When the COVID-19 pandemic engulfed the nation well over a year ago, Rebecca Hendrickson, MD, PhD, immersed herself in the shell-shocking revelations that clinicians began posting on social media. The accounts offered just a snapshot of the pandemic’s heavy psychological toll, and Dr. Hendrickson, a psychiatrist at the University of Washington in Seattle and an expert in posttraumatic stress disorder (PTSD), wanted to know more.

xavierarnau/Getty Images

She and her colleagues devised a survey to assess the impact of several pandemic-related factors, including increased work hours, social distancing restrictions, and lack of adequate personal protective equipment.

What began as a survey of health care workers soon expanded in scope. Of the more than 600 survey respondents to date, health care workers account for about 60%, while the rest are first responders – police officers, firefighters, paramedics, and emergency medical technicians – and nonclinical personnel, such as security guards and office staff, in health care settings. The respondents range in age from 19 to 72, and hail from all regions of the country.

“Our findings were really striking,” Dr. Hendrickson said, “including very high rates of thoughts of suicide and thoughts of leaving one’s current field, which were both strongly linked to COVID-19–related occupational stress exposure.”

The distress stemmed from a multitude of factors. Among the most demoralizing: witnessing patients die in isolation and being stretched thin to provide optimal care for all patients amid an unrelenting onslaught of COVID-19 cases, she said. For some health care workers, living in the garage or basement – to avoid infecting family members with the virus – also wore on their psyches.

Of all health care workers in the study, more than three-quarters reported symptoms that fell within the clinical range for depression (76%) and anxiety (78%). More than 25% noted that they had lost a family member or close colleague to the virus.

Dr. Hendrickson, who works with military veterans at the VA Puget Sound Hospital System’s Mental Illness Research, Education, and Clinical Center and its PTSD outpatient clinic, hadn’t expected the experience of loss to be so pervasive. She said the sheer number of people who “crossed the threshold” into despair concerned her deeply.
 

Signs and symptoms of PTSD

PTSD’s prevalence among health care workers has always been variable, said Jessica Gold, MD, assistant professor and director of wellness, engagement, and outreach in the department of psychiatry at Washington University in St. Louis.

As a psychiatrist who sees health care workers in her clinical practice, Dr. Gold has noted poor baseline mental health, including depression and trauma. Significant data have pointed to a relatively higher suicide rate among physicians than among the general population. These problems have been compounded by COVID-19.

“It has been an unrelenting series of new stressors,” she said, citing lack of resources; a feeling of being unable to help; and the high frequency of risk of death to patients, family and friends, and the caregivers themselves as just as few examples. “It is very likely going to increase our baseline trauma, and honestly, I don’t know that we can predict how. To me, trauma has no real timeline and can show up months or even years after the pandemic.”

PTSD can manifest itself in health care workers in several different ways. A few commonalities Dr. Gold has observed are sleep disruption (including insomnia and nightmares), work avoidance by taking disability or quitting, irritability or other changes in mood, trouble concentrating, and hypervigilance.

She said she has seen physical manifestations of trauma – such as body pain, stomachaches, and teeth grinding, which “you might not realize are at all related to trauma but ultimately are.” Sometimes, she added, “people have panic attacks on the way to work or right when they get to work, or are thinking about work.”

Dr. Gold noted that different types of treatment, such as cognitive-behavioral therapy and eye movement desensitization and reprocessing (EMDR), can be effective for PTSD. Medication is often necessary because of comorbid anxiety, depression, or eating disorders, said Dr. Gold, who is conducting a study on the pandemic’s effects on medical students.
 

The difficulties in isolating COVID-19 as a contributor

Not all researchers are convinced that a causal relationship has been established between the pandemic and worsening mental health among those in the health care sector.

With provider burnout being a long-standing concern in medicine, Ankur A. Butala, MD, assistant professor of neurology, psychiatry, and behavioral sciences at the Johns Hopkins University, Baltimore, said he remains a bit skeptical that acute stressors during the pandemic amounted to a uniquely potent driving force that can be extrapolated and quantified in a study.

“It’s hard to interpret a chronic, rolling, ongoing trauma like COVID-19 against tools or scales developed to investigate symptoms from a singular and acute trauma, like a school shooting or a [military] firefight,” Dr. Butala said.

In addition, he noted a reluctance to generalizing results from a study in which participants were recruited via social media as opposed to research methods involving more rigorous selection protocols.

Although Dr. Hendrickson acknowledged the study’s limitations, she said her team nonetheless found strong correlations between COVID-19-related stressors and self-reported struggles in completing work-related tasks, as well as increasing thoughts of leaving one’s current field. They adjusted for previous lifetime trauma exposure, age, gender, and a personal history of contracting COVID-19.

The underlying premise of the study could be confirmed with repeated surveys over time, Dr. Butala said, as the COVID-19 pandemic evolves and the vaccination effort unfolds.

Follow-up surveys are being sent to participants every 2 weeks and every 3 months to gauge their mood, for a total follow-up period of 9 months per individual. New participants are still welcome. “We will continue to enroll as long as it seems relevant,” Dr. Hendrickson said.

Carol S. North, MD, MPE, who has added to the growing research on the pandemic’s toll on mental health, noted that because symptom scales do not provide psychiatric diagnoses, it is difficult to attribute the prevalence of psychiatric disorders to the pandemic. Dr. North is chair and professor of crisis psychiatry at UT Southwestern Medical Center in Dallas, and director of the program in trauma and disaster at VA North Texas Health Care System.

The DSM-5 criteria exclude naturally occurring illness, such as a virus (even during a pandemic) as a qualifying trauma for the diagnosis of PTSD. According to current criteria by the American Psychiatric Association, COVID-19 and the pandemic are not defined as trauma, Dr. North said, while noting that “just because it’s not trauma or PTSD does not mean that the pandemic should be discounted as not stressful; people are finding it very stressful.”

Identifying the exact source of distress would still be difficult, Dr. North said, as the pandemic has produced severe economic consequences and prolonged social isolation, as well as occurring alongside nationwide protests over racial and ethnic divisions. Studies to date haven’t effectively separated out for these stressors, making it impossible to weigh their relative impact.

Furthermore, “most of us face many other stressors in our daily lives, such as grief, losses, broken relationships, and personal failures,” she said. “All of these may contribute to psychological distress, and research is needed to determine how much was a product of the virus, other aspects of the pandemic, or unrelated life stressors.”
 

A rallying cry for new interventions

Despite such doubts, a growing number of studies are reporting that health care workers and first responders are experiencing intensified PTSD, depression, anxiety, and insomnia as a result of the pandemic, said Hrayr Pierre Attarian, MD, professor of neurology at Northwestern University, Chicago. These results should act as a rallying cry for implementing more policies tailored to prevent burnout, he said.

“What we are seeing during this terrible pandemic is burnout on steroids,” said Dr. Attarian, medical director of Northwestern’s Center for Sleep Disorders. There are already high burnout rates, “so this should be doubly important.”

Rooting out this problem starts at the institutional level, but merely advising providers to “be well” wouldn’t make inroads. “There needs to be fluid dialogue between health care workers and the leadership,” he said.

Among his proposed remedies: Access to confidential and free mental health resources, increased administrative support, flexible hours, respect for work-life balance, and forgiveness for occasional errors that don’t result in harm.

“Sometimes even the perception that a mistake has been made is taken as proof of guilt,” Dr. Attarian said. “It is not conducive to wellness. Extra income does not replace a nurturing work environment.”

Furthermore, “as a profession, we must stop glorifying ‘overwork.’ We must stop wearing ‘lack of sleep’ as badge of honor,” he said. “Sleep is a biological imperative like self-preservation, hunger, and thirst. When we don’t sleep anxiety, pain, and depression get amplified. Our perception of distress is off, as is our judgment.”

The Federation of State Physician Health Programs provides a directory that physicians can use for referrals to confidential consultation or treatment.

Christopher Bundy, MD, MPH, executive medical director of Washington Physicians Health Program in Seattle, has been following Dr. Hendrickson’s longitudinal study with keen interest. As president of the Federation of State Physician Health Programs, he hopes to translate the findings into practice.

“Obviously, the COVID-19 pandemic has been a ‘black swan’ in terms of workforce sustainability issues,” Dr. Bundy said, citing “high rates of burnout, disillusionment, and dissatisfaction.” He sees some similarities with his former role in treating war veterans.

“The invisible wounds of combat, the psychological scars don’t really become apparent until after you’re out of the war zone,” said Dr. Bundy, clinical associate professor of psychiatry at the University of Washington.

Likewise, he expects the “emotional chickens will come home to roost as the pandemic subsides.” Until then, “people are just focused on survival, and in doing their jobs and protecting their patients.” Eventually, “their own wounds inside the pandemic will take hold.”
 

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

When the COVID-19 pandemic engulfed the nation well over a year ago, Rebecca Hendrickson, MD, PhD, immersed herself in the shell-shocking revelations that clinicians began posting on social media. The accounts offered just a snapshot of the pandemic’s heavy psychological toll, and Dr. Hendrickson, a psychiatrist at the University of Washington in Seattle and an expert in posttraumatic stress disorder (PTSD), wanted to know more.

xavierarnau/Getty Images

She and her colleagues devised a survey to assess the impact of several pandemic-related factors, including increased work hours, social distancing restrictions, and lack of adequate personal protective equipment.

What began as a survey of health care workers soon expanded in scope. Of the more than 600 survey respondents to date, health care workers account for about 60%, while the rest are first responders – police officers, firefighters, paramedics, and emergency medical technicians – and nonclinical personnel, such as security guards and office staff, in health care settings. The respondents range in age from 19 to 72, and hail from all regions of the country.

“Our findings were really striking,” Dr. Hendrickson said, “including very high rates of thoughts of suicide and thoughts of leaving one’s current field, which were both strongly linked to COVID-19–related occupational stress exposure.”

The distress stemmed from a multitude of factors. Among the most demoralizing: witnessing patients die in isolation and being stretched thin to provide optimal care for all patients amid an unrelenting onslaught of COVID-19 cases, she said. For some health care workers, living in the garage or basement – to avoid infecting family members with the virus – also wore on their psyches.

Of all health care workers in the study, more than three-quarters reported symptoms that fell within the clinical range for depression (76%) and anxiety (78%). More than 25% noted that they had lost a family member or close colleague to the virus.

Dr. Hendrickson, who works with military veterans at the VA Puget Sound Hospital System’s Mental Illness Research, Education, and Clinical Center and its PTSD outpatient clinic, hadn’t expected the experience of loss to be so pervasive. She said the sheer number of people who “crossed the threshold” into despair concerned her deeply.
 

Signs and symptoms of PTSD

PTSD’s prevalence among health care workers has always been variable, said Jessica Gold, MD, assistant professor and director of wellness, engagement, and outreach in the department of psychiatry at Washington University in St. Louis.

As a psychiatrist who sees health care workers in her clinical practice, Dr. Gold has noted poor baseline mental health, including depression and trauma. Significant data have pointed to a relatively higher suicide rate among physicians than among the general population. These problems have been compounded by COVID-19.

“It has been an unrelenting series of new stressors,” she said, citing lack of resources; a feeling of being unable to help; and the high frequency of risk of death to patients, family and friends, and the caregivers themselves as just as few examples. “It is very likely going to increase our baseline trauma, and honestly, I don’t know that we can predict how. To me, trauma has no real timeline and can show up months or even years after the pandemic.”

PTSD can manifest itself in health care workers in several different ways. A few commonalities Dr. Gold has observed are sleep disruption (including insomnia and nightmares), work avoidance by taking disability or quitting, irritability or other changes in mood, trouble concentrating, and hypervigilance.

She said she has seen physical manifestations of trauma – such as body pain, stomachaches, and teeth grinding, which “you might not realize are at all related to trauma but ultimately are.” Sometimes, she added, “people have panic attacks on the way to work or right when they get to work, or are thinking about work.”

Dr. Gold noted that different types of treatment, such as cognitive-behavioral therapy and eye movement desensitization and reprocessing (EMDR), can be effective for PTSD. Medication is often necessary because of comorbid anxiety, depression, or eating disorders, said Dr. Gold, who is conducting a study on the pandemic’s effects on medical students.
 

The difficulties in isolating COVID-19 as a contributor

Not all researchers are convinced that a causal relationship has been established between the pandemic and worsening mental health among those in the health care sector.

With provider burnout being a long-standing concern in medicine, Ankur A. Butala, MD, assistant professor of neurology, psychiatry, and behavioral sciences at the Johns Hopkins University, Baltimore, said he remains a bit skeptical that acute stressors during the pandemic amounted to a uniquely potent driving force that can be extrapolated and quantified in a study.

“It’s hard to interpret a chronic, rolling, ongoing trauma like COVID-19 against tools or scales developed to investigate symptoms from a singular and acute trauma, like a school shooting or a [military] firefight,” Dr. Butala said.

In addition, he noted a reluctance to generalizing results from a study in which participants were recruited via social media as opposed to research methods involving more rigorous selection protocols.

Although Dr. Hendrickson acknowledged the study’s limitations, she said her team nonetheless found strong correlations between COVID-19-related stressors and self-reported struggles in completing work-related tasks, as well as increasing thoughts of leaving one’s current field. They adjusted for previous lifetime trauma exposure, age, gender, and a personal history of contracting COVID-19.

The underlying premise of the study could be confirmed with repeated surveys over time, Dr. Butala said, as the COVID-19 pandemic evolves and the vaccination effort unfolds.

Follow-up surveys are being sent to participants every 2 weeks and every 3 months to gauge their mood, for a total follow-up period of 9 months per individual. New participants are still welcome. “We will continue to enroll as long as it seems relevant,” Dr. Hendrickson said.

Carol S. North, MD, MPE, who has added to the growing research on the pandemic’s toll on mental health, noted that because symptom scales do not provide psychiatric diagnoses, it is difficult to attribute the prevalence of psychiatric disorders to the pandemic. Dr. North is chair and professor of crisis psychiatry at UT Southwestern Medical Center in Dallas, and director of the program in trauma and disaster at VA North Texas Health Care System.

The DSM-5 criteria exclude naturally occurring illness, such as a virus (even during a pandemic) as a qualifying trauma for the diagnosis of PTSD. According to current criteria by the American Psychiatric Association, COVID-19 and the pandemic are not defined as trauma, Dr. North said, while noting that “just because it’s not trauma or PTSD does not mean that the pandemic should be discounted as not stressful; people are finding it very stressful.”

Identifying the exact source of distress would still be difficult, Dr. North said, as the pandemic has produced severe economic consequences and prolonged social isolation, as well as occurring alongside nationwide protests over racial and ethnic divisions. Studies to date haven’t effectively separated out for these stressors, making it impossible to weigh their relative impact.

Furthermore, “most of us face many other stressors in our daily lives, such as grief, losses, broken relationships, and personal failures,” she said. “All of these may contribute to psychological distress, and research is needed to determine how much was a product of the virus, other aspects of the pandemic, or unrelated life stressors.”
 

A rallying cry for new interventions

Despite such doubts, a growing number of studies are reporting that health care workers and first responders are experiencing intensified PTSD, depression, anxiety, and insomnia as a result of the pandemic, said Hrayr Pierre Attarian, MD, professor of neurology at Northwestern University, Chicago. These results should act as a rallying cry for implementing more policies tailored to prevent burnout, he said.

“What we are seeing during this terrible pandemic is burnout on steroids,” said Dr. Attarian, medical director of Northwestern’s Center for Sleep Disorders. There are already high burnout rates, “so this should be doubly important.”

Rooting out this problem starts at the institutional level, but merely advising providers to “be well” wouldn’t make inroads. “There needs to be fluid dialogue between health care workers and the leadership,” he said.

Among his proposed remedies: Access to confidential and free mental health resources, increased administrative support, flexible hours, respect for work-life balance, and forgiveness for occasional errors that don’t result in harm.

“Sometimes even the perception that a mistake has been made is taken as proof of guilt,” Dr. Attarian said. “It is not conducive to wellness. Extra income does not replace a nurturing work environment.”

Furthermore, “as a profession, we must stop glorifying ‘overwork.’ We must stop wearing ‘lack of sleep’ as badge of honor,” he said. “Sleep is a biological imperative like self-preservation, hunger, and thirst. When we don’t sleep anxiety, pain, and depression get amplified. Our perception of distress is off, as is our judgment.”

The Federation of State Physician Health Programs provides a directory that physicians can use for referrals to confidential consultation or treatment.

Christopher Bundy, MD, MPH, executive medical director of Washington Physicians Health Program in Seattle, has been following Dr. Hendrickson’s longitudinal study with keen interest. As president of the Federation of State Physician Health Programs, he hopes to translate the findings into practice.

“Obviously, the COVID-19 pandemic has been a ‘black swan’ in terms of workforce sustainability issues,” Dr. Bundy said, citing “high rates of burnout, disillusionment, and dissatisfaction.” He sees some similarities with his former role in treating war veterans.

“The invisible wounds of combat, the psychological scars don’t really become apparent until after you’re out of the war zone,” said Dr. Bundy, clinical associate professor of psychiatry at the University of Washington.

Likewise, he expects the “emotional chickens will come home to roost as the pandemic subsides.” Until then, “people are just focused on survival, and in doing their jobs and protecting their patients.” Eventually, “their own wounds inside the pandemic will take hold.”
 

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

When the COVID-19 pandemic engulfed the nation well over a year ago, Rebecca Hendrickson, MD, PhD, immersed herself in the shell-shocking revelations that clinicians began posting on social media. The accounts offered just a snapshot of the pandemic’s heavy psychological toll, and Dr. Hendrickson, a psychiatrist at the University of Washington in Seattle and an expert in posttraumatic stress disorder (PTSD), wanted to know more.

xavierarnau/Getty Images

She and her colleagues devised a survey to assess the impact of several pandemic-related factors, including increased work hours, social distancing restrictions, and lack of adequate personal protective equipment.

What began as a survey of health care workers soon expanded in scope. Of the more than 600 survey respondents to date, health care workers account for about 60%, while the rest are first responders – police officers, firefighters, paramedics, and emergency medical technicians – and nonclinical personnel, such as security guards and office staff, in health care settings. The respondents range in age from 19 to 72, and hail from all regions of the country.

“Our findings were really striking,” Dr. Hendrickson said, “including very high rates of thoughts of suicide and thoughts of leaving one’s current field, which were both strongly linked to COVID-19–related occupational stress exposure.”

The distress stemmed from a multitude of factors. Among the most demoralizing: witnessing patients die in isolation and being stretched thin to provide optimal care for all patients amid an unrelenting onslaught of COVID-19 cases, she said. For some health care workers, living in the garage or basement – to avoid infecting family members with the virus – also wore on their psyches.

Of all health care workers in the study, more than three-quarters reported symptoms that fell within the clinical range for depression (76%) and anxiety (78%). More than 25% noted that they had lost a family member or close colleague to the virus.

Dr. Hendrickson, who works with military veterans at the VA Puget Sound Hospital System’s Mental Illness Research, Education, and Clinical Center and its PTSD outpatient clinic, hadn’t expected the experience of loss to be so pervasive. She said the sheer number of people who “crossed the threshold” into despair concerned her deeply.
 

Signs and symptoms of PTSD

PTSD’s prevalence among health care workers has always been variable, said Jessica Gold, MD, assistant professor and director of wellness, engagement, and outreach in the department of psychiatry at Washington University in St. Louis.

As a psychiatrist who sees health care workers in her clinical practice, Dr. Gold has noted poor baseline mental health, including depression and trauma. Significant data have pointed to a relatively higher suicide rate among physicians than among the general population. These problems have been compounded by COVID-19.

“It has been an unrelenting series of new stressors,” she said, citing lack of resources; a feeling of being unable to help; and the high frequency of risk of death to patients, family and friends, and the caregivers themselves as just as few examples. “It is very likely going to increase our baseline trauma, and honestly, I don’t know that we can predict how. To me, trauma has no real timeline and can show up months or even years after the pandemic.”

PTSD can manifest itself in health care workers in several different ways. A few commonalities Dr. Gold has observed are sleep disruption (including insomnia and nightmares), work avoidance by taking disability or quitting, irritability or other changes in mood, trouble concentrating, and hypervigilance.

She said she has seen physical manifestations of trauma – such as body pain, stomachaches, and teeth grinding, which “you might not realize are at all related to trauma but ultimately are.” Sometimes, she added, “people have panic attacks on the way to work or right when they get to work, or are thinking about work.”

Dr. Gold noted that different types of treatment, such as cognitive-behavioral therapy and eye movement desensitization and reprocessing (EMDR), can be effective for PTSD. Medication is often necessary because of comorbid anxiety, depression, or eating disorders, said Dr. Gold, who is conducting a study on the pandemic’s effects on medical students.
 

The difficulties in isolating COVID-19 as a contributor

Not all researchers are convinced that a causal relationship has been established between the pandemic and worsening mental health among those in the health care sector.

With provider burnout being a long-standing concern in medicine, Ankur A. Butala, MD, assistant professor of neurology, psychiatry, and behavioral sciences at the Johns Hopkins University, Baltimore, said he remains a bit skeptical that acute stressors during the pandemic amounted to a uniquely potent driving force that can be extrapolated and quantified in a study.

“It’s hard to interpret a chronic, rolling, ongoing trauma like COVID-19 against tools or scales developed to investigate symptoms from a singular and acute trauma, like a school shooting or a [military] firefight,” Dr. Butala said.

In addition, he noted a reluctance to generalizing results from a study in which participants were recruited via social media as opposed to research methods involving more rigorous selection protocols.

Although Dr. Hendrickson acknowledged the study’s limitations, she said her team nonetheless found strong correlations between COVID-19-related stressors and self-reported struggles in completing work-related tasks, as well as increasing thoughts of leaving one’s current field. They adjusted for previous lifetime trauma exposure, age, gender, and a personal history of contracting COVID-19.

The underlying premise of the study could be confirmed with repeated surveys over time, Dr. Butala said, as the COVID-19 pandemic evolves and the vaccination effort unfolds.

Follow-up surveys are being sent to participants every 2 weeks and every 3 months to gauge their mood, for a total follow-up period of 9 months per individual. New participants are still welcome. “We will continue to enroll as long as it seems relevant,” Dr. Hendrickson said.

Carol S. North, MD, MPE, who has added to the growing research on the pandemic’s toll on mental health, noted that because symptom scales do not provide psychiatric diagnoses, it is difficult to attribute the prevalence of psychiatric disorders to the pandemic. Dr. North is chair and professor of crisis psychiatry at UT Southwestern Medical Center in Dallas, and director of the program in trauma and disaster at VA North Texas Health Care System.

The DSM-5 criteria exclude naturally occurring illness, such as a virus (even during a pandemic) as a qualifying trauma for the diagnosis of PTSD. According to current criteria by the American Psychiatric Association, COVID-19 and the pandemic are not defined as trauma, Dr. North said, while noting that “just because it’s not trauma or PTSD does not mean that the pandemic should be discounted as not stressful; people are finding it very stressful.”

Identifying the exact source of distress would still be difficult, Dr. North said, as the pandemic has produced severe economic consequences and prolonged social isolation, as well as occurring alongside nationwide protests over racial and ethnic divisions. Studies to date haven’t effectively separated out for these stressors, making it impossible to weigh their relative impact.

Furthermore, “most of us face many other stressors in our daily lives, such as grief, losses, broken relationships, and personal failures,” she said. “All of these may contribute to psychological distress, and research is needed to determine how much was a product of the virus, other aspects of the pandemic, or unrelated life stressors.”
 

A rallying cry for new interventions

Despite such doubts, a growing number of studies are reporting that health care workers and first responders are experiencing intensified PTSD, depression, anxiety, and insomnia as a result of the pandemic, said Hrayr Pierre Attarian, MD, professor of neurology at Northwestern University, Chicago. These results should act as a rallying cry for implementing more policies tailored to prevent burnout, he said.

“What we are seeing during this terrible pandemic is burnout on steroids,” said Dr. Attarian, medical director of Northwestern’s Center for Sleep Disorders. There are already high burnout rates, “so this should be doubly important.”

Rooting out this problem starts at the institutional level, but merely advising providers to “be well” wouldn’t make inroads. “There needs to be fluid dialogue between health care workers and the leadership,” he said.

Among his proposed remedies: Access to confidential and free mental health resources, increased administrative support, flexible hours, respect for work-life balance, and forgiveness for occasional errors that don’t result in harm.

“Sometimes even the perception that a mistake has been made is taken as proof of guilt,” Dr. Attarian said. “It is not conducive to wellness. Extra income does not replace a nurturing work environment.”

Furthermore, “as a profession, we must stop glorifying ‘overwork.’ We must stop wearing ‘lack of sleep’ as badge of honor,” he said. “Sleep is a biological imperative like self-preservation, hunger, and thirst. When we don’t sleep anxiety, pain, and depression get amplified. Our perception of distress is off, as is our judgment.”

The Federation of State Physician Health Programs provides a directory that physicians can use for referrals to confidential consultation or treatment.

Christopher Bundy, MD, MPH, executive medical director of Washington Physicians Health Program in Seattle, has been following Dr. Hendrickson’s longitudinal study with keen interest. As president of the Federation of State Physician Health Programs, he hopes to translate the findings into practice.

“Obviously, the COVID-19 pandemic has been a ‘black swan’ in terms of workforce sustainability issues,” Dr. Bundy said, citing “high rates of burnout, disillusionment, and dissatisfaction.” He sees some similarities with his former role in treating war veterans.

“The invisible wounds of combat, the psychological scars don’t really become apparent until after you’re out of the war zone,” said Dr. Bundy, clinical associate professor of psychiatry at the University of Washington.

Likewise, he expects the “emotional chickens will come home to roost as the pandemic subsides.” Until then, “people are just focused on survival, and in doing their jobs and protecting their patients.” Eventually, “their own wounds inside the pandemic will take hold.”
 

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

Irritable bowel syndrome (IBS) continues to pose a diagnostic and therapeutic challenge to clinicians and patients—a challenge that arises from the varying manifestations of the condition, its complex pathophysiology, lack of effective treatment, and psychological consequences for patients. In this article, I explore new findings related to the pathophysiology, diagnosis, and management of IBS subtypes.

Start with the Rome IV classification of IBS

The Rome Foundation published its latest IBS classification and diagnostic criteria (known as Rome IV) in 2016.¹ IBS is defined as abdominal pain that (1) has recurred, on average, ≥ 1 time per week during the past 3 months and (2) is associated with ≥ 2 of these criteria¹:

• related to defecation
• associated with a change in stool frequency
• associated with a change in the appearance of stool.

Onset of symptoms should be present for 6 months before a diagnosis of IBS is made.¹

IBS subtypes—constipation-predominant (IBS-C), diarrhea-predominant (IBS-D), mixed (IBS-M), and unclassified (IBS-U) (TABLE 1)¹—are based on the frequency of specific stool forms, as described and illustrated in the Bristol Stool Scale (www.webmd.com/digestive-disorders/poop-chart-bristol-stool-scale).²

A widespread, costly, potentially debilitating disorder

IBS affects 10% to 12% of adults worldwide. The condition is more common among women and people younger than 50 years.^1,3 Women with IBS tend to have more constipation ­symptoms (IBS-C); men with IBS, more diarrhea symptoms (IBS-D).⁴

The financial burden of IBS on the health care system and patients is significant. In a 2013 appraisal of 35 studies, the authors note that estimates of the direct cost of IBS care in the United States vary considerably—from $1562 to $7547 for a patient annually.⁵

A recent study found that almost 25% of IBS patients report absenteeism from work due to IBS symptoms.⁶ A Danish study that followed 7278 patients for 5 years found that IBS patients utilized more health care, sick days, and disability pension benefits than non-IBS patients, and had increased utilization of medical resources because of psychiatric conditions.⁷

Continue to: IBS patients also have comorbidities

IBS patients also have comorbidities:

• More than 20% of IBS patients have functional dyspepsia, gastroesophageal reflux disease, incontinence, or pelvic floor dyssynergia.⁴
• The frequency of fibromyalgia syndrome in IBS patients is reported to be 20% to 65%.⁸
• 14% of IBS patients meet criteria for chronic fatigue syndrome.⁸
• Interstitial cystitis and dyspareunia are common among IBS patients.⁹

Pathophysiology is complex

Models describing the pathophysiology of IBS have evolved through the years. Recent models describe it as a combination of altered gastrointestinal motility, visceral hyperalgesia, increased intestinal permeability, immune activation, altered intestinal microbiota, and dysfunction in the brain–gut axis. Certain environmental and psychological variables (eg, previous gastroenteritis, food intolerance, chronic stress, diverticulitis, and surgery) increase the risk of IBS.^1,10,11

In the past several years, considerable attention has been paid to the roles played by the immune system, brain–gut axis function, and intestinal microbiota in IBS manifestations. Research focus in these areas might assist in the development of specific treatment modalities targeting IBS subtypes.

Immune system. A recent meta-­analysis of the records of 706 IBS patients found an increased number of mast cells and CD3 T cells in biopsy specimens from the rectosigmoid and descending colon of IBS patients.¹² Another study found a significant increase in mast cells in the ileum of IBS patients¹³; this increase is evident not only on intestinal biopsy but also at the serologic level. IBS-D patients have a higher plasma interleukin (IL)-6 level than the general population.¹⁴ Another meta-analysis found an imbalance in the serum level of tumor necrosis factor-α and IL-10 in IBS patients.¹⁵

Brain–gut axis. A 2016 meta-analysis showed that patients with anxiety and depression have a 2-fold increased risk of IBS.¹⁶ A more recent study, using data from the National Health Insurance Research Database that included 22,356 patients with IBS, found a 3.6-fold increased risk of psychiatric disorders in IBS.¹⁷ These findings reflect the complex interaction between the brain and the intestinal tract in IBS.

Continue to: Intestinal microbiota

Intestinal microbiota. Research evaluating the role of altered intestinal microbiota in IBS has yielded mixed results. A meta-­analysis of 777 IBS patients showed an increase in Firmicutes spp, a decrease in Bacteroidetes spp, and an increase in the ratio of Firmicutes spp to Bacteroidetes spp in subjects’ fecal specimens.¹⁸ Another study, of 1340 patients, found no difference in Bacteroides spp and Enterococcus spp between healthy controls and IBS patients, but did find (1) lower fecal counts of Lactobacillus spp and Bifidobacterium spp and (2) higher fecal counts of Escherichia coli and Enterobacter spp in IBS patients.¹⁹

Postinfectious IBS. The Rome Foundation introduced the diagnosis of postinfectious IBS (PI-IBS) in 2019. PI-IBS develops in 10% of patients who have had infectious enteritis. Female gender, younger age, psychological distress during or before the enteritis episode, and severity of the acute episode are risk factors for this IBS variant.²⁰ A study of 21,421 enteritis patients found that 42% with protozoal or parasitic infection and 14% with bacterial infection developed IBS.

To identify possible "red flags" or other disorders, take a history that includes the course of symptoms, triggers, and alleviating factors.

Patients with nonviral enteritis often have a more severe course of enteritis, typically requiring antibiotics. It is believed that the resulting irregularities in the intestinal microbiota make these patients more likely to develop PI-IBS.²¹ PI-IBS patients are likely to improve or fully recover over time. Symptoms of PI-IBS are managed in a manner similar to how non-PI-IBS patients are managed.²⁰

Challenges in making the IBS diagnosis

Historically, the diagnosis of IBS has been made clinically after excluding red flags (ie, signs or symptoms that might reflect other underlying medical problems) in the clinical presentation. For this reason, obtain a thorough clinical history that includes the course of symptoms, triggers, and alleviating factors. Any of the following are considered red flags^1,22,23:

• age > 50 years at onset of symptoms
• new-onset constipation in the elderly
• rectal bleeding
• unexplained weight loss or anemia
• family history of organic gastrointestinal disease
• palpable abdominal or rectal mass
• nocturnal symptoms.

New studies demonstrate that several inflammatory markers can help exclude inflammatory bowel disease from the differential diagnosis in patients in whom IBS is suspected and being investigated.²⁴ In 2019, the American Gastroenterological Association published a clinical practice guideline updating the laboratory evaluation of functional diarrhea and IBS-D in adults,²⁵ and made several recommendations:

• Obtain the level of fecal calprotectin (normal level, ≤ 50 mcg/g) or fecal lactoferrin (≤ 4.0-7.25 mcg/g); if these tests are not available or results are not accessible, the C-reactive protein level is a reasonable option.
• Do not routinely use the erythrocyte sedimentation rate or C-reactive protein level to screen for inflammatory bowel disease.
• Test for Giardia lamblia with an antigen or polymerase chain reaction test.
• Do not test for ova and parasites (other than Giardia) in patients who do not have a history of travel or who have not emigrated from a high-risk area recently.
• Obtain testing for celiac disease with immunoglobulin A (IgA) tissue transglutaminase and with a second test, of immunoglobulin G (IgG) tissue transglutaminase and IgG or IgA deaminated gliadin peptides, to detect celiac disease in IgA-deficient patients.
• Order testing for bile-acid diarrhea with selenium homotaurocholic acid nuclear medicine scanning (if available in your region; the test is available in Europe); measurement of bile acid from a 48-hour stool collection; or an assay of fibroblast growth factor 19, which measures defective feedback of bile-acid synthesis. If these tests are unavailable, consider an empiric trial of a bile-acid binder.
• Do not use available serologic IBS testing.

Continue to: Continue to obtain a...

Continue to obtain a complete blood count for the evaluation of anemia. Endoscopic procedures are indicated in patients with a red flag.¹

Treat based on subtype

The first step in the treatment of all IBS patients (TABLE 2^{1,3,4,9,26,27}) is for you to develop a strong relationship with the patient: You must acknowledge the disease and empower the patient to manage their symptoms. A strong physician–patient relationship leads to more effective outcomes.⁴

Low cost and low risk of adverse effects makes exercise worth recommending to all IBS patients.

IBS treatment modalities target abdominal pain, bloating, abdominal distention, and altered bowel function—described in the literature as global symptoms. IBS-M patients should direct their treatment to the predominant symptom (constipation or diarrhea). The following sections describe available treatment options. The FIGURE^1,3,4,9,25 shows a treatment workflow based on IBS subtype and symptom severity.

Treatments for all IBS subtypes

Lifestyle modification. Exercise provides overall positive health benefits. With such a variety of exercise forms, however, it is difficult to identify specific exercises that are better for IBS patients.²⁸ A study of 305 IBS patients found that exercise alleviated constipation but not other IBS symptoms, and did not improve quality of life.³ Based on low cost and low risk of adverse effects, exercise should be recommended to all IBS patients.

Dietary restriction therapies have become an area of focus for patients, clinicians, and researchers. Modification of the diet is thought to improve global symptoms and intestinal health through modification of gut microbiota, immune activation, and a decrease in levels of fecal short-chain fatty acids.²⁹

Continue to: The 2 main diets...

The 2 main diets studied for the treatment of IBS are a diet low in fermentable oligo-, di- and monosaccharides and polyols—the so-called low-FODMAP diet (TABLE 3³⁰)—and a gluten-free diet. Evidence behind the benefits of both diets conflicts; trials of the low-FODMAP diet are more favorable.

A small study with 20 patients with IBS-D and IBS-M who followed a low-FODMAP diet found improvement in IBS symptoms and a reduction in serum levels of proinflammatory cytokines, fecal bacteria, and total fecal short-chain fatty acid levels.²⁹ Several meta-analyses have shown improvement in overall IBS symptoms for patients who follow a low-FODMAP diet. Because of the heterogeneity of the studies, however, the quality of the data is low.^31-34

Data supporting the use of a gluten-free diet for IBS patients are insufficient.³¹

The American College of Gastroenterology (ACG) gave a weak recommendation for the low-FODMAP diet and recommended against the gluten-free diet in IBS patients.³ More data are needed regarding the safety profile of using a low-FODMAP diet for an extended period: There is concern about the risk of nutritional deficiencies associated with long-term use of this diet.³

Supplementation with poorly fermentable soluble fiber has been shown to alleviate global IBS symptoms; insoluble fiber does not yield improvement of symptoms. Psyllium fiber is recommended over wheat bran.^3,35

Continue to: Consider a low-FODMAP diet...

Consider a low-FODMAP diet and soluble fiber as initial treatment for all IBS patients.

Modification of intestinal microbiota. Understanding the difference between prebiotics and probiotics is important when considering treatment for IBS. Prebiotics are foods or dietary supplements that generate changes in the composition and activity of intestinal microbiota. Probiotics are live microorganisms that can improve intestinal health.³

A meta-analysis of 729 IBS patients found that prebiotics do not reduce gastrointestinal symptoms or improve the quality of life of IBS patients.³⁶ Evidence supporting the benefit of probiotics is favorable; however, data in these studies have significant heterogeneity. Several meta-analyses studied the benefits of Lactobacillus spp and Bifidobacterium spp in alleviating IBS symptoms. The studies found improvement in abdominal pain, bloating and distention, and flatulence.^3,37-40 Consider recommending probiotics for all IBS patients; for some, however, the high cost of some of these products might be an obstacle.

Consider recommending probiotics for all IBS patients, although high cost might be an obstacle for some.

Researchers are also studying the use of fecal microbiota transplantation (FMT) to treat IBS. Studies have evaluated the delivery of FMT orally (as capsules) and endoscopically. Evidence does not show improvement in global IBS symptoms with FMT. More studies, with larger sample populations, are needed.^41-43

Antispasmodic medications and peppermint oil. Antispasmodic medications have been considered a mainstay therapy for IBS because of their effect on intestinal dysmotility. Hyoscine and dicyclomine are commonly used. Meta-analyses have shown improvement in global symptoms and abdominal pain, but effects were modest.^3,44 Use this class of drugs as first-line treatment for mild IBS symptoms.

Continue to: Peppermint oil has been...

Peppermint oil has been found useful in improving IBS global symptoms and abdominal pain in several studies.^44-46 A common adverse effect of peppermint oil is heartburn, resulting from relaxation of esophageal muscle.³ Peppermint oil can be considered an adjuvant agent in treating IBS.

Antidepressants. Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) have been studied for the treatment of IBS. Meta-analyses show that both are effective in reducing pain and overall IBS symptoms.^1,3,47 The number needed to treat (NNT) for TCAs is 4.5; for SSRIs, 5.⁴⁷ Data do not show that either drug class is superior to the other for IBS. Based on the adverse effect profile, TCAs are more suitable for IBS-D patients; SSRIs are better for IBS-C patients.⁴⁷

New data show that serotonin-­norepinephrine reuptake inhibitors, such as duloxetine and milnacipran, can alleviate IBS symptoms through their pain-modifying properties.⁴⁷

Based on the adverse effect profile and stigma associated with antidepressant medications, patients might be less likely to take them for IBS symptoms than for these drugs’ primary indications. Clinicians should still consider this drug class if other first-line treatments do not provide full resolution of symptoms.

Psychotherapy. Several psychotherapeutic modalities have been evaluated for efficacy in reducing global IBS symptoms. The approaches studied most often were provider-directed cognitive behavioral therapy, relaxation therapy, hypnotherapy, and multicomponent psychological therapy. The NNT for these modalities is 4, but studies had significant heterogeneity.³ Consider referring patients for psychotherapeutic intervention if they have not responded to medical therapy after 12 months.⁴

Continue to Treatment of IBS-C

Treatment of IBS-C

Prosecretory agents. Linaclotide and plecanatide are amino-acid peptides that act as a guanylate cyclase C agonist. Both increase gastrointestinal transit rate by increasing electrolyte and fluid transport into the intestinal lumen. They also decrease the activity of pain-sensing nerves by increasing extracellular cyclic guanosine-3'5'-monophosphate levels.^3,48 In a recent meta-analysis, both treatments produced improvement in global symptoms. However, linaclotide showed superior improvement in abdominal pain and global symptoms compared to other secretory agents.^48,49 Diarrhea was the most common adverse effect of linaclotide and plecanatide, although less so with plecanatide.⁴⁹

Lubiprostone activates the intestinal chloride channel type 2 on the small intestine, leading to an increase in chloride and water efflux into the intestinal lumen, in turn accelerating gastrointestinal transit.³ A meta-analysis with 1468 IBS patients found that lubiprostone improved constipation, stool consistency, abdominal pain, degree of straining, and abdominal bloating.⁵⁰ Diarrhea and nausea are commonly reported adverse effects of lubiprostone.^49,50

Linaclotide, plecanatide, and lubiprostone should be considered first-line therapies for patients with IBS-C. High cost is still a roadblock to the use of these agents.

Use antispasmodic medications as first-line treatment for mild IBS symptoms.

The US Food and Drug Administration (FDA) approved tenapanor in September 2019; however, the drug is not commercially available in the United States (it is available in Canada). Tenapanor is a sodium–­hydrogen exchanger 3 inhibitor that reduces sodium absorption from the intestine and colon. The drug increases water secretion into the intestinal lumen, thus accelerating gut transit time. It also inhibits active absorption of phosphate in the intestine.

Tenapanor was approved for treating both IBS-C and hyperphosphatemia in patients with chronic kidney disease on dialysis or end-stage renal disease.²⁶ In a recent meta-analysis, the drug showed benefit in alleviating global IBS symptoms, and ranked first in reducing bloating.⁴⁹ It is too soon to know if tenapanor will perform clinically better than other prosecretory agents.

Continue to: Serotonergic agents

Serotonergic agents. Serotonin (5-hydroxytryptamine [5-HT]) modulates gastrointestinal secretions, gut motility, and visceral sensation. Researchers have developed IBS treatments that target receptors involved in these functions.

Tegaserod is a partial, selective 5-HT₄ agonist indicated for the treatment of IBS-C in women. A study with 661 women with IBS-M and IBS-C showed that tegaserod increased the number of bowel movement episodes. Patients also reported higher stool consistency scores and fewer days with straining compared to placebo.²⁷ The medication was removed from the market in 2007 because of its potential for cardiovascular adverse effects³; however, it was reintroduced in 2019 for women < 65 years of age with IBS-C. Consider prescribing tegaserod if other treatment options fail to alleviate symptoms.

Treatment of IBS-D

Antibiotics. The nonabsorbable antibiotic rifaximin is approved by the FDA for IBS-D at a dosage of 550 mg tid for 2 weeks.¹ Several studies show improvement in IBS global symptoms with the recommended treatment course^51-53; benefit persisted for the 10-week follow-up study period.¹ A meta-analysis found that the NNT for rifaximin is 8-11.⁵⁴ Preliminary data indicate that the rates of Clostridioides difficile infection and microbial resistance among rifaximin users are low.³ Consider using rifaximin as a first-line treatment option for patients with IBS-D. Retreatment might be necessary because the drug’s effect gradually disappears.⁹

Antidiarrheals. Eluxadoline is a µ-opioid and κ-opioid receptor agonist and δ-opioid receptor antagonist with effects on the intestinal nervous system.³ Several meta-analyses demonstrated that eluxadoline improves abdominal pain scores and daily stool consistency in IBS-D patients.^53,54 Eluxadoline should be considered early in the management of IBS-D patients. The most common adverse effect is constipation.

The FDA issued a safety warning in 2017 regarding an increased risk of pancreatitis in patients taking eluxadoline who do not have a gallbladder. In addition, eluxadoline should be avoided in patients with a history of sphincter of Oddi dysfunction, alcohol abuse, or severe liver problems.^3,54

Continue to: The high cost of...

The high cost of eluxadoline can be a significant barrier to use.

Serotonergic agents. Alosetron is a selective 5-HT₃ antagonist developed to treat IBS-D.³ In a meta-analysis comprising 9844 patients, alosetron showed superior abdominal pain scores and improved stool consistency compared to ramosetron, rifaximin, and eluxadoline.⁵³ In 2001, the FDA withdrew alosetron, due to severe constipation and a risk of ischemic colitis; however, the medication has become commercially available again through a risk evaluation and mitigation strategy (REMS) program for women who have disabling IBS-D symptoms.^3,54 Because of this special circumstance, alosetron is not considered first-line therapy for IBS-D.

Linaclotide, plecanatide, and lubiprostone should be considered firstline therapies for IBS-C.

Ondansetron has also been used to treat IBS-D. In a meta-analysis with 294 patients, ondansetron showed improvement in stool consistency.⁵⁵ Ondansetron does not improve abdominal pain.⁴ It can be used in patients who have mild-to-moderate symptoms.⁹ Ondansetron is not FDA approved for the treatment of IBS-D.

Bile-acid sequestrants. Traditionally, bile-acid sequestrants have been used to treat bile-acid diarrhea. A meta-analysis of 6 studies of 908 patients with IBS-D found that 28.1% were affected by bile-acid malabsorption. Two small studies that evaluated the benefits of colesevelam for IBS-D found significant improvement in stool consistency.⁵⁴ Another study, which evaluated the benefits of cholestyramine, found improvement in stool consistency, but findings were not significant.⁵⁴ Many patients taking a bile-acid sequestrant stop taking the medication because of considerable adverse effects (constipation, nausea, bloating, flatulence, and abdominal pain).⁵⁴ For that reason, this class of medication is not recommended as first-line treatment for IBS-D and is not FDA approved for IBS-D.

A role for complementaryand integrative medicine?

Recently, complementary and integrative modalities for treating IBS have sparked the interest of researchers.

Continue to: Acupuncture

Acupuncture. In a meta-analysis with 3440 patients, acupuncture was more effective than Western medicine in alleviating IBS symptoms for as long as 3 months. The authors concluded that acupuncture could be used in combination with other therapies to reduce the severity of IBS symptoms.⁵⁶

Concomitant acupuncture and Chinese herbal medicine. In a systematic review and meta-analysis comprising 21 randomized controlled trials, researchers reported that acupuncture combined with Chinese herbal medicine improved IBS symptoms, compared to what was noted in matched controls who were treated with Western medicine or with Western medicine combined with Chinese herbal medicine. The authors were cautious about the results of the meta-analysis, however, because the studies examined were small and of low quality, and presented a high risk of bias.⁵⁷

Agents not to be used routinely for IBS

Loperamide. This peripheral µ-opioid receptor agonist controls diarrhea. However, recent studies showed no significant benefit to loperamide over placebo in IBS-M and IBS-D. In 2018, the FDA issued a safety alert regarding an elevated risk of serious cardiac adverse effects in patients taking loperamide. The ACG recommends against using loperamide to treat IBS symptoms.^3,54

Polyethylene glycol. An osmotic laxative that is not absorbed in the intestinal lumen, polyethylene glycol is highly efficacious for alleviating constipation, but it does not reduce pain or other IBS symptoms. For that reason, the ACG recommends against its use.³

CORRESPONDENCE
Jose M. Villalon-Gomez, MD, MPH, Emory Healthcare Family Medicine, 4500 North Shallowford Road, Dunwoody, GA 30338; jose.villalon-gomez@emory.edu

Irritable bowel syndrome (IBS) continues to pose a diagnostic and therapeutic challenge to clinicians and patients—a challenge that arises from the varying manifestations of the condition, its complex pathophysiology, lack of effective treatment, and psychological consequences for patients. In this article, I explore new findings related to the pathophysiology, diagnosis, and management of IBS subtypes.

Start with the Rome IV classification of IBS

The Rome Foundation published its latest IBS classification and diagnostic criteria (known as Rome IV) in 2016.¹ IBS is defined as abdominal pain that (1) has recurred, on average, ≥ 1 time per week during the past 3 months and (2) is associated with ≥ 2 of these criteria¹:

• related to defecation
• associated with a change in stool frequency
• associated with a change in the appearance of stool.

Onset of symptoms should be present for 6 months before a diagnosis of IBS is made.¹

IBS subtypes—constipation-predominant (IBS-C), diarrhea-predominant (IBS-D), mixed (IBS-M), and unclassified (IBS-U) (TABLE 1)¹—are based on the frequency of specific stool forms, as described and illustrated in the Bristol Stool Scale (www.webmd.com/digestive-disorders/poop-chart-bristol-stool-scale).²

A widespread, costly, potentially debilitating disorder

IBS affects 10% to 12% of adults worldwide. The condition is more common among women and people younger than 50 years.^1,3 Women with IBS tend to have more constipation ­symptoms (IBS-C); men with IBS, more diarrhea symptoms (IBS-D).⁴

The financial burden of IBS on the health care system and patients is significant. In a 2013 appraisal of 35 studies, the authors note that estimates of the direct cost of IBS care in the United States vary considerably—from $1562 to $7547 for a patient annually.⁵

A recent study found that almost 25% of IBS patients report absenteeism from work due to IBS symptoms.⁶ A Danish study that followed 7278 patients for 5 years found that IBS patients utilized more health care, sick days, and disability pension benefits than non-IBS patients, and had increased utilization of medical resources because of psychiatric conditions.⁷

Continue to: IBS patients also have comorbidities

IBS patients also have comorbidities:

• More than 20% of IBS patients have functional dyspepsia, gastroesophageal reflux disease, incontinence, or pelvic floor dyssynergia.⁴
• The frequency of fibromyalgia syndrome in IBS patients is reported to be 20% to 65%.⁸
• 14% of IBS patients meet criteria for chronic fatigue syndrome.⁸
• Interstitial cystitis and dyspareunia are common among IBS patients.⁹

Pathophysiology is complex

Models describing the pathophysiology of IBS have evolved through the years. Recent models describe it as a combination of altered gastrointestinal motility, visceral hyperalgesia, increased intestinal permeability, immune activation, altered intestinal microbiota, and dysfunction in the brain–gut axis. Certain environmental and psychological variables (eg, previous gastroenteritis, food intolerance, chronic stress, diverticulitis, and surgery) increase the risk of IBS.^1,10,11

In the past several years, considerable attention has been paid to the roles played by the immune system, brain–gut axis function, and intestinal microbiota in IBS manifestations. Research focus in these areas might assist in the development of specific treatment modalities targeting IBS subtypes.

Immune system. A recent meta-­analysis of the records of 706 IBS patients found an increased number of mast cells and CD3 T cells in biopsy specimens from the rectosigmoid and descending colon of IBS patients.¹² Another study found a significant increase in mast cells in the ileum of IBS patients¹³; this increase is evident not only on intestinal biopsy but also at the serologic level. IBS-D patients have a higher plasma interleukin (IL)-6 level than the general population.¹⁴ Another meta-analysis found an imbalance in the serum level of tumor necrosis factor-α and IL-10 in IBS patients.¹⁵

Brain–gut axis. A 2016 meta-analysis showed that patients with anxiety and depression have a 2-fold increased risk of IBS.¹⁶ A more recent study, using data from the National Health Insurance Research Database that included 22,356 patients with IBS, found a 3.6-fold increased risk of psychiatric disorders in IBS.¹⁷ These findings reflect the complex interaction between the brain and the intestinal tract in IBS.

Continue to: Intestinal microbiota

Intestinal microbiota. Research evaluating the role of altered intestinal microbiota in IBS has yielded mixed results. A meta-­analysis of 777 IBS patients showed an increase in Firmicutes spp, a decrease in Bacteroidetes spp, and an increase in the ratio of Firmicutes spp to Bacteroidetes spp in subjects’ fecal specimens.¹⁸ Another study, of 1340 patients, found no difference in Bacteroides spp and Enterococcus spp between healthy controls and IBS patients, but did find (1) lower fecal counts of Lactobacillus spp and Bifidobacterium spp and (2) higher fecal counts of Escherichia coli and Enterobacter spp in IBS patients.¹⁹

Postinfectious IBS. The Rome Foundation introduced the diagnosis of postinfectious IBS (PI-IBS) in 2019. PI-IBS develops in 10% of patients who have had infectious enteritis. Female gender, younger age, psychological distress during or before the enteritis episode, and severity of the acute episode are risk factors for this IBS variant.²⁰ A study of 21,421 enteritis patients found that 42% with protozoal or parasitic infection and 14% with bacterial infection developed IBS.

To identify possible "red flags" or other disorders, take a history that includes the course of symptoms, triggers, and alleviating factors.

Patients with nonviral enteritis often have a more severe course of enteritis, typically requiring antibiotics. It is believed that the resulting irregularities in the intestinal microbiota make these patients more likely to develop PI-IBS.²¹ PI-IBS patients are likely to improve or fully recover over time. Symptoms of PI-IBS are managed in a manner similar to how non-PI-IBS patients are managed.²⁰

Challenges in making the IBS diagnosis

Historically, the diagnosis of IBS has been made clinically after excluding red flags (ie, signs or symptoms that might reflect other underlying medical problems) in the clinical presentation. For this reason, obtain a thorough clinical history that includes the course of symptoms, triggers, and alleviating factors. Any of the following are considered red flags^1,22,23:

• age > 50 years at onset of symptoms
• new-onset constipation in the elderly
• rectal bleeding
• unexplained weight loss or anemia
• family history of organic gastrointestinal disease
• palpable abdominal or rectal mass
• nocturnal symptoms.

New studies demonstrate that several inflammatory markers can help exclude inflammatory bowel disease from the differential diagnosis in patients in whom IBS is suspected and being investigated.²⁴ In 2019, the American Gastroenterological Association published a clinical practice guideline updating the laboratory evaluation of functional diarrhea and IBS-D in adults,²⁵ and made several recommendations:

• Obtain the level of fecal calprotectin (normal level, ≤ 50 mcg/g) or fecal lactoferrin (≤ 4.0-7.25 mcg/g); if these tests are not available or results are not accessible, the C-reactive protein level is a reasonable option.
• Do not routinely use the erythrocyte sedimentation rate or C-reactive protein level to screen for inflammatory bowel disease.
• Test for Giardia lamblia with an antigen or polymerase chain reaction test.
• Do not test for ova and parasites (other than Giardia) in patients who do not have a history of travel or who have not emigrated from a high-risk area recently.
• Obtain testing for celiac disease with immunoglobulin A (IgA) tissue transglutaminase and with a second test, of immunoglobulin G (IgG) tissue transglutaminase and IgG or IgA deaminated gliadin peptides, to detect celiac disease in IgA-deficient patients.
• Order testing for bile-acid diarrhea with selenium homotaurocholic acid nuclear medicine scanning (if available in your region; the test is available in Europe); measurement of bile acid from a 48-hour stool collection; or an assay of fibroblast growth factor 19, which measures defective feedback of bile-acid synthesis. If these tests are unavailable, consider an empiric trial of a bile-acid binder.
• Do not use available serologic IBS testing.

Continue to: Continue to obtain a...

Continue to obtain a complete blood count for the evaluation of anemia. Endoscopic procedures are indicated in patients with a red flag.¹

Treat based on subtype

The first step in the treatment of all IBS patients (TABLE 2^{1,3,4,9,26,27}) is for you to develop a strong relationship with the patient: You must acknowledge the disease and empower the patient to manage their symptoms. A strong physician–patient relationship leads to more effective outcomes.⁴

Low cost and low risk of adverse effects makes exercise worth recommending to all IBS patients.

IBS treatment modalities target abdominal pain, bloating, abdominal distention, and altered bowel function—described in the literature as global symptoms. IBS-M patients should direct their treatment to the predominant symptom (constipation or diarrhea). The following sections describe available treatment options. The FIGURE^1,3,4,9,25 shows a treatment workflow based on IBS subtype and symptom severity.

Treatments for all IBS subtypes

Lifestyle modification. Exercise provides overall positive health benefits. With such a variety of exercise forms, however, it is difficult to identify specific exercises that are better for IBS patients.²⁸ A study of 305 IBS patients found that exercise alleviated constipation but not other IBS symptoms, and did not improve quality of life.³ Based on low cost and low risk of adverse effects, exercise should be recommended to all IBS patients.

Dietary restriction therapies have become an area of focus for patients, clinicians, and researchers. Modification of the diet is thought to improve global symptoms and intestinal health through modification of gut microbiota, immune activation, and a decrease in levels of fecal short-chain fatty acids.²⁹

Continue to: The 2 main diets...

The 2 main diets studied for the treatment of IBS are a diet low in fermentable oligo-, di- and monosaccharides and polyols—the so-called low-FODMAP diet (TABLE 3³⁰)—and a gluten-free diet. Evidence behind the benefits of both diets conflicts; trials of the low-FODMAP diet are more favorable.

A small study with 20 patients with IBS-D and IBS-M who followed a low-FODMAP diet found improvement in IBS symptoms and a reduction in serum levels of proinflammatory cytokines, fecal bacteria, and total fecal short-chain fatty acid levels.²⁹ Several meta-analyses have shown improvement in overall IBS symptoms for patients who follow a low-FODMAP diet. Because of the heterogeneity of the studies, however, the quality of the data is low.^31-34

Data supporting the use of a gluten-free diet for IBS patients are insufficient.³¹

The American College of Gastroenterology (ACG) gave a weak recommendation for the low-FODMAP diet and recommended against the gluten-free diet in IBS patients.³ More data are needed regarding the safety profile of using a low-FODMAP diet for an extended period: There is concern about the risk of nutritional deficiencies associated with long-term use of this diet.³

Supplementation with poorly fermentable soluble fiber has been shown to alleviate global IBS symptoms; insoluble fiber does not yield improvement of symptoms. Psyllium fiber is recommended over wheat bran.^3,35

Continue to: Consider a low-FODMAP diet...

Consider a low-FODMAP diet and soluble fiber as initial treatment for all IBS patients.

Modification of intestinal microbiota. Understanding the difference between prebiotics and probiotics is important when considering treatment for IBS. Prebiotics are foods or dietary supplements that generate changes in the composition and activity of intestinal microbiota. Probiotics are live microorganisms that can improve intestinal health.³

A meta-analysis of 729 IBS patients found that prebiotics do not reduce gastrointestinal symptoms or improve the quality of life of IBS patients.³⁶ Evidence supporting the benefit of probiotics is favorable; however, data in these studies have significant heterogeneity. Several meta-analyses studied the benefits of Lactobacillus spp and Bifidobacterium spp in alleviating IBS symptoms. The studies found improvement in abdominal pain, bloating and distention, and flatulence.^3,37-40 Consider recommending probiotics for all IBS patients; for some, however, the high cost of some of these products might be an obstacle.

Consider recommending probiotics for all IBS patients, although high cost might be an obstacle for some.

Researchers are also studying the use of fecal microbiota transplantation (FMT) to treat IBS. Studies have evaluated the delivery of FMT orally (as capsules) and endoscopically. Evidence does not show improvement in global IBS symptoms with FMT. More studies, with larger sample populations, are needed.^41-43

Antispasmodic medications and peppermint oil. Antispasmodic medications have been considered a mainstay therapy for IBS because of their effect on intestinal dysmotility. Hyoscine and dicyclomine are commonly used. Meta-analyses have shown improvement in global symptoms and abdominal pain, but effects were modest.^3,44 Use this class of drugs as first-line treatment for mild IBS symptoms.

Continue to: Peppermint oil has been...

Peppermint oil has been found useful in improving IBS global symptoms and abdominal pain in several studies.^44-46 A common adverse effect of peppermint oil is heartburn, resulting from relaxation of esophageal muscle.³ Peppermint oil can be considered an adjuvant agent in treating IBS.

Antidepressants. Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) have been studied for the treatment of IBS. Meta-analyses show that both are effective in reducing pain and overall IBS symptoms.^1,3,47 The number needed to treat (NNT) for TCAs is 4.5; for SSRIs, 5.⁴⁷ Data do not show that either drug class is superior to the other for IBS. Based on the adverse effect profile, TCAs are more suitable for IBS-D patients; SSRIs are better for IBS-C patients.⁴⁷

New data show that serotonin-­norepinephrine reuptake inhibitors, such as duloxetine and milnacipran, can alleviate IBS symptoms through their pain-modifying properties.⁴⁷

Based on the adverse effect profile and stigma associated with antidepressant medications, patients might be less likely to take them for IBS symptoms than for these drugs’ primary indications. Clinicians should still consider this drug class if other first-line treatments do not provide full resolution of symptoms.

Psychotherapy. Several psychotherapeutic modalities have been evaluated for efficacy in reducing global IBS symptoms. The approaches studied most often were provider-directed cognitive behavioral therapy, relaxation therapy, hypnotherapy, and multicomponent psychological therapy. The NNT for these modalities is 4, but studies had significant heterogeneity.³ Consider referring patients for psychotherapeutic intervention if they have not responded to medical therapy after 12 months.⁴

Continue to Treatment of IBS-C

Treatment of IBS-C

Prosecretory agents. Linaclotide and plecanatide are amino-acid peptides that act as a guanylate cyclase C agonist. Both increase gastrointestinal transit rate by increasing electrolyte and fluid transport into the intestinal lumen. They also decrease the activity of pain-sensing nerves by increasing extracellular cyclic guanosine-3'5'-monophosphate levels.^3,48 In a recent meta-analysis, both treatments produced improvement in global symptoms. However, linaclotide showed superior improvement in abdominal pain and global symptoms compared to other secretory agents.^48,49 Diarrhea was the most common adverse effect of linaclotide and plecanatide, although less so with plecanatide.⁴⁹

Lubiprostone activates the intestinal chloride channel type 2 on the small intestine, leading to an increase in chloride and water efflux into the intestinal lumen, in turn accelerating gastrointestinal transit.³ A meta-analysis with 1468 IBS patients found that lubiprostone improved constipation, stool consistency, abdominal pain, degree of straining, and abdominal bloating.⁵⁰ Diarrhea and nausea are commonly reported adverse effects of lubiprostone.^49,50

Linaclotide, plecanatide, and lubiprostone should be considered first-line therapies for patients with IBS-C. High cost is still a roadblock to the use of these agents.

Use antispasmodic medications as first-line treatment for mild IBS symptoms.

The US Food and Drug Administration (FDA) approved tenapanor in September 2019; however, the drug is not commercially available in the United States (it is available in Canada). Tenapanor is a sodium–­hydrogen exchanger 3 inhibitor that reduces sodium absorption from the intestine and colon. The drug increases water secretion into the intestinal lumen, thus accelerating gut transit time. It also inhibits active absorption of phosphate in the intestine.

Tenapanor was approved for treating both IBS-C and hyperphosphatemia in patients with chronic kidney disease on dialysis or end-stage renal disease.²⁶ In a recent meta-analysis, the drug showed benefit in alleviating global IBS symptoms, and ranked first in reducing bloating.⁴⁹ It is too soon to know if tenapanor will perform clinically better than other prosecretory agents.

Continue to: Serotonergic agents

Serotonergic agents. Serotonin (5-hydroxytryptamine [5-HT]) modulates gastrointestinal secretions, gut motility, and visceral sensation. Researchers have developed IBS treatments that target receptors involved in these functions.

Tegaserod is a partial, selective 5-HT₄ agonist indicated for the treatment of IBS-C in women. A study with 661 women with IBS-M and IBS-C showed that tegaserod increased the number of bowel movement episodes. Patients also reported higher stool consistency scores and fewer days with straining compared to placebo.²⁷ The medication was removed from the market in 2007 because of its potential for cardiovascular adverse effects³; however, it was reintroduced in 2019 for women < 65 years of age with IBS-C. Consider prescribing tegaserod if other treatment options fail to alleviate symptoms.

Treatment of IBS-D

Antibiotics. The nonabsorbable antibiotic rifaximin is approved by the FDA for IBS-D at a dosage of 550 mg tid for 2 weeks.¹ Several studies show improvement in IBS global symptoms with the recommended treatment course^51-53; benefit persisted for the 10-week follow-up study period.¹ A meta-analysis found that the NNT for rifaximin is 8-11.⁵⁴ Preliminary data indicate that the rates of Clostridioides difficile infection and microbial resistance among rifaximin users are low.³ Consider using rifaximin as a first-line treatment option for patients with IBS-D. Retreatment might be necessary because the drug’s effect gradually disappears.⁹

Antidiarrheals. Eluxadoline is a µ-opioid and κ-opioid receptor agonist and δ-opioid receptor antagonist with effects on the intestinal nervous system.³ Several meta-analyses demonstrated that eluxadoline improves abdominal pain scores and daily stool consistency in IBS-D patients.^53,54 Eluxadoline should be considered early in the management of IBS-D patients. The most common adverse effect is constipation.

The FDA issued a safety warning in 2017 regarding an increased risk of pancreatitis in patients taking eluxadoline who do not have a gallbladder. In addition, eluxadoline should be avoided in patients with a history of sphincter of Oddi dysfunction, alcohol abuse, or severe liver problems.^3,54

Continue to: The high cost of...

The high cost of eluxadoline can be a significant barrier to use.

Serotonergic agents. Alosetron is a selective 5-HT₃ antagonist developed to treat IBS-D.³ In a meta-analysis comprising 9844 patients, alosetron showed superior abdominal pain scores and improved stool consistency compared to ramosetron, rifaximin, and eluxadoline.⁵³ In 2001, the FDA withdrew alosetron, due to severe constipation and a risk of ischemic colitis; however, the medication has become commercially available again through a risk evaluation and mitigation strategy (REMS) program for women who have disabling IBS-D symptoms.^3,54 Because of this special circumstance, alosetron is not considered first-line therapy for IBS-D.

Linaclotide, plecanatide, and lubiprostone should be considered firstline therapies for IBS-C.

Ondansetron has also been used to treat IBS-D. In a meta-analysis with 294 patients, ondansetron showed improvement in stool consistency.⁵⁵ Ondansetron does not improve abdominal pain.⁴ It can be used in patients who have mild-to-moderate symptoms.⁹ Ondansetron is not FDA approved for the treatment of IBS-D.

Bile-acid sequestrants. Traditionally, bile-acid sequestrants have been used to treat bile-acid diarrhea. A meta-analysis of 6 studies of 908 patients with IBS-D found that 28.1% were affected by bile-acid malabsorption. Two small studies that evaluated the benefits of colesevelam for IBS-D found significant improvement in stool consistency.⁵⁴ Another study, which evaluated the benefits of cholestyramine, found improvement in stool consistency, but findings were not significant.⁵⁴ Many patients taking a bile-acid sequestrant stop taking the medication because of considerable adverse effects (constipation, nausea, bloating, flatulence, and abdominal pain).⁵⁴ For that reason, this class of medication is not recommended as first-line treatment for IBS-D and is not FDA approved for IBS-D.

A role for complementaryand integrative medicine?

Recently, complementary and integrative modalities for treating IBS have sparked the interest of researchers.

Continue to: Acupuncture

Acupuncture. In a meta-analysis with 3440 patients, acupuncture was more effective than Western medicine in alleviating IBS symptoms for as long as 3 months. The authors concluded that acupuncture could be used in combination with other therapies to reduce the severity of IBS symptoms.⁵⁶

Concomitant acupuncture and Chinese herbal medicine. In a systematic review and meta-analysis comprising 21 randomized controlled trials, researchers reported that acupuncture combined with Chinese herbal medicine improved IBS symptoms, compared to what was noted in matched controls who were treated with Western medicine or with Western medicine combined with Chinese herbal medicine. The authors were cautious about the results of the meta-analysis, however, because the studies examined were small and of low quality, and presented a high risk of bias.⁵⁷

Agents not to be used routinely for IBS

Loperamide. This peripheral µ-opioid receptor agonist controls diarrhea. However, recent studies showed no significant benefit to loperamide over placebo in IBS-M and IBS-D. In 2018, the FDA issued a safety alert regarding an elevated risk of serious cardiac adverse effects in patients taking loperamide. The ACG recommends against using loperamide to treat IBS symptoms.^3,54

Polyethylene glycol. An osmotic laxative that is not absorbed in the intestinal lumen, polyethylene glycol is highly efficacious for alleviating constipation, but it does not reduce pain or other IBS symptoms. For that reason, the ACG recommends against its use.³

CORRESPONDENCE
Jose M. Villalon-Gomez, MD, MPH, Emory Healthcare Family Medicine, 4500 North Shallowford Road, Dunwoody, GA 30338; jose.villalon-gomez@emory.edu

Irritable bowel syndrome (IBS) continues to pose a diagnostic and therapeutic challenge to clinicians and patients—a challenge that arises from the varying manifestations of the condition, its complex pathophysiology, lack of effective treatment, and psychological consequences for patients. In this article, I explore new findings related to the pathophysiology, diagnosis, and management of IBS subtypes.

Start with the Rome IV classification of IBS

The Rome Foundation published its latest IBS classification and diagnostic criteria (known as Rome IV) in 2016.¹ IBS is defined as abdominal pain that (1) has recurred, on average, ≥ 1 time per week during the past 3 months and (2) is associated with ≥ 2 of these criteria¹:

• related to defecation
• associated with a change in stool frequency
• associated with a change in the appearance of stool.

Onset of symptoms should be present for 6 months before a diagnosis of IBS is made.¹

IBS subtypes—constipation-predominant (IBS-C), diarrhea-predominant (IBS-D), mixed (IBS-M), and unclassified (IBS-U) (TABLE 1)¹—are based on the frequency of specific stool forms, as described and illustrated in the Bristol Stool Scale (www.webmd.com/digestive-disorders/poop-chart-bristol-stool-scale).²

A widespread, costly, potentially debilitating disorder

IBS affects 10% to 12% of adults worldwide. The condition is more common among women and people younger than 50 years.^1,3 Women with IBS tend to have more constipation ­symptoms (IBS-C); men with IBS, more diarrhea symptoms (IBS-D).⁴

The financial burden of IBS on the health care system and patients is significant. In a 2013 appraisal of 35 studies, the authors note that estimates of the direct cost of IBS care in the United States vary considerably—from $1562 to $7547 for a patient annually.⁵

A recent study found that almost 25% of IBS patients report absenteeism from work due to IBS symptoms.⁶ A Danish study that followed 7278 patients for 5 years found that IBS patients utilized more health care, sick days, and disability pension benefits than non-IBS patients, and had increased utilization of medical resources because of psychiatric conditions.⁷

Continue to: IBS patients also have comorbidities

IBS patients also have comorbidities:

• More than 20% of IBS patients have functional dyspepsia, gastroesophageal reflux disease, incontinence, or pelvic floor dyssynergia.⁴
• The frequency of fibromyalgia syndrome in IBS patients is reported to be 20% to 65%.⁸
• 14% of IBS patients meet criteria for chronic fatigue syndrome.⁸
• Interstitial cystitis and dyspareunia are common among IBS patients.⁹

Pathophysiology is complex

Models describing the pathophysiology of IBS have evolved through the years. Recent models describe it as a combination of altered gastrointestinal motility, visceral hyperalgesia, increased intestinal permeability, immune activation, altered intestinal microbiota, and dysfunction in the brain–gut axis. Certain environmental and psychological variables (eg, previous gastroenteritis, food intolerance, chronic stress, diverticulitis, and surgery) increase the risk of IBS.^1,10,11

In the past several years, considerable attention has been paid to the roles played by the immune system, brain–gut axis function, and intestinal microbiota in IBS manifestations. Research focus in these areas might assist in the development of specific treatment modalities targeting IBS subtypes.

Immune system. A recent meta-­analysis of the records of 706 IBS patients found an increased number of mast cells and CD3 T cells in biopsy specimens from the rectosigmoid and descending colon of IBS patients.¹² Another study found a significant increase in mast cells in the ileum of IBS patients¹³; this increase is evident not only on intestinal biopsy but also at the serologic level. IBS-D patients have a higher plasma interleukin (IL)-6 level than the general population.¹⁴ Another meta-analysis found an imbalance in the serum level of tumor necrosis factor-α and IL-10 in IBS patients.¹⁵

Brain–gut axis. A 2016 meta-analysis showed that patients with anxiety and depression have a 2-fold increased risk of IBS.¹⁶ A more recent study, using data from the National Health Insurance Research Database that included 22,356 patients with IBS, found a 3.6-fold increased risk of psychiatric disorders in IBS.¹⁷ These findings reflect the complex interaction between the brain and the intestinal tract in IBS.

Continue to: Intestinal microbiota

Intestinal microbiota. Research evaluating the role of altered intestinal microbiota in IBS has yielded mixed results. A meta-­analysis of 777 IBS patients showed an increase in Firmicutes spp, a decrease in Bacteroidetes spp, and an increase in the ratio of Firmicutes spp to Bacteroidetes spp in subjects’ fecal specimens.¹⁸ Another study, of 1340 patients, found no difference in Bacteroides spp and Enterococcus spp between healthy controls and IBS patients, but did find (1) lower fecal counts of Lactobacillus spp and Bifidobacterium spp and (2) higher fecal counts of Escherichia coli and Enterobacter spp in IBS patients.¹⁹

Postinfectious IBS. The Rome Foundation introduced the diagnosis of postinfectious IBS (PI-IBS) in 2019. PI-IBS develops in 10% of patients who have had infectious enteritis. Female gender, younger age, psychological distress during or before the enteritis episode, and severity of the acute episode are risk factors for this IBS variant.²⁰ A study of 21,421 enteritis patients found that 42% with protozoal or parasitic infection and 14% with bacterial infection developed IBS.

To identify possible "red flags" or other disorders, take a history that includes the course of symptoms, triggers, and alleviating factors.

Patients with nonviral enteritis often have a more severe course of enteritis, typically requiring antibiotics. It is believed that the resulting irregularities in the intestinal microbiota make these patients more likely to develop PI-IBS.²¹ PI-IBS patients are likely to improve or fully recover over time. Symptoms of PI-IBS are managed in a manner similar to how non-PI-IBS patients are managed.²⁰

Challenges in making the IBS diagnosis

Historically, the diagnosis of IBS has been made clinically after excluding red flags (ie, signs or symptoms that might reflect other underlying medical problems) in the clinical presentation. For this reason, obtain a thorough clinical history that includes the course of symptoms, triggers, and alleviating factors. Any of the following are considered red flags^1,22,23:

• age > 50 years at onset of symptoms
• new-onset constipation in the elderly
• rectal bleeding
• unexplained weight loss or anemia
• family history of organic gastrointestinal disease
• palpable abdominal or rectal mass
• nocturnal symptoms.

New studies demonstrate that several inflammatory markers can help exclude inflammatory bowel disease from the differential diagnosis in patients in whom IBS is suspected and being investigated.²⁴ In 2019, the American Gastroenterological Association published a clinical practice guideline updating the laboratory evaluation of functional diarrhea and IBS-D in adults,²⁵ and made several recommendations:

• Obtain the level of fecal calprotectin (normal level, ≤ 50 mcg/g) or fecal lactoferrin (≤ 4.0-7.25 mcg/g); if these tests are not available or results are not accessible, the C-reactive protein level is a reasonable option.
• Do not routinely use the erythrocyte sedimentation rate or C-reactive protein level to screen for inflammatory bowel disease.
• Test for Giardia lamblia with an antigen or polymerase chain reaction test.
• Do not test for ova and parasites (other than Giardia) in patients who do not have a history of travel or who have not emigrated from a high-risk area recently.
• Obtain testing for celiac disease with immunoglobulin A (IgA) tissue transglutaminase and with a second test, of immunoglobulin G (IgG) tissue transglutaminase and IgG or IgA deaminated gliadin peptides, to detect celiac disease in IgA-deficient patients.
• Order testing for bile-acid diarrhea with selenium homotaurocholic acid nuclear medicine scanning (if available in your region; the test is available in Europe); measurement of bile acid from a 48-hour stool collection; or an assay of fibroblast growth factor 19, which measures defective feedback of bile-acid synthesis. If these tests are unavailable, consider an empiric trial of a bile-acid binder.
• Do not use available serologic IBS testing.

Continue to: Continue to obtain a...

Continue to obtain a complete blood count for the evaluation of anemia. Endoscopic procedures are indicated in patients with a red flag.¹

Treat based on subtype

The first step in the treatment of all IBS patients (TABLE 2^{1,3,4,9,26,27}) is for you to develop a strong relationship with the patient: You must acknowledge the disease and empower the patient to manage their symptoms. A strong physician–patient relationship leads to more effective outcomes.⁴

Low cost and low risk of adverse effects makes exercise worth recommending to all IBS patients.

IBS treatment modalities target abdominal pain, bloating, abdominal distention, and altered bowel function—described in the literature as global symptoms. IBS-M patients should direct their treatment to the predominant symptom (constipation or diarrhea). The following sections describe available treatment options. The FIGURE^1,3,4,9,25 shows a treatment workflow based on IBS subtype and symptom severity.

Treatments for all IBS subtypes

Lifestyle modification. Exercise provides overall positive health benefits. With such a variety of exercise forms, however, it is difficult to identify specific exercises that are better for IBS patients.²⁸ A study of 305 IBS patients found that exercise alleviated constipation but not other IBS symptoms, and did not improve quality of life.³ Based on low cost and low risk of adverse effects, exercise should be recommended to all IBS patients.

Dietary restriction therapies have become an area of focus for patients, clinicians, and researchers. Modification of the diet is thought to improve global symptoms and intestinal health through modification of gut microbiota, immune activation, and a decrease in levels of fecal short-chain fatty acids.²⁹

Continue to: The 2 main diets...

The 2 main diets studied for the treatment of IBS are a diet low in fermentable oligo-, di- and monosaccharides and polyols—the so-called low-FODMAP diet (TABLE 3³⁰)—and a gluten-free diet. Evidence behind the benefits of both diets conflicts; trials of the low-FODMAP diet are more favorable.

A small study with 20 patients with IBS-D and IBS-M who followed a low-FODMAP diet found improvement in IBS symptoms and a reduction in serum levels of proinflammatory cytokines, fecal bacteria, and total fecal short-chain fatty acid levels.²⁹ Several meta-analyses have shown improvement in overall IBS symptoms for patients who follow a low-FODMAP diet. Because of the heterogeneity of the studies, however, the quality of the data is low.^31-34

Data supporting the use of a gluten-free diet for IBS patients are insufficient.³¹

The American College of Gastroenterology (ACG) gave a weak recommendation for the low-FODMAP diet and recommended against the gluten-free diet in IBS patients.³ More data are needed regarding the safety profile of using a low-FODMAP diet for an extended period: There is concern about the risk of nutritional deficiencies associated with long-term use of this diet.³

Supplementation with poorly fermentable soluble fiber has been shown to alleviate global IBS symptoms; insoluble fiber does not yield improvement of symptoms. Psyllium fiber is recommended over wheat bran.^3,35

Continue to: Consider a low-FODMAP diet...

Consider a low-FODMAP diet and soluble fiber as initial treatment for all IBS patients.

Modification of intestinal microbiota. Understanding the difference between prebiotics and probiotics is important when considering treatment for IBS. Prebiotics are foods or dietary supplements that generate changes in the composition and activity of intestinal microbiota. Probiotics are live microorganisms that can improve intestinal health.³

A meta-analysis of 729 IBS patients found that prebiotics do not reduce gastrointestinal symptoms or improve the quality of life of IBS patients.³⁶ Evidence supporting the benefit of probiotics is favorable; however, data in these studies have significant heterogeneity. Several meta-analyses studied the benefits of Lactobacillus spp and Bifidobacterium spp in alleviating IBS symptoms. The studies found improvement in abdominal pain, bloating and distention, and flatulence.^3,37-40 Consider recommending probiotics for all IBS patients; for some, however, the high cost of some of these products might be an obstacle.

Consider recommending probiotics for all IBS patients, although high cost might be an obstacle for some.

Researchers are also studying the use of fecal microbiota transplantation (FMT) to treat IBS. Studies have evaluated the delivery of FMT orally (as capsules) and endoscopically. Evidence does not show improvement in global IBS symptoms with FMT. More studies, with larger sample populations, are needed.^41-43

Antispasmodic medications and peppermint oil. Antispasmodic medications have been considered a mainstay therapy for IBS because of their effect on intestinal dysmotility. Hyoscine and dicyclomine are commonly used. Meta-analyses have shown improvement in global symptoms and abdominal pain, but effects were modest.^3,44 Use this class of drugs as first-line treatment for mild IBS symptoms.

Continue to: Peppermint oil has been...

Peppermint oil has been found useful in improving IBS global symptoms and abdominal pain in several studies.^44-46 A common adverse effect of peppermint oil is heartburn, resulting from relaxation of esophageal muscle.³ Peppermint oil can be considered an adjuvant agent in treating IBS.

Antidepressants. Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) have been studied for the treatment of IBS. Meta-analyses show that both are effective in reducing pain and overall IBS symptoms.^1,3,47 The number needed to treat (NNT) for TCAs is 4.5; for SSRIs, 5.⁴⁷ Data do not show that either drug class is superior to the other for IBS. Based on the adverse effect profile, TCAs are more suitable for IBS-D patients; SSRIs are better for IBS-C patients.⁴⁷

New data show that serotonin-­norepinephrine reuptake inhibitors, such as duloxetine and milnacipran, can alleviate IBS symptoms through their pain-modifying properties.⁴⁷

Based on the adverse effect profile and stigma associated with antidepressant medications, patients might be less likely to take them for IBS symptoms than for these drugs’ primary indications. Clinicians should still consider this drug class if other first-line treatments do not provide full resolution of symptoms.

Psychotherapy. Several psychotherapeutic modalities have been evaluated for efficacy in reducing global IBS symptoms. The approaches studied most often were provider-directed cognitive behavioral therapy, relaxation therapy, hypnotherapy, and multicomponent psychological therapy. The NNT for these modalities is 4, but studies had significant heterogeneity.³ Consider referring patients for psychotherapeutic intervention if they have not responded to medical therapy after 12 months.⁴

Continue to Treatment of IBS-C

Treatment of IBS-C

Prosecretory agents. Linaclotide and plecanatide are amino-acid peptides that act as a guanylate cyclase C agonist. Both increase gastrointestinal transit rate by increasing electrolyte and fluid transport into the intestinal lumen. They also decrease the activity of pain-sensing nerves by increasing extracellular cyclic guanosine-3'5'-monophosphate levels.^3,48 In a recent meta-analysis, both treatments produced improvement in global symptoms. However, linaclotide showed superior improvement in abdominal pain and global symptoms compared to other secretory agents.^48,49 Diarrhea was the most common adverse effect of linaclotide and plecanatide, although less so with plecanatide.⁴⁹

Lubiprostone activates the intestinal chloride channel type 2 on the small intestine, leading to an increase in chloride and water efflux into the intestinal lumen, in turn accelerating gastrointestinal transit.³ A meta-analysis with 1468 IBS patients found that lubiprostone improved constipation, stool consistency, abdominal pain, degree of straining, and abdominal bloating.⁵⁰ Diarrhea and nausea are commonly reported adverse effects of lubiprostone.^49,50

Linaclotide, plecanatide, and lubiprostone should be considered first-line therapies for patients with IBS-C. High cost is still a roadblock to the use of these agents.

Use antispasmodic medications as first-line treatment for mild IBS symptoms.

The US Food and Drug Administration (FDA) approved tenapanor in September 2019; however, the drug is not commercially available in the United States (it is available in Canada). Tenapanor is a sodium–­hydrogen exchanger 3 inhibitor that reduces sodium absorption from the intestine and colon. The drug increases water secretion into the intestinal lumen, thus accelerating gut transit time. It also inhibits active absorption of phosphate in the intestine.

Tenapanor was approved for treating both IBS-C and hyperphosphatemia in patients with chronic kidney disease on dialysis or end-stage renal disease.²⁶ In a recent meta-analysis, the drug showed benefit in alleviating global IBS symptoms, and ranked first in reducing bloating.⁴⁹ It is too soon to know if tenapanor will perform clinically better than other prosecretory agents.

Continue to: Serotonergic agents

Serotonergic agents. Serotonin (5-hydroxytryptamine [5-HT]) modulates gastrointestinal secretions, gut motility, and visceral sensation. Researchers have developed IBS treatments that target receptors involved in these functions.

Tegaserod is a partial, selective 5-HT₄ agonist indicated for the treatment of IBS-C in women. A study with 661 women with IBS-M and IBS-C showed that tegaserod increased the number of bowel movement episodes. Patients also reported higher stool consistency scores and fewer days with straining compared to placebo.²⁷ The medication was removed from the market in 2007 because of its potential for cardiovascular adverse effects³; however, it was reintroduced in 2019 for women < 65 years of age with IBS-C. Consider prescribing tegaserod if other treatment options fail to alleviate symptoms.

Treatment of IBS-D

Antibiotics. The nonabsorbable antibiotic rifaximin is approved by the FDA for IBS-D at a dosage of 550 mg tid for 2 weeks.¹ Several studies show improvement in IBS global symptoms with the recommended treatment course^51-53; benefit persisted for the 10-week follow-up study period.¹ A meta-analysis found that the NNT for rifaximin is 8-11.⁵⁴ Preliminary data indicate that the rates of Clostridioides difficile infection and microbial resistance among rifaximin users are low.³ Consider using rifaximin as a first-line treatment option for patients with IBS-D. Retreatment might be necessary because the drug’s effect gradually disappears.⁹

Antidiarrheals. Eluxadoline is a µ-opioid and κ-opioid receptor agonist and δ-opioid receptor antagonist with effects on the intestinal nervous system.³ Several meta-analyses demonstrated that eluxadoline improves abdominal pain scores and daily stool consistency in IBS-D patients.^53,54 Eluxadoline should be considered early in the management of IBS-D patients. The most common adverse effect is constipation.

The FDA issued a safety warning in 2017 regarding an increased risk of pancreatitis in patients taking eluxadoline who do not have a gallbladder. In addition, eluxadoline should be avoided in patients with a history of sphincter of Oddi dysfunction, alcohol abuse, or severe liver problems.^3,54

Continue to: The high cost of...

The high cost of eluxadoline can be a significant barrier to use.

Serotonergic agents. Alosetron is a selective 5-HT₃ antagonist developed to treat IBS-D.³ In a meta-analysis comprising 9844 patients, alosetron showed superior abdominal pain scores and improved stool consistency compared to ramosetron, rifaximin, and eluxadoline.⁵³ In 2001, the FDA withdrew alosetron, due to severe constipation and a risk of ischemic colitis; however, the medication has become commercially available again through a risk evaluation and mitigation strategy (REMS) program for women who have disabling IBS-D symptoms.^3,54 Because of this special circumstance, alosetron is not considered first-line therapy for IBS-D.

Linaclotide, plecanatide, and lubiprostone should be considered firstline therapies for IBS-C.

Ondansetron has also been used to treat IBS-D. In a meta-analysis with 294 patients, ondansetron showed improvement in stool consistency.⁵⁵ Ondansetron does not improve abdominal pain.⁴ It can be used in patients who have mild-to-moderate symptoms.⁹ Ondansetron is not FDA approved for the treatment of IBS-D.

Bile-acid sequestrants. Traditionally, bile-acid sequestrants have been used to treat bile-acid diarrhea. A meta-analysis of 6 studies of 908 patients with IBS-D found that 28.1% were affected by bile-acid malabsorption. Two small studies that evaluated the benefits of colesevelam for IBS-D found significant improvement in stool consistency.⁵⁴ Another study, which evaluated the benefits of cholestyramine, found improvement in stool consistency, but findings were not significant.⁵⁴ Many patients taking a bile-acid sequestrant stop taking the medication because of considerable adverse effects (constipation, nausea, bloating, flatulence, and abdominal pain).⁵⁴ For that reason, this class of medication is not recommended as first-line treatment for IBS-D and is not FDA approved for IBS-D.

A role for complementaryand integrative medicine?

Recently, complementary and integrative modalities for treating IBS have sparked the interest of researchers.

Continue to: Acupuncture

Acupuncture. In a meta-analysis with 3440 patients, acupuncture was more effective than Western medicine in alleviating IBS symptoms for as long as 3 months. The authors concluded that acupuncture could be used in combination with other therapies to reduce the severity of IBS symptoms.⁵⁶

Concomitant acupuncture and Chinese herbal medicine. In a systematic review and meta-analysis comprising 21 randomized controlled trials, researchers reported that acupuncture combined with Chinese herbal medicine improved IBS symptoms, compared to what was noted in matched controls who were treated with Western medicine or with Western medicine combined with Chinese herbal medicine. The authors were cautious about the results of the meta-analysis, however, because the studies examined were small and of low quality, and presented a high risk of bias.⁵⁷

Agents not to be used routinely for IBS

Loperamide. This peripheral µ-opioid receptor agonist controls diarrhea. However, recent studies showed no significant benefit to loperamide over placebo in IBS-M and IBS-D. In 2018, the FDA issued a safety alert regarding an elevated risk of serious cardiac adverse effects in patients taking loperamide. The ACG recommends against using loperamide to treat IBS symptoms.^3,54

Polyethylene glycol. An osmotic laxative that is not absorbed in the intestinal lumen, polyethylene glycol is highly efficacious for alleviating constipation, but it does not reduce pain or other IBS symptoms. For that reason, the ACG recommends against its use.³

CORRESPONDENCE
Jose M. Villalon-Gomez, MD, MPH, Emory Healthcare Family Medicine, 4500 North Shallowford Road, Dunwoody, GA 30338; jose.villalon-gomez@emory.edu

Patients with idiopathic pulmonary fibrosis (IPF) complete and respond to pulmonary rehabilitation at rates similar to patients with chronic obstructive pulmonary disease (COPD), according to results of a real-world study. The findings reported in an article published in the journal CHEST^® reinforce pulmonary rehabilitation’s benefits for this population.

A progressive decline in respiratory and physical function characterizes IPF, with median survival from diagnosis of 3-5 years, according to Claire Nolan, PhD, of Harefield Hospital, Middlesex, England, and colleagues. The effects of pharmacologic therapies on IPF on symptom burden and quality of life are modest, although lung function decline may be slowed. Supporting evidence for pulmonary rehabilitation benefit in IPF is more modest than it is for COPD, for which exercise capacity, dyspnea, and health-related quality of life improvement have been demonstrated.

“We did not design a randomized, controlled trial,” Dr. Nolan said in an interview, “as it was considered unethical by the local ethics committee to withhold pulmonary rehabilitation based on clinical guidance in the United Kingdom.” She pointed out that initial pulmonary rehabilitation trials in COPD included an intervention (pulmonary rehabilitation) and a control (standard medical care) arm.

The study aims were to compare the effects of pulmonary rehabilitation with real-world data between IPF and COPD with respect to magnitude of effect and survival. The authors’ hypothesis was that IPF patients would have a blunted response to pulmonary rehabilitation with reduced completion rates, compared with a matched COPD group, and with increased mortality.
 

Study details

Investigators use propensity score matching of 163 IPF patients with a control group of 163 patients with COPD referred to pulmonary rehabilitation. Completion rates, responses, and survival status were recorded for 1-year following pulmonary rehabilitation discharge. The 8-week outpatient program was composed of two supervised exercise and education sessions with additional unsupervised home-based exercise each week.

While spirometry data, as expected, showed a higher proportion of IPF patients using supplemental oxygen, pulmonary rehabilitation completion rates were similar for both groups (IPF, 69%; COPD, 63%; P = .24) and there was no between group difference in the number of sessions attended (P = .39). Medical Research Council (muscle strength) (MRC), incremental shuttle walk test (ISW), and Chronic Respiratory Questionnaire total score (CRQ-T) improved significantly in both groups, again with no significant difference between groups.

Over the study course, there was progressive, significant worsening of forced vital capacity percentage, predicted, prescription supplemental oxygen, resting peripheral oxygen saturation, exercise capacity, health-related quality of life and pulmonary rehabilitation adherence across groups of responders (n = 63; 38%), nonresponders (n = 50; 31%) and noncompleters (n = 50; 31%). Among the IPF patients, 6 died before completing pulmonary rehabilitation, with 42 (27%) dying during follow-up.
 

Benefits of rehabilitation

Multivariable analyses showed that noncompletion and nonresponse were associated with significantly higher risk of all-cause mortality at 1-year. Also, time to all-cause mortality was shorter (P = .001) for noncompleters and nonresponders, compared with completers. A trend toward higher completion rates in the IPF group, compared with the COPD group, may be explained, the researchers explained, by fewer hospitalizations over the prior 12 months in the IPF group.

“Although many programs are designed for people with COPD,” Dr. Nolan and colleagues concluded, “our study demonstrates that people with IPF have similar clinical benefits and completion rates to those with COPD. These data reinforce the importance of referral to and engagement in pulmonary rehabilitation amongst the IPF population.”

These findings, Dr. Nolan emphasized, emerged from a single center, and validation in other settings is needed.

This study was funded by a National Institute for Health Research Doctoral Research Fellowship (2014-07-089) and a Medical Research Council New Investigator Research Grant (98576).

Patients with idiopathic pulmonary fibrosis (IPF) complete and respond to pulmonary rehabilitation at rates similar to patients with chronic obstructive pulmonary disease (COPD), according to results of a real-world study. The findings reported in an article published in the journal CHEST^® reinforce pulmonary rehabilitation’s benefits for this population.

A progressive decline in respiratory and physical function characterizes IPF, with median survival from diagnosis of 3-5 years, according to Claire Nolan, PhD, of Harefield Hospital, Middlesex, England, and colleagues. The effects of pharmacologic therapies on IPF on symptom burden and quality of life are modest, although lung function decline may be slowed. Supporting evidence for pulmonary rehabilitation benefit in IPF is more modest than it is for COPD, for which exercise capacity, dyspnea, and health-related quality of life improvement have been demonstrated.

“We did not design a randomized, controlled trial,” Dr. Nolan said in an interview, “as it was considered unethical by the local ethics committee to withhold pulmonary rehabilitation based on clinical guidance in the United Kingdom.” She pointed out that initial pulmonary rehabilitation trials in COPD included an intervention (pulmonary rehabilitation) and a control (standard medical care) arm.

The study aims were to compare the effects of pulmonary rehabilitation with real-world data between IPF and COPD with respect to magnitude of effect and survival. The authors’ hypothesis was that IPF patients would have a blunted response to pulmonary rehabilitation with reduced completion rates, compared with a matched COPD group, and with increased mortality.
 

Study details

Investigators use propensity score matching of 163 IPF patients with a control group of 163 patients with COPD referred to pulmonary rehabilitation. Completion rates, responses, and survival status were recorded for 1-year following pulmonary rehabilitation discharge. The 8-week outpatient program was composed of two supervised exercise and education sessions with additional unsupervised home-based exercise each week.

While spirometry data, as expected, showed a higher proportion of IPF patients using supplemental oxygen, pulmonary rehabilitation completion rates were similar for both groups (IPF, 69%; COPD, 63%; P = .24) and there was no between group difference in the number of sessions attended (P = .39). Medical Research Council (muscle strength) (MRC), incremental shuttle walk test (ISW), and Chronic Respiratory Questionnaire total score (CRQ-T) improved significantly in both groups, again with no significant difference between groups.

Over the study course, there was progressive, significant worsening of forced vital capacity percentage, predicted, prescription supplemental oxygen, resting peripheral oxygen saturation, exercise capacity, health-related quality of life and pulmonary rehabilitation adherence across groups of responders (n = 63; 38%), nonresponders (n = 50; 31%) and noncompleters (n = 50; 31%). Among the IPF patients, 6 died before completing pulmonary rehabilitation, with 42 (27%) dying during follow-up.
 

Benefits of rehabilitation

Multivariable analyses showed that noncompletion and nonresponse were associated with significantly higher risk of all-cause mortality at 1-year. Also, time to all-cause mortality was shorter (P = .001) for noncompleters and nonresponders, compared with completers. A trend toward higher completion rates in the IPF group, compared with the COPD group, may be explained, the researchers explained, by fewer hospitalizations over the prior 12 months in the IPF group.

“Although many programs are designed for people with COPD,” Dr. Nolan and colleagues concluded, “our study demonstrates that people with IPF have similar clinical benefits and completion rates to those with COPD. These data reinforce the importance of referral to and engagement in pulmonary rehabilitation amongst the IPF population.”

These findings, Dr. Nolan emphasized, emerged from a single center, and validation in other settings is needed.

This study was funded by a National Institute for Health Research Doctoral Research Fellowship (2014-07-089) and a Medical Research Council New Investigator Research Grant (98576).

Patients with idiopathic pulmonary fibrosis (IPF) complete and respond to pulmonary rehabilitation at rates similar to patients with chronic obstructive pulmonary disease (COPD), according to results of a real-world study. The findings reported in an article published in the journal CHEST^® reinforce pulmonary rehabilitation’s benefits for this population.

A progressive decline in respiratory and physical function characterizes IPF, with median survival from diagnosis of 3-5 years, according to Claire Nolan, PhD, of Harefield Hospital, Middlesex, England, and colleagues. The effects of pharmacologic therapies on IPF on symptom burden and quality of life are modest, although lung function decline may be slowed. Supporting evidence for pulmonary rehabilitation benefit in IPF is more modest than it is for COPD, for which exercise capacity, dyspnea, and health-related quality of life improvement have been demonstrated.

“We did not design a randomized, controlled trial,” Dr. Nolan said in an interview, “as it was considered unethical by the local ethics committee to withhold pulmonary rehabilitation based on clinical guidance in the United Kingdom.” She pointed out that initial pulmonary rehabilitation trials in COPD included an intervention (pulmonary rehabilitation) and a control (standard medical care) arm.

The study aims were to compare the effects of pulmonary rehabilitation with real-world data between IPF and COPD with respect to magnitude of effect and survival. The authors’ hypothesis was that IPF patients would have a blunted response to pulmonary rehabilitation with reduced completion rates, compared with a matched COPD group, and with increased mortality.
 

Study details

Investigators use propensity score matching of 163 IPF patients with a control group of 163 patients with COPD referred to pulmonary rehabilitation. Completion rates, responses, and survival status were recorded for 1-year following pulmonary rehabilitation discharge. The 8-week outpatient program was composed of two supervised exercise and education sessions with additional unsupervised home-based exercise each week.

While spirometry data, as expected, showed a higher proportion of IPF patients using supplemental oxygen, pulmonary rehabilitation completion rates were similar for both groups (IPF, 69%; COPD, 63%; P = .24) and there was no between group difference in the number of sessions attended (P = .39). Medical Research Council (muscle strength) (MRC), incremental shuttle walk test (ISW), and Chronic Respiratory Questionnaire total score (CRQ-T) improved significantly in both groups, again with no significant difference between groups.

Over the study course, there was progressive, significant worsening of forced vital capacity percentage, predicted, prescription supplemental oxygen, resting peripheral oxygen saturation, exercise capacity, health-related quality of life and pulmonary rehabilitation adherence across groups of responders (n = 63; 38%), nonresponders (n = 50; 31%) and noncompleters (n = 50; 31%). Among the IPF patients, 6 died before completing pulmonary rehabilitation, with 42 (27%) dying during follow-up.
 

Benefits of rehabilitation

Multivariable analyses showed that noncompletion and nonresponse were associated with significantly higher risk of all-cause mortality at 1-year. Also, time to all-cause mortality was shorter (P = .001) for noncompleters and nonresponders, compared with completers. A trend toward higher completion rates in the IPF group, compared with the COPD group, may be explained, the researchers explained, by fewer hospitalizations over the prior 12 months in the IPF group.

“Although many programs are designed for people with COPD,” Dr. Nolan and colleagues concluded, “our study demonstrates that people with IPF have similar clinical benefits and completion rates to those with COPD. These data reinforce the importance of referral to and engagement in pulmonary rehabilitation amongst the IPF population.”

These findings, Dr. Nolan emphasized, emerged from a single center, and validation in other settings is needed.

This study was funded by a National Institute for Health Research Doctoral Research Fellowship (2014-07-089) and a Medical Research Council New Investigator Research Grant (98576).

On the basis of outcomes, there was no clear winner from a trial that directly compared two modern devices used in patients undergoing percutaneous left atrial appendage (LAA) closure.

But the devices were not interchangeable for rates of complications or leaks, according to results of the open-label SWISS APERO trial, which compared the Amplatzer Amulet to the Watchman FLX device at eight participating centers in Europe.

At 45 days, the overall rates of leaks and the clinical outcomes in the two randomized groups were not significantly different, but there were differences in secondary endpoints, such as rates of peridevice leak (PDL), which were lower in the Amulet device group, and procedural complications, which were higher, Roberto Galea, MD, reported at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando.

LAA closure devices were developed as an alternative to oral anticoagulation in patients with nonvalvular atrial fibrillation. Although a similar comparison of LAA closure devices, called Amulet IDE, was recently published, that trial compared Amulet to Watchman 2.5, an earlier generation device.

Started later, SWISS APERO was also a planned comparison of Amulet and the Watchman 2.5, but the comparison switched to the Watchman FLX, when it was released in March of 2019.
 

First randomized comparison with Watchman FLX

“This is the first multicenter randomized controlled trial to include the Watchman FLX,” said Dr. Galea, a clinical investigator in the department of cardiology, Bern (Switzerland) University Hospital. He noted that Watchman FLX included some adjustments in design with the potential to reduce leak rates.

After preprocedural transesophageal echocardiography confirmed that patients had suitable anatomy to receive either device, the 221 patients who qualified for SWISS APERO were randomized. The primary endpoint was a composite of a justified crossover to a device other than the one to which they were assigned or residual patency detected by coronary computed tomography angiography (CCTA) at 45 days.

The primary endpoint was reached by 67.6% of patients randomized to the Amulet device and 70% of those randomized to Watchman Flex, a statistically nonsignificant difference (P = .71).

Because only one patient in the Amulet group and none in the Watchman group had a justified crossover to a nonrandomized device, most of the differences in the 45-day CCTA involved patency, defined as LAA density of at least 100 Hounsfield units. While the proportion of patients with leaks was similar, the types of leaks, which were stratified by underlying leak mechanism into PDL, mixed leaks (including incomplete side sealing), intradevice leaks, and leaks of unclear origin, were different.
 

Peridevice leaks twofold greater with Watchman

Those randomized to the Watchman device were more than twice as likely to have PDL (27.5% vs. 13.7%; P = .02), although no visible leak exceeded 5 mm in size. They were also more likely to have mixed leaks (14% vs. 3.8%; P = .01) and patency with no visible leak (21.0% vs. 9.5%; P = .02). There were also more device-related thrombi in the Watchman group even though the difference did not reach statistical significance (9.9% vs. 3.7%; P = .08).

Intradevice leaks (44.8% vs. 23.0%; P = .001) were the only type of patency significantly more common among patients randomized to Amulet, but the difference was relatively large. In addition, procedural complications of any type (32.4% vs. 19.1%; P = .023) were higher in the Amulet group. Most of these involved non–clinically relevant pericardial effusions, Dr. Galea said at the meeting, sponsored by the Cardiovascular Research Foundation.

The proportion of patients with adverse outcomes by 45 days was similar, but the types of complications differed. Of the six deaths, two occurred in the Amulet group as a result of periprocedural complications (one stemming from an air embolism and the other from a series of events following pericardial effusion). Three of the four deaths in the Watchman group were due to fatal bleeding. The fourth was a sudden death that occurred 30 days after the procedure.
 

Amulet IDE trial generates similar data

The much larger Amulet IDE trial, which compared Amulet to the Watchman 2.5 device, produced generally similar results. Again, the proportion of patients reaching the composite primary endpoints was similar.

The primary safety endpoint, which included death and major bleeding within 12 months of randomization, occurred in 14.5% and 14.7% of the Amulet and Watchman patients, respectively (P < .001 for noninferiority). The primary efficacy endpoint, which included stroke or systemic embolism within 18 months of randomization, occurred in 2.8% of patients in both groups.

As in SWISS APERO, the 1,878-patient Amulet IDE trial showed that the devices are similarly effective and safe but not necessarily interchangeable. Ultimately, the rate of LAA occlusion was higher for Amulet than the older generation Watchman (98.9% vs. 96.8%; P = .003) but procedural complication occurred more frequently among those randomized to the Amulet device (4.5% vs. 2.5%).

“The closure mechanisms are not the same, which might explain why we see differences in some secondary outcomes even when they perform similarly on the primary outcomes,” said Dhanunjaya R. Lakkireddy, MD, executive medical director, Kansas City (Kansas) Heart Rhythm Institute.

The lead investigator of the Amulet IDE trial, Dr. Lakkireddy was referring to both the AMULET IDE and the SWISS APERO study when he said that the currently available data do not allow one device to be considered superior to the other. He did suggest that differences between devices might still be considered meaningful in specific clinical situations or to specific clinicians.

Without studies to show objective differences, Dr. Lakkireddy suggested that training and experience is probably the most important variable in achieving treatment goals. “Operator comfort is certainly important,” he said.

Dr. Galea reports no significant financial relationships. The investigator-initiated study received funding from Abbott, the manufacturer of the Amulet device. Dr. Lakkireddy has financial relationships with Abbott, AltaThera, Medtronic, Biotronik, and Boston Scientific, which makes the Watchman device.

On the basis of outcomes, there was no clear winner from a trial that directly compared two modern devices used in patients undergoing percutaneous left atrial appendage (LAA) closure.

But the devices were not interchangeable for rates of complications or leaks, according to results of the open-label SWISS APERO trial, which compared the Amplatzer Amulet to the Watchman FLX device at eight participating centers in Europe.

At 45 days, the overall rates of leaks and the clinical outcomes in the two randomized groups were not significantly different, but there were differences in secondary endpoints, such as rates of peridevice leak (PDL), which were lower in the Amulet device group, and procedural complications, which were higher, Roberto Galea, MD, reported at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando.

LAA closure devices were developed as an alternative to oral anticoagulation in patients with nonvalvular atrial fibrillation. Although a similar comparison of LAA closure devices, called Amulet IDE, was recently published, that trial compared Amulet to Watchman 2.5, an earlier generation device.

Started later, SWISS APERO was also a planned comparison of Amulet and the Watchman 2.5, but the comparison switched to the Watchman FLX, when it was released in March of 2019.
 

First randomized comparison with Watchman FLX

“This is the first multicenter randomized controlled trial to include the Watchman FLX,” said Dr. Galea, a clinical investigator in the department of cardiology, Bern (Switzerland) University Hospital. He noted that Watchman FLX included some adjustments in design with the potential to reduce leak rates.

After preprocedural transesophageal echocardiography confirmed that patients had suitable anatomy to receive either device, the 221 patients who qualified for SWISS APERO were randomized. The primary endpoint was a composite of a justified crossover to a device other than the one to which they were assigned or residual patency detected by coronary computed tomography angiography (CCTA) at 45 days.

The primary endpoint was reached by 67.6% of patients randomized to the Amulet device and 70% of those randomized to Watchman Flex, a statistically nonsignificant difference (P = .71).

Because only one patient in the Amulet group and none in the Watchman group had a justified crossover to a nonrandomized device, most of the differences in the 45-day CCTA involved patency, defined as LAA density of at least 100 Hounsfield units. While the proportion of patients with leaks was similar, the types of leaks, which were stratified by underlying leak mechanism into PDL, mixed leaks (including incomplete side sealing), intradevice leaks, and leaks of unclear origin, were different.
 

Peridevice leaks twofold greater with Watchman

Those randomized to the Watchman device were more than twice as likely to have PDL (27.5% vs. 13.7%; P = .02), although no visible leak exceeded 5 mm in size. They were also more likely to have mixed leaks (14% vs. 3.8%; P = .01) and patency with no visible leak (21.0% vs. 9.5%; P = .02). There were also more device-related thrombi in the Watchman group even though the difference did not reach statistical significance (9.9% vs. 3.7%; P = .08).

Intradevice leaks (44.8% vs. 23.0%; P = .001) were the only type of patency significantly more common among patients randomized to Amulet, but the difference was relatively large. In addition, procedural complications of any type (32.4% vs. 19.1%; P = .023) were higher in the Amulet group. Most of these involved non–clinically relevant pericardial effusions, Dr. Galea said at the meeting, sponsored by the Cardiovascular Research Foundation.

The proportion of patients with adverse outcomes by 45 days was similar, but the types of complications differed. Of the six deaths, two occurred in the Amulet group as a result of periprocedural complications (one stemming from an air embolism and the other from a series of events following pericardial effusion). Three of the four deaths in the Watchman group were due to fatal bleeding. The fourth was a sudden death that occurred 30 days after the procedure.
 

Amulet IDE trial generates similar data

The much larger Amulet IDE trial, which compared Amulet to the Watchman 2.5 device, produced generally similar results. Again, the proportion of patients reaching the composite primary endpoints was similar.

The primary safety endpoint, which included death and major bleeding within 12 months of randomization, occurred in 14.5% and 14.7% of the Amulet and Watchman patients, respectively (P < .001 for noninferiority). The primary efficacy endpoint, which included stroke or systemic embolism within 18 months of randomization, occurred in 2.8% of patients in both groups.

As in SWISS APERO, the 1,878-patient Amulet IDE trial showed that the devices are similarly effective and safe but not necessarily interchangeable. Ultimately, the rate of LAA occlusion was higher for Amulet than the older generation Watchman (98.9% vs. 96.8%; P = .003) but procedural complication occurred more frequently among those randomized to the Amulet device (4.5% vs. 2.5%).

“The closure mechanisms are not the same, which might explain why we see differences in some secondary outcomes even when they perform similarly on the primary outcomes,” said Dhanunjaya R. Lakkireddy, MD, executive medical director, Kansas City (Kansas) Heart Rhythm Institute.

The lead investigator of the Amulet IDE trial, Dr. Lakkireddy was referring to both the AMULET IDE and the SWISS APERO study when he said that the currently available data do not allow one device to be considered superior to the other. He did suggest that differences between devices might still be considered meaningful in specific clinical situations or to specific clinicians.

Without studies to show objective differences, Dr. Lakkireddy suggested that training and experience is probably the most important variable in achieving treatment goals. “Operator comfort is certainly important,” he said.

Dr. Galea reports no significant financial relationships. The investigator-initiated study received funding from Abbott, the manufacturer of the Amulet device. Dr. Lakkireddy has financial relationships with Abbott, AltaThera, Medtronic, Biotronik, and Boston Scientific, which makes the Watchman device.

On the basis of outcomes, there was no clear winner from a trial that directly compared two modern devices used in patients undergoing percutaneous left atrial appendage (LAA) closure.

But the devices were not interchangeable for rates of complications or leaks, according to results of the open-label SWISS APERO trial, which compared the Amplatzer Amulet to the Watchman FLX device at eight participating centers in Europe.

At 45 days, the overall rates of leaks and the clinical outcomes in the two randomized groups were not significantly different, but there were differences in secondary endpoints, such as rates of peridevice leak (PDL), which were lower in the Amulet device group, and procedural complications, which were higher, Roberto Galea, MD, reported at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando.

LAA closure devices were developed as an alternative to oral anticoagulation in patients with nonvalvular atrial fibrillation. Although a similar comparison of LAA closure devices, called Amulet IDE, was recently published, that trial compared Amulet to Watchman 2.5, an earlier generation device.

Started later, SWISS APERO was also a planned comparison of Amulet and the Watchman 2.5, but the comparison switched to the Watchman FLX, when it was released in March of 2019.
 

First randomized comparison with Watchman FLX

“This is the first multicenter randomized controlled trial to include the Watchman FLX,” said Dr. Galea, a clinical investigator in the department of cardiology, Bern (Switzerland) University Hospital. He noted that Watchman FLX included some adjustments in design with the potential to reduce leak rates.

After preprocedural transesophageal echocardiography confirmed that patients had suitable anatomy to receive either device, the 221 patients who qualified for SWISS APERO were randomized. The primary endpoint was a composite of a justified crossover to a device other than the one to which they were assigned or residual patency detected by coronary computed tomography angiography (CCTA) at 45 days.

The primary endpoint was reached by 67.6% of patients randomized to the Amulet device and 70% of those randomized to Watchman Flex, a statistically nonsignificant difference (P = .71).

Because only one patient in the Amulet group and none in the Watchman group had a justified crossover to a nonrandomized device, most of the differences in the 45-day CCTA involved patency, defined as LAA density of at least 100 Hounsfield units. While the proportion of patients with leaks was similar, the types of leaks, which were stratified by underlying leak mechanism into PDL, mixed leaks (including incomplete side sealing), intradevice leaks, and leaks of unclear origin, were different.
 

Peridevice leaks twofold greater with Watchman

Those randomized to the Watchman device were more than twice as likely to have PDL (27.5% vs. 13.7%; P = .02), although no visible leak exceeded 5 mm in size. They were also more likely to have mixed leaks (14% vs. 3.8%; P = .01) and patency with no visible leak (21.0% vs. 9.5%; P = .02). There were also more device-related thrombi in the Watchman group even though the difference did not reach statistical significance (9.9% vs. 3.7%; P = .08).

Intradevice leaks (44.8% vs. 23.0%; P = .001) were the only type of patency significantly more common among patients randomized to Amulet, but the difference was relatively large. In addition, procedural complications of any type (32.4% vs. 19.1%; P = .023) were higher in the Amulet group. Most of these involved non–clinically relevant pericardial effusions, Dr. Galea said at the meeting, sponsored by the Cardiovascular Research Foundation.

The proportion of patients with adverse outcomes by 45 days was similar, but the types of complications differed. Of the six deaths, two occurred in the Amulet group as a result of periprocedural complications (one stemming from an air embolism and the other from a series of events following pericardial effusion). Three of the four deaths in the Watchman group were due to fatal bleeding. The fourth was a sudden death that occurred 30 days after the procedure.
 

Amulet IDE trial generates similar data

The much larger Amulet IDE trial, which compared Amulet to the Watchman 2.5 device, produced generally similar results. Again, the proportion of patients reaching the composite primary endpoints was similar.

The primary safety endpoint, which included death and major bleeding within 12 months of randomization, occurred in 14.5% and 14.7% of the Amulet and Watchman patients, respectively (P < .001 for noninferiority). The primary efficacy endpoint, which included stroke or systemic embolism within 18 months of randomization, occurred in 2.8% of patients in both groups.

As in SWISS APERO, the 1,878-patient Amulet IDE trial showed that the devices are similarly effective and safe but not necessarily interchangeable. Ultimately, the rate of LAA occlusion was higher for Amulet than the older generation Watchman (98.9% vs. 96.8%; P = .003) but procedural complication occurred more frequently among those randomized to the Amulet device (4.5% vs. 2.5%).

“The closure mechanisms are not the same, which might explain why we see differences in some secondary outcomes even when they perform similarly on the primary outcomes,” said Dhanunjaya R. Lakkireddy, MD, executive medical director, Kansas City (Kansas) Heart Rhythm Institute.

The lead investigator of the Amulet IDE trial, Dr. Lakkireddy was referring to both the AMULET IDE and the SWISS APERO study when he said that the currently available data do not allow one device to be considered superior to the other. He did suggest that differences between devices might still be considered meaningful in specific clinical situations or to specific clinicians.

Without studies to show objective differences, Dr. Lakkireddy suggested that training and experience is probably the most important variable in achieving treatment goals. “Operator comfort is certainly important,” he said.

Dr. Galea reports no significant financial relationships. The investigator-initiated study received funding from Abbott, the manufacturer of the Amulet device. Dr. Lakkireddy has financial relationships with Abbott, AltaThera, Medtronic, Biotronik, and Boston Scientific, which makes the Watchman device.

A single infusion of ketamine rapidly improves distorted thinking and reasoning to reduce suicidal thoughts, independent of the drug’s effect on severe depression, new research shows.

“Previously it was shown that ketamine rapidly improved depression and that explained part of the rapid improvement in suicidal ideation,” senior author J. John Mann, MD, with Columbia University, New York, said in an interview.

“What was unclear was what else changed that could decrease suicidal ideation and the risk for suicidal behavior. This study identifies a second new domain of improvement – namely rapid improvement in several cognitive functions that can potentially reduce suicide risk,” said Dr. Mann.

The study was published online Nov. 2, 2021, in the Journal of Clinical Psychiatry.
 

Boosts cognitive function

A total of 78 adults with major depressive disorder and clinically significant suicidal ideation underwent neuropsychological testing before, and 1 day after, double-blind treatment with a single intravenous infusion of ketamine or midazolam.

“Ketamine produced rapid improvement in suicidal ideation and mood” compared with midazolam, the authors reported.

Ketamine was linked to specific improvement in reaction time and cognitive control/interference processing – a measure that has been associated with previous suicide attempt in depression.

A subgroup of patients whose suicidal ideation did not remit on midazolam were later treated with unblinded ketamine and retested. In these individuals, reaction time and cognitive control/interference processing also improved relative to preketamine assessments.

Neurocognitive improvement, however, was not correlated with changes in depression, suicidal thinking, or general mood, the researchers noted.

Nonetheless, they say ketamine had a “positive therapeutic effect” on neurocognition 1 day after treatment on at least one measure associated with suicidal behavior in the context of depression.

The results suggest “additional independent therapeutic effects for ketamine in the treatment of depressed patients at risk for suicidal behavior,” they wrote.

“Ketamine modulates many neurotransmitter systems including glutamate transmission which is crucial for learning and memory. It increases the number of synapses or connections between neurons. These effects are fundamental to cognition and are logical explanations of the beneficial effects observed in this study,” Dr. Mann said in an interview.

“Our study helped us gain a better understanding of how ketamine works in the brain and how quickly it can improve distorted thinking. Being able to think more clearly can make someone feel less suicidal,” study investigator Ravi. N. Shah, MD, chief innovation officer, Columbia Psychiatry, said in a news release.
 

Important research with caveats

In a comment, James Murrough, MD, PhD, director of the Depression and Anxiety Center for Discovery and Treatment at Mount Sinai in New York, said the study is important and “adds to a growing understanding of how ketamine affects brain systems and thinking in the context of depression and suicide risk.”

“One reason this study is significant is that prior studies have shown that ketamine can have harmful effects on cognitive functioning in the context of ketamine misuse and exposures to high doses for long periods of time,” Dr. Murrough, who wasn’t involved in the study, said in an interview.

“In contrast in this study, a single low-dose treatment of ketamine can have the opposite effects, actually boosting some markers of cognitive functioning, at least in the short-term,” he noted.

Dr. Murrough said one caveat to the study is that it only examined the effect of ketamine on cognition once, 1 day after a single treatment.

“While this is an important initial observation, we don’t yet have any understanding of how persistent this effect on cognition is, or how this observed change may be related to any benefit ketamine may have on depression or suicide risk,” Dr. Murrough said.

“In fact, the researchers found that there was no association between change in cognitive functioning following ketamine and change in depression or suicidal thinking. The patients who showed improved cognitive function following ketamine did not differ in terms of mood or suicide risk compared to patients who did not show an improvement in cognition,” Dr. Murrough noted.

“This raises the important question of what is the relevance of change in cognition to the potential benefits of ketamine. This is an important area and should be the focus of future research in order to improve outcomes for patients with depression and who are at risk for suicide,” he added.

Also weighing in, Roger S. McIntyre, MD, professor of psychiatry and pharmacology and head of the mood disorders psychopharmacology unit, University of Toronto, said the study is “very interesting and in keeping” with some previous work that he and his colleagues have done showing that ketamine “seems to benefit aspects of cognition which is a core element in depression.”

“It’s a testable hypothesis that the improvement in cognition now being reported and replicated could play some role in the improved quality of life and functioning with this treatment and as well reduce reducing suicide,” said Dr. McIntyre.

This study was supported by the National Institute of Mental Health. Dr. Mann receives royalties for commercial use of the Columbia-Suicide Severity Rating Scale, which was not used in this study. Dr. Murrough’s institution was involved in research involving esketamine (Spravato) for treatment-resistant depression and receives financial remuneration from the manufacturer of esketamine. Dr. McIntyre has received research grant support from the Canadian Institutes of Health Research/Global Alliance for Chronic Diseases/Chinese National Natural Research Foundation and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, Eisai, Minerva, Intra-Cellular, and AbbVie. Dr. McIntyre is also CEO of AltMed.

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

A single infusion of ketamine rapidly improves distorted thinking and reasoning to reduce suicidal thoughts, independent of the drug’s effect on severe depression, new research shows.

“Previously it was shown that ketamine rapidly improved depression and that explained part of the rapid improvement in suicidal ideation,” senior author J. John Mann, MD, with Columbia University, New York, said in an interview.

“What was unclear was what else changed that could decrease suicidal ideation and the risk for suicidal behavior. This study identifies a second new domain of improvement – namely rapid improvement in several cognitive functions that can potentially reduce suicide risk,” said Dr. Mann.

The study was published online Nov. 2, 2021, in the Journal of Clinical Psychiatry.
 

Boosts cognitive function

A total of 78 adults with major depressive disorder and clinically significant suicidal ideation underwent neuropsychological testing before, and 1 day after, double-blind treatment with a single intravenous infusion of ketamine or midazolam.

“Ketamine produced rapid improvement in suicidal ideation and mood” compared with midazolam, the authors reported.

Ketamine was linked to specific improvement in reaction time and cognitive control/interference processing – a measure that has been associated with previous suicide attempt in depression.

A subgroup of patients whose suicidal ideation did not remit on midazolam were later treated with unblinded ketamine and retested. In these individuals, reaction time and cognitive control/interference processing also improved relative to preketamine assessments.

Neurocognitive improvement, however, was not correlated with changes in depression, suicidal thinking, or general mood, the researchers noted.

Nonetheless, they say ketamine had a “positive therapeutic effect” on neurocognition 1 day after treatment on at least one measure associated with suicidal behavior in the context of depression.

The results suggest “additional independent therapeutic effects for ketamine in the treatment of depressed patients at risk for suicidal behavior,” they wrote.

“Ketamine modulates many neurotransmitter systems including glutamate transmission which is crucial for learning and memory. It increases the number of synapses or connections between neurons. These effects are fundamental to cognition and are logical explanations of the beneficial effects observed in this study,” Dr. Mann said in an interview.

“Our study helped us gain a better understanding of how ketamine works in the brain and how quickly it can improve distorted thinking. Being able to think more clearly can make someone feel less suicidal,” study investigator Ravi. N. Shah, MD, chief innovation officer, Columbia Psychiatry, said in a news release.
 

Important research with caveats

In a comment, James Murrough, MD, PhD, director of the Depression and Anxiety Center for Discovery and Treatment at Mount Sinai in New York, said the study is important and “adds to a growing understanding of how ketamine affects brain systems and thinking in the context of depression and suicide risk.”

“One reason this study is significant is that prior studies have shown that ketamine can have harmful effects on cognitive functioning in the context of ketamine misuse and exposures to high doses for long periods of time,” Dr. Murrough, who wasn’t involved in the study, said in an interview.

“In contrast in this study, a single low-dose treatment of ketamine can have the opposite effects, actually boosting some markers of cognitive functioning, at least in the short-term,” he noted.

Dr. Murrough said one caveat to the study is that it only examined the effect of ketamine on cognition once, 1 day after a single treatment.

“While this is an important initial observation, we don’t yet have any understanding of how persistent this effect on cognition is, or how this observed change may be related to any benefit ketamine may have on depression or suicide risk,” Dr. Murrough said.

“In fact, the researchers found that there was no association between change in cognitive functioning following ketamine and change in depression or suicidal thinking. The patients who showed improved cognitive function following ketamine did not differ in terms of mood or suicide risk compared to patients who did not show an improvement in cognition,” Dr. Murrough noted.

“This raises the important question of what is the relevance of change in cognition to the potential benefits of ketamine. This is an important area and should be the focus of future research in order to improve outcomes for patients with depression and who are at risk for suicide,” he added.

Also weighing in, Roger S. McIntyre, MD, professor of psychiatry and pharmacology and head of the mood disorders psychopharmacology unit, University of Toronto, said the study is “very interesting and in keeping” with some previous work that he and his colleagues have done showing that ketamine “seems to benefit aspects of cognition which is a core element in depression.”

“It’s a testable hypothesis that the improvement in cognition now being reported and replicated could play some role in the improved quality of life and functioning with this treatment and as well reduce reducing suicide,” said Dr. McIntyre.

This study was supported by the National Institute of Mental Health. Dr. Mann receives royalties for commercial use of the Columbia-Suicide Severity Rating Scale, which was not used in this study. Dr. Murrough’s institution was involved in research involving esketamine (Spravato) for treatment-resistant depression and receives financial remuneration from the manufacturer of esketamine. Dr. McIntyre has received research grant support from the Canadian Institutes of Health Research/Global Alliance for Chronic Diseases/Chinese National Natural Research Foundation and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, Eisai, Minerva, Intra-Cellular, and AbbVie. Dr. McIntyre is also CEO of AltMed.

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

A single infusion of ketamine rapidly improves distorted thinking and reasoning to reduce suicidal thoughts, independent of the drug’s effect on severe depression, new research shows.

“Previously it was shown that ketamine rapidly improved depression and that explained part of the rapid improvement in suicidal ideation,” senior author J. John Mann, MD, with Columbia University, New York, said in an interview.

“What was unclear was what else changed that could decrease suicidal ideation and the risk for suicidal behavior. This study identifies a second new domain of improvement – namely rapid improvement in several cognitive functions that can potentially reduce suicide risk,” said Dr. Mann.

The study was published online Nov. 2, 2021, in the Journal of Clinical Psychiatry.
 

Boosts cognitive function

A total of 78 adults with major depressive disorder and clinically significant suicidal ideation underwent neuropsychological testing before, and 1 day after, double-blind treatment with a single intravenous infusion of ketamine or midazolam.

“Ketamine produced rapid improvement in suicidal ideation and mood” compared with midazolam, the authors reported.

Ketamine was linked to specific improvement in reaction time and cognitive control/interference processing – a measure that has been associated with previous suicide attempt in depression.

A subgroup of patients whose suicidal ideation did not remit on midazolam were later treated with unblinded ketamine and retested. In these individuals, reaction time and cognitive control/interference processing also improved relative to preketamine assessments.

Neurocognitive improvement, however, was not correlated with changes in depression, suicidal thinking, or general mood, the researchers noted.

Nonetheless, they say ketamine had a “positive therapeutic effect” on neurocognition 1 day after treatment on at least one measure associated with suicidal behavior in the context of depression.

The results suggest “additional independent therapeutic effects for ketamine in the treatment of depressed patients at risk for suicidal behavior,” they wrote.

“Ketamine modulates many neurotransmitter systems including glutamate transmission which is crucial for learning and memory. It increases the number of synapses or connections between neurons. These effects are fundamental to cognition and are logical explanations of the beneficial effects observed in this study,” Dr. Mann said in an interview.

“Our study helped us gain a better understanding of how ketamine works in the brain and how quickly it can improve distorted thinking. Being able to think more clearly can make someone feel less suicidal,” study investigator Ravi. N. Shah, MD, chief innovation officer, Columbia Psychiatry, said in a news release.
 

Important research with caveats

In a comment, James Murrough, MD, PhD, director of the Depression and Anxiety Center for Discovery and Treatment at Mount Sinai in New York, said the study is important and “adds to a growing understanding of how ketamine affects brain systems and thinking in the context of depression and suicide risk.”

“One reason this study is significant is that prior studies have shown that ketamine can have harmful effects on cognitive functioning in the context of ketamine misuse and exposures to high doses for long periods of time,” Dr. Murrough, who wasn’t involved in the study, said in an interview.

“In contrast in this study, a single low-dose treatment of ketamine can have the opposite effects, actually boosting some markers of cognitive functioning, at least in the short-term,” he noted.

Dr. Murrough said one caveat to the study is that it only examined the effect of ketamine on cognition once, 1 day after a single treatment.

“While this is an important initial observation, we don’t yet have any understanding of how persistent this effect on cognition is, or how this observed change may be related to any benefit ketamine may have on depression or suicide risk,” Dr. Murrough said.

“In fact, the researchers found that there was no association between change in cognitive functioning following ketamine and change in depression or suicidal thinking. The patients who showed improved cognitive function following ketamine did not differ in terms of mood or suicide risk compared to patients who did not show an improvement in cognition,” Dr. Murrough noted.

“This raises the important question of what is the relevance of change in cognition to the potential benefits of ketamine. This is an important area and should be the focus of future research in order to improve outcomes for patients with depression and who are at risk for suicide,” he added.

Also weighing in, Roger S. McIntyre, MD, professor of psychiatry and pharmacology and head of the mood disorders psychopharmacology unit, University of Toronto, said the study is “very interesting and in keeping” with some previous work that he and his colleagues have done showing that ketamine “seems to benefit aspects of cognition which is a core element in depression.”

“It’s a testable hypothesis that the improvement in cognition now being reported and replicated could play some role in the improved quality of life and functioning with this treatment and as well reduce reducing suicide,” said Dr. McIntyre.

This study was supported by the National Institute of Mental Health. Dr. Mann receives royalties for commercial use of the Columbia-Suicide Severity Rating Scale, which was not used in this study. Dr. Murrough’s institution was involved in research involving esketamine (Spravato) for treatment-resistant depression and receives financial remuneration from the manufacturer of esketamine. Dr. McIntyre has received research grant support from the Canadian Institutes of Health Research/Global Alliance for Chronic Diseases/Chinese National Natural Research Foundation and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, Eisai, Minerva, Intra-Cellular, and AbbVie. Dr. McIntyre is also CEO of AltMed.

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

As 2021 winds down, I reflect on the achievements the rheumatology community has had in the realm of advocacy throughout the year. And there were many: Seven states signed accumulator program bans into law, five states reformed the use of step therapy protocols, Texas passed an innovative “gold carding” law to reduce the burden of prior authorization, and West Virginia passed a rebate pass-through law to directly assist patients with high out-of-pocket costs – the first of its kind in the nation.

Of course, the close of another year also means gearing up for the year ahead. The majority of state legislatures are getting ready to open legislative sessions in the New Year. This means a year of new opportunities and new challenges. As a community, there are some key areas rheumatology will need to focus on during the course of the upcoming year as policy makers return to the business of policy making.

Many in the rheumatology community are aware that the buy and bill acquisition system has come under threat in recent years, mainly from payer mandates to use the alternative white bagging model. In some cases, payers have gone as far as to mandate the practice of “brown bagging,” or home infusion. These practices can endanger patient safety and overall quality of care. A study led by Matthew Baker, MD, of Stanford (Calif.) University found that biologic infusions administered at home, compared with those administered at a facility, were associated with increased adverse events requiring escalation of care; specifically, home infusions were associated with 25% increased odds of ED or hospital admission on the same or next day after infusion, compared with facility infusions, and 28% increased odds of permanent discontinuation of the biologic after emergency department or hospital admission. Additionally, site-of-care research by Paul Fronstin, PhD, at Employee Benefit Research Institute clearly shows that in-office infusion with physician supervision is far more cost effective than hospital and, in some cases, home infusion as well.

Further, the metastasis of these payer mandates is likely to severely limit availability of and access to care. It is unclear whether outpatient infusion, especially in private rheumatology practices, will prove sustainable in a world of white bagging. The net result of an expansion of the white-bagging requirements may well be broad access challenges that inconvenience patients deeply and irresponsibly.

The expansion of these mandates has not come without pushback, and rheumatologists should be prepared to advocate for policy that prohibits payers from mandating the use of white bagging, brown bagging, and home infusion. It is abundantly clear that arguments of safety and cost effectiveness are sufficient grounds for policy makers to curtail the mandatory use of these practices.

Similar to white bagging, another key issue in the year ahead is formulary construction based on the rebate system and proposed policies to address its attendant problems. Propagated by pharmacy benefit managers (PBMs), the rebate-based, or kickback, system of formulary construction often rewards higher-priced drugs with preferred placement regardless of whether they are the best and most affordable medications for our patients. A few states are beginning to address the affordability issue by mandating that the rebate/kickback acquired by the PBM be passed back to the patient at the point of sale. West Virginia passed a first-of-its-kind law to ensure that patients who generate drug rebates benefit from them by requiring that their cost shares are reduced by an amount equivalent to the rebate received by a health plan. This policy does not get at the root of the formulary construction problem, but if it is adopted more broadly across the country, it will deliver direct relief to patients who are struggling with out-of-pocket costs associated with prescription drugs. I anticipate that this will be a prominent issue nationwide during the upcoming year with opportunity for rheumatologists to lend their voices.

Many of the rheumatology community’s longstanding issues persist, and while progress has been made, more work remains to be done. Whether it’s accumulator programs, prior authorization, nonmedical switching, or step therapy, there will be opportunities in almost every state to engage in improving our ability to provide excellent care to our patients.

We tend to be motivated into action when one of these individual issues appear in our own state’s legislature; however, consistency of engagement is also important. While it is important to talk to your legislators when you need them to vote a certain way on a certain bill, scheduling a meeting with them or sending them a message detailing some of the issues that the rheumatology community faces before legislatures return in full swing is equally important to establish the relationship.

By making “rheum for action” now, you’ll have more impact when legislation relevant to our daily work does appear in the state legislatures. You can find your state representatives at the Coalition for State Rheumatology Organization’s Action Center.

Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is President of the CSRO, past chair of the Alliance for Safe Biologic Medicines, and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at rhnews@mdedge.com.

As 2021 winds down, I reflect on the achievements the rheumatology community has had in the realm of advocacy throughout the year. And there were many: Seven states signed accumulator program bans into law, five states reformed the use of step therapy protocols, Texas passed an innovative “gold carding” law to reduce the burden of prior authorization, and West Virginia passed a rebate pass-through law to directly assist patients with high out-of-pocket costs – the first of its kind in the nation.

Of course, the close of another year also means gearing up for the year ahead. The majority of state legislatures are getting ready to open legislative sessions in the New Year. This means a year of new opportunities and new challenges. As a community, there are some key areas rheumatology will need to focus on during the course of the upcoming year as policy makers return to the business of policy making.

Many in the rheumatology community are aware that the buy and bill acquisition system has come under threat in recent years, mainly from payer mandates to use the alternative white bagging model. In some cases, payers have gone as far as to mandate the practice of “brown bagging,” or home infusion. These practices can endanger patient safety and overall quality of care. A study led by Matthew Baker, MD, of Stanford (Calif.) University found that biologic infusions administered at home, compared with those administered at a facility, were associated with increased adverse events requiring escalation of care; specifically, home infusions were associated with 25% increased odds of ED or hospital admission on the same or next day after infusion, compared with facility infusions, and 28% increased odds of permanent discontinuation of the biologic after emergency department or hospital admission. Additionally, site-of-care research by Paul Fronstin, PhD, at Employee Benefit Research Institute clearly shows that in-office infusion with physician supervision is far more cost effective than hospital and, in some cases, home infusion as well.

Further, the metastasis of these payer mandates is likely to severely limit availability of and access to care. It is unclear whether outpatient infusion, especially in private rheumatology practices, will prove sustainable in a world of white bagging. The net result of an expansion of the white-bagging requirements may well be broad access challenges that inconvenience patients deeply and irresponsibly.

The expansion of these mandates has not come without pushback, and rheumatologists should be prepared to advocate for policy that prohibits payers from mandating the use of white bagging, brown bagging, and home infusion. It is abundantly clear that arguments of safety and cost effectiveness are sufficient grounds for policy makers to curtail the mandatory use of these practices.

Similar to white bagging, another key issue in the year ahead is formulary construction based on the rebate system and proposed policies to address its attendant problems. Propagated by pharmacy benefit managers (PBMs), the rebate-based, or kickback, system of formulary construction often rewards higher-priced drugs with preferred placement regardless of whether they are the best and most affordable medications for our patients. A few states are beginning to address the affordability issue by mandating that the rebate/kickback acquired by the PBM be passed back to the patient at the point of sale. West Virginia passed a first-of-its-kind law to ensure that patients who generate drug rebates benefit from them by requiring that their cost shares are reduced by an amount equivalent to the rebate received by a health plan. This policy does not get at the root of the formulary construction problem, but if it is adopted more broadly across the country, it will deliver direct relief to patients who are struggling with out-of-pocket costs associated with prescription drugs. I anticipate that this will be a prominent issue nationwide during the upcoming year with opportunity for rheumatologists to lend their voices.

Many of the rheumatology community’s longstanding issues persist, and while progress has been made, more work remains to be done. Whether it’s accumulator programs, prior authorization, nonmedical switching, or step therapy, there will be opportunities in almost every state to engage in improving our ability to provide excellent care to our patients.

We tend to be motivated into action when one of these individual issues appear in our own state’s legislature; however, consistency of engagement is also important. While it is important to talk to your legislators when you need them to vote a certain way on a certain bill, scheduling a meeting with them or sending them a message detailing some of the issues that the rheumatology community faces before legislatures return in full swing is equally important to establish the relationship.

By making “rheum for action” now, you’ll have more impact when legislation relevant to our daily work does appear in the state legislatures. You can find your state representatives at the Coalition for State Rheumatology Organization’s Action Center.

Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is President of the CSRO, past chair of the Alliance for Safe Biologic Medicines, and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at rhnews@mdedge.com.

As 2021 winds down, I reflect on the achievements the rheumatology community has had in the realm of advocacy throughout the year. And there were many: Seven states signed accumulator program bans into law, five states reformed the use of step therapy protocols, Texas passed an innovative “gold carding” law to reduce the burden of prior authorization, and West Virginia passed a rebate pass-through law to directly assist patients with high out-of-pocket costs – the first of its kind in the nation.

Of course, the close of another year also means gearing up for the year ahead. The majority of state legislatures are getting ready to open legislative sessions in the New Year. This means a year of new opportunities and new challenges. As a community, there are some key areas rheumatology will need to focus on during the course of the upcoming year as policy makers return to the business of policy making.

Many in the rheumatology community are aware that the buy and bill acquisition system has come under threat in recent years, mainly from payer mandates to use the alternative white bagging model. In some cases, payers have gone as far as to mandate the practice of “brown bagging,” or home infusion. These practices can endanger patient safety and overall quality of care. A study led by Matthew Baker, MD, of Stanford (Calif.) University found that biologic infusions administered at home, compared with those administered at a facility, were associated with increased adverse events requiring escalation of care; specifically, home infusions were associated with 25% increased odds of ED or hospital admission on the same or next day after infusion, compared with facility infusions, and 28% increased odds of permanent discontinuation of the biologic after emergency department or hospital admission. Additionally, site-of-care research by Paul Fronstin, PhD, at Employee Benefit Research Institute clearly shows that in-office infusion with physician supervision is far more cost effective than hospital and, in some cases, home infusion as well.

Further, the metastasis of these payer mandates is likely to severely limit availability of and access to care. It is unclear whether outpatient infusion, especially in private rheumatology practices, will prove sustainable in a world of white bagging. The net result of an expansion of the white-bagging requirements may well be broad access challenges that inconvenience patients deeply and irresponsibly.

The expansion of these mandates has not come without pushback, and rheumatologists should be prepared to advocate for policy that prohibits payers from mandating the use of white bagging, brown bagging, and home infusion. It is abundantly clear that arguments of safety and cost effectiveness are sufficient grounds for policy makers to curtail the mandatory use of these practices.

Similar to white bagging, another key issue in the year ahead is formulary construction based on the rebate system and proposed policies to address its attendant problems. Propagated by pharmacy benefit managers (PBMs), the rebate-based, or kickback, system of formulary construction often rewards higher-priced drugs with preferred placement regardless of whether they are the best and most affordable medications for our patients. A few states are beginning to address the affordability issue by mandating that the rebate/kickback acquired by the PBM be passed back to the patient at the point of sale. West Virginia passed a first-of-its-kind law to ensure that patients who generate drug rebates benefit from them by requiring that their cost shares are reduced by an amount equivalent to the rebate received by a health plan. This policy does not get at the root of the formulary construction problem, but if it is adopted more broadly across the country, it will deliver direct relief to patients who are struggling with out-of-pocket costs associated with prescription drugs. I anticipate that this will be a prominent issue nationwide during the upcoming year with opportunity for rheumatologists to lend their voices.

Many of the rheumatology community’s longstanding issues persist, and while progress has been made, more work remains to be done. Whether it’s accumulator programs, prior authorization, nonmedical switching, or step therapy, there will be opportunities in almost every state to engage in improving our ability to provide excellent care to our patients.

We tend to be motivated into action when one of these individual issues appear in our own state’s legislature; however, consistency of engagement is also important. While it is important to talk to your legislators when you need them to vote a certain way on a certain bill, scheduling a meeting with them or sending them a message detailing some of the issues that the rheumatology community faces before legislatures return in full swing is equally important to establish the relationship.

By making “rheum for action” now, you’ll have more impact when legislation relevant to our daily work does appear in the state legislatures. You can find your state representatives at the Coalition for State Rheumatology Organization’s Action Center.

Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is President of the CSRO, past chair of the Alliance for Safe Biologic Medicines, and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at rhnews@mdedge.com.

It remains early days for transcatheter mitral-valve replacement (TMVR) as a minimally invasive way to treat severe, mitral regurgitation (MR), but it’s even earlier days for TMVR as an endovascular procedure. Most of the technique’s limited experience with a dedicated mitral prosthesis has involved transapical delivery.

But now a 15-patient study of transfemoral, transeptal TMVR – with a prosthesis designed for the mitral position and previously tested only transapically – has shown good 30-day results in that MR was essentially abolished with virtually no paravalvular leakage.

Nor were there adverse clinical events such as death, stroke, reintervention, or new need for a pacemaker in any of the high-surgical-risk patients with MR in this feasibility study of the transfemoral Intrepid TMVR System (Medtronic). Implantation failed, however, in one patient who then received a surgical valve via sternotomy.

The current cohort is part of a larger ongoing trial that will track whether patients implanted transfemorally with the Intrepid also show reverse remodeling and good clinical outcomes over at least a year. That study, called APOLLO, is one of several exploring dedicated TMVR valves from different companies, with names like SUMMIT, MISCEND, and TIARA-2.

Currently, TMVR is approved in the United States only using one device designed for the aortic position and only for treating failed surgical mitral bioprostheses in high-risk patients.

If the Intrepid transfemoral system has an Achilles’ heel, at least in the current iteration, it might be its 35 F catheter delivery system that requires surgical access to the femoral vein. Seven of the patients in the small series experienced major bleeding events, including six at the femoral access site, listed as major vascular complications.

Overall, the study’s patients “were extremely sick with a lot of comorbidity. A lot of them had atrial fibrillation, a lot of them were on anticoagulation to start with,” observed Firas Zahr, MD, Oregon Health & Science University, Portland, as part of his presentation of the study at Transcatheter Cardiovascular Therapeutics (TCT) 2021, held virtually as well as onsite in Orlando, Florida.

All had moderate-to-severe, usually primary MR; two thirds of the cohort had been in NYHA class III or IV at baseline, and 40% had been hospitalized for heart failure within the past year. Eight had a history of cardiovascular surgery, and eight had diabetes. Their mean Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score was 4.7, Dr. Zahr reported.

“At 30 days, there was a significant improvement in their heart failure classification; the vast majority of the patients were [NYHA] class I and class II,” said Dr. Zahr, who is also lead author on the study’s Nov. 6 publication in JACC: Cardiovascular Interventions.

Observers of the study at TCT 2021 seemed enthusiastic about the study’s results but recognized that TMVR in its current form still has formidable limitations.

“This is clearly an exciting look into the future and very reassuring to a degree, aside from the complications, which are somewhat expected as we go with 30-plus French devices,” Rajiv Tayal, MD, MPH, said at a press conference on the Intrepid study held before Dr. Zahr’s formal presentation. Dr. Tayal is an interventional cardiologist with Valley Health System, Ridgewood, New Jersey, and New York Medical College, Valhalla.

“I think we’ve all learned that transapical [access] is just not a viable procedure for a lot of these patients, and so we’ve got to get to transfemoral,” Susheel K. Kodali, MD, interventional cardiologist at New York-Presbyterian/Columbia University Irving Medical Center, said at the same forum.

A 35 F device “is going to be too big,” he said. However, “it is the first step to iterate to a smaller device.” Dr. Kodali said his center contributed a patient to the study, and he is listed as a coauthor on the publication.

The delivery system’s large profile is only part of the vascular complication issue. Not only did the procedure require surgical cutdown for venous access, but “we were fairly aggressive in anticoagulating these patients with the fear of thrombus formation,” Dr. Zahr said in the discussion following his presentation.

“A postprocedure anticoagulation regimen is recommended within the protocol, but ultimate therapy was left to the discretion of the treating site physician,” the published report states, noting that all 14 patients with successful TMVR were discharged on warfarin. They included 12 who were also put on a single antiplatelet and one given dual antiplatelet therapy on top of the oral anticoagulant.

“One thing that we learned is that we probably should standardize our approach to perioperative anticoagulation,” Dr. Zahr observed. Also, a 29 F sheath for the system is in the works, “and we’re hoping that with smaller sheath size, and hopefully going even to percutaneous, might have an impact on lowering the vascular complications.”

Explanations for the “higher-than-expected vascular complication rate” remains somewhat unclear, agreed an editorial accompanying the study’s publication, “but may include a learning curve with the system, the large introducer sheath, the need for surgical cutdown, and postprocedural anticoagulation.”

For trans-septal TMVR to become a default approach, “venous access will need to be achieved percutaneously and vascular complications need to be infrequent,” contends the editorial, with lead author Mohamad Alkhouli, MD, Mayo Clinic, Rochester, Minn.

“These data provide a glimpse into the future of TMVR. The excellent short-term safety and effectiveness of this still very early-stage procedure represent a major step forward in the field,” they write.

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

It remains early days for transcatheter mitral-valve replacement (TMVR) as a minimally invasive way to treat severe, mitral regurgitation (MR), but it’s even earlier days for TMVR as an endovascular procedure. Most of the technique’s limited experience with a dedicated mitral prosthesis has involved transapical delivery.

But now a 15-patient study of transfemoral, transeptal TMVR – with a prosthesis designed for the mitral position and previously tested only transapically – has shown good 30-day results in that MR was essentially abolished with virtually no paravalvular leakage.

Nor were there adverse clinical events such as death, stroke, reintervention, or new need for a pacemaker in any of the high-surgical-risk patients with MR in this feasibility study of the transfemoral Intrepid TMVR System (Medtronic). Implantation failed, however, in one patient who then received a surgical valve via sternotomy.

The current cohort is part of a larger ongoing trial that will track whether patients implanted transfemorally with the Intrepid also show reverse remodeling and good clinical outcomes over at least a year. That study, called APOLLO, is one of several exploring dedicated TMVR valves from different companies, with names like SUMMIT, MISCEND, and TIARA-2.

Currently, TMVR is approved in the United States only using one device designed for the aortic position and only for treating failed surgical mitral bioprostheses in high-risk patients.

If the Intrepid transfemoral system has an Achilles’ heel, at least in the current iteration, it might be its 35 F catheter delivery system that requires surgical access to the femoral vein. Seven of the patients in the small series experienced major bleeding events, including six at the femoral access site, listed as major vascular complications.

Overall, the study’s patients “were extremely sick with a lot of comorbidity. A lot of them had atrial fibrillation, a lot of them were on anticoagulation to start with,” observed Firas Zahr, MD, Oregon Health & Science University, Portland, as part of his presentation of the study at Transcatheter Cardiovascular Therapeutics (TCT) 2021, held virtually as well as onsite in Orlando, Florida.

All had moderate-to-severe, usually primary MR; two thirds of the cohort had been in NYHA class III or IV at baseline, and 40% had been hospitalized for heart failure within the past year. Eight had a history of cardiovascular surgery, and eight had diabetes. Their mean Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score was 4.7, Dr. Zahr reported.

“At 30 days, there was a significant improvement in their heart failure classification; the vast majority of the patients were [NYHA] class I and class II,” said Dr. Zahr, who is also lead author on the study’s Nov. 6 publication in JACC: Cardiovascular Interventions.

Observers of the study at TCT 2021 seemed enthusiastic about the study’s results but recognized that TMVR in its current form still has formidable limitations.

“This is clearly an exciting look into the future and very reassuring to a degree, aside from the complications, which are somewhat expected as we go with 30-plus French devices,” Rajiv Tayal, MD, MPH, said at a press conference on the Intrepid study held before Dr. Zahr’s formal presentation. Dr. Tayal is an interventional cardiologist with Valley Health System, Ridgewood, New Jersey, and New York Medical College, Valhalla.

“I think we’ve all learned that transapical [access] is just not a viable procedure for a lot of these patients, and so we’ve got to get to transfemoral,” Susheel K. Kodali, MD, interventional cardiologist at New York-Presbyterian/Columbia University Irving Medical Center, said at the same forum.

A 35 F device “is going to be too big,” he said. However, “it is the first step to iterate to a smaller device.” Dr. Kodali said his center contributed a patient to the study, and he is listed as a coauthor on the publication.

The delivery system’s large profile is only part of the vascular complication issue. Not only did the procedure require surgical cutdown for venous access, but “we were fairly aggressive in anticoagulating these patients with the fear of thrombus formation,” Dr. Zahr said in the discussion following his presentation.

“A postprocedure anticoagulation regimen is recommended within the protocol, but ultimate therapy was left to the discretion of the treating site physician,” the published report states, noting that all 14 patients with successful TMVR were discharged on warfarin. They included 12 who were also put on a single antiplatelet and one given dual antiplatelet therapy on top of the oral anticoagulant.

“One thing that we learned is that we probably should standardize our approach to perioperative anticoagulation,” Dr. Zahr observed. Also, a 29 F sheath for the system is in the works, “and we’re hoping that with smaller sheath size, and hopefully going even to percutaneous, might have an impact on lowering the vascular complications.”

Explanations for the “higher-than-expected vascular complication rate” remains somewhat unclear, agreed an editorial accompanying the study’s publication, “but may include a learning curve with the system, the large introducer sheath, the need for surgical cutdown, and postprocedural anticoagulation.”

For trans-septal TMVR to become a default approach, “venous access will need to be achieved percutaneously and vascular complications need to be infrequent,” contends the editorial, with lead author Mohamad Alkhouli, MD, Mayo Clinic, Rochester, Minn.

“These data provide a glimpse into the future of TMVR. The excellent short-term safety and effectiveness of this still very early-stage procedure represent a major step forward in the field,” they write.

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

It remains early days for transcatheter mitral-valve replacement (TMVR) as a minimally invasive way to treat severe, mitral regurgitation (MR), but it’s even earlier days for TMVR as an endovascular procedure. Most of the technique’s limited experience with a dedicated mitral prosthesis has involved transapical delivery.

But now a 15-patient study of transfemoral, transeptal TMVR – with a prosthesis designed for the mitral position and previously tested only transapically – has shown good 30-day results in that MR was essentially abolished with virtually no paravalvular leakage.

Nor were there adverse clinical events such as death, stroke, reintervention, or new need for a pacemaker in any of the high-surgical-risk patients with MR in this feasibility study of the transfemoral Intrepid TMVR System (Medtronic). Implantation failed, however, in one patient who then received a surgical valve via sternotomy.

The current cohort is part of a larger ongoing trial that will track whether patients implanted transfemorally with the Intrepid also show reverse remodeling and good clinical outcomes over at least a year. That study, called APOLLO, is one of several exploring dedicated TMVR valves from different companies, with names like SUMMIT, MISCEND, and TIARA-2.

Currently, TMVR is approved in the United States only using one device designed for the aortic position and only for treating failed surgical mitral bioprostheses in high-risk patients.

If the Intrepid transfemoral system has an Achilles’ heel, at least in the current iteration, it might be its 35 F catheter delivery system that requires surgical access to the femoral vein. Seven of the patients in the small series experienced major bleeding events, including six at the femoral access site, listed as major vascular complications.

Overall, the study’s patients “were extremely sick with a lot of comorbidity. A lot of them had atrial fibrillation, a lot of them were on anticoagulation to start with,” observed Firas Zahr, MD, Oregon Health & Science University, Portland, as part of his presentation of the study at Transcatheter Cardiovascular Therapeutics (TCT) 2021, held virtually as well as onsite in Orlando, Florida.

All had moderate-to-severe, usually primary MR; two thirds of the cohort had been in NYHA class III or IV at baseline, and 40% had been hospitalized for heart failure within the past year. Eight had a history of cardiovascular surgery, and eight had diabetes. Their mean Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score was 4.7, Dr. Zahr reported.

“At 30 days, there was a significant improvement in their heart failure classification; the vast majority of the patients were [NYHA] class I and class II,” said Dr. Zahr, who is also lead author on the study’s Nov. 6 publication in JACC: Cardiovascular Interventions.

Observers of the study at TCT 2021 seemed enthusiastic about the study’s results but recognized that TMVR in its current form still has formidable limitations.

“This is clearly an exciting look into the future and very reassuring to a degree, aside from the complications, which are somewhat expected as we go with 30-plus French devices,” Rajiv Tayal, MD, MPH, said at a press conference on the Intrepid study held before Dr. Zahr’s formal presentation. Dr. Tayal is an interventional cardiologist with Valley Health System, Ridgewood, New Jersey, and New York Medical College, Valhalla.

“I think we’ve all learned that transapical [access] is just not a viable procedure for a lot of these patients, and so we’ve got to get to transfemoral,” Susheel K. Kodali, MD, interventional cardiologist at New York-Presbyterian/Columbia University Irving Medical Center, said at the same forum.

A 35 F device “is going to be too big,” he said. However, “it is the first step to iterate to a smaller device.” Dr. Kodali said his center contributed a patient to the study, and he is listed as a coauthor on the publication.

The delivery system’s large profile is only part of the vascular complication issue. Not only did the procedure require surgical cutdown for venous access, but “we were fairly aggressive in anticoagulating these patients with the fear of thrombus formation,” Dr. Zahr said in the discussion following his presentation.

“A postprocedure anticoagulation regimen is recommended within the protocol, but ultimate therapy was left to the discretion of the treating site physician,” the published report states, noting that all 14 patients with successful TMVR were discharged on warfarin. They included 12 who were also put on a single antiplatelet and one given dual antiplatelet therapy on top of the oral anticoagulant.

“One thing that we learned is that we probably should standardize our approach to perioperative anticoagulation,” Dr. Zahr observed. Also, a 29 F sheath for the system is in the works, “and we’re hoping that with smaller sheath size, and hopefully going even to percutaneous, might have an impact on lowering the vascular complications.”

Explanations for the “higher-than-expected vascular complication rate” remains somewhat unclear, agreed an editorial accompanying the study’s publication, “but may include a learning curve with the system, the large introducer sheath, the need for surgical cutdown, and postprocedural anticoagulation.”

For trans-septal TMVR to become a default approach, “venous access will need to be achieved percutaneously and vascular complications need to be infrequent,” contends the editorial, with lead author Mohamad Alkhouli, MD, Mayo Clinic, Rochester, Minn.

“These data provide a glimpse into the future of TMVR. The excellent short-term safety and effectiveness of this still very early-stage procedure represent a major step forward in the field,” they write.

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

The Food and Drug Administration has long kept a watchful eye over successive iterations of endovascular stent graphs in the Endologix AFX line, designed for repair of abdominal aortic aneurysms (AAA). For years, the devices, first approved in 2011, have drawn safety alerts and recalls , stemming from what the agency says was a “higher than expected” risk for potentially injurious or fatal type III endoleaks.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

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

The Food and Drug Administration has long kept a watchful eye over successive iterations of endovascular stent graphs in the Endologix AFX line, designed for repair of abdominal aortic aneurysms (AAA). For years, the devices, first approved in 2011, have drawn safety alerts and recalls , stemming from what the agency says was a “higher than expected” risk for potentially injurious or fatal type III endoleaks.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

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

The Food and Drug Administration has long kept a watchful eye over successive iterations of endovascular stent graphs in the Endologix AFX line, designed for repair of abdominal aortic aneurysms (AAA). For years, the devices, first approved in 2011, have drawn safety alerts and recalls , stemming from what the agency says was a “higher than expected” risk for potentially injurious or fatal type III endoleaks.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

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

Up to one-third of patients with multiple sclerosis (MS) treated with the B-cell depleting monoclonal antibody ocrelizumab (Ocrevus) show some degree of repletion of B-cells toward the end of the 6-month infusion cycle. However, there are no corresponding worsening of symptoms or signs of a “wearing off” effect, new research shows.

“Most people expect that since this is a B-cell depleting drug, that if you are not depleting B cells, then that should be reflected clinically and there should be some breakthrough activity,” said study investigator Joshua D. Katz, MD, codirector of the Elliot Lewis Center for Multiple Sclerosis Care in Wellesley, Massachusetts.

Real-world study

Preapproval clinical trials of ocrelizumab suggest about 5% of patients experience a repletion of B cells. However, the timing and association with breakthrough symptoms were unclear.

To investigate, Dr. Katz and colleagues conducted two studies. The first is a substudy of the prospective ACAPELLA trial to assess ocrelizumab-associated adverse events in a real-world population. The study included 294 patients with relapsing and progressive forms of MS treated with at least two cycles of ocrelizumab, given as infusion once every 6 months.

The results showed that overall, 91 (31%) of the 294 patients had some degree of repletion at one or more timepoints.

In categorizing patients according to their highest CD19 measure after two cycles, 108 patients (64.7%) had no significant repletion of B-cells after infusion, defined as an increase of less than 10 cells/μL, while 45 (26.9%) were considered mild repleters, defined as having increases of 10-49 cells/μL.

Seven patients (4.2%) were moderate repleters, with an increase of 50-79 cells/μL, and 7 (4.2%) were categorized as marked repleters, with increases of 80 or more cells/μL.

Eight patients in the study fully repleted, with values from 114-319 cells/μL, occurring between 23 and 34 weeks of the last infusion.

However, there was no relationship between repletion of the B-cells and clinical or MRI evidence of relapse.

Of note, the proportion of patients who did not have B-cell repletion increased with greater numbers of infusions. Whereas 64.7% were non-repleters at cycle 2, that number increased to 88.8% by cycle 6, with a slight drop to 85.6% being non-repleters by cycle 7 (36 months).

“Mild B-cell repletion was fairly common after two cycles of ocrelizumab, but with repeated dosing, a greater proportion of patients were non-repleters, suggesting that cumulative exposure to ocrelizumab results in greater depletion,” the researchers noted.

However, “while the number of moderate or marked repleters in our study was small, they had a tendency to remain repleters over time with subsequent infusions,” they added.

In looking at patient characteristics, moderate and marketed repleters had higher mean BMI (34.1 and 32.6, respectively) compared with the non- and mild repleters (27.0 and 29.4, respectively; P < .0001).

Dr. Katz noted that the increased risk of B-cell repletion with higher BMI was not a surprise. This association, he said, “makes sense” because patients’ relative exposure to ocrelizumab decreases with higher BMI. Similar patterns with BMI were observed in the clinical trial for ocrelizumab approval, in which patients with lower BMI tended to have greater improvement.
 

No symptom worsening

In the second study, the investigators further examined changes in symptom burden related to the amount of time from ocrelizumab infusion. They evaluated 110 patients, aged 18-80 (mean age 44.8) who had Expanded Disability Status Scale (EDSS) scores between 0-7. Study participants were either initiating ocrelizumab or had been on the drug for at least 1 year.

Symptom burden was evaluated with the Neurological Disorders (Neuro-Qol) questionnaire and SymptoMScreen patient-reported outcomes at the beginning of the study at week 4, and near the end of the ocrelizumab infusion cycle, at week 22.

The researchers found that among 69 participants who completed the questionnaires, there were no significant differences at week 22 versus week 4 across a wide range of symptoms, including walking, spasticity, pain, fatigue, cognitive function, dizziness, and depression between the two timepoints.

The only change on the Neuro-QoL score was in the sleep disturbance domain, which improved marginally at the end of the cycle (P = .052). This study did not evaluate changes in B-cells.

Dr. Katz noted that the inclusion of patients over age of 55 in the study offered important insights.

“Our hypothesis was that we were going to start seeing a higher rate of complications, especially infections, in people who are older and may be at a higher risk of infection and disability,” Dr. Katz noted. “But so far, we haven’t seen any higher risk in older patients or those with more disability than anyone else, which is good news.”
 

Amplification of baseline symptoms not uncommon

Commenting on the research, Scott D. Newsome, DO, current president of the CMSC, noted that although no association was observed between the B-cell repletion and symptoms, amplification of flare-up symptoms that are linked to B-cell depleting therapy infusion timing are not uncommon.

“The ‘wearing-off’ phenomenon is not unique to the B-cell therapies,” said Dr. Newsome, who is also director of Johns Hopkins University’s Neurosciences Consultation and Infusion Center and an associate professor of neurology at the JHU med school. “With natalizumab (Tysabri), patients can have an amplification of baseline symptoms as they come closer to their next infusion, and it has been speculated that maybe it was something biologically happening, such as inflammatory cytokines ramping back up or some other mechanisms.”

“Now that we have the B-cell depleting therapies, we tend see the same kind of pattern, where a few weeks leading up to the next infusion, people will develop these amplified symptoms,” he said.

The possibility of a cumulative effect, appearing to address the B-cell repletion associated with early infusions, could have implications over time, Dr. Newsome noted.

“This is important because if people are going on these therapies long-term, the question we may need to ask is whether they actually need to continue to get an infusion every 6 months,” he said.

As these questions around the safety of long-term immunosuppressant drug use continue, different dosing regimens may need to be considered in order to mitigate potential infection risk, he added.

Dr. Katz reports consulting and/or speakers’ bureau relationships with Alexion, Biogen, EMD Serono, Genentech, Novartis, and Sanofi. Dr. Newsome reports relationships with Autobahn, BioIncept, Biogen, Genentech, Novartis, Bristol Myers Squibb, EMD Serono, Greenwich Biosciences, and MedDay Pharmaceuticals.

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

Up to one-third of patients with multiple sclerosis (MS) treated with the B-cell depleting monoclonal antibody ocrelizumab (Ocrevus) show some degree of repletion of B-cells toward the end of the 6-month infusion cycle. However, there are no corresponding worsening of symptoms or signs of a “wearing off” effect, new research shows.

“Most people expect that since this is a B-cell depleting drug, that if you are not depleting B cells, then that should be reflected clinically and there should be some breakthrough activity,” said study investigator Joshua D. Katz, MD, codirector of the Elliot Lewis Center for Multiple Sclerosis Care in Wellesley, Massachusetts.

Real-world study

Preapproval clinical trials of ocrelizumab suggest about 5% of patients experience a repletion of B cells. However, the timing and association with breakthrough symptoms were unclear.

To investigate, Dr. Katz and colleagues conducted two studies. The first is a substudy of the prospective ACAPELLA trial to assess ocrelizumab-associated adverse events in a real-world population. The study included 294 patients with relapsing and progressive forms of MS treated with at least two cycles of ocrelizumab, given as infusion once every 6 months.

The results showed that overall, 91 (31%) of the 294 patients had some degree of repletion at one or more timepoints.

In categorizing patients according to their highest CD19 measure after two cycles, 108 patients (64.7%) had no significant repletion of B-cells after infusion, defined as an increase of less than 10 cells/μL, while 45 (26.9%) were considered mild repleters, defined as having increases of 10-49 cells/μL.

Seven patients (4.2%) were moderate repleters, with an increase of 50-79 cells/μL, and 7 (4.2%) were categorized as marked repleters, with increases of 80 or more cells/μL.

Eight patients in the study fully repleted, with values from 114-319 cells/μL, occurring between 23 and 34 weeks of the last infusion.

However, there was no relationship between repletion of the B-cells and clinical or MRI evidence of relapse.

Of note, the proportion of patients who did not have B-cell repletion increased with greater numbers of infusions. Whereas 64.7% were non-repleters at cycle 2, that number increased to 88.8% by cycle 6, with a slight drop to 85.6% being non-repleters by cycle 7 (36 months).

“Mild B-cell repletion was fairly common after two cycles of ocrelizumab, but with repeated dosing, a greater proportion of patients were non-repleters, suggesting that cumulative exposure to ocrelizumab results in greater depletion,” the researchers noted.

However, “while the number of moderate or marked repleters in our study was small, they had a tendency to remain repleters over time with subsequent infusions,” they added.

In looking at patient characteristics, moderate and marketed repleters had higher mean BMI (34.1 and 32.6, respectively) compared with the non- and mild repleters (27.0 and 29.4, respectively; P < .0001).

Dr. Katz noted that the increased risk of B-cell repletion with higher BMI was not a surprise. This association, he said, “makes sense” because patients’ relative exposure to ocrelizumab decreases with higher BMI. Similar patterns with BMI were observed in the clinical trial for ocrelizumab approval, in which patients with lower BMI tended to have greater improvement.
 

No symptom worsening

In the second study, the investigators further examined changes in symptom burden related to the amount of time from ocrelizumab infusion. They evaluated 110 patients, aged 18-80 (mean age 44.8) who had Expanded Disability Status Scale (EDSS) scores between 0-7. Study participants were either initiating ocrelizumab or had been on the drug for at least 1 year.

Symptom burden was evaluated with the Neurological Disorders (Neuro-Qol) questionnaire and SymptoMScreen patient-reported outcomes at the beginning of the study at week 4, and near the end of the ocrelizumab infusion cycle, at week 22.

The researchers found that among 69 participants who completed the questionnaires, there were no significant differences at week 22 versus week 4 across a wide range of symptoms, including walking, spasticity, pain, fatigue, cognitive function, dizziness, and depression between the two timepoints.

The only change on the Neuro-QoL score was in the sleep disturbance domain, which improved marginally at the end of the cycle (P = .052). This study did not evaluate changes in B-cells.

Dr. Katz noted that the inclusion of patients over age of 55 in the study offered important insights.

“Our hypothesis was that we were going to start seeing a higher rate of complications, especially infections, in people who are older and may be at a higher risk of infection and disability,” Dr. Katz noted. “But so far, we haven’t seen any higher risk in older patients or those with more disability than anyone else, which is good news.”
 

Amplification of baseline symptoms not uncommon

Commenting on the research, Scott D. Newsome, DO, current president of the CMSC, noted that although no association was observed between the B-cell repletion and symptoms, amplification of flare-up symptoms that are linked to B-cell depleting therapy infusion timing are not uncommon.

“The ‘wearing-off’ phenomenon is not unique to the B-cell therapies,” said Dr. Newsome, who is also director of Johns Hopkins University’s Neurosciences Consultation and Infusion Center and an associate professor of neurology at the JHU med school. “With natalizumab (Tysabri), patients can have an amplification of baseline symptoms as they come closer to their next infusion, and it has been speculated that maybe it was something biologically happening, such as inflammatory cytokines ramping back up or some other mechanisms.”

“Now that we have the B-cell depleting therapies, we tend see the same kind of pattern, where a few weeks leading up to the next infusion, people will develop these amplified symptoms,” he said.

The possibility of a cumulative effect, appearing to address the B-cell repletion associated with early infusions, could have implications over time, Dr. Newsome noted.

“This is important because if people are going on these therapies long-term, the question we may need to ask is whether they actually need to continue to get an infusion every 6 months,” he said.

As these questions around the safety of long-term immunosuppressant drug use continue, different dosing regimens may need to be considered in order to mitigate potential infection risk, he added.

Dr. Katz reports consulting and/or speakers’ bureau relationships with Alexion, Biogen, EMD Serono, Genentech, Novartis, and Sanofi. Dr. Newsome reports relationships with Autobahn, BioIncept, Biogen, Genentech, Novartis, Bristol Myers Squibb, EMD Serono, Greenwich Biosciences, and MedDay Pharmaceuticals.

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

Up to one-third of patients with multiple sclerosis (MS) treated with the B-cell depleting monoclonal antibody ocrelizumab (Ocrevus) show some degree of repletion of B-cells toward the end of the 6-month infusion cycle. However, there are no corresponding worsening of symptoms or signs of a “wearing off” effect, new research shows.

“Most people expect that since this is a B-cell depleting drug, that if you are not depleting B cells, then that should be reflected clinically and there should be some breakthrough activity,” said study investigator Joshua D. Katz, MD, codirector of the Elliot Lewis Center for Multiple Sclerosis Care in Wellesley, Massachusetts.

Real-world study

Preapproval clinical trials of ocrelizumab suggest about 5% of patients experience a repletion of B cells. However, the timing and association with breakthrough symptoms were unclear.

To investigate, Dr. Katz and colleagues conducted two studies. The first is a substudy of the prospective ACAPELLA trial to assess ocrelizumab-associated adverse events in a real-world population. The study included 294 patients with relapsing and progressive forms of MS treated with at least two cycles of ocrelizumab, given as infusion once every 6 months.

The results showed that overall, 91 (31%) of the 294 patients had some degree of repletion at one or more timepoints.

In categorizing patients according to their highest CD19 measure after two cycles, 108 patients (64.7%) had no significant repletion of B-cells after infusion, defined as an increase of less than 10 cells/μL, while 45 (26.9%) were considered mild repleters, defined as having increases of 10-49 cells/μL.

Seven patients (4.2%) were moderate repleters, with an increase of 50-79 cells/μL, and 7 (4.2%) were categorized as marked repleters, with increases of 80 or more cells/μL.

Eight patients in the study fully repleted, with values from 114-319 cells/μL, occurring between 23 and 34 weeks of the last infusion.

However, there was no relationship between repletion of the B-cells and clinical or MRI evidence of relapse.

Of note, the proportion of patients who did not have B-cell repletion increased with greater numbers of infusions. Whereas 64.7% were non-repleters at cycle 2, that number increased to 88.8% by cycle 6, with a slight drop to 85.6% being non-repleters by cycle 7 (36 months).

“Mild B-cell repletion was fairly common after two cycles of ocrelizumab, but with repeated dosing, a greater proportion of patients were non-repleters, suggesting that cumulative exposure to ocrelizumab results in greater depletion,” the researchers noted.

However, “while the number of moderate or marked repleters in our study was small, they had a tendency to remain repleters over time with subsequent infusions,” they added.

In looking at patient characteristics, moderate and marketed repleters had higher mean BMI (34.1 and 32.6, respectively) compared with the non- and mild repleters (27.0 and 29.4, respectively; P < .0001).

Dr. Katz noted that the increased risk of B-cell repletion with higher BMI was not a surprise. This association, he said, “makes sense” because patients’ relative exposure to ocrelizumab decreases with higher BMI. Similar patterns with BMI were observed in the clinical trial for ocrelizumab approval, in which patients with lower BMI tended to have greater improvement.
 

No symptom worsening

In the second study, the investigators further examined changes in symptom burden related to the amount of time from ocrelizumab infusion. They evaluated 110 patients, aged 18-80 (mean age 44.8) who had Expanded Disability Status Scale (EDSS) scores between 0-7. Study participants were either initiating ocrelizumab or had been on the drug for at least 1 year.

Symptom burden was evaluated with the Neurological Disorders (Neuro-Qol) questionnaire and SymptoMScreen patient-reported outcomes at the beginning of the study at week 4, and near the end of the ocrelizumab infusion cycle, at week 22.

The researchers found that among 69 participants who completed the questionnaires, there were no significant differences at week 22 versus week 4 across a wide range of symptoms, including walking, spasticity, pain, fatigue, cognitive function, dizziness, and depression between the two timepoints.

The only change on the Neuro-QoL score was in the sleep disturbance domain, which improved marginally at the end of the cycle (P = .052). This study did not evaluate changes in B-cells.

Dr. Katz noted that the inclusion of patients over age of 55 in the study offered important insights.

“Our hypothesis was that we were going to start seeing a higher rate of complications, especially infections, in people who are older and may be at a higher risk of infection and disability,” Dr. Katz noted. “But so far, we haven’t seen any higher risk in older patients or those with more disability than anyone else, which is good news.”
 

Amplification of baseline symptoms not uncommon

Commenting on the research, Scott D. Newsome, DO, current president of the CMSC, noted that although no association was observed between the B-cell repletion and symptoms, amplification of flare-up symptoms that are linked to B-cell depleting therapy infusion timing are not uncommon.

“The ‘wearing-off’ phenomenon is not unique to the B-cell therapies,” said Dr. Newsome, who is also director of Johns Hopkins University’s Neurosciences Consultation and Infusion Center and an associate professor of neurology at the JHU med school. “With natalizumab (Tysabri), patients can have an amplification of baseline symptoms as they come closer to their next infusion, and it has been speculated that maybe it was something biologically happening, such as inflammatory cytokines ramping back up or some other mechanisms.”

“Now that we have the B-cell depleting therapies, we tend see the same kind of pattern, where a few weeks leading up to the next infusion, people will develop these amplified symptoms,” he said.

The possibility of a cumulative effect, appearing to address the B-cell repletion associated with early infusions, could have implications over time, Dr. Newsome noted.

“This is important because if people are going on these therapies long-term, the question we may need to ask is whether they actually need to continue to get an infusion every 6 months,” he said.

As these questions around the safety of long-term immunosuppressant drug use continue, different dosing regimens may need to be considered in order to mitigate potential infection risk, he added.

Dr. Katz reports consulting and/or speakers’ bureau relationships with Alexion, Biogen, EMD Serono, Genentech, Novartis, and Sanofi. Dr. Newsome reports relationships with Autobahn, BioIncept, Biogen, Genentech, Novartis, Bristol Myers Squibb, EMD Serono, Greenwich Biosciences, and MedDay Pharmaceuticals.

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

The death rate from Parkinson’s disease has increased by about 63% over the past 2 decades in the United States, according to what investigators say is the most comprehensive study in the nation of temporal trends in Parkinson’s disease mortality.

“The reason behind the rising death rates from Parkinson’s disease is not clear at present and warrants further investigation,” Wei Bao, MD, PhD, associate professor in the department of epidemiology at the University of Iowa College of Public Health, in Iowa City, said in an interview. “We know that people are living longer and the general population is getting older, but that doesn’t fully explain the increase we saw in the death rate in people with Parkinson’s disease,” Dr. Bao added in a statement.

“Understanding why more people are dying from this disease is critical if we are going to reverse the trend,” Dr. Bao said.

The study was published online Oct. 27 in Neurology.

Long-term data

The researchers used data from the National Vital Statistics System to determine national trends in Parkinson’s disease mortality overall and in several key subgroups. The analyses included 479,059 people who died of Parkinson’s disease between 1999 and 2019.

Over the 21-year period, the age-adjusted mortality from Parkinson’s disease rose from 5.4 per 100,000 in 1999 to 8.8 per 100,000 in 2019. The average annual percent change (APC) was 2.4% for the entire period.

During the study period, the number of deaths from Parkinson’s disease more than doubled, from 14,593 to 35,311.

The death rate from Parkinson’s disease increased significantly across all age groups. The average APC was 5.0% among adults younger than 65 years, 1.9% among those aged 65-74 years, 2.2% among those 75-84 years, and 2.7% among those 85 and older.

The death rate increased in both men and women, but age-adjusted Parkinson’s disease mortality was twice as high in men as in women. The researchers say one possible explanation for the sex difference is estrogen, which leads to higher dopamine levels in areas of the brain that control motor responses and may protect women from Parkinson’s disease.

The study also showed that White people are more likely to die from Parkinson’s disease than persons of other racial and ethnic groups. In 2019, the death rate per 100,000 was 9.7 for Whites, 6.5 for Hispanics, and 4.7 for non-Hispanic Blacks.

Previous studies have shown that compared with White people, Black and Hispanic people are less likely to see a neurologist, owing to socioeconomic barriers. This suggests that White people may be more likely to receive a Parkinson’s disease diagnosis, the researchers noted.

“It’s important to continue to evaluate long-term trends in Parkinson’s death rates,” Dr. Bao said.

“This can inform future research that may help pinpoint why more people are dying of the disease. Also, updating vital statistics about Parkinson’s death rates may be used for priority setting and financing of health care and policy,” Dr. Bao added.
 

1.2 million patients by 2030

Reached for comment, James Beck, PhD, chief scientific officer for the Parkinson’s Foundation, said these findings are not surprising. “They are aligned with the work the Parkinson’s Foundation has done to show that the number of people with Parkinson’s disease has increased over time. We are working on an improved estimate of Parkinson’s disease incidence and predict that Parkinson’s disease will continue to rise as the population ages, so an increase in mortality rates would be expected,” Dr. Beck said.

He noted that much of the public health statistics regarding Parkinson’s disease are outdated and that the Parkinson’s Foundation has been partnering with others to update them.

“For instance, to calculate an accurate estimate of the prevalence of Parkinson’s disease, the Parkinson’s Foundation Prevalence Project was formed. The findings from this group demonstrated that the number of people living with Parkinson’s disease will rise to nearly 1.2 million by 2030, a substantial increase from the estimate of 930,000 for 2020,” Dr. Beck said.

“The overarching message is that more people are being diagnosed with Parkinson’s disease, not that more people are dying from the disease,” he added.

“Over the last 20 years, our understanding of Parkinson’s disease has changed and developed, so clinicians are more aware and better able to properly diagnose Parkinson’s disease. This could mean that the cause is likely due to an increase in diagnosis rates and better recognition of Parkinson’s disease, which would lead to higher rates of identifying Parkinson’s disease as a cause of death,” said Dr. Beck.

The study had no targeted funding. Dr. Bao and Dr. Beck have indicated no relevant financial relationships.
 

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

The death rate from Parkinson’s disease has increased by about 63% over the past 2 decades in the United States, according to what investigators say is the most comprehensive study in the nation of temporal trends in Parkinson’s disease mortality.

“The reason behind the rising death rates from Parkinson’s disease is not clear at present and warrants further investigation,” Wei Bao, MD, PhD, associate professor in the department of epidemiology at the University of Iowa College of Public Health, in Iowa City, said in an interview. “We know that people are living longer and the general population is getting older, but that doesn’t fully explain the increase we saw in the death rate in people with Parkinson’s disease,” Dr. Bao added in a statement.

“Understanding why more people are dying from this disease is critical if we are going to reverse the trend,” Dr. Bao said.

The study was published online Oct. 27 in Neurology.

Long-term data

The researchers used data from the National Vital Statistics System to determine national trends in Parkinson’s disease mortality overall and in several key subgroups. The analyses included 479,059 people who died of Parkinson’s disease between 1999 and 2019.

Over the 21-year period, the age-adjusted mortality from Parkinson’s disease rose from 5.4 per 100,000 in 1999 to 8.8 per 100,000 in 2019. The average annual percent change (APC) was 2.4% for the entire period.

During the study period, the number of deaths from Parkinson’s disease more than doubled, from 14,593 to 35,311.

The death rate from Parkinson’s disease increased significantly across all age groups. The average APC was 5.0% among adults younger than 65 years, 1.9% among those aged 65-74 years, 2.2% among those 75-84 years, and 2.7% among those 85 and older.

The death rate increased in both men and women, but age-adjusted Parkinson’s disease mortality was twice as high in men as in women. The researchers say one possible explanation for the sex difference is estrogen, which leads to higher dopamine levels in areas of the brain that control motor responses and may protect women from Parkinson’s disease.

The study also showed that White people are more likely to die from Parkinson’s disease than persons of other racial and ethnic groups. In 2019, the death rate per 100,000 was 9.7 for Whites, 6.5 for Hispanics, and 4.7 for non-Hispanic Blacks.

Previous studies have shown that compared with White people, Black and Hispanic people are less likely to see a neurologist, owing to socioeconomic barriers. This suggests that White people may be more likely to receive a Parkinson’s disease diagnosis, the researchers noted.

“It’s important to continue to evaluate long-term trends in Parkinson’s death rates,” Dr. Bao said.

“This can inform future research that may help pinpoint why more people are dying of the disease. Also, updating vital statistics about Parkinson’s death rates may be used for priority setting and financing of health care and policy,” Dr. Bao added.
 

1.2 million patients by 2030

Reached for comment, James Beck, PhD, chief scientific officer for the Parkinson’s Foundation, said these findings are not surprising. “They are aligned with the work the Parkinson’s Foundation has done to show that the number of people with Parkinson’s disease has increased over time. We are working on an improved estimate of Parkinson’s disease incidence and predict that Parkinson’s disease will continue to rise as the population ages, so an increase in mortality rates would be expected,” Dr. Beck said.

He noted that much of the public health statistics regarding Parkinson’s disease are outdated and that the Parkinson’s Foundation has been partnering with others to update them.

“For instance, to calculate an accurate estimate of the prevalence of Parkinson’s disease, the Parkinson’s Foundation Prevalence Project was formed. The findings from this group demonstrated that the number of people living with Parkinson’s disease will rise to nearly 1.2 million by 2030, a substantial increase from the estimate of 930,000 for 2020,” Dr. Beck said.

“The overarching message is that more people are being diagnosed with Parkinson’s disease, not that more people are dying from the disease,” he added.

“Over the last 20 years, our understanding of Parkinson’s disease has changed and developed, so clinicians are more aware and better able to properly diagnose Parkinson’s disease. This could mean that the cause is likely due to an increase in diagnosis rates and better recognition of Parkinson’s disease, which would lead to higher rates of identifying Parkinson’s disease as a cause of death,” said Dr. Beck.

The study had no targeted funding. Dr. Bao and Dr. Beck have indicated no relevant financial relationships.
 

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

The death rate from Parkinson’s disease has increased by about 63% over the past 2 decades in the United States, according to what investigators say is the most comprehensive study in the nation of temporal trends in Parkinson’s disease mortality.

“The reason behind the rising death rates from Parkinson’s disease is not clear at present and warrants further investigation,” Wei Bao, MD, PhD, associate professor in the department of epidemiology at the University of Iowa College of Public Health, in Iowa City, said in an interview. “We know that people are living longer and the general population is getting older, but that doesn’t fully explain the increase we saw in the death rate in people with Parkinson’s disease,” Dr. Bao added in a statement.

“Understanding why more people are dying from this disease is critical if we are going to reverse the trend,” Dr. Bao said.

The study was published online Oct. 27 in Neurology.

Long-term data

The researchers used data from the National Vital Statistics System to determine national trends in Parkinson’s disease mortality overall and in several key subgroups. The analyses included 479,059 people who died of Parkinson’s disease between 1999 and 2019.

Over the 21-year period, the age-adjusted mortality from Parkinson’s disease rose from 5.4 per 100,000 in 1999 to 8.8 per 100,000 in 2019. The average annual percent change (APC) was 2.4% for the entire period.

During the study period, the number of deaths from Parkinson’s disease more than doubled, from 14,593 to 35,311.

The death rate from Parkinson’s disease increased significantly across all age groups. The average APC was 5.0% among adults younger than 65 years, 1.9% among those aged 65-74 years, 2.2% among those 75-84 years, and 2.7% among those 85 and older.

The death rate increased in both men and women, but age-adjusted Parkinson’s disease mortality was twice as high in men as in women. The researchers say one possible explanation for the sex difference is estrogen, which leads to higher dopamine levels in areas of the brain that control motor responses and may protect women from Parkinson’s disease.

The study also showed that White people are more likely to die from Parkinson’s disease than persons of other racial and ethnic groups. In 2019, the death rate per 100,000 was 9.7 for Whites, 6.5 for Hispanics, and 4.7 for non-Hispanic Blacks.

Previous studies have shown that compared with White people, Black and Hispanic people are less likely to see a neurologist, owing to socioeconomic barriers. This suggests that White people may be more likely to receive a Parkinson’s disease diagnosis, the researchers noted.

“It’s important to continue to evaluate long-term trends in Parkinson’s death rates,” Dr. Bao said.

“This can inform future research that may help pinpoint why more people are dying of the disease. Also, updating vital statistics about Parkinson’s death rates may be used for priority setting and financing of health care and policy,” Dr. Bao added.
 

1.2 million patients by 2030

Reached for comment, James Beck, PhD, chief scientific officer for the Parkinson’s Foundation, said these findings are not surprising. “They are aligned with the work the Parkinson’s Foundation has done to show that the number of people with Parkinson’s disease has increased over time. We are working on an improved estimate of Parkinson’s disease incidence and predict that Parkinson’s disease will continue to rise as the population ages, so an increase in mortality rates would be expected,” Dr. Beck said.

He noted that much of the public health statistics regarding Parkinson’s disease are outdated and that the Parkinson’s Foundation has been partnering with others to update them.

“For instance, to calculate an accurate estimate of the prevalence of Parkinson’s disease, the Parkinson’s Foundation Prevalence Project was formed. The findings from this group demonstrated that the number of people living with Parkinson’s disease will rise to nearly 1.2 million by 2030, a substantial increase from the estimate of 930,000 for 2020,” Dr. Beck said.

“The overarching message is that more people are being diagnosed with Parkinson’s disease, not that more people are dying from the disease,” he added.

“Over the last 20 years, our understanding of Parkinson’s disease has changed and developed, so clinicians are more aware and better able to properly diagnose Parkinson’s disease. This could mean that the cause is likely due to an increase in diagnosis rates and better recognition of Parkinson’s disease, which would lead to higher rates of identifying Parkinson’s disease as a cause of death,” said Dr. Beck.

The study had no targeted funding. Dr. Bao and Dr. Beck have indicated no relevant financial relationships.
 

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