be very careful that we are not detecting prodromal symptoms and mistaking that for a causal MS risk factor. We need to make sure we look further back than just the last few years when looking for risk factors.”
She gave the example of the observation that women in the years before MS diagnosis are less likely to have a pregnancy and more likely to fill a prescription for contraception. “This has led to the idea that avoiding pregnancy and using contraceptives increases the risk of MS, but I interpret it as these women know that something odd is going on and make the lifestyle decision not to become pregnant.”
She believes the longer-term impact of the prodrome is going to require much thought. “There is no such diagnosis of prodromal MS at the moment, but there could be in future. But the idea that we can use this information to detect MS earlier is going to require collaboration from many international stakeholders and MS organizations. We can’t automatically suspect MS in people who have these symptoms because they are so nonspecific. I think to request an MRI in patients experiencing headaches/fatigue/bowel issues is jumping the gun at the present moment as these symptoms are very common.”
On the idea of measuring NfL in patients with some of these symptoms, she believes that may be a possibility in the future but much more data are required.“We do have some evidence suggesting that the NfL blood biomarker is raised before MS diagnosis, and this was from a very well-designed study, but it was small so I think it is too early to start looking at this in clinical practice,” she said. “But it does justify doing this as part of a research study. We definitely need more data on this. We must be cautious as NfL is not specific for MS – many other conditions are also associated with raised levels, but it is certainly an interesting marker if used carefully.”
Following in the footsteps of Parkinson disease
She suggested that the way forward will be to package up these symptoms with information on biomarkers, such as NfL and imaging information, to enhance the ability to identify prodromal MS. “We could create a risk score and when a certain level of confidence is reached that this could be prodromal MS, then these patients could be enrolled in an intervention research study.”
Dr. Tremlett pointed out that, in the Parkinson disease field, a set of validated criteria for a prodrome have already been identified. “This is not used in clinical practice yet, but it is being used to identify patients for enrollment into clinical trials. I’m hoping that MS will follow in their footsteps.”
Commenting on the presentation, ACTRIMS president, Jeffrey Cohen, MD, Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, said: “There is no doubt that the MS disease process begins prior to the first attack (in the case of relapsing MS) or the onset of overt disability progression (in the case of primary progressive MS).”
He explained that this is demonstrated by the presence of old lesions on MRI in most patients at the time of presentation, the existence of so-called radiologically isolated syndrome (patients without symptoms of MS who undergo MRI for another reason and are found to have lesions suggesting of MS, many of whom go on to develop MS at a later date), and the occurrence of a variety of symptoms 5-10 years before presentation to a neurologist.
“Those symptoms are ones that are common in MS, though not specific for MS,” Dr. Cohen noted. “The main implication is that the timeline for MS needs to be moved earlier – for diagnosis, categorization of disease course, prognostic studies, and treatment. The issue is that the symptoms of the prodrome are rather nonspecific and most people with those symptoms do not have MS.”
New incoming president of ECTRIMS, Maria Pia Amato, MD, professor of neurology at the University of Florence (Italy), added: “The million-dollar question is when does progression really begin? This plenary talk tells us the disease is there years and years before it manifests itself with first demyelinating event. This opens up an immense opportunity for research and to open the window to the possibility of earlier diagnosis and treatment.”
Dr. Tremlett reports an investment in Precision NanoSystems.
A version of this article originally appeared on Medscape.com.
“It is time that the prodromal phase of multiple sclerosis [MS] is formally recognized.” That was the conclusion of Helen Tremlett, PhD, delivering the opening plenary session lecture at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
There is a myriad of prodromal features but none that are specific to MS,” Dr. Tremlett said.
“These findings show that in future there could be an earlier window of opportunity to identify and manage MS,” she suggested.
In an interview, Dr. Tremlett, who is professor and Canada Research Chair in Neuroepidemiology and Multiple Sclerosis at the University of British Columbia, Vancouver, explained that for MS a prodrome is a relatively new concept. “Right up until the year 2000, MS leaders were specifically saying that a prodrome did not exist,” she said. “But things have changed. Studies started emerging in the last decade suggestive of a prodrome, and I think we can now say there is definitely proof that a prodrome does exist. If you ask MS patients, the vast majority of them will say they had an increase in health issues in the years before diagnosis.”
In her plenary talk, Dr. Tremlett summarized the available evidence showing that, in the years before the first demyelinating event, patients are more likely to be have multiple health issues and an increase in hospitalizations and physician visits.
In a 2018 study, her group analyzed data from four Canadian provinces, including 14,000 patients with MS and 75,000 matched controls, and found a 75% increase in the rate of hospitalization, a 88% higher rate of physician service use, and a 49% increase in prescription numbers in the 5 years before the first demyelinating event in the patients with MS, compared with controls.
This included a 50% increase in mental health visits to physicians and increased rates of fibromyalgia, pain, headache, migraine, sleep disturbances, urology, and dermatology referrals, as well as irritable bowel syndrome. In addition, there were fewer pregnancies and increased prescriptions for contraception in the female patients later diagnosed with MS.
“There is a huge range of nonspecific symptoms in the 5 years before MS diagnosis, and some of these are really intriguing and unanticipated,” Dr. Tremlett said. “We are not surprised by the findings that fatigue, mental health issues, and bladder and bowel symptoms are increased, but the finding that there are more visits to a dermatologist and an increase in prescriptions for skin conditions was completely unexpected.”
The researchers found that dermatology referrals increased in patients who went on to develop relapsing remitting but not primary progressive forms of MS, which correlates with the established knowledge that the relapsing form has an inflammatory component not seen in progressive MS.
In a large U.K. population study of 10,000 patients with MS and 39,000 matched controls sourced from primary care doctors’ records, there was an increase in gastrointestinal and urinary issues, pain, anxiety and depression, insomnia, and fatigue in the 10 years before the first diagnosis of MS or clinically isolated syndrome (CIS) in patients later diagnosed with those conditions, compared with controls, Dr. Tremlett reported.
Other data have suggested that sex and age may affect the prodrome. In a study published this year, anemia was increased in the year before the first demyelinating event and pain was increased for 5 years beforehand. But anemia was more common in male patients later diagnosed with MS/CIS (odds ratio compared with controls, 2.4) than in female patients (OR compared with controls, 1.2).
The increase in pain seemed to be greater with age, with ORs of 1.8 for those younger than 30 years, 2.1 for those age 30-49 years, and 2.4 for those older than 50 years compared with controls.
A Norwegian military study in men that included 900 patients with MS and 19,000 matched controls found that cognitive performance was reduced in the 2 years before MS symptoms developed and up to 20 years before symptoms in those who developed primary progressive MS. “This suggests that primary progressive MS could start decades before the first apparent symptoms become obvious,” Dr. Tremlett commented.
A study in pediatric MS found that the mothers of the patients had higher use of health care (rate ratio, 1.16) and mental health (rate ratio, 1.33) services in the 5 years before their children had their first demyelinating event.
A study in Bavaria, Germany, including 10,000 patients with MS and 73,000 controls, concluded that “many physician visits before MS diagnosis were, in hindsight, likely a demyelinating event,” with the implication that this is evidence of missed opportunity for earlier diagnosis, Dr. Tremlett noted.
In a 2019 study, psychiatric symptoms were more common before MS diagnosis across various different immune-mediated disease (MS, rheumatoid arthritis, inflammatory bowel disease), with an incidence rate ratio of 1.6. The rate was even increased 10 years before diagnosis (incidence rate ratio, 1.5).
“This is evidence for shared prodromal features across immune diseases, but there isn’t a single feature specific to MS,” Dr. Tremlett said. She also referred to evidence that the blood biomarker of neuronal damage, neurofilament light chain (NfL), is raised several years before MS diagnosis. In a U.S. military study that examined serum repository samples, NfL was increased for 6 years before disease onset in 30 patients with MS, compared with 30 matched controls.
What are the implications?
Dr. Tremlett said the immediate impact of these observations about the prodrome is focused on research, particularly investigation of risk factors for MS. “If we want to know what causes MS, we have to be very careful that we are not detecting prodromal symptoms and mistaking that for a causal MS risk factor. We need to make sure we look further back than just the last few years when looking for risk factors.”
She gave the example of the observation that women in the years before MS diagnosis are less likely to have a pregnancy and more likely to fill a prescription for contraception. “This has led to the idea that avoiding pregnancy and using contraceptives increases the risk of MS, but I interpret it as these women know that something odd is going on and make the lifestyle decision not to become pregnant.”
She believes the longer-term impact of the prodrome is going to require much thought. “There is no such diagnosis of prodromal MS at the moment, but there could be in future. But the idea that we can use this information to detect MS earlier is going to require collaboration from many international stakeholders and MS organizations. We can’t automatically suspect MS in people who have these symptoms because they are so nonspecific. I think to request an MRI in patients experiencing headaches/fatigue/bowel issues is jumping the gun at the present moment as these symptoms are very common.”
On the idea of measuring NfL in patients with some of these symptoms, she believes that may be a possibility in the future but much more data are required.“We do have some evidence suggesting that the NfL blood biomarker is raised before MS diagnosis, and this was from a very well-designed study, but it was small so I think it is too early to start looking at this in clinical practice,” she said. “But it does justify doing this as part of a research study. We definitely need more data on this. We must be cautious as NfL is not specific for MS – many other conditions are also associated with raised levels, but it is certainly an interesting marker if used carefully.”
Following in the footsteps of Parkinson disease
She suggested that the way forward will be to package up these symptoms with information on biomarkers, such as NfL and imaging information, to enhance the ability to identify prodromal MS. “We could create a risk score and when a certain level of confidence is reached that this could be prodromal MS, then these patients could be enrolled in an intervention research study.”
Dr. Tremlett pointed out that, in the Parkinson disease field, a set of validated criteria for a prodrome have already been identified. “This is not used in clinical practice yet, but it is being used to identify patients for enrollment into clinical trials. I’m hoping that MS will follow in their footsteps.”
Commenting on the presentation, ACTRIMS president, Jeffrey Cohen, MD, Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, said: “There is no doubt that the MS disease process begins prior to the first attack (in the case of relapsing MS) or the onset of overt disability progression (in the case of primary progressive MS).”
He explained that this is demonstrated by the presence of old lesions on MRI in most patients at the time of presentation, the existence of so-called radiologically isolated syndrome (patients without symptoms of MS who undergo MRI for another reason and are found to have lesions suggesting of MS, many of whom go on to develop MS at a later date), and the occurrence of a variety of symptoms 5-10 years before presentation to a neurologist.
“Those symptoms are ones that are common in MS, though not specific for MS,” Dr. Cohen noted. “The main implication is that the timeline for MS needs to be moved earlier – for diagnosis, categorization of disease course, prognostic studies, and treatment. The issue is that the symptoms of the prodrome are rather nonspecific and most people with those symptoms do not have MS.”
New incoming president of ECTRIMS, Maria Pia Amato, MD, professor of neurology at the University of Florence (Italy), added: “The million-dollar question is when does progression really begin? This plenary talk tells us the disease is there years and years before it manifests itself with first demyelinating event. This opens up an immense opportunity for research and to open the window to the possibility of earlier diagnosis and treatment.”
Dr. Tremlett reports an investment in Precision NanoSystems.
A version of this article originally appeared on Medscape.com.
FROM MSVIRTUAL2020
Sleep EEG may predict later antidepressant response
A change in rapid eye movement sleeping pattern as measured by quantitative EEG in patients with major depressive disorder after just a single week on a first-line antidepressant predicts eventual clinical response or nonresponse to the medication weeks later, Thorsten Mikoteit, MD, reported at the virtual congress of the European College of Neuropsychopharmacology.
This finding from a small, randomized, controlled trial opens the door to a novel biomarker-based treatment strategy: namely, an immediate switch to a different antidepressant in predicted nonresponders to the first agent. The goal is to improve the final treatment response rate while collapsing the time required to get there, explained Dr. Mikoteit, a psychiatrist affiliated with the University of Basel (Switzerland).
“In real terms, it means that patients, often in the depths of despair, might not need to wait weeks to see if their therapy is working before modifying their treatment,” he observed.
There is a huge unmet need for a biomarker predictive of response to antidepressant medication in patients with major depression, the psychiatrist added. At present, the treatment response rate is unsatisfactory. Moreover, clinical improvement takes a long time to achieve, often requiring several rounds of therapeutic trials during which patients are exposed to weeks of unpleasant side effects of drugs that are ultimately switched out for lack of efficacy or poor tolerance.
The quantitative EEG biomarker under investigation is prefrontal theta cordance (PTC) during REM sleep. It is computed from the absolute and relative theta power in tonic REM sleep. PTC has been shown to correlate with frontocingulate brain activity and cerebral blood perfusion. In an earlier pilot study, Dr. Mikoteit and coinvestigators demonstrated in 33 patients who were experiencing a depressive episode that an increase in PTC after their first week on an antidepressant was associated a significantly increased treatment response rate at the end of the fourth week on the drug, while nonresponders failed to show such increase (J Psychiatr Res. 2017 Sep;92:64-73).
At ECNP 2020, Dr. Mikoteit presented preliminary results from an ongoing randomized, controlled trial including 37 patients hospitalized for major depressive disorder. All underwent baseline evaluation using the Hamilton Depression Rating Scale (HAMD) and were placed on the first-line antidepressant of their psychiatrist’s choice. After 1 week of therapy, participants underwent polysomnography with PTC measurement during tonic REM sleep.
Twenty-two patients were randomized to the intervention arm, in which investigators informed treating psychiatrists of the PTC results. The clinicians were instructed to change to another antidepressant if the biomarker predicted nonresponse or stay the course if the PTC results were favorable. Polysomnography was repeated 1 week later in the intervention arm, and the second-line antidepressant was either continued or switched out depending on the PTC findings. In the control arm, psychiatrists weren’t informed of the PTC results and patients continued on their initial antidepressant. The intervention and control groups were comparable in terms of age, sex, and severity of depression, with an average baseline HAMD score of 22.
A treatment response was defined as at least a 50% reduction in HAMD score from baseline to week 5. About 86% of patients who switched antidepressants based upon their 1-week quantitative EEG findings were categorized as treatment responders at week 5, compared with 20% of controls.
The overall 5-week response rate in the intervention group was 73%, compared with 60% in the control arm. This favorable trend didn’t achieve statistical significance, presumably because of the study’s sample size; however, the study is continuing to enroll participants in order to achieve a definitive result.
Dr. Mikoteit noted that the cost and inconvenience of spending a night in a sleep laboratory would be worthwhile if it resulted in the ability to give effective treatment much sooner. This would be particularly advantageous in patients at increased risk for suicide.
he said.
Study could have “enormous implications”
Of note, in the landmark National Institute of Mental Health–sponsored Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, slightly less than half of patients with major depressive disorder achieved a treatment response to their first-line antidepressant, and it took an average of 6 weeks of therapy to do. About one in four nonresponders who chose to switch to a different antidepressant got better.
“The STAR*D trial is still the gold standard for understanding antidepressant response, and so being able to see if an antidepressant works within 1 week would be a real breakthrough,” Catherine Harmer, DPhil, said in an interview.
“Most of the time, patients need to wait for around 4 weeks before they can tell if they are responding to a particular antidepressant or not. This is a hugely disabling and lengthy process, and often a different treatment then needs to be started,” added Dr. Harmer, professor of cognitive neuroscience and director of the Psychopharmacology and Emotional Research Lab at the University of Oxford (England).
“If the study results presented by Dr. Mikoteit are replicated in a larger blinded study, then it would have enormous implications for the future treatment of individuals with depression,” according to Dr. Harmer, who was not involved in the study and has no conflicts of interest related to it.
Dr. Mikoteit reported having no financial conflicts regarding the study, funded by the Psychiatric University Hospital of Basel.
SOURCE: Mikoteit T et al. ECNP 2020, Abstract P.733.
A change in rapid eye movement sleeping pattern as measured by quantitative EEG in patients with major depressive disorder after just a single week on a first-line antidepressant predicts eventual clinical response or nonresponse to the medication weeks later, Thorsten Mikoteit, MD, reported at the virtual congress of the European College of Neuropsychopharmacology.
This finding from a small, randomized, controlled trial opens the door to a novel biomarker-based treatment strategy: namely, an immediate switch to a different antidepressant in predicted nonresponders to the first agent. The goal is to improve the final treatment response rate while collapsing the time required to get there, explained Dr. Mikoteit, a psychiatrist affiliated with the University of Basel (Switzerland).
“In real terms, it means that patients, often in the depths of despair, might not need to wait weeks to see if their therapy is working before modifying their treatment,” he observed.
There is a huge unmet need for a biomarker predictive of response to antidepressant medication in patients with major depression, the psychiatrist added. At present, the treatment response rate is unsatisfactory. Moreover, clinical improvement takes a long time to achieve, often requiring several rounds of therapeutic trials during which patients are exposed to weeks of unpleasant side effects of drugs that are ultimately switched out for lack of efficacy or poor tolerance.
The quantitative EEG biomarker under investigation is prefrontal theta cordance (PTC) during REM sleep. It is computed from the absolute and relative theta power in tonic REM sleep. PTC has been shown to correlate with frontocingulate brain activity and cerebral blood perfusion. In an earlier pilot study, Dr. Mikoteit and coinvestigators demonstrated in 33 patients who were experiencing a depressive episode that an increase in PTC after their first week on an antidepressant was associated a significantly increased treatment response rate at the end of the fourth week on the drug, while nonresponders failed to show such increase (J Psychiatr Res. 2017 Sep;92:64-73).
At ECNP 2020, Dr. Mikoteit presented preliminary results from an ongoing randomized, controlled trial including 37 patients hospitalized for major depressive disorder. All underwent baseline evaluation using the Hamilton Depression Rating Scale (HAMD) and were placed on the first-line antidepressant of their psychiatrist’s choice. After 1 week of therapy, participants underwent polysomnography with PTC measurement during tonic REM sleep.
Twenty-two patients were randomized to the intervention arm, in which investigators informed treating psychiatrists of the PTC results. The clinicians were instructed to change to another antidepressant if the biomarker predicted nonresponse or stay the course if the PTC results were favorable. Polysomnography was repeated 1 week later in the intervention arm, and the second-line antidepressant was either continued or switched out depending on the PTC findings. In the control arm, psychiatrists weren’t informed of the PTC results and patients continued on their initial antidepressant. The intervention and control groups were comparable in terms of age, sex, and severity of depression, with an average baseline HAMD score of 22.
A treatment response was defined as at least a 50% reduction in HAMD score from baseline to week 5. About 86% of patients who switched antidepressants based upon their 1-week quantitative EEG findings were categorized as treatment responders at week 5, compared with 20% of controls.
The overall 5-week response rate in the intervention group was 73%, compared with 60% in the control arm. This favorable trend didn’t achieve statistical significance, presumably because of the study’s sample size; however, the study is continuing to enroll participants in order to achieve a definitive result.
Dr. Mikoteit noted that the cost and inconvenience of spending a night in a sleep laboratory would be worthwhile if it resulted in the ability to give effective treatment much sooner. This would be particularly advantageous in patients at increased risk for suicide.
he said.
Study could have “enormous implications”
Of note, in the landmark National Institute of Mental Health–sponsored Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, slightly less than half of patients with major depressive disorder achieved a treatment response to their first-line antidepressant, and it took an average of 6 weeks of therapy to do. About one in four nonresponders who chose to switch to a different antidepressant got better.
“The STAR*D trial is still the gold standard for understanding antidepressant response, and so being able to see if an antidepressant works within 1 week would be a real breakthrough,” Catherine Harmer, DPhil, said in an interview.
“Most of the time, patients need to wait for around 4 weeks before they can tell if they are responding to a particular antidepressant or not. This is a hugely disabling and lengthy process, and often a different treatment then needs to be started,” added Dr. Harmer, professor of cognitive neuroscience and director of the Psychopharmacology and Emotional Research Lab at the University of Oxford (England).
“If the study results presented by Dr. Mikoteit are replicated in a larger blinded study, then it would have enormous implications for the future treatment of individuals with depression,” according to Dr. Harmer, who was not involved in the study and has no conflicts of interest related to it.
Dr. Mikoteit reported having no financial conflicts regarding the study, funded by the Psychiatric University Hospital of Basel.
SOURCE: Mikoteit T et al. ECNP 2020, Abstract P.733.
A change in rapid eye movement sleeping pattern as measured by quantitative EEG in patients with major depressive disorder after just a single week on a first-line antidepressant predicts eventual clinical response or nonresponse to the medication weeks later, Thorsten Mikoteit, MD, reported at the virtual congress of the European College of Neuropsychopharmacology.
This finding from a small, randomized, controlled trial opens the door to a novel biomarker-based treatment strategy: namely, an immediate switch to a different antidepressant in predicted nonresponders to the first agent. The goal is to improve the final treatment response rate while collapsing the time required to get there, explained Dr. Mikoteit, a psychiatrist affiliated with the University of Basel (Switzerland).
“In real terms, it means that patients, often in the depths of despair, might not need to wait weeks to see if their therapy is working before modifying their treatment,” he observed.
There is a huge unmet need for a biomarker predictive of response to antidepressant medication in patients with major depression, the psychiatrist added. At present, the treatment response rate is unsatisfactory. Moreover, clinical improvement takes a long time to achieve, often requiring several rounds of therapeutic trials during which patients are exposed to weeks of unpleasant side effects of drugs that are ultimately switched out for lack of efficacy or poor tolerance.
The quantitative EEG biomarker under investigation is prefrontal theta cordance (PTC) during REM sleep. It is computed from the absolute and relative theta power in tonic REM sleep. PTC has been shown to correlate with frontocingulate brain activity and cerebral blood perfusion. In an earlier pilot study, Dr. Mikoteit and coinvestigators demonstrated in 33 patients who were experiencing a depressive episode that an increase in PTC after their first week on an antidepressant was associated a significantly increased treatment response rate at the end of the fourth week on the drug, while nonresponders failed to show such increase (J Psychiatr Res. 2017 Sep;92:64-73).
At ECNP 2020, Dr. Mikoteit presented preliminary results from an ongoing randomized, controlled trial including 37 patients hospitalized for major depressive disorder. All underwent baseline evaluation using the Hamilton Depression Rating Scale (HAMD) and were placed on the first-line antidepressant of their psychiatrist’s choice. After 1 week of therapy, participants underwent polysomnography with PTC measurement during tonic REM sleep.
Twenty-two patients were randomized to the intervention arm, in which investigators informed treating psychiatrists of the PTC results. The clinicians were instructed to change to another antidepressant if the biomarker predicted nonresponse or stay the course if the PTC results were favorable. Polysomnography was repeated 1 week later in the intervention arm, and the second-line antidepressant was either continued or switched out depending on the PTC findings. In the control arm, psychiatrists weren’t informed of the PTC results and patients continued on their initial antidepressant. The intervention and control groups were comparable in terms of age, sex, and severity of depression, with an average baseline HAMD score of 22.
A treatment response was defined as at least a 50% reduction in HAMD score from baseline to week 5. About 86% of patients who switched antidepressants based upon their 1-week quantitative EEG findings were categorized as treatment responders at week 5, compared with 20% of controls.
The overall 5-week response rate in the intervention group was 73%, compared with 60% in the control arm. This favorable trend didn’t achieve statistical significance, presumably because of the study’s sample size; however, the study is continuing to enroll participants in order to achieve a definitive result.
Dr. Mikoteit noted that the cost and inconvenience of spending a night in a sleep laboratory would be worthwhile if it resulted in the ability to give effective treatment much sooner. This would be particularly advantageous in patients at increased risk for suicide.
he said.
Study could have “enormous implications”
Of note, in the landmark National Institute of Mental Health–sponsored Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, slightly less than half of patients with major depressive disorder achieved a treatment response to their first-line antidepressant, and it took an average of 6 weeks of therapy to do. About one in four nonresponders who chose to switch to a different antidepressant got better.
“The STAR*D trial is still the gold standard for understanding antidepressant response, and so being able to see if an antidepressant works within 1 week would be a real breakthrough,” Catherine Harmer, DPhil, said in an interview.
“Most of the time, patients need to wait for around 4 weeks before they can tell if they are responding to a particular antidepressant or not. This is a hugely disabling and lengthy process, and often a different treatment then needs to be started,” added Dr. Harmer, professor of cognitive neuroscience and director of the Psychopharmacology and Emotional Research Lab at the University of Oxford (England).
“If the study results presented by Dr. Mikoteit are replicated in a larger blinded study, then it would have enormous implications for the future treatment of individuals with depression,” according to Dr. Harmer, who was not involved in the study and has no conflicts of interest related to it.
Dr. Mikoteit reported having no financial conflicts regarding the study, funded by the Psychiatric University Hospital of Basel.
SOURCE: Mikoteit T et al. ECNP 2020, Abstract P.733.
FROM ECNP 2020
High plasma GFAP level predicts disability accumulation in secondary progressive MS
according to investigators. The biomarker appears to have a stronger correlation with disability in people with nonactive disease, compared with those with active disease. These data were presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
Astroglial injury and activation is one of the characteristic features of progressive MS. Following such injury, GFAP is released into the cerebrospinal fluid and blood.
“It may be that GFAP plays an especially important role in patients without focal inflammatory activity and is more associated with insidious progression,” said Jens Kuhle, MD, PhD, head of the MS center at University Hospital Basel (Switzerland). “This [finding] needs to be investigated further within the same cohort, but also [within] additional well-characterized other cohorts.”
Dr. Kuhle and colleagues examined GFAP as a prognostic biomarker of disability worsening by analyzing data for patients with active or nonactive secondary progressive MS who participated in the phase 3 EXPAND study, which compared siponimod with placebo. In this post hoc analysis, the investigators quantified baseline GFAP in plasma samples using single-molecule array technology. They categorized GFAP as high or low according to the gender-stratified 80th percentile.
Dr. Kuhle’s group assessed the effect of GFAP on time to an Expanded Disability Status Scale score of 7 (i.e., restriction to wheelchair) using a Cox regression model adjusted for age, gender, disease duration, treatment, relapses in the 24 months prior to study start, and baseline EDSS. In addition, they performed subgroup analyses in patients with active secondary progressive MS and those with nonactive secondary progressive MS. They defined active disease as having relapses at 24 or fewer months before study entry or gadolinium-enhancing T1 lesions at baseline. Participants without these characteristics were classified as having nonactive disease. The investigators also stratified the results by gender.
Correlation was strongest in nonactive disease
The current analysis included samples for 1,405 of the 1,651 patients who had been randomly assigned to treatment in the EXPAND study. The median GFAP level was 119.6 pg/mL among men and 141.4 pg/mL among women.
The risk of reaching an EDSS score of 7 was higher in patients with a high baseline GFAP level. Of 281 (12.1%) participants with a high baseline GFAP level, 34 reached this endpoint, compared with 54 of 1,117 (4.8%) participants with a low baseline GFAP level. For patients with a high GFAP level at baseline, the hazard ratio of this outcome was 1.96.
Subgroup analyses indicated that the increased risk of reaching an EDSS score of 7 was seen mainly in women. Of 169 women (13.6%) with high baseline GFAP level, 23 reached this endpoint, compared with 34 of 673 women (5.1%) without a high baseline GFAP level (HR, 2.22). Among men, the difference was not significant. Of 112 men (9.8%) with a high baseline GFAP level, 11 reached an EDSS score of 7, compared with 20 of 444 men (4.5%) without a high baseline GFAP level (HR, 1.45). The reason for this sex difference is unknown, said Dr. Kuhle. “A next important step is to ensure this [finding] is not influenced by other hidden factors.”
Dr. Kuhle and colleagues also found that the increase in risk of reaching an EDSS score of 7 was mainly observed in patients with nonactive secondary progressive MS. Among 133 such patients with a high baseline GFAP level, 14 (10.5%) reached this endpoint, compared with 22 of 570 patients (3.9%) without a high baseline GFAP level (HR, 3.40). The difference among patients with active secondary progressive MS was not significant (20 of 144 patients [13.9%] with high baseline GFAP level, compared with 30 of 521 patients [5.8%] without a high baseline GFAP level; HR, 1.58). Dr. Kuhle and colleagues found similar trends in the associations between baseline GFAP levels and time to 6-month confirmed disability progression, but these trends were less pronounced.
“The measurement of plasma or blood neurofilament light chain [NfL] is certainly closer to a potential clinical application than [the measurement of] GFAP,” Dr. Kuhle admitted. “However, highly sensitive platforms open the field to the fascinating possibility of finding meaningful biomarkers in the blood compartment in MS.” This development should be developed further. It is necessary to validate the significance of GFAP measures in individual patients and describe them with greater precision before they can be applied clinically. It also is necessary to create normative data and explore for the impact of other variables like age and comorbidities, he added.
“We are currently analyzing the EXPAND data further to see which characteristics at baseline and at end of study are driving plasma GFAP concentrations,” said Dr. Kuhle. “We also need to investigate whether progression events are captured accurately by GFAP in plasma. It will also be important to combine the GFAP data with NfL measures that are already available in this cohort.”
Study addresses a clinical need
“There is great need for a reliable, easy-to-measure, and relevant fluid biomarker for use in MS,” said Robert J. Fox, MD, staff neurologist at the Cleveland Clinic’s Mellen Center for MS. Neurofilaments have been a leading candidate among biomarkers, but researchers are exploring other candidates as well. An advantage of the present study is that Dr. Kuhle and colleagues examined a large number of patients with secondary progressive MS who underwent highly structured follow-up over several years, Dr. Fox said.
“What is most interesting is that the predictive capacity was greater in nonrelapsing secondary progressive MS, and so may have advantages over neurofilament in this group of patients,” he added. “Currently, GFAP is a research test and isn’t available for clinical practice.”
Researchers should investigate other ways in which GFAP is related to future disease activity (e.g., in the form of relapses or new MRI lesions) as well as to other measures of disability progression besides restriction to a wheelchair, said Dr. Fox. “Future research needs to examine whether this biomarker is helpful at the individual patient level. Can it guide a patient’s clinician toward treatment recommendations?”
This study was funded by Novartis. Neither Dr. Kuhle nor Dr. Fox had no relevant disclosures to report.
This article was updated 9/14/2020.
according to investigators. The biomarker appears to have a stronger correlation with disability in people with nonactive disease, compared with those with active disease. These data were presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
Astroglial injury and activation is one of the characteristic features of progressive MS. Following such injury, GFAP is released into the cerebrospinal fluid and blood.
“It may be that GFAP plays an especially important role in patients without focal inflammatory activity and is more associated with insidious progression,” said Jens Kuhle, MD, PhD, head of the MS center at University Hospital Basel (Switzerland). “This [finding] needs to be investigated further within the same cohort, but also [within] additional well-characterized other cohorts.”
Dr. Kuhle and colleagues examined GFAP as a prognostic biomarker of disability worsening by analyzing data for patients with active or nonactive secondary progressive MS who participated in the phase 3 EXPAND study, which compared siponimod with placebo. In this post hoc analysis, the investigators quantified baseline GFAP in plasma samples using single-molecule array technology. They categorized GFAP as high or low according to the gender-stratified 80th percentile.
Dr. Kuhle’s group assessed the effect of GFAP on time to an Expanded Disability Status Scale score of 7 (i.e., restriction to wheelchair) using a Cox regression model adjusted for age, gender, disease duration, treatment, relapses in the 24 months prior to study start, and baseline EDSS. In addition, they performed subgroup analyses in patients with active secondary progressive MS and those with nonactive secondary progressive MS. They defined active disease as having relapses at 24 or fewer months before study entry or gadolinium-enhancing T1 lesions at baseline. Participants without these characteristics were classified as having nonactive disease. The investigators also stratified the results by gender.
Correlation was strongest in nonactive disease
The current analysis included samples for 1,405 of the 1,651 patients who had been randomly assigned to treatment in the EXPAND study. The median GFAP level was 119.6 pg/mL among men and 141.4 pg/mL among women.
The risk of reaching an EDSS score of 7 was higher in patients with a high baseline GFAP level. Of 281 (12.1%) participants with a high baseline GFAP level, 34 reached this endpoint, compared with 54 of 1,117 (4.8%) participants with a low baseline GFAP level. For patients with a high GFAP level at baseline, the hazard ratio of this outcome was 1.96.
Subgroup analyses indicated that the increased risk of reaching an EDSS score of 7 was seen mainly in women. Of 169 women (13.6%) with high baseline GFAP level, 23 reached this endpoint, compared with 34 of 673 women (5.1%) without a high baseline GFAP level (HR, 2.22). Among men, the difference was not significant. Of 112 men (9.8%) with a high baseline GFAP level, 11 reached an EDSS score of 7, compared with 20 of 444 men (4.5%) without a high baseline GFAP level (HR, 1.45). The reason for this sex difference is unknown, said Dr. Kuhle. “A next important step is to ensure this [finding] is not influenced by other hidden factors.”
Dr. Kuhle and colleagues also found that the increase in risk of reaching an EDSS score of 7 was mainly observed in patients with nonactive secondary progressive MS. Among 133 such patients with a high baseline GFAP level, 14 (10.5%) reached this endpoint, compared with 22 of 570 patients (3.9%) without a high baseline GFAP level (HR, 3.40). The difference among patients with active secondary progressive MS was not significant (20 of 144 patients [13.9%] with high baseline GFAP level, compared with 30 of 521 patients [5.8%] without a high baseline GFAP level; HR, 1.58). Dr. Kuhle and colleagues found similar trends in the associations between baseline GFAP levels and time to 6-month confirmed disability progression, but these trends were less pronounced.
“The measurement of plasma or blood neurofilament light chain [NfL] is certainly closer to a potential clinical application than [the measurement of] GFAP,” Dr. Kuhle admitted. “However, highly sensitive platforms open the field to the fascinating possibility of finding meaningful biomarkers in the blood compartment in MS.” This development should be developed further. It is necessary to validate the significance of GFAP measures in individual patients and describe them with greater precision before they can be applied clinically. It also is necessary to create normative data and explore for the impact of other variables like age and comorbidities, he added.
“We are currently analyzing the EXPAND data further to see which characteristics at baseline and at end of study are driving plasma GFAP concentrations,” said Dr. Kuhle. “We also need to investigate whether progression events are captured accurately by GFAP in plasma. It will also be important to combine the GFAP data with NfL measures that are already available in this cohort.”
Study addresses a clinical need
“There is great need for a reliable, easy-to-measure, and relevant fluid biomarker for use in MS,” said Robert J. Fox, MD, staff neurologist at the Cleveland Clinic’s Mellen Center for MS. Neurofilaments have been a leading candidate among biomarkers, but researchers are exploring other candidates as well. An advantage of the present study is that Dr. Kuhle and colleagues examined a large number of patients with secondary progressive MS who underwent highly structured follow-up over several years, Dr. Fox said.
“What is most interesting is that the predictive capacity was greater in nonrelapsing secondary progressive MS, and so may have advantages over neurofilament in this group of patients,” he added. “Currently, GFAP is a research test and isn’t available for clinical practice.”
Researchers should investigate other ways in which GFAP is related to future disease activity (e.g., in the form of relapses or new MRI lesions) as well as to other measures of disability progression besides restriction to a wheelchair, said Dr. Fox. “Future research needs to examine whether this biomarker is helpful at the individual patient level. Can it guide a patient’s clinician toward treatment recommendations?”
This study was funded by Novartis. Neither Dr. Kuhle nor Dr. Fox had no relevant disclosures to report.
This article was updated 9/14/2020.
according to investigators. The biomarker appears to have a stronger correlation with disability in people with nonactive disease, compared with those with active disease. These data were presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
Astroglial injury and activation is one of the characteristic features of progressive MS. Following such injury, GFAP is released into the cerebrospinal fluid and blood.
“It may be that GFAP plays an especially important role in patients without focal inflammatory activity and is more associated with insidious progression,” said Jens Kuhle, MD, PhD, head of the MS center at University Hospital Basel (Switzerland). “This [finding] needs to be investigated further within the same cohort, but also [within] additional well-characterized other cohorts.”
Dr. Kuhle and colleagues examined GFAP as a prognostic biomarker of disability worsening by analyzing data for patients with active or nonactive secondary progressive MS who participated in the phase 3 EXPAND study, which compared siponimod with placebo. In this post hoc analysis, the investigators quantified baseline GFAP in plasma samples using single-molecule array technology. They categorized GFAP as high or low according to the gender-stratified 80th percentile.
Dr. Kuhle’s group assessed the effect of GFAP on time to an Expanded Disability Status Scale score of 7 (i.e., restriction to wheelchair) using a Cox regression model adjusted for age, gender, disease duration, treatment, relapses in the 24 months prior to study start, and baseline EDSS. In addition, they performed subgroup analyses in patients with active secondary progressive MS and those with nonactive secondary progressive MS. They defined active disease as having relapses at 24 or fewer months before study entry or gadolinium-enhancing T1 lesions at baseline. Participants without these characteristics were classified as having nonactive disease. The investigators also stratified the results by gender.
Correlation was strongest in nonactive disease
The current analysis included samples for 1,405 of the 1,651 patients who had been randomly assigned to treatment in the EXPAND study. The median GFAP level was 119.6 pg/mL among men and 141.4 pg/mL among women.
The risk of reaching an EDSS score of 7 was higher in patients with a high baseline GFAP level. Of 281 (12.1%) participants with a high baseline GFAP level, 34 reached this endpoint, compared with 54 of 1,117 (4.8%) participants with a low baseline GFAP level. For patients with a high GFAP level at baseline, the hazard ratio of this outcome was 1.96.
Subgroup analyses indicated that the increased risk of reaching an EDSS score of 7 was seen mainly in women. Of 169 women (13.6%) with high baseline GFAP level, 23 reached this endpoint, compared with 34 of 673 women (5.1%) without a high baseline GFAP level (HR, 2.22). Among men, the difference was not significant. Of 112 men (9.8%) with a high baseline GFAP level, 11 reached an EDSS score of 7, compared with 20 of 444 men (4.5%) without a high baseline GFAP level (HR, 1.45). The reason for this sex difference is unknown, said Dr. Kuhle. “A next important step is to ensure this [finding] is not influenced by other hidden factors.”
Dr. Kuhle and colleagues also found that the increase in risk of reaching an EDSS score of 7 was mainly observed in patients with nonactive secondary progressive MS. Among 133 such patients with a high baseline GFAP level, 14 (10.5%) reached this endpoint, compared with 22 of 570 patients (3.9%) without a high baseline GFAP level (HR, 3.40). The difference among patients with active secondary progressive MS was not significant (20 of 144 patients [13.9%] with high baseline GFAP level, compared with 30 of 521 patients [5.8%] without a high baseline GFAP level; HR, 1.58). Dr. Kuhle and colleagues found similar trends in the associations between baseline GFAP levels and time to 6-month confirmed disability progression, but these trends were less pronounced.
“The measurement of plasma or blood neurofilament light chain [NfL] is certainly closer to a potential clinical application than [the measurement of] GFAP,” Dr. Kuhle admitted. “However, highly sensitive platforms open the field to the fascinating possibility of finding meaningful biomarkers in the blood compartment in MS.” This development should be developed further. It is necessary to validate the significance of GFAP measures in individual patients and describe them with greater precision before they can be applied clinically. It also is necessary to create normative data and explore for the impact of other variables like age and comorbidities, he added.
“We are currently analyzing the EXPAND data further to see which characteristics at baseline and at end of study are driving plasma GFAP concentrations,” said Dr. Kuhle. “We also need to investigate whether progression events are captured accurately by GFAP in plasma. It will also be important to combine the GFAP data with NfL measures that are already available in this cohort.”
Study addresses a clinical need
“There is great need for a reliable, easy-to-measure, and relevant fluid biomarker for use in MS,” said Robert J. Fox, MD, staff neurologist at the Cleveland Clinic’s Mellen Center for MS. Neurofilaments have been a leading candidate among biomarkers, but researchers are exploring other candidates as well. An advantage of the present study is that Dr. Kuhle and colleagues examined a large number of patients with secondary progressive MS who underwent highly structured follow-up over several years, Dr. Fox said.
“What is most interesting is that the predictive capacity was greater in nonrelapsing secondary progressive MS, and so may have advantages over neurofilament in this group of patients,” he added. “Currently, GFAP is a research test and isn’t available for clinical practice.”
Researchers should investigate other ways in which GFAP is related to future disease activity (e.g., in the form of relapses or new MRI lesions) as well as to other measures of disability progression besides restriction to a wheelchair, said Dr. Fox. “Future research needs to examine whether this biomarker is helpful at the individual patient level. Can it guide a patient’s clinician toward treatment recommendations?”
This study was funded by Novartis. Neither Dr. Kuhle nor Dr. Fox had no relevant disclosures to report.
This article was updated 9/14/2020.
FROM MSVIRTUAL2020
ISCHEMIA trial revisited: Some MAY benefit from invasive strategy
The landmark ISCHEMIA trial rattled the cardiology world with its message that clinical outcomes weren’t significantly better with a routine initial invasive strategy than with medical therapy alone in patients with stable coronary artery disease and moderate or severe myocardial ischemia on noninvasive testing. But
ISCHEMIA participants in the sweet spot for an initial invasive strategy were the ones with a baseline history of mild to moderate heart failure symptoms and a left ventricular ejection fraction (LVEF) of 35%-45%, Renato Lopes, MD, PhD, reported at the virtual annual congress of the European Society of Cardiology.
“An invasive approach may be beneficial in this subgroup of high-risk patients with moderate to severe ischemia and a history of heart failure and left ventricular dysfunction,” declared Dr. Lopes, professor of medicine at Duke University, Durham, N.C.
He was quick to add, however, that this finding from ISCHEMIA should be considered hypothesis generating in light of the small sample size in the subgroup analysis.
The ISCHEMIA trial randomized 5,179 patients with stable CAD and at least moderate myocardial ischemia on noninvasive testing to a routine invasive or conservative management strategy. At 4 years of follow-up there was no significant between-group difference in cardiovascular outcomes (N Engl J Med. 2020 Apr 9;382[15]:1395-407).
Patients with a baseline LVEF below 35% weren’t eligible for enrollment in ISCHEMIA. That’s because the prior Surgical Treatment for Ischemic Heart Failure Extension Study (STICHES) showed patients with ischemic cardiomyopathy and an LVEF below 35% had a significantly lower cardiovascular death rate with surgical revascularization plus medical therapy than optimal medical therapy alone at 10 years of follow-up (N Engl J Med. 2016 Apr 21;374[16]:1511-20).
But what about the impact of immediate revascularization as compared with medical management alone in patients with milder impairment of LVEF in the 35%-45% range and/or a history of symptomatic heart failure? Theoretically, the improved blood flow to ischemic myocardium obtained via revascularization in such patients might activate hibernating myocardium and reduce ventricular dysfunction, thereby reducing the risk of cardiovascular events. The ISCHEMIA trial provided a unique opportunity to prospectively examine this question in 398 affected study participants, Dr. Lopes explained.
This 398-patient subgroup with a baseline history of heart failure and/or left ventricular dysfunction (HF/LVD) was at higher risk than patients without those features. Indeed, the primary outcome in ISCHEMIA – a composite of cardiovascular death, nonfatal MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest – occurred in 22.7% of the HF/LVD group at 4 years of follow-up, compared with 13.8% of the much larger group without HF/LVD. The HF/LVD group also had significantly higher rates of the secondary composite endpoints of cardiovascular death or MI (19.7% vs. 12.3%) and all-cause mortality or heart failure (15% vs. 6.9%).
The provocative central finding in this new subanalysis was that patients in the HF/LVD subgroup fared significantly better in terms of cardiovascular events if randomized to the initial invasive approach. Indeed, their 4-year rate of the primary outcome was 17.2%, compared with 29.3% with an initial conservative approach. The various secondary outcomes followed suit. In contrast, the primary outcome occurred in 13% of patients without HF/LVD who were randomized to the invasive strategy, not significantly different from the 14.6% rate with conservative management.
Drilling deeper into the data, Dr. Lopes and coinvestigators found that the enhanced event-free survival benefit of an initial invasive strategy was restricted to the 28 patients having both a baseline history of symptomatic heart failure and an LVEF of 35%-45%. There was no significant difference in outcomes with an invasive versus conservative strategy in the 177 patients with a history of heart failure whose LVEF was greater than 50% – that is, patients with heart failure with preserved ejection fraction – nor in the 193 participants with an LVEF of 35%-45% but no history of symptomatic heart failure.
In an interview, Mark H. Drazner, MD, commented, “this is an interesting hypothesis, for sure, that warrants further study to confirm whether it’s valid. And if it is valid, there could be real implications. If this is true, I think there could be a decent number of patients out there that this would have implications for.
“The ISCHEMIA trial was a heroic effort. While there are certainly logistical hurdles involved in anybody doing an ISCHEMIA 2 trial based on this small subgroup analysis, other people could start looking at retrospective datasets and see if they can confirm these findings to build momentum to study this further,” said Dr. Drazner, professor of medicine and chief of clinical cardiology at the University of Texas Southwestern Medical Center, Dallas, as well as an associate editor at Circulation.
Dr. Lopes reported receiving research grants from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi-Aventis as well as serving as a consultant to a handful of pharmaceutical companies, none relevant to his presentation.
Simultaneous with his presentation at ESC Congress 2020, Dr. Lopes’ study was published online in Circulation.
SOURCE: Lopes R et al. Circulation. 2020 Aug 29. doi: 10.1161/CIRCULATIONAHA.120.050304.
The landmark ISCHEMIA trial rattled the cardiology world with its message that clinical outcomes weren’t significantly better with a routine initial invasive strategy than with medical therapy alone in patients with stable coronary artery disease and moderate or severe myocardial ischemia on noninvasive testing. But
ISCHEMIA participants in the sweet spot for an initial invasive strategy were the ones with a baseline history of mild to moderate heart failure symptoms and a left ventricular ejection fraction (LVEF) of 35%-45%, Renato Lopes, MD, PhD, reported at the virtual annual congress of the European Society of Cardiology.
“An invasive approach may be beneficial in this subgroup of high-risk patients with moderate to severe ischemia and a history of heart failure and left ventricular dysfunction,” declared Dr. Lopes, professor of medicine at Duke University, Durham, N.C.
He was quick to add, however, that this finding from ISCHEMIA should be considered hypothesis generating in light of the small sample size in the subgroup analysis.
The ISCHEMIA trial randomized 5,179 patients with stable CAD and at least moderate myocardial ischemia on noninvasive testing to a routine invasive or conservative management strategy. At 4 years of follow-up there was no significant between-group difference in cardiovascular outcomes (N Engl J Med. 2020 Apr 9;382[15]:1395-407).
Patients with a baseline LVEF below 35% weren’t eligible for enrollment in ISCHEMIA. That’s because the prior Surgical Treatment for Ischemic Heart Failure Extension Study (STICHES) showed patients with ischemic cardiomyopathy and an LVEF below 35% had a significantly lower cardiovascular death rate with surgical revascularization plus medical therapy than optimal medical therapy alone at 10 years of follow-up (N Engl J Med. 2016 Apr 21;374[16]:1511-20).
But what about the impact of immediate revascularization as compared with medical management alone in patients with milder impairment of LVEF in the 35%-45% range and/or a history of symptomatic heart failure? Theoretically, the improved blood flow to ischemic myocardium obtained via revascularization in such patients might activate hibernating myocardium and reduce ventricular dysfunction, thereby reducing the risk of cardiovascular events. The ISCHEMIA trial provided a unique opportunity to prospectively examine this question in 398 affected study participants, Dr. Lopes explained.
This 398-patient subgroup with a baseline history of heart failure and/or left ventricular dysfunction (HF/LVD) was at higher risk than patients without those features. Indeed, the primary outcome in ISCHEMIA – a composite of cardiovascular death, nonfatal MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest – occurred in 22.7% of the HF/LVD group at 4 years of follow-up, compared with 13.8% of the much larger group without HF/LVD. The HF/LVD group also had significantly higher rates of the secondary composite endpoints of cardiovascular death or MI (19.7% vs. 12.3%) and all-cause mortality or heart failure (15% vs. 6.9%).
The provocative central finding in this new subanalysis was that patients in the HF/LVD subgroup fared significantly better in terms of cardiovascular events if randomized to the initial invasive approach. Indeed, their 4-year rate of the primary outcome was 17.2%, compared with 29.3% with an initial conservative approach. The various secondary outcomes followed suit. In contrast, the primary outcome occurred in 13% of patients without HF/LVD who were randomized to the invasive strategy, not significantly different from the 14.6% rate with conservative management.
Drilling deeper into the data, Dr. Lopes and coinvestigators found that the enhanced event-free survival benefit of an initial invasive strategy was restricted to the 28 patients having both a baseline history of symptomatic heart failure and an LVEF of 35%-45%. There was no significant difference in outcomes with an invasive versus conservative strategy in the 177 patients with a history of heart failure whose LVEF was greater than 50% – that is, patients with heart failure with preserved ejection fraction – nor in the 193 participants with an LVEF of 35%-45% but no history of symptomatic heart failure.
In an interview, Mark H. Drazner, MD, commented, “this is an interesting hypothesis, for sure, that warrants further study to confirm whether it’s valid. And if it is valid, there could be real implications. If this is true, I think there could be a decent number of patients out there that this would have implications for.
“The ISCHEMIA trial was a heroic effort. While there are certainly logistical hurdles involved in anybody doing an ISCHEMIA 2 trial based on this small subgroup analysis, other people could start looking at retrospective datasets and see if they can confirm these findings to build momentum to study this further,” said Dr. Drazner, professor of medicine and chief of clinical cardiology at the University of Texas Southwestern Medical Center, Dallas, as well as an associate editor at Circulation.
Dr. Lopes reported receiving research grants from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi-Aventis as well as serving as a consultant to a handful of pharmaceutical companies, none relevant to his presentation.
Simultaneous with his presentation at ESC Congress 2020, Dr. Lopes’ study was published online in Circulation.
SOURCE: Lopes R et al. Circulation. 2020 Aug 29. doi: 10.1161/CIRCULATIONAHA.120.050304.
The landmark ISCHEMIA trial rattled the cardiology world with its message that clinical outcomes weren’t significantly better with a routine initial invasive strategy than with medical therapy alone in patients with stable coronary artery disease and moderate or severe myocardial ischemia on noninvasive testing. But
ISCHEMIA participants in the sweet spot for an initial invasive strategy were the ones with a baseline history of mild to moderate heart failure symptoms and a left ventricular ejection fraction (LVEF) of 35%-45%, Renato Lopes, MD, PhD, reported at the virtual annual congress of the European Society of Cardiology.
“An invasive approach may be beneficial in this subgroup of high-risk patients with moderate to severe ischemia and a history of heart failure and left ventricular dysfunction,” declared Dr. Lopes, professor of medicine at Duke University, Durham, N.C.
He was quick to add, however, that this finding from ISCHEMIA should be considered hypothesis generating in light of the small sample size in the subgroup analysis.
The ISCHEMIA trial randomized 5,179 patients with stable CAD and at least moderate myocardial ischemia on noninvasive testing to a routine invasive or conservative management strategy. At 4 years of follow-up there was no significant between-group difference in cardiovascular outcomes (N Engl J Med. 2020 Apr 9;382[15]:1395-407).
Patients with a baseline LVEF below 35% weren’t eligible for enrollment in ISCHEMIA. That’s because the prior Surgical Treatment for Ischemic Heart Failure Extension Study (STICHES) showed patients with ischemic cardiomyopathy and an LVEF below 35% had a significantly lower cardiovascular death rate with surgical revascularization plus medical therapy than optimal medical therapy alone at 10 years of follow-up (N Engl J Med. 2016 Apr 21;374[16]:1511-20).
But what about the impact of immediate revascularization as compared with medical management alone in patients with milder impairment of LVEF in the 35%-45% range and/or a history of symptomatic heart failure? Theoretically, the improved blood flow to ischemic myocardium obtained via revascularization in such patients might activate hibernating myocardium and reduce ventricular dysfunction, thereby reducing the risk of cardiovascular events. The ISCHEMIA trial provided a unique opportunity to prospectively examine this question in 398 affected study participants, Dr. Lopes explained.
This 398-patient subgroup with a baseline history of heart failure and/or left ventricular dysfunction (HF/LVD) was at higher risk than patients without those features. Indeed, the primary outcome in ISCHEMIA – a composite of cardiovascular death, nonfatal MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest – occurred in 22.7% of the HF/LVD group at 4 years of follow-up, compared with 13.8% of the much larger group without HF/LVD. The HF/LVD group also had significantly higher rates of the secondary composite endpoints of cardiovascular death or MI (19.7% vs. 12.3%) and all-cause mortality or heart failure (15% vs. 6.9%).
The provocative central finding in this new subanalysis was that patients in the HF/LVD subgroup fared significantly better in terms of cardiovascular events if randomized to the initial invasive approach. Indeed, their 4-year rate of the primary outcome was 17.2%, compared with 29.3% with an initial conservative approach. The various secondary outcomes followed suit. In contrast, the primary outcome occurred in 13% of patients without HF/LVD who were randomized to the invasive strategy, not significantly different from the 14.6% rate with conservative management.
Drilling deeper into the data, Dr. Lopes and coinvestigators found that the enhanced event-free survival benefit of an initial invasive strategy was restricted to the 28 patients having both a baseline history of symptomatic heart failure and an LVEF of 35%-45%. There was no significant difference in outcomes with an invasive versus conservative strategy in the 177 patients with a history of heart failure whose LVEF was greater than 50% – that is, patients with heart failure with preserved ejection fraction – nor in the 193 participants with an LVEF of 35%-45% but no history of symptomatic heart failure.
In an interview, Mark H. Drazner, MD, commented, “this is an interesting hypothesis, for sure, that warrants further study to confirm whether it’s valid. And if it is valid, there could be real implications. If this is true, I think there could be a decent number of patients out there that this would have implications for.
“The ISCHEMIA trial was a heroic effort. While there are certainly logistical hurdles involved in anybody doing an ISCHEMIA 2 trial based on this small subgroup analysis, other people could start looking at retrospective datasets and see if they can confirm these findings to build momentum to study this further,” said Dr. Drazner, professor of medicine and chief of clinical cardiology at the University of Texas Southwestern Medical Center, Dallas, as well as an associate editor at Circulation.
Dr. Lopes reported receiving research grants from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi-Aventis as well as serving as a consultant to a handful of pharmaceutical companies, none relevant to his presentation.
Simultaneous with his presentation at ESC Congress 2020, Dr. Lopes’ study was published online in Circulation.
SOURCE: Lopes R et al. Circulation. 2020 Aug 29. doi: 10.1161/CIRCULATIONAHA.120.050304.
FROM ESC CONGRESS 2020