Neil Osterweil

They have gone by many different names over the centuries: hysteria, psychosomatic illnesses, psychogenic neurological disorders, conversion disorders, dissociative neurological symptom disorders. The terminology may change, but functional neurological disorders by any other name are still real and serious yet treatable phenomena.

Functional neurological disorders, or FNDs, live at the crossroads of neurology and psychiatry, and they are as much a product of the body as they are of the brain, say neurologists who specialize in treating these complex and clinically challenging conditions.

“Whether they’re easily recognized or not depends on someone’s training and experience in this regard,” said Mark Hallett, MD, of the Human Motor Control Section of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland.

“The difficulty has been that there hasn’t been very good education about functional disorders over the last 50 years or so,” he said in an interview.

However, with training and experience, clinicians can learn to identify these common and disabling conditions, Dr. Hallett said.
 

Varying Definitions

The Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) labels FND as “conversion disorder,” and lists diagnostic criteria that include “one or more symptoms of altered voluntary motor or sensory function; clinical findings provide evidence of incompatibility between the symptom and recognized neurological or medical conditions; the symptom or deficit is not better explained by another medical or mental disorder;” and “the symptom or deficit causes clinically significant distress or impairment in social, occupational, or other important areas of functioning or warrants medical evaluation.”

Dr. Hallett offers his own definition of FND, which includes the following characteristics:

• A neurological disorder, characterized by almost any type of neurological symptom
• Not voluntarily produced
• Caused by a brain network dysfunction that does not exclude the possibility of normal function
• Sometimes due in part to a psychological cause, and not explained by other neurological pathology that may or may not be present
• Symptoms may be inconsistent (variable) or incompatible (incongruent) with other known neurological disorders or human anatomy and physiology.

The two most common types of FND are psychogenic nonepileptic seizures and functional movement disorders, but patients may also have functional sensory, visual, auditory, speech, and urologic disorders, and even functional coma.

Dr. Hallett cited studies showing that an estimated 9% of neurology hospital admission are for FNDS, and that among patients in neurology clinics 5.4% had a diagnosis of FND, and 30% had an FND as part of the diagnosis.

Women comprise between 60% and 75% of the population with FNDs.
 

Diagnosis

FND is not, as once thought, a diagnosis of exclusion, but is based on signs and symptoms, which may be either inconsistent or irreversible and may occur in the absence of a stressor, said Sara Finkelstein, MD, MSc, of the Functional Neurological Disorder Unit in the Department of Neurology at Massachusetts General Hospital in Boston.

She emphasized that there are several diagnostic pitfalls that clinicians need to be aware of.

For example, “just because a patient has a psychiatric history does not mean that they have a functional neurological disorder,” she said in an interview.

Massachusetts General Hospital

Functional seizures

A definitive diagnosis can depend on the type of disorder.

“Many functional seizures have some clinical manifestations that are apparent, but as seizures are intermittent the doctor may not see one, and it may depend upon someone taking a video of the person with the seizure perhaps, or bringing them into a hospital and watching them until they do have the seizure,” Dr. Hallett said.

There are some manifestations that indicate the likelihood that a seizure has a functional origin, and when there is uncertainty EEG can help to nail down a diagnosis, he added.

Dr. Finkelstein noted that exam signs with good reliability for functional seizures include eye closure or resistance to opening; duration longer than 2 minutes; stopping and starting; asynchronous limb movements; patient maintenance of awareness during a generalized event; and ictal weeping.

Differential diagnoses included migraine with complex aura, dissociation related to posttraumatic stress disorder, or anxiety.
 

Functional movement disorders

Dr. Finkelstein cautioned that when evaluating patients for potential functional movement disorders, it’s important to not jump to conclusions.

For example, the amplitude of tremor can vary in Parkinson’s disease and essential tremor as well as in functional tremor. The clinician should not read too much into the observation that a patient’s tremor gets worse with increasing stress as stress can exacerbate most tremor types, she said.

One sign that tremor could be functional (dystonic tremor) is irregularity of amplitude and frequency, she noted.

When assessing patients with gait disorder, it’s important to understand that there is no single sign that is specially characteristic for a given disorder, and just because a patient has a “bizarre” gait, it doesn’t necessarily signal a functional disorder.

“A dystonic gait may improve with an alternate motor pattern or be inconsistent over time,” Dr. Finkelstein said.
 

Treatment

In a comprehensive review published in The Lancet: Neurology in 2022, Dr. Hallett and colleagues said that good doctor-patient communications and understanding of each patient’s needs and goals are essential for effective treatment of all FNDs.

“Neurologists have traditionally avoided taking responsibility for people with FND, although are often most appropriate to engage patients in treatment. Explaining the diagnosis with clarity, confidence, using the principles of a ‘rule in’ process, is a key step in treatment,” they wrote.

Treatment can take several forms, depending on the FND, and may include physiotherapy for patients with functional movement disorders and psychological therapy for patients with functional seizures.

“With increasing evidence-based treatment, the diagnosis of FND should be seen as a process of looking for potentially reversible cause of disability and distress whether or not an individual has abnormalities on conventional laboratory or radiological testing,” Dr. Hallett and colleagues concluded.

This article was based on interviews and from presentations by Dr. Hallett and Dr. Finkelstein at a 2023 meeting of the Indiana Neurological Society. Dr. Hallett and Dr. Finkelstein declared no conflicts of interest.

They have gone by many different names over the centuries: hysteria, psychosomatic illnesses, psychogenic neurological disorders, conversion disorders, dissociative neurological symptom disorders. The terminology may change, but functional neurological disorders by any other name are still real and serious yet treatable phenomena.

Functional neurological disorders, or FNDs, live at the crossroads of neurology and psychiatry, and they are as much a product of the body as they are of the brain, say neurologists who specialize in treating these complex and clinically challenging conditions.

“Whether they’re easily recognized or not depends on someone’s training and experience in this regard,” said Mark Hallett, MD, of the Human Motor Control Section of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland.

“The difficulty has been that there hasn’t been very good education about functional disorders over the last 50 years or so,” he said in an interview.

However, with training and experience, clinicians can learn to identify these common and disabling conditions, Dr. Hallett said.
 

Varying Definitions

The Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) labels FND as “conversion disorder,” and lists diagnostic criteria that include “one or more symptoms of altered voluntary motor or sensory function; clinical findings provide evidence of incompatibility between the symptom and recognized neurological or medical conditions; the symptom or deficit is not better explained by another medical or mental disorder;” and “the symptom or deficit causes clinically significant distress or impairment in social, occupational, or other important areas of functioning or warrants medical evaluation.”

Dr. Hallett offers his own definition of FND, which includes the following characteristics:

• A neurological disorder, characterized by almost any type of neurological symptom
• Not voluntarily produced
• Caused by a brain network dysfunction that does not exclude the possibility of normal function
• Sometimes due in part to a psychological cause, and not explained by other neurological pathology that may or may not be present
• Symptoms may be inconsistent (variable) or incompatible (incongruent) with other known neurological disorders or human anatomy and physiology.

The two most common types of FND are psychogenic nonepileptic seizures and functional movement disorders, but patients may also have functional sensory, visual, auditory, speech, and urologic disorders, and even functional coma.

Dr. Hallett cited studies showing that an estimated 9% of neurology hospital admission are for FNDS, and that among patients in neurology clinics 5.4% had a diagnosis of FND, and 30% had an FND as part of the diagnosis.

Women comprise between 60% and 75% of the population with FNDs.
 

Diagnosis

FND is not, as once thought, a diagnosis of exclusion, but is based on signs and symptoms, which may be either inconsistent or irreversible and may occur in the absence of a stressor, said Sara Finkelstein, MD, MSc, of the Functional Neurological Disorder Unit in the Department of Neurology at Massachusetts General Hospital in Boston.

She emphasized that there are several diagnostic pitfalls that clinicians need to be aware of.

For example, “just because a patient has a psychiatric history does not mean that they have a functional neurological disorder,” she said in an interview.

Massachusetts General Hospital

Functional seizures

A definitive diagnosis can depend on the type of disorder.

“Many functional seizures have some clinical manifestations that are apparent, but as seizures are intermittent the doctor may not see one, and it may depend upon someone taking a video of the person with the seizure perhaps, or bringing them into a hospital and watching them until they do have the seizure,” Dr. Hallett said.

There are some manifestations that indicate the likelihood that a seizure has a functional origin, and when there is uncertainty EEG can help to nail down a diagnosis, he added.

Dr. Finkelstein noted that exam signs with good reliability for functional seizures include eye closure or resistance to opening; duration longer than 2 minutes; stopping and starting; asynchronous limb movements; patient maintenance of awareness during a generalized event; and ictal weeping.

Differential diagnoses included migraine with complex aura, dissociation related to posttraumatic stress disorder, or anxiety.
 

Functional movement disorders

Dr. Finkelstein cautioned that when evaluating patients for potential functional movement disorders, it’s important to not jump to conclusions.

For example, the amplitude of tremor can vary in Parkinson’s disease and essential tremor as well as in functional tremor. The clinician should not read too much into the observation that a patient’s tremor gets worse with increasing stress as stress can exacerbate most tremor types, she said.

One sign that tremor could be functional (dystonic tremor) is irregularity of amplitude and frequency, she noted.

When assessing patients with gait disorder, it’s important to understand that there is no single sign that is specially characteristic for a given disorder, and just because a patient has a “bizarre” gait, it doesn’t necessarily signal a functional disorder.

“A dystonic gait may improve with an alternate motor pattern or be inconsistent over time,” Dr. Finkelstein said.
 

Treatment

In a comprehensive review published in The Lancet: Neurology in 2022, Dr. Hallett and colleagues said that good doctor-patient communications and understanding of each patient’s needs and goals are essential for effective treatment of all FNDs.

“Neurologists have traditionally avoided taking responsibility for people with FND, although are often most appropriate to engage patients in treatment. Explaining the diagnosis with clarity, confidence, using the principles of a ‘rule in’ process, is a key step in treatment,” they wrote.

Treatment can take several forms, depending on the FND, and may include physiotherapy for patients with functional movement disorders and psychological therapy for patients with functional seizures.

“With increasing evidence-based treatment, the diagnosis of FND should be seen as a process of looking for potentially reversible cause of disability and distress whether or not an individual has abnormalities on conventional laboratory or radiological testing,” Dr. Hallett and colleagues concluded.

This article was based on interviews and from presentations by Dr. Hallett and Dr. Finkelstein at a 2023 meeting of the Indiana Neurological Society. Dr. Hallett and Dr. Finkelstein declared no conflicts of interest.

They have gone by many different names over the centuries: hysteria, psychosomatic illnesses, psychogenic neurological disorders, conversion disorders, dissociative neurological symptom disorders. The terminology may change, but functional neurological disorders by any other name are still real and serious yet treatable phenomena.

Functional neurological disorders, or FNDs, live at the crossroads of neurology and psychiatry, and they are as much a product of the body as they are of the brain, say neurologists who specialize in treating these complex and clinically challenging conditions.

“Whether they’re easily recognized or not depends on someone’s training and experience in this regard,” said Mark Hallett, MD, of the Human Motor Control Section of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland.

“The difficulty has been that there hasn’t been very good education about functional disorders over the last 50 years or so,” he said in an interview.

However, with training and experience, clinicians can learn to identify these common and disabling conditions, Dr. Hallett said.
 

Varying Definitions

The Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) labels FND as “conversion disorder,” and lists diagnostic criteria that include “one or more symptoms of altered voluntary motor or sensory function; clinical findings provide evidence of incompatibility between the symptom and recognized neurological or medical conditions; the symptom or deficit is not better explained by another medical or mental disorder;” and “the symptom or deficit causes clinically significant distress or impairment in social, occupational, or other important areas of functioning or warrants medical evaluation.”

Dr. Hallett offers his own definition of FND, which includes the following characteristics:

• A neurological disorder, characterized by almost any type of neurological symptom
• Not voluntarily produced
• Caused by a brain network dysfunction that does not exclude the possibility of normal function
• Sometimes due in part to a psychological cause, and not explained by other neurological pathology that may or may not be present
• Symptoms may be inconsistent (variable) or incompatible (incongruent) with other known neurological disorders or human anatomy and physiology.

The two most common types of FND are psychogenic nonepileptic seizures and functional movement disorders, but patients may also have functional sensory, visual, auditory, speech, and urologic disorders, and even functional coma.

Dr. Hallett cited studies showing that an estimated 9% of neurology hospital admission are for FNDS, and that among patients in neurology clinics 5.4% had a diagnosis of FND, and 30% had an FND as part of the diagnosis.

Women comprise between 60% and 75% of the population with FNDs.
 

Diagnosis

FND is not, as once thought, a diagnosis of exclusion, but is based on signs and symptoms, which may be either inconsistent or irreversible and may occur in the absence of a stressor, said Sara Finkelstein, MD, MSc, of the Functional Neurological Disorder Unit in the Department of Neurology at Massachusetts General Hospital in Boston.

She emphasized that there are several diagnostic pitfalls that clinicians need to be aware of.

For example, “just because a patient has a psychiatric history does not mean that they have a functional neurological disorder,” she said in an interview.

Massachusetts General Hospital

Functional seizures

A definitive diagnosis can depend on the type of disorder.

“Many functional seizures have some clinical manifestations that are apparent, but as seizures are intermittent the doctor may not see one, and it may depend upon someone taking a video of the person with the seizure perhaps, or bringing them into a hospital and watching them until they do have the seizure,” Dr. Hallett said.

There are some manifestations that indicate the likelihood that a seizure has a functional origin, and when there is uncertainty EEG can help to nail down a diagnosis, he added.

Dr. Finkelstein noted that exam signs with good reliability for functional seizures include eye closure or resistance to opening; duration longer than 2 minutes; stopping and starting; asynchronous limb movements; patient maintenance of awareness during a generalized event; and ictal weeping.

Differential diagnoses included migraine with complex aura, dissociation related to posttraumatic stress disorder, or anxiety.
 

Functional movement disorders

Dr. Finkelstein cautioned that when evaluating patients for potential functional movement disorders, it’s important to not jump to conclusions.

For example, the amplitude of tremor can vary in Parkinson’s disease and essential tremor as well as in functional tremor. The clinician should not read too much into the observation that a patient’s tremor gets worse with increasing stress as stress can exacerbate most tremor types, she said.

One sign that tremor could be functional (dystonic tremor) is irregularity of amplitude and frequency, she noted.

When assessing patients with gait disorder, it’s important to understand that there is no single sign that is specially characteristic for a given disorder, and just because a patient has a “bizarre” gait, it doesn’t necessarily signal a functional disorder.

“A dystonic gait may improve with an alternate motor pattern or be inconsistent over time,” Dr. Finkelstein said.
 

Treatment

In a comprehensive review published in The Lancet: Neurology in 2022, Dr. Hallett and colleagues said that good doctor-patient communications and understanding of each patient’s needs and goals are essential for effective treatment of all FNDs.

“Neurologists have traditionally avoided taking responsibility for people with FND, although are often most appropriate to engage patients in treatment. Explaining the diagnosis with clarity, confidence, using the principles of a ‘rule in’ process, is a key step in treatment,” they wrote.

Treatment can take several forms, depending on the FND, and may include physiotherapy for patients with functional movement disorders and psychological therapy for patients with functional seizures.

“With increasing evidence-based treatment, the diagnosis of FND should be seen as a process of looking for potentially reversible cause of disability and distress whether or not an individual has abnormalities on conventional laboratory or radiological testing,” Dr. Hallett and colleagues concluded.

This article was based on interviews and from presentations by Dr. Hallett and Dr. Finkelstein at a 2023 meeting of the Indiana Neurological Society. Dr. Hallett and Dr. Finkelstein declared no conflicts of interest.

Many patients with chronic progressive pulmonary disease feel anxious and depressed as their conditions advance, as breathing becomes increasingly labored and difficult, and as performing even small daily tasks leaves them exhausted.

Persons with severe COPD frequently report fears of suffocation and death, as well as anxieties about abandoning family and friends, and these negative, intrusive thoughts can have an adverse effect on COPD outcomes.

Disease-related mental distress can lead to increased disability, more frequent use of costly healthcare resources, higher morbidity, and elevated risk of death, investigators say.

“Individuals with severe COPD are twice as likely to develop depression than patients with mild COPD. Prevalence rates for clinical anxiety in COPD range from 13% to 46% in outpatients and 10% to 55% among inpatients,” wrote Abebaw Mengitsu Yohannes, PhD, then from Azusa Pacific University in Azusa, California, and colleagues in an article published jointly by The Journal of Family Practice and The Cleveland Clinic Journal of Medicine.

Patients with COPD may experience major depressive disorders, chronic mild depression (dysthymias), and minor depression, as well as generalized anxiety disorder, phobias, and panic disorders, the investigators say.

“Growing evidence suggests that the relationship between mood disorders — particularly depression — and COPD is bidirectional, meaning that mood disorders adversely impact prognosis in COPD, whereas COPD increases the risk of developing depression,” Yohannes et al. wrote.

Jamie Garfield, MD, professor of thoracic medicine and surgery at Temple University’s Lewis Katz School of Medicine in Philadelphia, Pennsylvania, told Chest Physician that the association between severe chronic diseases and mood disorders is well known.

“I don’t think that it’s specific to chronic lung diseases; in people with chronic heart disease or malignancies we see that coexistence of depression and anxiety will worsen the course of disease,” she said.

Dr. Johannes, who is currently a professor of physical therapy at the University of Alabama School of Health Professionals in Birmingham, said that depression and anxiety are often underdiagnosed and undertreated in patients with obstructive pulmonary diseases because the conditions can share symptoms such as dyspnea (for example, in anxiety) or fatigue (in depression).

“Therefore, unless one begins to explore further, it’s hard for physicians to be able to identify these conditions,” he said in an interview with Chest Physician.

Fears of dying (and living)

The causes of depression and anxiety among patients with obstructive pulmonary disorders are multifactorial, and may require a variety of treatment and coping strategies, according to Susann Strang, RN, PhD, and colleagues from the University of Gothenburg, Gothenburg, Sweden.

They conducted qualitative in-depth interviews with 31 men and women with stage III or IV COPD, and found that the majority of patients had anxiety associated with their disease.

“Analyses revealed three major themes: death anxiety, life anxiety, and counterweights to anxiety,” the investigators wrote in a study published in the journal Palliative and Supportive Care in 2014.

Factors contributing to anxiety surrounding death included fear of suffocation, awareness of impending death, fear of the process of death, and anxiety about being separated from loved ones.

In contrast, some patients expressed dread of living with the limitations and loneliness imposed on them by their disease — so-called “life anxiety.”

The patients also reported “counterweights” to anxiety as a way of coping. For some this involved trust in their healthcare professionals and adherence to medication, inhalers, and supplemental oxygen.

“The patients also placed hope in new treatments, better medication, surgery, stem cell treatment, or lung transplants,” Dr. Strang and colleagues reported.

Others reported avoiding talking about death, sleeping more, or using humor to “laugh off this difficult subject.”

Screening and diagnosis

Primary care practitioners are often the first health professionals that patients with COPD see, but these clinicians often don’t have the time to add screening to their already crammed schedules. In addition, “the lack of a standardized approach in diagnosis, and inadequate knowledge or confidence in assessing psychological status (particularly given the number of strategies available for screening patients for mood disorders),” can make it difficult for PCPs to detect and manage anxiety and depression in their patients with significant healthcare burdens from COPD and other obstructive lung diseases, Dr. Yohannes and colleagues noted.

In addition to commonly used screening tools for anxiety and depression such as the Primary Care Evaluation of Mental Disorders (PRIME-MD) Patient Health Questionnaire (PHQ-9), there are at least two designed to evaluate patients with lung disease: the Anxiety Inventory for Respiratory (AIR) Disease scale, developed by Dr. Yohannes and colleagues, and the COPD Anxiety Questionnaire.

The COPD Assessment Test and Clinical COPD Questionnaire, while not specifically designed to screen for mental disorders, include questions that can point to symptoms of distress in patients with COPD, Dr. Yohannes said.

“In truth I think that there are few providers who will routinely do this on all their patients in terms of quantifying the severity or the presence or absence of depression, but in my own practice I very much ask questions that align with the questions in these tools to determine whether my patient appears to have high levels of anxiety and depression,” Dr. Garfield said.

Listen to patients and families

Among the most powerful tools that clinicians have at their disposal for treating anxiety and depression in patients with chronic lung disease are their ears and their minds, said Anthony Saleh, MD, a pulmonologist at New York-Presbyterian Brooklyn Methodist Hospital in Brooklyn, New York.

“I think just listening to the patient, that’s a little bit forgotten yet so important,” he said in an interview with CHEST Physician.

“When I have someone with advanced lung disease, like idiopathic pulmonary fibrosis, like advanced emphysema, one of the most important things I think is to listen to the patient, and not just to listen to the answers of your perfunctory ‘how’s your breathing? Any chest pain?’ and those sort of rote medical questions, but listen to their thoughts, and it will given them a safe space to say ‘Hey, I’m nervous, hey I’m worried about my family, hey I’m worried if I die what’s going to happen to my wife and kids,’ and that’s something I think is invaluable.”

It’s also vital to listen to the concerns of the patients family members, who may be the primary caregivers and may share the patient’s stresses and anxieties, he said.

Pulmonary Rehabilitation

All of the experts interviewed for this article agreed that a combination of medical, social and mental health support services is important for treatment for patients with chronic obstructive lung diseases.

One of the most effective means of helping patients with both acute breathing problems and with disease-related anxiety and depression is pulmonary rehabilitation. Depending on disease severity, this multidisciplinary approach may involve exercise, patient education, psychological and nutrition counseling, and training patients how to conserve energy and adopt breathing strategies to help them better manage their symptoms.

“I think that pulmonary rehabilitation is one of the first interventions that we should be recommending for our patients,” Dr. Garfield said. “It’s physical therapy for patients with chronic lung diseases, backed by respiratory therapists, and it offers not only physical rehabilitation — improving strength and coordination, but also it helps our patients get as much as possible out of what they’ve got.”

For example, patients can be taught how to decrease their respiratory rate when they’re feeling a sense of urgency or panic. Patients can also learn how to change body positions to help them breathe more effectively when they feel that their breath is limited or restricted, she said.

“Once you’re into medical interventions, pulmonary rehab is phenomenal,” Dr. Saleh said.

Pulmonary rehabilitation helps patients to feel better about themselves and about their abilities, but “unfortunately it’s not as available as we like,” he said.

Many patients don’t live near a pulmonary rehabilitation center, and the typical two to three weekly sessions for 4-12 weeks or longer can be a significant burden for patients and caregivers, he acknowledged.

“You have to sit [with the patient] and be honest and tell them it’s a lot of diligence involved and you have to be really motivated,” he said.

Other treatment options include pharmacological therapy with antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and anxiolytic agents.

“SSRIs are the current first-line drug treatment for depression, and have been shown to significantly improve depression and anxiety in patients with COPD in some, but not all, trials published to date. However, it is important to note that a diagnosis of bipolar disorder must be ruled out before initiating standard antidepressant therapy,” Dr. Johannes and colleagues wrote.

Defiant joy

Importantly, even with the burden of life with COPD, many patients found ways to experience what Strang et al. called “a defiant joy.”

“It was remarkable that when the patients were asked about what gave their lives meaning today, many talked about what had given their life meaning in the past, prior to becoming ill. In the light of the things they had lost because of the disease, many felt that their previous sources of joy no longer existed. Despite this, many still hoped to be able to get out into the fresh air, to be able to do errands, or that tomorrow might be better,” the investigators wrote.

Dr. Yohannes, Dr. Garfield, and Dr. Saleh all reported having no relevant conflicts of interest to report.

Many patients with chronic progressive pulmonary disease feel anxious and depressed as their conditions advance, as breathing becomes increasingly labored and difficult, and as performing even small daily tasks leaves them exhausted.

Persons with severe COPD frequently report fears of suffocation and death, as well as anxieties about abandoning family and friends, and these negative, intrusive thoughts can have an adverse effect on COPD outcomes.

Disease-related mental distress can lead to increased disability, more frequent use of costly healthcare resources, higher morbidity, and elevated risk of death, investigators say.

“Individuals with severe COPD are twice as likely to develop depression than patients with mild COPD. Prevalence rates for clinical anxiety in COPD range from 13% to 46% in outpatients and 10% to 55% among inpatients,” wrote Abebaw Mengitsu Yohannes, PhD, then from Azusa Pacific University in Azusa, California, and colleagues in an article published jointly by The Journal of Family Practice and The Cleveland Clinic Journal of Medicine.

Patients with COPD may experience major depressive disorders, chronic mild depression (dysthymias), and minor depression, as well as generalized anxiety disorder, phobias, and panic disorders, the investigators say.

“Growing evidence suggests that the relationship between mood disorders — particularly depression — and COPD is bidirectional, meaning that mood disorders adversely impact prognosis in COPD, whereas COPD increases the risk of developing depression,” Yohannes et al. wrote.

Jamie Garfield, MD, professor of thoracic medicine and surgery at Temple University’s Lewis Katz School of Medicine in Philadelphia, Pennsylvania, told Chest Physician that the association between severe chronic diseases and mood disorders is well known.

“I don’t think that it’s specific to chronic lung diseases; in people with chronic heart disease or malignancies we see that coexistence of depression and anxiety will worsen the course of disease,” she said.

Dr. Johannes, who is currently a professor of physical therapy at the University of Alabama School of Health Professionals in Birmingham, said that depression and anxiety are often underdiagnosed and undertreated in patients with obstructive pulmonary diseases because the conditions can share symptoms such as dyspnea (for example, in anxiety) or fatigue (in depression).

“Therefore, unless one begins to explore further, it’s hard for physicians to be able to identify these conditions,” he said in an interview with Chest Physician.

Fears of dying (and living)

The causes of depression and anxiety among patients with obstructive pulmonary disorders are multifactorial, and may require a variety of treatment and coping strategies, according to Susann Strang, RN, PhD, and colleagues from the University of Gothenburg, Gothenburg, Sweden.

They conducted qualitative in-depth interviews with 31 men and women with stage III or IV COPD, and found that the majority of patients had anxiety associated with their disease.

“Analyses revealed three major themes: death anxiety, life anxiety, and counterweights to anxiety,” the investigators wrote in a study published in the journal Palliative and Supportive Care in 2014.

Factors contributing to anxiety surrounding death included fear of suffocation, awareness of impending death, fear of the process of death, and anxiety about being separated from loved ones.

In contrast, some patients expressed dread of living with the limitations and loneliness imposed on them by their disease — so-called “life anxiety.”

The patients also reported “counterweights” to anxiety as a way of coping. For some this involved trust in their healthcare professionals and adherence to medication, inhalers, and supplemental oxygen.

“The patients also placed hope in new treatments, better medication, surgery, stem cell treatment, or lung transplants,” Dr. Strang and colleagues reported.

Others reported avoiding talking about death, sleeping more, or using humor to “laugh off this difficult subject.”

Screening and diagnosis

Primary care practitioners are often the first health professionals that patients with COPD see, but these clinicians often don’t have the time to add screening to their already crammed schedules. In addition, “the lack of a standardized approach in diagnosis, and inadequate knowledge or confidence in assessing psychological status (particularly given the number of strategies available for screening patients for mood disorders),” can make it difficult for PCPs to detect and manage anxiety and depression in their patients with significant healthcare burdens from COPD and other obstructive lung diseases, Dr. Yohannes and colleagues noted.

In addition to commonly used screening tools for anxiety and depression such as the Primary Care Evaluation of Mental Disorders (PRIME-MD) Patient Health Questionnaire (PHQ-9), there are at least two designed to evaluate patients with lung disease: the Anxiety Inventory for Respiratory (AIR) Disease scale, developed by Dr. Yohannes and colleagues, and the COPD Anxiety Questionnaire.

The COPD Assessment Test and Clinical COPD Questionnaire, while not specifically designed to screen for mental disorders, include questions that can point to symptoms of distress in patients with COPD, Dr. Yohannes said.

“In truth I think that there are few providers who will routinely do this on all their patients in terms of quantifying the severity or the presence or absence of depression, but in my own practice I very much ask questions that align with the questions in these tools to determine whether my patient appears to have high levels of anxiety and depression,” Dr. Garfield said.

Listen to patients and families

Among the most powerful tools that clinicians have at their disposal for treating anxiety and depression in patients with chronic lung disease are their ears and their minds, said Anthony Saleh, MD, a pulmonologist at New York-Presbyterian Brooklyn Methodist Hospital in Brooklyn, New York.

“I think just listening to the patient, that’s a little bit forgotten yet so important,” he said in an interview with CHEST Physician.

“When I have someone with advanced lung disease, like idiopathic pulmonary fibrosis, like advanced emphysema, one of the most important things I think is to listen to the patient, and not just to listen to the answers of your perfunctory ‘how’s your breathing? Any chest pain?’ and those sort of rote medical questions, but listen to their thoughts, and it will given them a safe space to say ‘Hey, I’m nervous, hey I’m worried about my family, hey I’m worried if I die what’s going to happen to my wife and kids,’ and that’s something I think is invaluable.”

It’s also vital to listen to the concerns of the patients family members, who may be the primary caregivers and may share the patient’s stresses and anxieties, he said.

Pulmonary Rehabilitation

All of the experts interviewed for this article agreed that a combination of medical, social and mental health support services is important for treatment for patients with chronic obstructive lung diseases.

One of the most effective means of helping patients with both acute breathing problems and with disease-related anxiety and depression is pulmonary rehabilitation. Depending on disease severity, this multidisciplinary approach may involve exercise, patient education, psychological and nutrition counseling, and training patients how to conserve energy and adopt breathing strategies to help them better manage their symptoms.

“I think that pulmonary rehabilitation is one of the first interventions that we should be recommending for our patients,” Dr. Garfield said. “It’s physical therapy for patients with chronic lung diseases, backed by respiratory therapists, and it offers not only physical rehabilitation — improving strength and coordination, but also it helps our patients get as much as possible out of what they’ve got.”

For example, patients can be taught how to decrease their respiratory rate when they’re feeling a sense of urgency or panic. Patients can also learn how to change body positions to help them breathe more effectively when they feel that their breath is limited or restricted, she said.

“Once you’re into medical interventions, pulmonary rehab is phenomenal,” Dr. Saleh said.

Pulmonary rehabilitation helps patients to feel better about themselves and about their abilities, but “unfortunately it’s not as available as we like,” he said.

Many patients don’t live near a pulmonary rehabilitation center, and the typical two to three weekly sessions for 4-12 weeks or longer can be a significant burden for patients and caregivers, he acknowledged.

“You have to sit [with the patient] and be honest and tell them it’s a lot of diligence involved and you have to be really motivated,” he said.

Other treatment options include pharmacological therapy with antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and anxiolytic agents.

“SSRIs are the current first-line drug treatment for depression, and have been shown to significantly improve depression and anxiety in patients with COPD in some, but not all, trials published to date. However, it is important to note that a diagnosis of bipolar disorder must be ruled out before initiating standard antidepressant therapy,” Dr. Johannes and colleagues wrote.

Defiant joy

Importantly, even with the burden of life with COPD, many patients found ways to experience what Strang et al. called “a defiant joy.”

“It was remarkable that when the patients were asked about what gave their lives meaning today, many talked about what had given their life meaning in the past, prior to becoming ill. In the light of the things they had lost because of the disease, many felt that their previous sources of joy no longer existed. Despite this, many still hoped to be able to get out into the fresh air, to be able to do errands, or that tomorrow might be better,” the investigators wrote.

Dr. Yohannes, Dr. Garfield, and Dr. Saleh all reported having no relevant conflicts of interest to report.

Many patients with chronic progressive pulmonary disease feel anxious and depressed as their conditions advance, as breathing becomes increasingly labored and difficult, and as performing even small daily tasks leaves them exhausted.

Persons with severe COPD frequently report fears of suffocation and death, as well as anxieties about abandoning family and friends, and these negative, intrusive thoughts can have an adverse effect on COPD outcomes.

Disease-related mental distress can lead to increased disability, more frequent use of costly healthcare resources, higher morbidity, and elevated risk of death, investigators say.

“Individuals with severe COPD are twice as likely to develop depression than patients with mild COPD. Prevalence rates for clinical anxiety in COPD range from 13% to 46% in outpatients and 10% to 55% among inpatients,” wrote Abebaw Mengitsu Yohannes, PhD, then from Azusa Pacific University in Azusa, California, and colleagues in an article published jointly by The Journal of Family Practice and The Cleveland Clinic Journal of Medicine.

Patients with COPD may experience major depressive disorders, chronic mild depression (dysthymias), and minor depression, as well as generalized anxiety disorder, phobias, and panic disorders, the investigators say.

“Growing evidence suggests that the relationship between mood disorders — particularly depression — and COPD is bidirectional, meaning that mood disorders adversely impact prognosis in COPD, whereas COPD increases the risk of developing depression,” Yohannes et al. wrote.

Jamie Garfield, MD, professor of thoracic medicine and surgery at Temple University’s Lewis Katz School of Medicine in Philadelphia, Pennsylvania, told Chest Physician that the association between severe chronic diseases and mood disorders is well known.

“I don’t think that it’s specific to chronic lung diseases; in people with chronic heart disease or malignancies we see that coexistence of depression and anxiety will worsen the course of disease,” she said.

Dr. Johannes, who is currently a professor of physical therapy at the University of Alabama School of Health Professionals in Birmingham, said that depression and anxiety are often underdiagnosed and undertreated in patients with obstructive pulmonary diseases because the conditions can share symptoms such as dyspnea (for example, in anxiety) or fatigue (in depression).

“Therefore, unless one begins to explore further, it’s hard for physicians to be able to identify these conditions,” he said in an interview with Chest Physician.

Fears of dying (and living)

The causes of depression and anxiety among patients with obstructive pulmonary disorders are multifactorial, and may require a variety of treatment and coping strategies, according to Susann Strang, RN, PhD, and colleagues from the University of Gothenburg, Gothenburg, Sweden.

They conducted qualitative in-depth interviews with 31 men and women with stage III or IV COPD, and found that the majority of patients had anxiety associated with their disease.

“Analyses revealed three major themes: death anxiety, life anxiety, and counterweights to anxiety,” the investigators wrote in a study published in the journal Palliative and Supportive Care in 2014.

Factors contributing to anxiety surrounding death included fear of suffocation, awareness of impending death, fear of the process of death, and anxiety about being separated from loved ones.

In contrast, some patients expressed dread of living with the limitations and loneliness imposed on them by their disease — so-called “life anxiety.”

The patients also reported “counterweights” to anxiety as a way of coping. For some this involved trust in their healthcare professionals and adherence to medication, inhalers, and supplemental oxygen.

“The patients also placed hope in new treatments, better medication, surgery, stem cell treatment, or lung transplants,” Dr. Strang and colleagues reported.

Others reported avoiding talking about death, sleeping more, or using humor to “laugh off this difficult subject.”

Screening and diagnosis

Primary care practitioners are often the first health professionals that patients with COPD see, but these clinicians often don’t have the time to add screening to their already crammed schedules. In addition, “the lack of a standardized approach in diagnosis, and inadequate knowledge or confidence in assessing psychological status (particularly given the number of strategies available for screening patients for mood disorders),” can make it difficult for PCPs to detect and manage anxiety and depression in their patients with significant healthcare burdens from COPD and other obstructive lung diseases, Dr. Yohannes and colleagues noted.

In addition to commonly used screening tools for anxiety and depression such as the Primary Care Evaluation of Mental Disorders (PRIME-MD) Patient Health Questionnaire (PHQ-9), there are at least two designed to evaluate patients with lung disease: the Anxiety Inventory for Respiratory (AIR) Disease scale, developed by Dr. Yohannes and colleagues, and the COPD Anxiety Questionnaire.

The COPD Assessment Test and Clinical COPD Questionnaire, while not specifically designed to screen for mental disorders, include questions that can point to symptoms of distress in patients with COPD, Dr. Yohannes said.

“In truth I think that there are few providers who will routinely do this on all their patients in terms of quantifying the severity or the presence or absence of depression, but in my own practice I very much ask questions that align with the questions in these tools to determine whether my patient appears to have high levels of anxiety and depression,” Dr. Garfield said.

Listen to patients and families

Among the most powerful tools that clinicians have at their disposal for treating anxiety and depression in patients with chronic lung disease are their ears and their minds, said Anthony Saleh, MD, a pulmonologist at New York-Presbyterian Brooklyn Methodist Hospital in Brooklyn, New York.

“I think just listening to the patient, that’s a little bit forgotten yet so important,” he said in an interview with CHEST Physician.

“When I have someone with advanced lung disease, like idiopathic pulmonary fibrosis, like advanced emphysema, one of the most important things I think is to listen to the patient, and not just to listen to the answers of your perfunctory ‘how’s your breathing? Any chest pain?’ and those sort of rote medical questions, but listen to their thoughts, and it will given them a safe space to say ‘Hey, I’m nervous, hey I’m worried about my family, hey I’m worried if I die what’s going to happen to my wife and kids,’ and that’s something I think is invaluable.”

It’s also vital to listen to the concerns of the patients family members, who may be the primary caregivers and may share the patient’s stresses and anxieties, he said.

Pulmonary Rehabilitation

All of the experts interviewed for this article agreed that a combination of medical, social and mental health support services is important for treatment for patients with chronic obstructive lung diseases.

One of the most effective means of helping patients with both acute breathing problems and with disease-related anxiety and depression is pulmonary rehabilitation. Depending on disease severity, this multidisciplinary approach may involve exercise, patient education, psychological and nutrition counseling, and training patients how to conserve energy and adopt breathing strategies to help them better manage their symptoms.

“I think that pulmonary rehabilitation is one of the first interventions that we should be recommending for our patients,” Dr. Garfield said. “It’s physical therapy for patients with chronic lung diseases, backed by respiratory therapists, and it offers not only physical rehabilitation — improving strength and coordination, but also it helps our patients get as much as possible out of what they’ve got.”

For example, patients can be taught how to decrease their respiratory rate when they’re feeling a sense of urgency or panic. Patients can also learn how to change body positions to help them breathe more effectively when they feel that their breath is limited or restricted, she said.

“Once you’re into medical interventions, pulmonary rehab is phenomenal,” Dr. Saleh said.

Pulmonary rehabilitation helps patients to feel better about themselves and about their abilities, but “unfortunately it’s not as available as we like,” he said.

Many patients don’t live near a pulmonary rehabilitation center, and the typical two to three weekly sessions for 4-12 weeks or longer can be a significant burden for patients and caregivers, he acknowledged.

“You have to sit [with the patient] and be honest and tell them it’s a lot of diligence involved and you have to be really motivated,” he said.

Other treatment options include pharmacological therapy with antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and anxiolytic agents.

“SSRIs are the current first-line drug treatment for depression, and have been shown to significantly improve depression and anxiety in patients with COPD in some, but not all, trials published to date. However, it is important to note that a diagnosis of bipolar disorder must be ruled out before initiating standard antidepressant therapy,” Dr. Johannes and colleagues wrote.

Defiant joy

Importantly, even with the burden of life with COPD, many patients found ways to experience what Strang et al. called “a defiant joy.”

“It was remarkable that when the patients were asked about what gave their lives meaning today, many talked about what had given their life meaning in the past, prior to becoming ill. In the light of the things they had lost because of the disease, many felt that their previous sources of joy no longer existed. Despite this, many still hoped to be able to get out into the fresh air, to be able to do errands, or that tomorrow might be better,” the investigators wrote.

Dr. Yohannes, Dr. Garfield, and Dr. Saleh all reported having no relevant conflicts of interest to report.

Soot, or in scientific parlance “fine particulate matter,” isn’t just the stuff that blackens window sills or dulls car finishes — it’s a serious health hazard, linked to cardiopulmonary disease, asthma, allergies, and lung cancer, as well as a host of other harmful conditions.

Until recently, the annual ambient air quality standard established by the US Environmental Protection Agency (EPA) was a maximum of 12 micrograms per cubic meter of air of fine particles smaller than 2.5 microns (PM2.5).

But on February 7, 2024, the EPA announced that the Biden-Harris administration had finalized a new standard of 9 mcg PM2.5/per cubic meter of air.

In addition, the EPA reported that it will be modifying its PM­­2.5 monitoring network to include a factor that will account for the proximity to pollution sources of at-risk populations.

In a press release, the EPA said that the modification “will advance environmental justice by ensuring localized data collection in overburdened areas,” with the goal of informing future National Ambient Air Quality Standards reviews.

In a statement supporting the new standard, Environment America, a network of 30 state environmental groups, noted that in “the United States, the largest human-caused sources of soot pollution are fossil fuels — coal, oil, and gas — burned for electricity and transportation. Since the government last updated its standards, new research has found there may be no safe amount of air pollution and the World Health Organization cut in half its guidelines for allowable particulate matter (soot) pollution. The final rule lowers allowable soot limits for annual exposure by 25%, although it leaves the 24-hour limit unchanged, allowing for temporary pollution spikes.”
 

A Good Start

Pulmonologists interviewed for this article also applauded the tightened PM2.5 standard, but said that the change doesn’t go far enough.

“We know that particulate matter, also called particulate pollution, is the most dangerous form of air pollution, and there has been an extensive body of literature which outlines the negative impact of air pollution and poor air quality not only on respiratory health, but also on cardiovascular disease, premature pregnancies, mental health, and death,” Anne C. Coates, MD, FCCP, a pediatric pulmonologist at MaineHealth in Portland, Maine, said in an interview with this news organization.

“Lowering the limits certainly can help promote overall health as well as reduce asthma, COPD exacerbations, heart attacks, hospitalizations and death,” she said.

However “I wish that the EPA had gone further to address lowering the daily particulate matter standards because, remember, what they issued on February 7th was the reduction in the annual particulate matter,” she noted.

With the tighter standards, “things are going the right way,” said Priya Balakrishnan, MD, MS, FCCP, assistant professor in the Section of Pulmonary and Critical Care Medicine at West Virginia University in Morgantown.

Following Trump administration efforts to weaken regulatory authority and reverse environmental regulations promulgated under President Obama, “this is the first kind of positive legislation moving forward,” she said in an interview with this news organization.

“Obviously, it’s not ideal, because it’s just monitoring the annual particulate matter 2.5 levels rather than daily ones, but it’s still a change in the right direction,” she said.
 

Deadly Air

As Dr. Coates and Dr. Balakrishnan noted, the revised ambient air standard is averaged over a year, and as such may not accurately capture periods where particulate matter concentrations are dangerously high, as occurs in many US states and Canadian provinces during wildfire season, or when one of the more than 200 remaining coal-fired power plants in the US release clouds of soot during daily operations or especially during periods of high electricity demand.

Some pollution sources are worse than others, as shown by a study published in the November 24, 2023, issue of Science. Health and environmental investigators reported that among Medicare beneficiaries, exposure to PM2.5 from sulfur dioxide released by coal burning for electricity generation was associated with a doubling in risk of death compared to PM2.5 exposure from all other sources.

Air pollution has also been identified as a key factor in the development of non–small cell lung cancer in nonsmokers, according to Charles Swanton, PhD, of the Francis Crick Institute, and chief clinician of Cancer Research UK, both in London, and his colleagues.

As Dr. Swanton reported at the 2022 European Society for Medical Oncology Congress, among 447,932 participants in the UK Biobank, increasing exposure to PM2.5 was significantly associated with seven cancer types, including lung cancer. They also saw an association between PM­­2.5 exposure levels and EGFR-mutated lung cancer incidence in the United Kingdom, South Korea, and Taiwan.

And as the investigators showed in mouse models, exposure to PM2.5 of lung cells bearing somatic EGFR and KRAS mutations causes recruitment of macrophages that in turn secrete interleukin-1B, resulting in a transdifferentiation of EGFR-mutated cells into a cancer stem cell state, and tumor formation.
 

Monitoring At-Risk Communities

Lisa Frank, executive director of the Washington legislative office of Environment America, explained in an interview how the revised standards may result in improvements in air quality, especially for at-risk populations such as lower-income urban dwellers.

“Regulations on particulate matter have been around for a few decades now, so there’s an established process that the state agencies and the EPA go through to make sure that air quality standards are met,” she said.

Over the next several years, the EPA will designate areas of the United States as either being in “attainment” (meeting primary or secondary ambient air quality standards) or in “nonattainment.”

“After that, implementation is up to the state and local air boards. They all are required to have a certain number of air quality monitors to keep track of pollution and they also handle reviewing permits for new construction, highways or other projects in that county that might affect air pollution,” she said.

Depending upon their size, counties are required under federal law to have air-quality monitoring sites in areas that are likely to have the worst air quality, such as major highways or urban traffic corridors.

Under the revised regulations, counties will be expected to have air-quality monitoring stations in or near at-risk communities, which should help to mitigate inequities that arise from proximity of polluting power plants in less-advantaged locations, Ms. Frank said.

“I think obviously any improvement in air quality is going to benefit everyone who breathes there, which I hope is all of us, but certainly people who already have the most air pollution hopefully should see bigger gains as well,” she said.

All persons interviewed for this article reported no relevant conflicts of interest. Dr. Coates and Dr. Balakrishnan are members of the editorial advisory board for CHEST Physician.

Soot, or in scientific parlance “fine particulate matter,” isn’t just the stuff that blackens window sills or dulls car finishes — it’s a serious health hazard, linked to cardiopulmonary disease, asthma, allergies, and lung cancer, as well as a host of other harmful conditions.

Until recently, the annual ambient air quality standard established by the US Environmental Protection Agency (EPA) was a maximum of 12 micrograms per cubic meter of air of fine particles smaller than 2.5 microns (PM2.5).

But on February 7, 2024, the EPA announced that the Biden-Harris administration had finalized a new standard of 9 mcg PM2.5/per cubic meter of air.

In addition, the EPA reported that it will be modifying its PM­­2.5 monitoring network to include a factor that will account for the proximity to pollution sources of at-risk populations.

In a press release, the EPA said that the modification “will advance environmental justice by ensuring localized data collection in overburdened areas,” with the goal of informing future National Ambient Air Quality Standards reviews.

In a statement supporting the new standard, Environment America, a network of 30 state environmental groups, noted that in “the United States, the largest human-caused sources of soot pollution are fossil fuels — coal, oil, and gas — burned for electricity and transportation. Since the government last updated its standards, new research has found there may be no safe amount of air pollution and the World Health Organization cut in half its guidelines for allowable particulate matter (soot) pollution. The final rule lowers allowable soot limits for annual exposure by 25%, although it leaves the 24-hour limit unchanged, allowing for temporary pollution spikes.”
 

A Good Start

Pulmonologists interviewed for this article also applauded the tightened PM2.5 standard, but said that the change doesn’t go far enough.

“We know that particulate matter, also called particulate pollution, is the most dangerous form of air pollution, and there has been an extensive body of literature which outlines the negative impact of air pollution and poor air quality not only on respiratory health, but also on cardiovascular disease, premature pregnancies, mental health, and death,” Anne C. Coates, MD, FCCP, a pediatric pulmonologist at MaineHealth in Portland, Maine, said in an interview with this news organization.

“Lowering the limits certainly can help promote overall health as well as reduce asthma, COPD exacerbations, heart attacks, hospitalizations and death,” she said.

However “I wish that the EPA had gone further to address lowering the daily particulate matter standards because, remember, what they issued on February 7th was the reduction in the annual particulate matter,” she noted.

With the tighter standards, “things are going the right way,” said Priya Balakrishnan, MD, MS, FCCP, assistant professor in the Section of Pulmonary and Critical Care Medicine at West Virginia University in Morgantown.

Following Trump administration efforts to weaken regulatory authority and reverse environmental regulations promulgated under President Obama, “this is the first kind of positive legislation moving forward,” she said in an interview with this news organization.

“Obviously, it’s not ideal, because it’s just monitoring the annual particulate matter 2.5 levels rather than daily ones, but it’s still a change in the right direction,” she said.
 

Deadly Air

As Dr. Coates and Dr. Balakrishnan noted, the revised ambient air standard is averaged over a year, and as such may not accurately capture periods where particulate matter concentrations are dangerously high, as occurs in many US states and Canadian provinces during wildfire season, or when one of the more than 200 remaining coal-fired power plants in the US release clouds of soot during daily operations or especially during periods of high electricity demand.

Some pollution sources are worse than others, as shown by a study published in the November 24, 2023, issue of Science. Health and environmental investigators reported that among Medicare beneficiaries, exposure to PM2.5 from sulfur dioxide released by coal burning for electricity generation was associated with a doubling in risk of death compared to PM2.5 exposure from all other sources.

Air pollution has also been identified as a key factor in the development of non–small cell lung cancer in nonsmokers, according to Charles Swanton, PhD, of the Francis Crick Institute, and chief clinician of Cancer Research UK, both in London, and his colleagues.

As Dr. Swanton reported at the 2022 European Society for Medical Oncology Congress, among 447,932 participants in the UK Biobank, increasing exposure to PM2.5 was significantly associated with seven cancer types, including lung cancer. They also saw an association between PM­­2.5 exposure levels and EGFR-mutated lung cancer incidence in the United Kingdom, South Korea, and Taiwan.

And as the investigators showed in mouse models, exposure to PM2.5 of lung cells bearing somatic EGFR and KRAS mutations causes recruitment of macrophages that in turn secrete interleukin-1B, resulting in a transdifferentiation of EGFR-mutated cells into a cancer stem cell state, and tumor formation.
 

Monitoring At-Risk Communities

Lisa Frank, executive director of the Washington legislative office of Environment America, explained in an interview how the revised standards may result in improvements in air quality, especially for at-risk populations such as lower-income urban dwellers.

“Regulations on particulate matter have been around for a few decades now, so there’s an established process that the state agencies and the EPA go through to make sure that air quality standards are met,” she said.

Over the next several years, the EPA will designate areas of the United States as either being in “attainment” (meeting primary or secondary ambient air quality standards) or in “nonattainment.”

“After that, implementation is up to the state and local air boards. They all are required to have a certain number of air quality monitors to keep track of pollution and they also handle reviewing permits for new construction, highways or other projects in that county that might affect air pollution,” she said.

Depending upon their size, counties are required under federal law to have air-quality monitoring sites in areas that are likely to have the worst air quality, such as major highways or urban traffic corridors.

Under the revised regulations, counties will be expected to have air-quality monitoring stations in or near at-risk communities, which should help to mitigate inequities that arise from proximity of polluting power plants in less-advantaged locations, Ms. Frank said.

“I think obviously any improvement in air quality is going to benefit everyone who breathes there, which I hope is all of us, but certainly people who already have the most air pollution hopefully should see bigger gains as well,” she said.

All persons interviewed for this article reported no relevant conflicts of interest. Dr. Coates and Dr. Balakrishnan are members of the editorial advisory board for CHEST Physician.

Soot, or in scientific parlance “fine particulate matter,” isn’t just the stuff that blackens window sills or dulls car finishes — it’s a serious health hazard, linked to cardiopulmonary disease, asthma, allergies, and lung cancer, as well as a host of other harmful conditions.

Until recently, the annual ambient air quality standard established by the US Environmental Protection Agency (EPA) was a maximum of 12 micrograms per cubic meter of air of fine particles smaller than 2.5 microns (PM2.5).

But on February 7, 2024, the EPA announced that the Biden-Harris administration had finalized a new standard of 9 mcg PM2.5/per cubic meter of air.

In addition, the EPA reported that it will be modifying its PM­­2.5 monitoring network to include a factor that will account for the proximity to pollution sources of at-risk populations.

In a press release, the EPA said that the modification “will advance environmental justice by ensuring localized data collection in overburdened areas,” with the goal of informing future National Ambient Air Quality Standards reviews.

In a statement supporting the new standard, Environment America, a network of 30 state environmental groups, noted that in “the United States, the largest human-caused sources of soot pollution are fossil fuels — coal, oil, and gas — burned for electricity and transportation. Since the government last updated its standards, new research has found there may be no safe amount of air pollution and the World Health Organization cut in half its guidelines for allowable particulate matter (soot) pollution. The final rule lowers allowable soot limits for annual exposure by 25%, although it leaves the 24-hour limit unchanged, allowing for temporary pollution spikes.”
 

A Good Start

Pulmonologists interviewed for this article also applauded the tightened PM2.5 standard, but said that the change doesn’t go far enough.

“We know that particulate matter, also called particulate pollution, is the most dangerous form of air pollution, and there has been an extensive body of literature which outlines the negative impact of air pollution and poor air quality not only on respiratory health, but also on cardiovascular disease, premature pregnancies, mental health, and death,” Anne C. Coates, MD, FCCP, a pediatric pulmonologist at MaineHealth in Portland, Maine, said in an interview with this news organization.

“Lowering the limits certainly can help promote overall health as well as reduce asthma, COPD exacerbations, heart attacks, hospitalizations and death,” she said.

However “I wish that the EPA had gone further to address lowering the daily particulate matter standards because, remember, what they issued on February 7th was the reduction in the annual particulate matter,” she noted.

With the tighter standards, “things are going the right way,” said Priya Balakrishnan, MD, MS, FCCP, assistant professor in the Section of Pulmonary and Critical Care Medicine at West Virginia University in Morgantown.

Following Trump administration efforts to weaken regulatory authority and reverse environmental regulations promulgated under President Obama, “this is the first kind of positive legislation moving forward,” she said in an interview with this news organization.

“Obviously, it’s not ideal, because it’s just monitoring the annual particulate matter 2.5 levels rather than daily ones, but it’s still a change in the right direction,” she said.
 

Deadly Air

As Dr. Coates and Dr. Balakrishnan noted, the revised ambient air standard is averaged over a year, and as such may not accurately capture periods where particulate matter concentrations are dangerously high, as occurs in many US states and Canadian provinces during wildfire season, or when one of the more than 200 remaining coal-fired power plants in the US release clouds of soot during daily operations or especially during periods of high electricity demand.

Some pollution sources are worse than others, as shown by a study published in the November 24, 2023, issue of Science. Health and environmental investigators reported that among Medicare beneficiaries, exposure to PM2.5 from sulfur dioxide released by coal burning for electricity generation was associated with a doubling in risk of death compared to PM2.5 exposure from all other sources.

Air pollution has also been identified as a key factor in the development of non–small cell lung cancer in nonsmokers, according to Charles Swanton, PhD, of the Francis Crick Institute, and chief clinician of Cancer Research UK, both in London, and his colleagues.

As Dr. Swanton reported at the 2022 European Society for Medical Oncology Congress, among 447,932 participants in the UK Biobank, increasing exposure to PM2.5 was significantly associated with seven cancer types, including lung cancer. They also saw an association between PM­­2.5 exposure levels and EGFR-mutated lung cancer incidence in the United Kingdom, South Korea, and Taiwan.

And as the investigators showed in mouse models, exposure to PM2.5 of lung cells bearing somatic EGFR and KRAS mutations causes recruitment of macrophages that in turn secrete interleukin-1B, resulting in a transdifferentiation of EGFR-mutated cells into a cancer stem cell state, and tumor formation.
 

Monitoring At-Risk Communities

Lisa Frank, executive director of the Washington legislative office of Environment America, explained in an interview how the revised standards may result in improvements in air quality, especially for at-risk populations such as lower-income urban dwellers.

“Regulations on particulate matter have been around for a few decades now, so there’s an established process that the state agencies and the EPA go through to make sure that air quality standards are met,” she said.

Over the next several years, the EPA will designate areas of the United States as either being in “attainment” (meeting primary or secondary ambient air quality standards) or in “nonattainment.”

“After that, implementation is up to the state and local air boards. They all are required to have a certain number of air quality monitors to keep track of pollution and they also handle reviewing permits for new construction, highways or other projects in that county that might affect air pollution,” she said.

Depending upon their size, counties are required under federal law to have air-quality monitoring sites in areas that are likely to have the worst air quality, such as major highways or urban traffic corridors.

Under the revised regulations, counties will be expected to have air-quality monitoring stations in or near at-risk communities, which should help to mitigate inequities that arise from proximity of polluting power plants in less-advantaged locations, Ms. Frank said.

“I think obviously any improvement in air quality is going to benefit everyone who breathes there, which I hope is all of us, but certainly people who already have the most air pollution hopefully should see bigger gains as well,” she said.

All persons interviewed for this article reported no relevant conflicts of interest. Dr. Coates and Dr. Balakrishnan are members of the editorial advisory board for CHEST Physician.

Many patients with chronic progressive pulmonary disease feel anxious and depressed as their conditions advance, as breathing becomes increasingly labored and difficult, and as performing even small daily tasks leaves them exhausted. 
Persons with severe COPD frequently report fears of suffocation and death, as well as anxieties about abandoning family and friends, and these negative, intrusive thoughts can have an adverse effect on COPD outcomes. 
Disease-related mental distress can lead to increased disability, more frequent use of costly health care resources, higher morbidity, and elevated risk of death, investigators say. 
"Individuals with severe COPD are twice as likely to develop depression than patients with mild COPD. Prevalence rates for clinical anxiety in COPD range from 13% to 46% in outpatients and 10% to 55% among inpatients," wrote Abebaw Mengitsu Yohannes, PhD, then from Azusa Pacific University in Azusa, California and colleagues in an article published jointly by The Journal of Family Practice and The Cleveland Clinic Journal of Medicine.  

Fears of dying (and living)  

The causes of depression and anxiety among patients with obstructive pulmonary disorders are multi-factorial, and may require a variety of treatment and coping strategies, according to Susann Strang, RN, PhD, and colleagues from the University of Gothenburg, Sweden.  
They conducted qualitative in-depth interviews with 31 men and women with stage III or IV COPD, and found that the majority of patients had anxiety associated with their disease. 
"Analyses revealed three major themes: death anxiety, life anxiety, and counterweights to anxiety," the investigators wrote in a study published in the journal Palliative and Supportive Care in 2014. 
Factors contributing to anxiety surrounding death included fear of suffocation, awareness of impending death, fear of the process of death, and anxiety about being separated from loved ones. 
In contrast, some patients expressed dread of living with the limitations and loneliness imposed on them by their disease, so called "life anxiety." 
The patients also reported "counterweights" to anxiety as a way of coping. For some this involved trust in their health care professionals and adherence to medication, inhalers, and supplemental oxygen. 
"The patients also placed hope in new treatments, better medication, surgery, stem cell treatment, or lung transplants," Dr. Strang and colleagues reported. 
Others reported avoiding talking about death, sleeping more, or using humor to "laugh off this difficult subject." 

Screening and diagnosis 

Primary care practitioners are often the first health professionals that patients with COPD see, but these clinicians often don't have the time to add screening to their already crammed schedules. In addition, "the lack of a standardized approach in diagnosis, and inadequate knowledge or confidence in assessing psychological status (particularly given the number of strategies available for screening patients for mood disorders)," can make it difficult for PCPs to detect and manage anxiety and depression in their patients with significant health care burdens from COPD and other obstructive lung diseases, Dr. Yohannes and colleagues noted. 
In addition to commonly used screening tools for anxiety and depression such as the Primary Care Evaluation of Mental Disorders (PRIME-MD) Patient Health Questionnaire (PHQ-9), there are at least two designed to evaluate patients with lung disease: the Anxiety Inventory for Respiratory (AIR) Disease scale, developed by Dr. Johannes and colleagues, and the COPD Anxiety Questionnaire. 
The COPD Assessment Testand Clinical COPD Questionnaire, while not specifically designed to screen for mental disorders, include questions that can point to symptoms of distress in patients with COPD, Dr. Yohannes said. 
"In truth I think that there are few providers who will routinely do this on all their patients in terms of quantifying the severity or the presence or absence of depression, but in my own practice I very much ask questions that align with the questions in these tools to determine whether my patient appears to have high levels of anxiety and depression," Dr. Garfield said. 

Listen to patients and families 

Among the most powerful tools that clinicians have at their disposal for treating anxiety and depression in patients with chronic lung disease are their ears and their minds, said Anthony Saleh, MD, a pulmonologist at New York-Presbyterian Brooklyn Methodist Hospital in Brooklyn, New York. 
"I think just listening to the patient, that's a little bit forgotten yet so important," he said in an interview with Chest Physician.  
"When I have someone with advanced lung disease, like idiopathic pulmonary fibrosis, like advanced emphysema, one of the most important things I think is to listen to the patient, and not just to listen to the answers of your perfunctory 'how's your breathing? Any chest pain?' and those sort of rote medical questions, but listen to their thoughts, and it will given them a safe space to say 'Hey, I'm nervous, hey I'm worried about my family, hey I'm worried if I die what's going to happen to my wife and kids,' and that's something I think is invaluable." 
It's also vital to listen to the concerns of the patients family members, who may be the primary caregivers and may share the patient's stresses and anxieties, he said. 

Pulmonary Rehabilitation 

All of the experts interviewed for this article agreed that a combination of medical, social and mental health support services is important for treatment for patients with chronic obstructive lung diseases. 
One of the most effective means of helping patients with both acute breathing problems and with disease-related anxiety and depression is pulmonary rehabilitation. Depending on disease severity, this multidisciplinary approach may involve exercise, patient education, psychological and nutrition counseling, and training patients how to conserve energy and adopt breathing strategies to help them better manage their symptoms. 
"I think that pulmonary rehabilitation is one of the first interventions that we should be recommending for our patients," Dr. Garfield said. "It's physical therapy for patients with chronic lung diseases, backed by respiratory therapists, and it offers not only physical rehabilitation - improving strength and coordination, but  also it helps our patients get as much as possible out of what they've got." 
For example, patients can be taught how to decrease their respiratory rate when they're feeling a sense of urgency or panic. Patients can also learn how to change body positions to help them breathe more effectively when they feel that their breath is limited or restricted, she said.  
"Once your into medical interventions, pulmonary rehab is phenomenal," Dr. Saleh said.  
Pulmonary rehabilitation helps patients to feel better about themselves and about their abilities, but "unfortunately it's not as available as we like," he said. 
Many patients don't live near a pulmonary rehabilitation center, and the typical two to three weekly sessions for 4 to 12 weeks or longer can be a significant burden for patients and caregivers, he acknowledged. 
"You have to sit [with the patient] and be honest and tell them it's a lot of diligence involved and you have to be really motivated," he said. 
Other treatment options include pharmacological therapy with antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and anxiolytic agents. 
"SSRIs are the current first-line drug treatment for depression, and have been shown to significantly improve depression and anxiety in patients with COPD in some, but not all, trials published to date. However, it is important to note that a diagnosis of bipolar disorder must be ruled out before initiating standard antidepressant therapy," Dr. Johannes and colleagues wrote. 

Defiant joy 

Importantly, even with the burden of life with COPD, many patients found ways to experience what Strang et al called "a defiant joy." 
 "It was remarkable that when the patients were asked about what gave their lives meaning today, many talked about what had given their life meaning in the past, prior to becoming ill. In the light of the things they had lost because of the disease, many felt that their previous sources of joy no longer existed. Despite this, many still hoped to be able to get out into the fresh air, to be able to do errands or that tomorrow might be better," the investigators wrote. 
Dr. Yohannes, Dr. Garfield, and Dr. Saleh all reported having no relevant conflicts of interest to report.

Many patients with chronic progressive pulmonary disease feel anxious and depressed as their conditions advance, as breathing becomes increasingly labored and difficult, and as performing even small daily tasks leaves them exhausted. 
Persons with severe COPD frequently report fears of suffocation and death, as well as anxieties about abandoning family and friends, and these negative, intrusive thoughts can have an adverse effect on COPD outcomes. 
Disease-related mental distress can lead to increased disability, more frequent use of costly health care resources, higher morbidity, and elevated risk of death, investigators say. 
"Individuals with severe COPD are twice as likely to develop depression than patients with mild COPD. Prevalence rates for clinical anxiety in COPD range from 13% to 46% in outpatients and 10% to 55% among inpatients," wrote Abebaw Mengitsu Yohannes, PhD, then from Azusa Pacific University in Azusa, California and colleagues in an article published jointly by The Journal of Family Practice and The Cleveland Clinic Journal of Medicine.  

Fears of dying (and living)  

The causes of depression and anxiety among patients with obstructive pulmonary disorders are multi-factorial, and may require a variety of treatment and coping strategies, according to Susann Strang, RN, PhD, and colleagues from the University of Gothenburg, Sweden.  
They conducted qualitative in-depth interviews with 31 men and women with stage III or IV COPD, and found that the majority of patients had anxiety associated with their disease. 
"Analyses revealed three major themes: death anxiety, life anxiety, and counterweights to anxiety," the investigators wrote in a study published in the journal Palliative and Supportive Care in 2014. 
Factors contributing to anxiety surrounding death included fear of suffocation, awareness of impending death, fear of the process of death, and anxiety about being separated from loved ones. 
In contrast, some patients expressed dread of living with the limitations and loneliness imposed on them by their disease, so called "life anxiety." 
The patients also reported "counterweights" to anxiety as a way of coping. For some this involved trust in their health care professionals and adherence to medication, inhalers, and supplemental oxygen. 
"The patients also placed hope in new treatments, better medication, surgery, stem cell treatment, or lung transplants," Dr. Strang and colleagues reported. 
Others reported avoiding talking about death, sleeping more, or using humor to "laugh off this difficult subject." 

Screening and diagnosis 

Primary care practitioners are often the first health professionals that patients with COPD see, but these clinicians often don't have the time to add screening to their already crammed schedules. In addition, "the lack of a standardized approach in diagnosis, and inadequate knowledge or confidence in assessing psychological status (particularly given the number of strategies available for screening patients for mood disorders)," can make it difficult for PCPs to detect and manage anxiety and depression in their patients with significant health care burdens from COPD and other obstructive lung diseases, Dr. Yohannes and colleagues noted. 
In addition to commonly used screening tools for anxiety and depression such as the Primary Care Evaluation of Mental Disorders (PRIME-MD) Patient Health Questionnaire (PHQ-9), there are at least two designed to evaluate patients with lung disease: the Anxiety Inventory for Respiratory (AIR) Disease scale, developed by Dr. Johannes and colleagues, and the COPD Anxiety Questionnaire. 
The COPD Assessment Testand Clinical COPD Questionnaire, while not specifically designed to screen for mental disorders, include questions that can point to symptoms of distress in patients with COPD, Dr. Yohannes said. 
"In truth I think that there are few providers who will routinely do this on all their patients in terms of quantifying the severity or the presence or absence of depression, but in my own practice I very much ask questions that align with the questions in these tools to determine whether my patient appears to have high levels of anxiety and depression," Dr. Garfield said. 

Listen to patients and families 

Among the most powerful tools that clinicians have at their disposal for treating anxiety and depression in patients with chronic lung disease are their ears and their minds, said Anthony Saleh, MD, a pulmonologist at New York-Presbyterian Brooklyn Methodist Hospital in Brooklyn, New York. 
"I think just listening to the patient, that's a little bit forgotten yet so important," he said in an interview with Chest Physician.  
"When I have someone with advanced lung disease, like idiopathic pulmonary fibrosis, like advanced emphysema, one of the most important things I think is to listen to the patient, and not just to listen to the answers of your perfunctory 'how's your breathing? Any chest pain?' and those sort of rote medical questions, but listen to their thoughts, and it will given them a safe space to say 'Hey, I'm nervous, hey I'm worried about my family, hey I'm worried if I die what's going to happen to my wife and kids,' and that's something I think is invaluable." 
It's also vital to listen to the concerns of the patients family members, who may be the primary caregivers and may share the patient's stresses and anxieties, he said. 

Pulmonary Rehabilitation 

All of the experts interviewed for this article agreed that a combination of medical, social and mental health support services is important for treatment for patients with chronic obstructive lung diseases. 
One of the most effective means of helping patients with both acute breathing problems and with disease-related anxiety and depression is pulmonary rehabilitation. Depending on disease severity, this multidisciplinary approach may involve exercise, patient education, psychological and nutrition counseling, and training patients how to conserve energy and adopt breathing strategies to help them better manage their symptoms. 
"I think that pulmonary rehabilitation is one of the first interventions that we should be recommending for our patients," Dr. Garfield said. "It's physical therapy for patients with chronic lung diseases, backed by respiratory therapists, and it offers not only physical rehabilitation - improving strength and coordination, but  also it helps our patients get as much as possible out of what they've got." 
For example, patients can be taught how to decrease their respiratory rate when they're feeling a sense of urgency or panic. Patients can also learn how to change body positions to help them breathe more effectively when they feel that their breath is limited or restricted, she said.  
"Once your into medical interventions, pulmonary rehab is phenomenal," Dr. Saleh said.  
Pulmonary rehabilitation helps patients to feel better about themselves and about their abilities, but "unfortunately it's not as available as we like," he said. 
Many patients don't live near a pulmonary rehabilitation center, and the typical two to three weekly sessions for 4 to 12 weeks or longer can be a significant burden for patients and caregivers, he acknowledged. 
"You have to sit [with the patient] and be honest and tell them it's a lot of diligence involved and you have to be really motivated," he said. 
Other treatment options include pharmacological therapy with antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and anxiolytic agents. 
"SSRIs are the current first-line drug treatment for depression, and have been shown to significantly improve depression and anxiety in patients with COPD in some, but not all, trials published to date. However, it is important to note that a diagnosis of bipolar disorder must be ruled out before initiating standard antidepressant therapy," Dr. Johannes and colleagues wrote. 

Defiant joy 

Importantly, even with the burden of life with COPD, many patients found ways to experience what Strang et al called "a defiant joy." 
 "It was remarkable that when the patients were asked about what gave their lives meaning today, many talked about what had given their life meaning in the past, prior to becoming ill. In the light of the things they had lost because of the disease, many felt that their previous sources of joy no longer existed. Despite this, many still hoped to be able to get out into the fresh air, to be able to do errands or that tomorrow might be better," the investigators wrote. 
Dr. Yohannes, Dr. Garfield, and Dr. Saleh all reported having no relevant conflicts of interest to report.

Many patients with chronic progressive pulmonary disease feel anxious and depressed as their conditions advance, as breathing becomes increasingly labored and difficult, and as performing even small daily tasks leaves them exhausted. 
Persons with severe COPD frequently report fears of suffocation and death, as well as anxieties about abandoning family and friends, and these negative, intrusive thoughts can have an adverse effect on COPD outcomes. 
Disease-related mental distress can lead to increased disability, more frequent use of costly health care resources, higher morbidity, and elevated risk of death, investigators say. 
"Individuals with severe COPD are twice as likely to develop depression than patients with mild COPD. Prevalence rates for clinical anxiety in COPD range from 13% to 46% in outpatients and 10% to 55% among inpatients," wrote Abebaw Mengitsu Yohannes, PhD, then from Azusa Pacific University in Azusa, California and colleagues in an article published jointly by The Journal of Family Practice and The Cleveland Clinic Journal of Medicine.  

Fears of dying (and living)  

The causes of depression and anxiety among patients with obstructive pulmonary disorders are multi-factorial, and may require a variety of treatment and coping strategies, according to Susann Strang, RN, PhD, and colleagues from the University of Gothenburg, Sweden.  
They conducted qualitative in-depth interviews with 31 men and women with stage III or IV COPD, and found that the majority of patients had anxiety associated with their disease. 
"Analyses revealed three major themes: death anxiety, life anxiety, and counterweights to anxiety," the investigators wrote in a study published in the journal Palliative and Supportive Care in 2014. 
Factors contributing to anxiety surrounding death included fear of suffocation, awareness of impending death, fear of the process of death, and anxiety about being separated from loved ones. 
In contrast, some patients expressed dread of living with the limitations and loneliness imposed on them by their disease, so called "life anxiety." 
The patients also reported "counterweights" to anxiety as a way of coping. For some this involved trust in their health care professionals and adherence to medication, inhalers, and supplemental oxygen. 
"The patients also placed hope in new treatments, better medication, surgery, stem cell treatment, or lung transplants," Dr. Strang and colleagues reported. 
Others reported avoiding talking about death, sleeping more, or using humor to "laugh off this difficult subject." 

Screening and diagnosis 

Primary care practitioners are often the first health professionals that patients with COPD see, but these clinicians often don't have the time to add screening to their already crammed schedules. In addition, "the lack of a standardized approach in diagnosis, and inadequate knowledge or confidence in assessing psychological status (particularly given the number of strategies available for screening patients for mood disorders)," can make it difficult for PCPs to detect and manage anxiety and depression in their patients with significant health care burdens from COPD and other obstructive lung diseases, Dr. Yohannes and colleagues noted. 
In addition to commonly used screening tools for anxiety and depression such as the Primary Care Evaluation of Mental Disorders (PRIME-MD) Patient Health Questionnaire (PHQ-9), there are at least two designed to evaluate patients with lung disease: the Anxiety Inventory for Respiratory (AIR) Disease scale, developed by Dr. Johannes and colleagues, and the COPD Anxiety Questionnaire. 
The COPD Assessment Testand Clinical COPD Questionnaire, while not specifically designed to screen for mental disorders, include questions that can point to symptoms of distress in patients with COPD, Dr. Yohannes said. 
"In truth I think that there are few providers who will routinely do this on all their patients in terms of quantifying the severity or the presence or absence of depression, but in my own practice I very much ask questions that align with the questions in these tools to determine whether my patient appears to have high levels of anxiety and depression," Dr. Garfield said. 

Listen to patients and families 

Among the most powerful tools that clinicians have at their disposal for treating anxiety and depression in patients with chronic lung disease are their ears and their minds, said Anthony Saleh, MD, a pulmonologist at New York-Presbyterian Brooklyn Methodist Hospital in Brooklyn, New York. 
"I think just listening to the patient, that's a little bit forgotten yet so important," he said in an interview with Chest Physician.  
"When I have someone with advanced lung disease, like idiopathic pulmonary fibrosis, like advanced emphysema, one of the most important things I think is to listen to the patient, and not just to listen to the answers of your perfunctory 'how's your breathing? Any chest pain?' and those sort of rote medical questions, but listen to their thoughts, and it will given them a safe space to say 'Hey, I'm nervous, hey I'm worried about my family, hey I'm worried if I die what's going to happen to my wife and kids,' and that's something I think is invaluable." 
It's also vital to listen to the concerns of the patients family members, who may be the primary caregivers and may share the patient's stresses and anxieties, he said. 

Pulmonary Rehabilitation 

All of the experts interviewed for this article agreed that a combination of medical, social and mental health support services is important for treatment for patients with chronic obstructive lung diseases. 
One of the most effective means of helping patients with both acute breathing problems and with disease-related anxiety and depression is pulmonary rehabilitation. Depending on disease severity, this multidisciplinary approach may involve exercise, patient education, psychological and nutrition counseling, and training patients how to conserve energy and adopt breathing strategies to help them better manage their symptoms. 
"I think that pulmonary rehabilitation is one of the first interventions that we should be recommending for our patients," Dr. Garfield said. "It's physical therapy for patients with chronic lung diseases, backed by respiratory therapists, and it offers not only physical rehabilitation - improving strength and coordination, but  also it helps our patients get as much as possible out of what they've got." 
For example, patients can be taught how to decrease their respiratory rate when they're feeling a sense of urgency or panic. Patients can also learn how to change body positions to help them breathe more effectively when they feel that their breath is limited or restricted, she said.  
"Once your into medical interventions, pulmonary rehab is phenomenal," Dr. Saleh said.  
Pulmonary rehabilitation helps patients to feel better about themselves and about their abilities, but "unfortunately it's not as available as we like," he said. 
Many patients don't live near a pulmonary rehabilitation center, and the typical two to three weekly sessions for 4 to 12 weeks or longer can be a significant burden for patients and caregivers, he acknowledged. 
"You have to sit [with the patient] and be honest and tell them it's a lot of diligence involved and you have to be really motivated," he said. 
Other treatment options include pharmacological therapy with antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and anxiolytic agents. 
"SSRIs are the current first-line drug treatment for depression, and have been shown to significantly improve depression and anxiety in patients with COPD in some, but not all, trials published to date. However, it is important to note that a diagnosis of bipolar disorder must be ruled out before initiating standard antidepressant therapy," Dr. Johannes and colleagues wrote. 

Defiant joy 

Importantly, even with the burden of life with COPD, many patients found ways to experience what Strang et al called "a defiant joy." 
 "It was remarkable that when the patients were asked about what gave their lives meaning today, many talked about what had given their life meaning in the past, prior to becoming ill. In the light of the things they had lost because of the disease, many felt that their previous sources of joy no longer existed. Despite this, many still hoped to be able to get out into the fresh air, to be able to do errands or that tomorrow might be better," the investigators wrote. 
Dr. Yohannes, Dr. Garfield, and Dr. Saleh all reported having no relevant conflicts of interest to report.

Localized melanoma of the skin is highly curable with surgery, especially when the malignancy is in its early stages. Yet many patients with successfully resected cutaneous melanoma may live in fear of recurrence and feel highly anxious about the prospect that their next skin examination may reveal a new lesion or metastasis.

These findings come from a study of 51 patients who were treated for stage 0 (melanoma in situ) to stage IIA (Breslow thickness 1.01-2.0 mm without lymph node invasion or metastasis) disease, and who were interviewed about their experiences as survivors and their fear of recurrence.

“Consistent themes and subthemes brought up by participants included anxiety associated with follow-up skin examinations, frequent biopsy procedures attributable to screening intensity, fear of the sun, changes in sun exposure behavior, and increasing thoughts about death. Many of these experiences profoundly affected participants’ lives, despite the favorable prognosis for this group,” wrote Ayisha N. Mahama, MD, MPH, from the Dell Medical School at the University of Texas at Austin, and colleagues, in an article published online in JAMA Dermatology.
 

Interviews and Inventory

The investigators sought to characterize the psychological well-being of localized melanoma survivors who were treated in their practice. Participants took part in a semistructured interview and the Fear of Cancer Recurrence Inventory short form, with a score of 13 or greater indicating potential cases of clinically significant fear of recurrence.

The mean patient age was 48.5 years, and there were twice as many women as men (34 and 17, respectively). In all, 17 of the patients were treated for stage 0 melanoma, and the remainder were treated for stage I-IIA disease.

The interviews and survey revealed four main “themes” among the patients: anxiety surrounding follow-up appointments and relief after a normal examination; concerns about intensity of melanoma surveillance, including anxiety or reassurance about frequent biopsies and worries regarding familial melanoma risk; lifestyle changes related to sun exposure, such as limiting time outdoors, using sunscreen, and wearing protective clothing; and thoughts about life and death.

On the Fear of Cancer Recurrence Inventory short form, 38 of the 51 participants (75%) had a score of 13 or more points, indicating clinically significant fear of cancer recurrence, and when a higher threshold of 16 or more points were was applied, 34 participants (67%) still met the definition for clinically significant fear of recurrence.
 

Inform, Reassure, Counsel

“Given the crucial role that dermatologists play in diagnosing melanomas, there may be an opportunity to provide reassurance and support for patients to mitigate the psychological consequences of the diagnosis, by emphasizing the excellent life expectancy at a localized stage, particularly at stage 0. In addition, a referral to a mental health practitioner could be placed for patients with higher levels of anxiety and fear of recurrence,” Dr. Mahama and her coauthors wrote.

They also noted that their findings suggest that some individuals who undergo screening for melanoma might experience “psychological harms” from receiving a melanoma diagnosis “particularly given that many or most screening-detected early-stage melanomas will not progress.”

In an interview seeking objective commentary, a surgical oncologist who was not involved in the study said that anxiety about recurrence is common among patients with melanoma, many of whom may be unfamiliar with significant recent advances such as immunotherapy in the care of patients with more advanced disease.

“Often what we will do in addition to just sharing statistics, which are historical and don’t even necessarily reflect how much better we can do for patients now if the melanoma does recur or metastasize, is recommend close surveillance by their dermatologist,” said Sonia Cohen, MD, PhD, from the Mass General Cancer Center in Boston.

“The earlier we capture a recurrence the better we can help the patients. So that’s something we’ll recommend for patients to help give them a sense of control, and that they’re doing everything they can to capture current or new skin cancers,” she said.

Dr. Cohen and colleagues also instruct patients how to look for potential signs of recurrence, such as swollen lymph nodes or suspicious lesions. Patients who express extreme anxiety may also be referred to an oncology social worker or other support services, she said.

Also asked to comment on the results, Allison Dibiaso MSW, LICSW, a social worker at Dana-Farber Cancer Institute, Boston, Massachusetts, who specializes in melanoma, said that she often sees patients who have been successfully treated for early localized malignant melanoma who experience a fear of recurrence. “These patients frequently express feelings of uncertainty and worry, with the fear of another occurrence always on their mind. Managing this fear on a day-to-day basis can be challenging,” she told this news organization.

Moreover, patients with previous treatment for melanoma often experience significant anxiety before skin exams. “Some may feel anxious and worried a few days or weeks before their appointment wondering if something will reoccur and be discovered during the examination,” she said. “While some individuals develop coping skills to manage their anxiety beforehand, many still feel anxious about the possibility of recurrence until after the exam is over and results are confirmed.”

At Dana-Farber, patients with completely resected lesions are provided with individual counseling and have access to support groups specifically designed for patients with melanoma. In addition, a caregiver group is also available for those supporting patients with melanoma, and, “if needed, we provide referrals to therapists in their local community,” Ms. Dibiaso said.

The study was supported by awards/grants to senior author Adewole S. Adamson, MD, MPP from the Robert Wood Johnson Foundation, Dermatology Foundation, National Institutes of Health, and the American Cancer Society. All authors reported having no conflicts of interest. Dr. Cohen had no relevant conflicts of interest to disclose. Ms. Dibiaso had no relevant conflicts to disclose.

Localized melanoma of the skin is highly curable with surgery, especially when the malignancy is in its early stages. Yet many patients with successfully resected cutaneous melanoma may live in fear of recurrence and feel highly anxious about the prospect that their next skin examination may reveal a new lesion or metastasis.

These findings come from a study of 51 patients who were treated for stage 0 (melanoma in situ) to stage IIA (Breslow thickness 1.01-2.0 mm without lymph node invasion or metastasis) disease, and who were interviewed about their experiences as survivors and their fear of recurrence.

“Consistent themes and subthemes brought up by participants included anxiety associated with follow-up skin examinations, frequent biopsy procedures attributable to screening intensity, fear of the sun, changes in sun exposure behavior, and increasing thoughts about death. Many of these experiences profoundly affected participants’ lives, despite the favorable prognosis for this group,” wrote Ayisha N. Mahama, MD, MPH, from the Dell Medical School at the University of Texas at Austin, and colleagues, in an article published online in JAMA Dermatology.
 

Interviews and Inventory

The investigators sought to characterize the psychological well-being of localized melanoma survivors who were treated in their practice. Participants took part in a semistructured interview and the Fear of Cancer Recurrence Inventory short form, with a score of 13 or greater indicating potential cases of clinically significant fear of recurrence.

The mean patient age was 48.5 years, and there were twice as many women as men (34 and 17, respectively). In all, 17 of the patients were treated for stage 0 melanoma, and the remainder were treated for stage I-IIA disease.

The interviews and survey revealed four main “themes” among the patients: anxiety surrounding follow-up appointments and relief after a normal examination; concerns about intensity of melanoma surveillance, including anxiety or reassurance about frequent biopsies and worries regarding familial melanoma risk; lifestyle changes related to sun exposure, such as limiting time outdoors, using sunscreen, and wearing protective clothing; and thoughts about life and death.

On the Fear of Cancer Recurrence Inventory short form, 38 of the 51 participants (75%) had a score of 13 or more points, indicating clinically significant fear of cancer recurrence, and when a higher threshold of 16 or more points were was applied, 34 participants (67%) still met the definition for clinically significant fear of recurrence.
 

Inform, Reassure, Counsel

“Given the crucial role that dermatologists play in diagnosing melanomas, there may be an opportunity to provide reassurance and support for patients to mitigate the psychological consequences of the diagnosis, by emphasizing the excellent life expectancy at a localized stage, particularly at stage 0. In addition, a referral to a mental health practitioner could be placed for patients with higher levels of anxiety and fear of recurrence,” Dr. Mahama and her coauthors wrote.

They also noted that their findings suggest that some individuals who undergo screening for melanoma might experience “psychological harms” from receiving a melanoma diagnosis “particularly given that many or most screening-detected early-stage melanomas will not progress.”

In an interview seeking objective commentary, a surgical oncologist who was not involved in the study said that anxiety about recurrence is common among patients with melanoma, many of whom may be unfamiliar with significant recent advances such as immunotherapy in the care of patients with more advanced disease.

“Often what we will do in addition to just sharing statistics, which are historical and don’t even necessarily reflect how much better we can do for patients now if the melanoma does recur or metastasize, is recommend close surveillance by their dermatologist,” said Sonia Cohen, MD, PhD, from the Mass General Cancer Center in Boston.

“The earlier we capture a recurrence the better we can help the patients. So that’s something we’ll recommend for patients to help give them a sense of control, and that they’re doing everything they can to capture current or new skin cancers,” she said.

Dr. Cohen and colleagues also instruct patients how to look for potential signs of recurrence, such as swollen lymph nodes or suspicious lesions. Patients who express extreme anxiety may also be referred to an oncology social worker or other support services, she said.

Also asked to comment on the results, Allison Dibiaso MSW, LICSW, a social worker at Dana-Farber Cancer Institute, Boston, Massachusetts, who specializes in melanoma, said that she often sees patients who have been successfully treated for early localized malignant melanoma who experience a fear of recurrence. “These patients frequently express feelings of uncertainty and worry, with the fear of another occurrence always on their mind. Managing this fear on a day-to-day basis can be challenging,” she told this news organization.

Moreover, patients with previous treatment for melanoma often experience significant anxiety before skin exams. “Some may feel anxious and worried a few days or weeks before their appointment wondering if something will reoccur and be discovered during the examination,” she said. “While some individuals develop coping skills to manage their anxiety beforehand, many still feel anxious about the possibility of recurrence until after the exam is over and results are confirmed.”

At Dana-Farber, patients with completely resected lesions are provided with individual counseling and have access to support groups specifically designed for patients with melanoma. In addition, a caregiver group is also available for those supporting patients with melanoma, and, “if needed, we provide referrals to therapists in their local community,” Ms. Dibiaso said.

The study was supported by awards/grants to senior author Adewole S. Adamson, MD, MPP from the Robert Wood Johnson Foundation, Dermatology Foundation, National Institutes of Health, and the American Cancer Society. All authors reported having no conflicts of interest. Dr. Cohen had no relevant conflicts of interest to disclose. Ms. Dibiaso had no relevant conflicts to disclose.

Localized melanoma of the skin is highly curable with surgery, especially when the malignancy is in its early stages. Yet many patients with successfully resected cutaneous melanoma may live in fear of recurrence and feel highly anxious about the prospect that their next skin examination may reveal a new lesion or metastasis.

These findings come from a study of 51 patients who were treated for stage 0 (melanoma in situ) to stage IIA (Breslow thickness 1.01-2.0 mm without lymph node invasion or metastasis) disease, and who were interviewed about their experiences as survivors and their fear of recurrence.

“Consistent themes and subthemes brought up by participants included anxiety associated with follow-up skin examinations, frequent biopsy procedures attributable to screening intensity, fear of the sun, changes in sun exposure behavior, and increasing thoughts about death. Many of these experiences profoundly affected participants’ lives, despite the favorable prognosis for this group,” wrote Ayisha N. Mahama, MD, MPH, from the Dell Medical School at the University of Texas at Austin, and colleagues, in an article published online in JAMA Dermatology.
 

Interviews and Inventory

The investigators sought to characterize the psychological well-being of localized melanoma survivors who were treated in their practice. Participants took part in a semistructured interview and the Fear of Cancer Recurrence Inventory short form, with a score of 13 or greater indicating potential cases of clinically significant fear of recurrence.

The mean patient age was 48.5 years, and there were twice as many women as men (34 and 17, respectively). In all, 17 of the patients were treated for stage 0 melanoma, and the remainder were treated for stage I-IIA disease.

The interviews and survey revealed four main “themes” among the patients: anxiety surrounding follow-up appointments and relief after a normal examination; concerns about intensity of melanoma surveillance, including anxiety or reassurance about frequent biopsies and worries regarding familial melanoma risk; lifestyle changes related to sun exposure, such as limiting time outdoors, using sunscreen, and wearing protective clothing; and thoughts about life and death.

On the Fear of Cancer Recurrence Inventory short form, 38 of the 51 participants (75%) had a score of 13 or more points, indicating clinically significant fear of cancer recurrence, and when a higher threshold of 16 or more points were was applied, 34 participants (67%) still met the definition for clinically significant fear of recurrence.
 

Inform, Reassure, Counsel

“Given the crucial role that dermatologists play in diagnosing melanomas, there may be an opportunity to provide reassurance and support for patients to mitigate the psychological consequences of the diagnosis, by emphasizing the excellent life expectancy at a localized stage, particularly at stage 0. In addition, a referral to a mental health practitioner could be placed for patients with higher levels of anxiety and fear of recurrence,” Dr. Mahama and her coauthors wrote.

They also noted that their findings suggest that some individuals who undergo screening for melanoma might experience “psychological harms” from receiving a melanoma diagnosis “particularly given that many or most screening-detected early-stage melanomas will not progress.”

In an interview seeking objective commentary, a surgical oncologist who was not involved in the study said that anxiety about recurrence is common among patients with melanoma, many of whom may be unfamiliar with significant recent advances such as immunotherapy in the care of patients with more advanced disease.

“Often what we will do in addition to just sharing statistics, which are historical and don’t even necessarily reflect how much better we can do for patients now if the melanoma does recur or metastasize, is recommend close surveillance by their dermatologist,” said Sonia Cohen, MD, PhD, from the Mass General Cancer Center in Boston.

“The earlier we capture a recurrence the better we can help the patients. So that’s something we’ll recommend for patients to help give them a sense of control, and that they’re doing everything they can to capture current or new skin cancers,” she said.

Dr. Cohen and colleagues also instruct patients how to look for potential signs of recurrence, such as swollen lymph nodes or suspicious lesions. Patients who express extreme anxiety may also be referred to an oncology social worker or other support services, she said.

Also asked to comment on the results, Allison Dibiaso MSW, LICSW, a social worker at Dana-Farber Cancer Institute, Boston, Massachusetts, who specializes in melanoma, said that she often sees patients who have been successfully treated for early localized malignant melanoma who experience a fear of recurrence. “These patients frequently express feelings of uncertainty and worry, with the fear of another occurrence always on their mind. Managing this fear on a day-to-day basis can be challenging,” she told this news organization.

Moreover, patients with previous treatment for melanoma often experience significant anxiety before skin exams. “Some may feel anxious and worried a few days or weeks before their appointment wondering if something will reoccur and be discovered during the examination,” she said. “While some individuals develop coping skills to manage their anxiety beforehand, many still feel anxious about the possibility of recurrence until after the exam is over and results are confirmed.”

At Dana-Farber, patients with completely resected lesions are provided with individual counseling and have access to support groups specifically designed for patients with melanoma. In addition, a caregiver group is also available for those supporting patients with melanoma, and, “if needed, we provide referrals to therapists in their local community,” Ms. Dibiaso said.

The study was supported by awards/grants to senior author Adewole S. Adamson, MD, MPP from the Robert Wood Johnson Foundation, Dermatology Foundation, National Institutes of Health, and the American Cancer Society. All authors reported having no conflicts of interest. Dr. Cohen had no relevant conflicts of interest to disclose. Ms. Dibiaso had no relevant conflicts to disclose.

A novel oral drug for plaque psoriasis that targets the same inflammatory pathway as currently available parenteral therapies showed promise for treating moderate to severe disease in a phase 2 dose-finding trial.

Among 255 patients with plaque psoriasis randomly assigned to receive either placebo or an oral interleukin (IL)–23 receptor antagonist peptide dubbed JNJ-77242113 (Janssen), 79% of those who were assigned to the oral agent at the highest dose of 100 mg twice daily had a reduction in the Psoriasis Area and Severity Index (PASI) score at week 16 of at least 75% (PASI 75) compared with 9% of patients assigned to placebo, reported Robert Bissonnette, MD, from Innovaderm Research in Montreal, Quebec, Canada, and colleagues.

“The level of reduction of psoriasis that was observed with higher doses of JNJ-77242113 at week 16 was similar in magnitude to the responses seen with several of the injectable biologics that are currently approved for psoriasis,” investigators in the FRONTIER 1 trial wrote in The New England Journal of Medicine.

The investigators noted that among patients assigned to the 100-mg dose of the active drug, 60% had a PASI 90 response, which compares favorably with that seen in phase 3 trials of two other orally available therapies for psoriasis, deucravacitinib (Sotyktu) and apremilast (Otezla). They cautioned, however, against drawing any further inferences from these data, because these agents have not been tested head-to-head against JNJ-77242113 in comparison trials.
 

Targets IL-23 and IL-17

The investigational agent is an oral IL-23 receptor antagonist peptide that selectively blocks IL-23 proximal signaling as well as the production of downstream inflammatory cytokines such as IL-17, according to the authors.

“Modulation of the interleukin-23 pathway with the use of monoclonal antibodies has shown efficacy in the treatment of psoriasis and is considered to be associated with a more favorable safety profile than older oral therapies (eg, cyclosporine, acitretin, methotrexate, and dimethyl fumarate),” the investigators wrote.

Currently available biologic agents targeting IL-23 include guselkumab (Tremfya), risankizumab (Skyrizi) and tildrakizumab (Ilumya). These agents require intravenous or subcutaneous administration, whereas JNJ-77242113 is taken orally, giving it a theoretical advantage in terms of patient preference.

The novel drug must be taken twice daily on an empty stomach at least 2 hours before food or drink, and those who take it must wait an additional 30 minutes to eat or drink after taking the drug. (This news organization has learned that in planned phase 3 studies, patients will be instructed to take a double daily dose on awakening and then wait 30 minutes for eating or drinking.)

‘Profoundly Effective’

The results of this study have convinced at least one former skeptic of the efficacy of the novel agent.

“They asked me to do the trial, and I turned it down, because I didn’t believe it would work,” said Mark G. Lebwohl, MD, dean for Clinical Therapeutics at the Icahn School of Medicine at Mount Sinai and professor and chairman emeritus of the Department of Dermatology at Mount Sinai Medicine in New York, NY.

In an interview with this news organization, Dr. Lebwohl said that he was initially dubious that a peptide, a short chain of amino acids directed against a receptor, could be effective because it would likely be digested in the intestinal tract.

“Indeed, more than 99% of it is digested, but the data show that the tiny amount that gets through is profoundly effective,” he said.

“I would never have believed that this was going to work – and it did,” Dr. Lebwohl added.

He has signed on as an investigator in the currently recruiting phase 3 ICONIC-LEAD trial, in which JNJ-77242113 will be tested against placebo in adolescents and adults with moderate to severe plaque psoriasis. 

In an editorial accompanying the study in the NEJM, Joel M. Gelfand, MD, MSCE, vice chair of clinical research and medical director of the Dermatology Clinical Studies Unit at the University of Pennsylvania in Philadelphia, noted that if confirmed in larger studies, the PASI 90 rate at the highest dose “would be similar to the most effective injectable biologics,” with no evidence of increased adverse events at higher doses.

“However, two occurrences of infection (COVID-19 and an infected cyst) and a suicide attempt were reported as serious adverse events; larger trials will be needed to determine whether such events are attributable to chance, psoriasis itself, or inhibition of interleukin-23 signaling,” cautioned Dr. Gelfand, director of the psoriasis and phototherapy treatment center at the University of Pennsylvania.

In an interview, Dr. Lebwohl said that currently available IL-23 signaling inhibitors have an excellent safety profile and that the investigational oral agent also appears to be very safe. “It’s seeing a target whose effects are known, and the effects are all good and not bad,” he said.
 

FRONTIER-1 Details

The investigators enrolled eligible adults aged 18 years or older who had moderate to severe plaque psoriasis as defined by an Investigator’s Global Assessment score ≥ 3, a total body-surface area of psoriasis involvement of at least 10%, and a PASI score ≥ 12 who had received their diagnosis of plaque psoriasis at least 6 months before starting the trial. The participants had to be candidates for phototherapy or systemic psoriasis therapy.

Patients were randomly assigned to the active agent at doses of 25 mg once or twice daily, 50 mg once daily, or 100 mg once or twice daily for 16 weeks. 

There was a clear dose response, with 37% of patients assigned to 25-mg once-daily dose meeting the primary endpoint of a PASI 75 response at week 16 compared with 51% of those assigned to the 25-mg twice-daily dose, 58% assigned to 50-mg once-daily dose, 65% assigned to 100-mg once-daily dose, and 79% assigned to 100-mg twice-daily dose (P for dose response < .001).

As noted previously, 9% of patients in the placebo group had a PASI 75 response at week 16.

After a mean duration of 15.9 weeks, adverse events after the first dose of JNJ-77242113 (all dose groups were pooled for the safety analysis) were reported in 47% of patients on the 25-mg once-daily dose, 49% on 25-mg twice-daily dose, 60% on 50-mg once-daily dose, 44% on 100-mg once-daily dose, and 62% on 100-mg twice-daily dose. Adverse events after the first dose occurred in 51% of patients assigned to placebo.

The incidence of adverse events did not increase significantly with successively higher dose levels.

As noted by Dr. Gelfand in his editorial, there were three serious adverse events, all occurring in patients on the active drug: a case of COVID-19 in one patient and a suicide attempt in one patient, both in the 100-mg once-daily dose group, and an infected cyst in the 50-mg once-daily group. All three events were determined by the principal investigator and the sponsor to be unrelated to JNJ-77242113. 

There were no reports of deaths, major adverse cardiovascular events, or incident cancers during the trial.

The study was supported by Janssen Research and Development. Dr. Bissonnette disclosed institutional research funding and advisory board participation and honoraria with Janssen. Dr. Gelfand disclosed consulting for Janssen Biotech. Dr. Lebwohl disclosed institutional research funding from Janssen but no personal fees.

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

A novel oral drug for plaque psoriasis that targets the same inflammatory pathway as currently available parenteral therapies showed promise for treating moderate to severe disease in a phase 2 dose-finding trial.

Among 255 patients with plaque psoriasis randomly assigned to receive either placebo or an oral interleukin (IL)–23 receptor antagonist peptide dubbed JNJ-77242113 (Janssen), 79% of those who were assigned to the oral agent at the highest dose of 100 mg twice daily had a reduction in the Psoriasis Area and Severity Index (PASI) score at week 16 of at least 75% (PASI 75) compared with 9% of patients assigned to placebo, reported Robert Bissonnette, MD, from Innovaderm Research in Montreal, Quebec, Canada, and colleagues.

“The level of reduction of psoriasis that was observed with higher doses of JNJ-77242113 at week 16 was similar in magnitude to the responses seen with several of the injectable biologics that are currently approved for psoriasis,” investigators in the FRONTIER 1 trial wrote in The New England Journal of Medicine.

The investigators noted that among patients assigned to the 100-mg dose of the active drug, 60% had a PASI 90 response, which compares favorably with that seen in phase 3 trials of two other orally available therapies for psoriasis, deucravacitinib (Sotyktu) and apremilast (Otezla). They cautioned, however, against drawing any further inferences from these data, because these agents have not been tested head-to-head against JNJ-77242113 in comparison trials.
 

Targets IL-23 and IL-17

The investigational agent is an oral IL-23 receptor antagonist peptide that selectively blocks IL-23 proximal signaling as well as the production of downstream inflammatory cytokines such as IL-17, according to the authors.

“Modulation of the interleukin-23 pathway with the use of monoclonal antibodies has shown efficacy in the treatment of psoriasis and is considered to be associated with a more favorable safety profile than older oral therapies (eg, cyclosporine, acitretin, methotrexate, and dimethyl fumarate),” the investigators wrote.

Currently available biologic agents targeting IL-23 include guselkumab (Tremfya), risankizumab (Skyrizi) and tildrakizumab (Ilumya). These agents require intravenous or subcutaneous administration, whereas JNJ-77242113 is taken orally, giving it a theoretical advantage in terms of patient preference.

The novel drug must be taken twice daily on an empty stomach at least 2 hours before food or drink, and those who take it must wait an additional 30 minutes to eat or drink after taking the drug. (This news organization has learned that in planned phase 3 studies, patients will be instructed to take a double daily dose on awakening and then wait 30 minutes for eating or drinking.)

‘Profoundly Effective’

The results of this study have convinced at least one former skeptic of the efficacy of the novel agent.

“They asked me to do the trial, and I turned it down, because I didn’t believe it would work,” said Mark G. Lebwohl, MD, dean for Clinical Therapeutics at the Icahn School of Medicine at Mount Sinai and professor and chairman emeritus of the Department of Dermatology at Mount Sinai Medicine in New York, NY.

In an interview with this news organization, Dr. Lebwohl said that he was initially dubious that a peptide, a short chain of amino acids directed against a receptor, could be effective because it would likely be digested in the intestinal tract.

“Indeed, more than 99% of it is digested, but the data show that the tiny amount that gets through is profoundly effective,” he said.

“I would never have believed that this was going to work – and it did,” Dr. Lebwohl added.

He has signed on as an investigator in the currently recruiting phase 3 ICONIC-LEAD trial, in which JNJ-77242113 will be tested against placebo in adolescents and adults with moderate to severe plaque psoriasis. 

In an editorial accompanying the study in the NEJM, Joel M. Gelfand, MD, MSCE, vice chair of clinical research and medical director of the Dermatology Clinical Studies Unit at the University of Pennsylvania in Philadelphia, noted that if confirmed in larger studies, the PASI 90 rate at the highest dose “would be similar to the most effective injectable biologics,” with no evidence of increased adverse events at higher doses.

“However, two occurrences of infection (COVID-19 and an infected cyst) and a suicide attempt were reported as serious adverse events; larger trials will be needed to determine whether such events are attributable to chance, psoriasis itself, or inhibition of interleukin-23 signaling,” cautioned Dr. Gelfand, director of the psoriasis and phototherapy treatment center at the University of Pennsylvania.

In an interview, Dr. Lebwohl said that currently available IL-23 signaling inhibitors have an excellent safety profile and that the investigational oral agent also appears to be very safe. “It’s seeing a target whose effects are known, and the effects are all good and not bad,” he said.
 

FRONTIER-1 Details

The investigators enrolled eligible adults aged 18 years or older who had moderate to severe plaque psoriasis as defined by an Investigator’s Global Assessment score ≥ 3, a total body-surface area of psoriasis involvement of at least 10%, and a PASI score ≥ 12 who had received their diagnosis of plaque psoriasis at least 6 months before starting the trial. The participants had to be candidates for phototherapy or systemic psoriasis therapy.

Patients were randomly assigned to the active agent at doses of 25 mg once or twice daily, 50 mg once daily, or 100 mg once or twice daily for 16 weeks. 

There was a clear dose response, with 37% of patients assigned to 25-mg once-daily dose meeting the primary endpoint of a PASI 75 response at week 16 compared with 51% of those assigned to the 25-mg twice-daily dose, 58% assigned to 50-mg once-daily dose, 65% assigned to 100-mg once-daily dose, and 79% assigned to 100-mg twice-daily dose (P for dose response < .001).

As noted previously, 9% of patients in the placebo group had a PASI 75 response at week 16.

After a mean duration of 15.9 weeks, adverse events after the first dose of JNJ-77242113 (all dose groups were pooled for the safety analysis) were reported in 47% of patients on the 25-mg once-daily dose, 49% on 25-mg twice-daily dose, 60% on 50-mg once-daily dose, 44% on 100-mg once-daily dose, and 62% on 100-mg twice-daily dose. Adverse events after the first dose occurred in 51% of patients assigned to placebo.

The incidence of adverse events did not increase significantly with successively higher dose levels.

As noted by Dr. Gelfand in his editorial, there were three serious adverse events, all occurring in patients on the active drug: a case of COVID-19 in one patient and a suicide attempt in one patient, both in the 100-mg once-daily dose group, and an infected cyst in the 50-mg once-daily group. All three events were determined by the principal investigator and the sponsor to be unrelated to JNJ-77242113. 

There were no reports of deaths, major adverse cardiovascular events, or incident cancers during the trial.

The study was supported by Janssen Research and Development. Dr. Bissonnette disclosed institutional research funding and advisory board participation and honoraria with Janssen. Dr. Gelfand disclosed consulting for Janssen Biotech. Dr. Lebwohl disclosed institutional research funding from Janssen but no personal fees.

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

A novel oral drug for plaque psoriasis that targets the same inflammatory pathway as currently available parenteral therapies showed promise for treating moderate to severe disease in a phase 2 dose-finding trial.

Among 255 patients with plaque psoriasis randomly assigned to receive either placebo or an oral interleukin (IL)–23 receptor antagonist peptide dubbed JNJ-77242113 (Janssen), 79% of those who were assigned to the oral agent at the highest dose of 100 mg twice daily had a reduction in the Psoriasis Area and Severity Index (PASI) score at week 16 of at least 75% (PASI 75) compared with 9% of patients assigned to placebo, reported Robert Bissonnette, MD, from Innovaderm Research in Montreal, Quebec, Canada, and colleagues.

“The level of reduction of psoriasis that was observed with higher doses of JNJ-77242113 at week 16 was similar in magnitude to the responses seen with several of the injectable biologics that are currently approved for psoriasis,” investigators in the FRONTIER 1 trial wrote in The New England Journal of Medicine.

The investigators noted that among patients assigned to the 100-mg dose of the active drug, 60% had a PASI 90 response, which compares favorably with that seen in phase 3 trials of two other orally available therapies for psoriasis, deucravacitinib (Sotyktu) and apremilast (Otezla). They cautioned, however, against drawing any further inferences from these data, because these agents have not been tested head-to-head against JNJ-77242113 in comparison trials.
 

Targets IL-23 and IL-17

The investigational agent is an oral IL-23 receptor antagonist peptide that selectively blocks IL-23 proximal signaling as well as the production of downstream inflammatory cytokines such as IL-17, according to the authors.

“Modulation of the interleukin-23 pathway with the use of monoclonal antibodies has shown efficacy in the treatment of psoriasis and is considered to be associated with a more favorable safety profile than older oral therapies (eg, cyclosporine, acitretin, methotrexate, and dimethyl fumarate),” the investigators wrote.

Currently available biologic agents targeting IL-23 include guselkumab (Tremfya), risankizumab (Skyrizi) and tildrakizumab (Ilumya). These agents require intravenous or subcutaneous administration, whereas JNJ-77242113 is taken orally, giving it a theoretical advantage in terms of patient preference.

The novel drug must be taken twice daily on an empty stomach at least 2 hours before food or drink, and those who take it must wait an additional 30 minutes to eat or drink after taking the drug. (This news organization has learned that in planned phase 3 studies, patients will be instructed to take a double daily dose on awakening and then wait 30 minutes for eating or drinking.)

‘Profoundly Effective’

The results of this study have convinced at least one former skeptic of the efficacy of the novel agent.

“They asked me to do the trial, and I turned it down, because I didn’t believe it would work,” said Mark G. Lebwohl, MD, dean for Clinical Therapeutics at the Icahn School of Medicine at Mount Sinai and professor and chairman emeritus of the Department of Dermatology at Mount Sinai Medicine in New York, NY.

In an interview with this news organization, Dr. Lebwohl said that he was initially dubious that a peptide, a short chain of amino acids directed against a receptor, could be effective because it would likely be digested in the intestinal tract.

“Indeed, more than 99% of it is digested, but the data show that the tiny amount that gets through is profoundly effective,” he said.

“I would never have believed that this was going to work – and it did,” Dr. Lebwohl added.

He has signed on as an investigator in the currently recruiting phase 3 ICONIC-LEAD trial, in which JNJ-77242113 will be tested against placebo in adolescents and adults with moderate to severe plaque psoriasis. 

In an editorial accompanying the study in the NEJM, Joel M. Gelfand, MD, MSCE, vice chair of clinical research and medical director of the Dermatology Clinical Studies Unit at the University of Pennsylvania in Philadelphia, noted that if confirmed in larger studies, the PASI 90 rate at the highest dose “would be similar to the most effective injectable biologics,” with no evidence of increased adverse events at higher doses.

“However, two occurrences of infection (COVID-19 and an infected cyst) and a suicide attempt were reported as serious adverse events; larger trials will be needed to determine whether such events are attributable to chance, psoriasis itself, or inhibition of interleukin-23 signaling,” cautioned Dr. Gelfand, director of the psoriasis and phototherapy treatment center at the University of Pennsylvania.

In an interview, Dr. Lebwohl said that currently available IL-23 signaling inhibitors have an excellent safety profile and that the investigational oral agent also appears to be very safe. “It’s seeing a target whose effects are known, and the effects are all good and not bad,” he said.
 

FRONTIER-1 Details

The investigators enrolled eligible adults aged 18 years or older who had moderate to severe plaque psoriasis as defined by an Investigator’s Global Assessment score ≥ 3, a total body-surface area of psoriasis involvement of at least 10%, and a PASI score ≥ 12 who had received their diagnosis of plaque psoriasis at least 6 months before starting the trial. The participants had to be candidates for phototherapy or systemic psoriasis therapy.

Patients were randomly assigned to the active agent at doses of 25 mg once or twice daily, 50 mg once daily, or 100 mg once or twice daily for 16 weeks. 

There was a clear dose response, with 37% of patients assigned to 25-mg once-daily dose meeting the primary endpoint of a PASI 75 response at week 16 compared with 51% of those assigned to the 25-mg twice-daily dose, 58% assigned to 50-mg once-daily dose, 65% assigned to 100-mg once-daily dose, and 79% assigned to 100-mg twice-daily dose (P for dose response < .001).

As noted previously, 9% of patients in the placebo group had a PASI 75 response at week 16.

After a mean duration of 15.9 weeks, adverse events after the first dose of JNJ-77242113 (all dose groups were pooled for the safety analysis) were reported in 47% of patients on the 25-mg once-daily dose, 49% on 25-mg twice-daily dose, 60% on 50-mg once-daily dose, 44% on 100-mg once-daily dose, and 62% on 100-mg twice-daily dose. Adverse events after the first dose occurred in 51% of patients assigned to placebo.

The incidence of adverse events did not increase significantly with successively higher dose levels.

As noted by Dr. Gelfand in his editorial, there were three serious adverse events, all occurring in patients on the active drug: a case of COVID-19 in one patient and a suicide attempt in one patient, both in the 100-mg once-daily dose group, and an infected cyst in the 50-mg once-daily group. All three events were determined by the principal investigator and the sponsor to be unrelated to JNJ-77242113. 

There were no reports of deaths, major adverse cardiovascular events, or incident cancers during the trial.

The study was supported by Janssen Research and Development. Dr. Bissonnette disclosed institutional research funding and advisory board participation and honoraria with Janssen. Dr. Gelfand disclosed consulting for Janssen Biotech. Dr. Lebwohl disclosed institutional research funding from Janssen but no personal fees.

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

Patients with quiescent systemic lupus erythematosus (SLE) who are on maintenance therapy with mycophenolate mofetil (MMF) may be able to be safely weaned off the drug with the understanding that disease flare may occur and may require restarting immunosuppressive therapy.

That’s the conclusion of investigators in a multicenter randomized trial conducted at 19 US centers and published in The Lancet Rheumatology. They found that among 100 patients with stable SLE who were on MMF for at least 2 years for renal indications or at least 1 year for nonrenal indications, MMF withdrawal was not significantly inferior to MMF maintenance in terms of clinically significant disease reactivation within at least 1 year.

Oklahoma Medical Research Foundation

“Our findings suggest that mycophenolate mofetil could be safely withdrawn in patients with stable SLE. However, larger studies with a longer follow-up are still needed,” wrote Eliza F. Chakravarty, MD, MS, from the University of Oklahoma College of Medicine in Oklahoma City, and colleagues.

“Our study was only for 60 weeks, so we don’t have long-term data on what happens when patients taper off, but my recommendation — and I think the data support this — is that even if you do have a history of lupus nephritis, if you had stable disease or very little to no activity for a year or 2, then I think it’s worth stopping the medication and following for any signs of disease flare,” Dr. Chakravarty said in an interview with this news organization. 

She added that “in clinical practice, we would follow patients regularly no matter what they’re on, even if they’re in remission, looking for clinical signs or laboratory evidence of flare, and then if they look like they might be having flare, treat them accordingly.”
 

Toxicities a Concern

Although MMF is effective for inducing prolonged disease quiescence, it is a known teratogen and has significant toxicities, and it’s desirable to wean patients off the drug if it can be done safely, Dr. Chakravarty said.

The optimal duration of maintenance therapy with MMF is not known, however, which prompted the researchers to conduct the open-label study.

Patients aged 18-70 years who met the American College of Rheumatology (ACR) 1997 SLE criteria and had a clinical SLE Disease Activity Index (SLEDAI) score ≤ 4 at screening and who also had been on stable or tapering MMF therapy for 2 or more years for renal indications or 1 or more year for nonrenal indications were eligible. All patients were on a background regimen of hydroxychloroquine.

Patients were randomly assigned on an equal basis to either withdrawal with a 12-week taper or to continued maintenance at their baseline dose, ranging from 1 to 3 g/day for 60 weeks. 

The investigators used an adaptive random-allocation strategy to ensure that the groups were balanced for study site, renal vs nonrenal disease, and baseline MMF dose (≥ 2 g/day vs < 2 g/day).

A total of 100 patients with an average age of 42 years were included in a modified intention-to-treat analysis: 49 were randomly assigned to maintenance and 51 to withdrawal.

Overall, 84% of patients were women, 40% were White, and 41% were Black. Most patients, 76%, had a history of lupus nephritis. 

Significant disease reactivation, the primary endpoints, was defined as the need to increase prednisone to ≥ 15 mg/day for 4 weeks, the need for two or more short steroid bursts, or the need to resume MMF or start patients on another immunosuppressive therapy.

By week 60, 18% of patients in the withdrawal group had clinically significant disease reactivation compared with 10% of patients in the maintenance group.

“Although the differences were not significant, this study used an estimation-based design to determine estimated increases in clinically significant disease reactivation risk with 75%, 85%, and 95% confidence limits to assist clinicians and patients in making informed treatment decisions. We found a 6%-8% increase with upper 85% confidence limits of 11%-19% in clinically significant disease reactivation and flare risk following mycophenolate mofetil withdrawal,” the investigators wrote.

Rates of adverse events were similar between the groups, occurring in 90% of patients in the maintenance arm and 88% of those in the withdrawal arm. Infections occurred more frequently among patients in the maintenance group, at 64% vs 46%.
 

Encouraging Data

In an accompanying editorial, Noémie Jourde-Chiche, MD, PhD, from Aix-Marseille University in Marseille, France, and Laurent Chiche, MD, from Hopital Europeen de Marseille, wrote that the study data “were clearly encouraging.” They noted that the results show that it’s feasible to wean select patients off immunosuppressive therapy and keep SLE in check and that the quantified risk assessment strategy will allow shared decision-making for each patient.

“Overall, the prospect of a time-limited (versus lifelong) treatment may favor compliance, as observed in other disease fields, which might consolidate remission and reduce the risk of subsequent relapse, using sequentially treat-to-target and think-to-untreat strategies for a win-wean era in SLE,” they wrote.

“We’ve been awaiting the results of this trial for quite a while, and so it is nice to see it out,” commented Karen H. Costenbader, MD, MPH, professor of medicine at Harvard Medical School, and chair of the division of rheumatology and director of the Lupus Program at Brigham and Women’s Hospital in Boston, Massachusetts.

“It does provide some data to address a question that comes up in discussions with patients all the time: A person with lupus has been doing really well, in what we call low disease activity state or remission, but on mycophenolate, possibly for several years,” she said in a reply to a request for objective commentary.

“The question is how and when to taper and can MMF be safely discontinued,” she said. “Personally, I always review the severity of the underlying disease and indication for the MMF in the first place. Really active SLE with rapidly progressing kidney or other organ damage has to be treated with tremendous respect and no one wants to go back there. I also think about how long it has been, which other medications are still being taken (hydroxychloroquine, belimumab [Benlysta], etc.) and whether the labs and symptoms have really returned to completely normal. Then I have discussions about all this with my patient and we often try a long, slow, gingerly taper with a lot of interim monitoring.”

The study was funded by the National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Chakravarty and Dr. Costenbader report no relevant financial relationships. Dr. Jourde-Chiche declares personal consulting fees from Otsuka and AstraZeneca, personal speaking fees from GlaxoSmithKline and Otsuka, and personal payment for expert testimony from Otsuka. Dr. Chiche declares research grants paid to his institution from AstraZeneca and GlaxoSmithKline, personal consulting fees from Novartis and AstraZeneca, and personal speaking fees from GlaxoSmithKline and Novartis.

A version of this article appeared on Medscape.com . 

Patients with quiescent systemic lupus erythematosus (SLE) who are on maintenance therapy with mycophenolate mofetil (MMF) may be able to be safely weaned off the drug with the understanding that disease flare may occur and may require restarting immunosuppressive therapy.

That’s the conclusion of investigators in a multicenter randomized trial conducted at 19 US centers and published in The Lancet Rheumatology. They found that among 100 patients with stable SLE who were on MMF for at least 2 years for renal indications or at least 1 year for nonrenal indications, MMF withdrawal was not significantly inferior to MMF maintenance in terms of clinically significant disease reactivation within at least 1 year.

Oklahoma Medical Research Foundation

“Our findings suggest that mycophenolate mofetil could be safely withdrawn in patients with stable SLE. However, larger studies with a longer follow-up are still needed,” wrote Eliza F. Chakravarty, MD, MS, from the University of Oklahoma College of Medicine in Oklahoma City, and colleagues.

“Our study was only for 60 weeks, so we don’t have long-term data on what happens when patients taper off, but my recommendation — and I think the data support this — is that even if you do have a history of lupus nephritis, if you had stable disease or very little to no activity for a year or 2, then I think it’s worth stopping the medication and following for any signs of disease flare,” Dr. Chakravarty said in an interview with this news organization. 

She added that “in clinical practice, we would follow patients regularly no matter what they’re on, even if they’re in remission, looking for clinical signs or laboratory evidence of flare, and then if they look like they might be having flare, treat them accordingly.”
 

Toxicities a Concern

Although MMF is effective for inducing prolonged disease quiescence, it is a known teratogen and has significant toxicities, and it’s desirable to wean patients off the drug if it can be done safely, Dr. Chakravarty said.

The optimal duration of maintenance therapy with MMF is not known, however, which prompted the researchers to conduct the open-label study.

Patients aged 18-70 years who met the American College of Rheumatology (ACR) 1997 SLE criteria and had a clinical SLE Disease Activity Index (SLEDAI) score ≤ 4 at screening and who also had been on stable or tapering MMF therapy for 2 or more years for renal indications or 1 or more year for nonrenal indications were eligible. All patients were on a background regimen of hydroxychloroquine.

Patients were randomly assigned on an equal basis to either withdrawal with a 12-week taper or to continued maintenance at their baseline dose, ranging from 1 to 3 g/day for 60 weeks. 

The investigators used an adaptive random-allocation strategy to ensure that the groups were balanced for study site, renal vs nonrenal disease, and baseline MMF dose (≥ 2 g/day vs < 2 g/day).

A total of 100 patients with an average age of 42 years were included in a modified intention-to-treat analysis: 49 were randomly assigned to maintenance and 51 to withdrawal.

Overall, 84% of patients were women, 40% were White, and 41% were Black. Most patients, 76%, had a history of lupus nephritis. 

Significant disease reactivation, the primary endpoints, was defined as the need to increase prednisone to ≥ 15 mg/day for 4 weeks, the need for two or more short steroid bursts, or the need to resume MMF or start patients on another immunosuppressive therapy.

By week 60, 18% of patients in the withdrawal group had clinically significant disease reactivation compared with 10% of patients in the maintenance group.

“Although the differences were not significant, this study used an estimation-based design to determine estimated increases in clinically significant disease reactivation risk with 75%, 85%, and 95% confidence limits to assist clinicians and patients in making informed treatment decisions. We found a 6%-8% increase with upper 85% confidence limits of 11%-19% in clinically significant disease reactivation and flare risk following mycophenolate mofetil withdrawal,” the investigators wrote.

Rates of adverse events were similar between the groups, occurring in 90% of patients in the maintenance arm and 88% of those in the withdrawal arm. Infections occurred more frequently among patients in the maintenance group, at 64% vs 46%.
 

Encouraging Data

In an accompanying editorial, Noémie Jourde-Chiche, MD, PhD, from Aix-Marseille University in Marseille, France, and Laurent Chiche, MD, from Hopital Europeen de Marseille, wrote that the study data “were clearly encouraging.” They noted that the results show that it’s feasible to wean select patients off immunosuppressive therapy and keep SLE in check and that the quantified risk assessment strategy will allow shared decision-making for each patient.

“Overall, the prospect of a time-limited (versus lifelong) treatment may favor compliance, as observed in other disease fields, which might consolidate remission and reduce the risk of subsequent relapse, using sequentially treat-to-target and think-to-untreat strategies for a win-wean era in SLE,” they wrote.

“We’ve been awaiting the results of this trial for quite a while, and so it is nice to see it out,” commented Karen H. Costenbader, MD, MPH, professor of medicine at Harvard Medical School, and chair of the division of rheumatology and director of the Lupus Program at Brigham and Women’s Hospital in Boston, Massachusetts.

“It does provide some data to address a question that comes up in discussions with patients all the time: A person with lupus has been doing really well, in what we call low disease activity state or remission, but on mycophenolate, possibly for several years,” she said in a reply to a request for objective commentary.

“The question is how and when to taper and can MMF be safely discontinued,” she said. “Personally, I always review the severity of the underlying disease and indication for the MMF in the first place. Really active SLE with rapidly progressing kidney or other organ damage has to be treated with tremendous respect and no one wants to go back there. I also think about how long it has been, which other medications are still being taken (hydroxychloroquine, belimumab [Benlysta], etc.) and whether the labs and symptoms have really returned to completely normal. Then I have discussions about all this with my patient and we often try a long, slow, gingerly taper with a lot of interim monitoring.”

The study was funded by the National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Chakravarty and Dr. Costenbader report no relevant financial relationships. Dr. Jourde-Chiche declares personal consulting fees from Otsuka and AstraZeneca, personal speaking fees from GlaxoSmithKline and Otsuka, and personal payment for expert testimony from Otsuka. Dr. Chiche declares research grants paid to his institution from AstraZeneca and GlaxoSmithKline, personal consulting fees from Novartis and AstraZeneca, and personal speaking fees from GlaxoSmithKline and Novartis.

A version of this article appeared on Medscape.com . 

Patients with quiescent systemic lupus erythematosus (SLE) who are on maintenance therapy with mycophenolate mofetil (MMF) may be able to be safely weaned off the drug with the understanding that disease flare may occur and may require restarting immunosuppressive therapy.

That’s the conclusion of investigators in a multicenter randomized trial conducted at 19 US centers and published in The Lancet Rheumatology. They found that among 100 patients with stable SLE who were on MMF for at least 2 years for renal indications or at least 1 year for nonrenal indications, MMF withdrawal was not significantly inferior to MMF maintenance in terms of clinically significant disease reactivation within at least 1 year.

Oklahoma Medical Research Foundation

“Our findings suggest that mycophenolate mofetil could be safely withdrawn in patients with stable SLE. However, larger studies with a longer follow-up are still needed,” wrote Eliza F. Chakravarty, MD, MS, from the University of Oklahoma College of Medicine in Oklahoma City, and colleagues.

“Our study was only for 60 weeks, so we don’t have long-term data on what happens when patients taper off, but my recommendation — and I think the data support this — is that even if you do have a history of lupus nephritis, if you had stable disease or very little to no activity for a year or 2, then I think it’s worth stopping the medication and following for any signs of disease flare,” Dr. Chakravarty said in an interview with this news organization. 

She added that “in clinical practice, we would follow patients regularly no matter what they’re on, even if they’re in remission, looking for clinical signs or laboratory evidence of flare, and then if they look like they might be having flare, treat them accordingly.”
 

Toxicities a Concern

Although MMF is effective for inducing prolonged disease quiescence, it is a known teratogen and has significant toxicities, and it’s desirable to wean patients off the drug if it can be done safely, Dr. Chakravarty said.

The optimal duration of maintenance therapy with MMF is not known, however, which prompted the researchers to conduct the open-label study.

Patients aged 18-70 years who met the American College of Rheumatology (ACR) 1997 SLE criteria and had a clinical SLE Disease Activity Index (SLEDAI) score ≤ 4 at screening and who also had been on stable or tapering MMF therapy for 2 or more years for renal indications or 1 or more year for nonrenal indications were eligible. All patients were on a background regimen of hydroxychloroquine.

Patients were randomly assigned on an equal basis to either withdrawal with a 12-week taper or to continued maintenance at their baseline dose, ranging from 1 to 3 g/day for 60 weeks. 

The investigators used an adaptive random-allocation strategy to ensure that the groups were balanced for study site, renal vs nonrenal disease, and baseline MMF dose (≥ 2 g/day vs < 2 g/day).

A total of 100 patients with an average age of 42 years were included in a modified intention-to-treat analysis: 49 were randomly assigned to maintenance and 51 to withdrawal.

Overall, 84% of patients were women, 40% were White, and 41% were Black. Most patients, 76%, had a history of lupus nephritis. 

Significant disease reactivation, the primary endpoints, was defined as the need to increase prednisone to ≥ 15 mg/day for 4 weeks, the need for two or more short steroid bursts, or the need to resume MMF or start patients on another immunosuppressive therapy.

By week 60, 18% of patients in the withdrawal group had clinically significant disease reactivation compared with 10% of patients in the maintenance group.

“Although the differences were not significant, this study used an estimation-based design to determine estimated increases in clinically significant disease reactivation risk with 75%, 85%, and 95% confidence limits to assist clinicians and patients in making informed treatment decisions. We found a 6%-8% increase with upper 85% confidence limits of 11%-19% in clinically significant disease reactivation and flare risk following mycophenolate mofetil withdrawal,” the investigators wrote.

Rates of adverse events were similar between the groups, occurring in 90% of patients in the maintenance arm and 88% of those in the withdrawal arm. Infections occurred more frequently among patients in the maintenance group, at 64% vs 46%.
 

Encouraging Data

In an accompanying editorial, Noémie Jourde-Chiche, MD, PhD, from Aix-Marseille University in Marseille, France, and Laurent Chiche, MD, from Hopital Europeen de Marseille, wrote that the study data “were clearly encouraging.” They noted that the results show that it’s feasible to wean select patients off immunosuppressive therapy and keep SLE in check and that the quantified risk assessment strategy will allow shared decision-making for each patient.

“Overall, the prospect of a time-limited (versus lifelong) treatment may favor compliance, as observed in other disease fields, which might consolidate remission and reduce the risk of subsequent relapse, using sequentially treat-to-target and think-to-untreat strategies for a win-wean era in SLE,” they wrote.

“We’ve been awaiting the results of this trial for quite a while, and so it is nice to see it out,” commented Karen H. Costenbader, MD, MPH, professor of medicine at Harvard Medical School, and chair of the division of rheumatology and director of the Lupus Program at Brigham and Women’s Hospital in Boston, Massachusetts.

“It does provide some data to address a question that comes up in discussions with patients all the time: A person with lupus has been doing really well, in what we call low disease activity state or remission, but on mycophenolate, possibly for several years,” she said in a reply to a request for objective commentary.

“The question is how and when to taper and can MMF be safely discontinued,” she said. “Personally, I always review the severity of the underlying disease and indication for the MMF in the first place. Really active SLE with rapidly progressing kidney or other organ damage has to be treated with tremendous respect and no one wants to go back there. I also think about how long it has been, which other medications are still being taken (hydroxychloroquine, belimumab [Benlysta], etc.) and whether the labs and symptoms have really returned to completely normal. Then I have discussions about all this with my patient and we often try a long, slow, gingerly taper with a lot of interim monitoring.”

The study was funded by the National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Chakravarty and Dr. Costenbader report no relevant financial relationships. Dr. Jourde-Chiche declares personal consulting fees from Otsuka and AstraZeneca, personal speaking fees from GlaxoSmithKline and Otsuka, and personal payment for expert testimony from Otsuka. Dr. Chiche declares research grants paid to his institution from AstraZeneca and GlaxoSmithKline, personal consulting fees from Novartis and AstraZeneca, and personal speaking fees from GlaxoSmithKline and Novartis.

A version of this article appeared on Medscape.com . 

Two years after the end of a randomized trial that showed a benefit of daily vitamin D and omega-3 fatty acid (n-3 FA) supplementation for reducing risk for autoimmune diseases, the salubrious effects of daily vitamin D appear to have waned after the supplement was discontinued, while the protection from n-3 lived on for at least 2 additional years.

As previously reported, the randomized VITAL, which was designed primarily to study the effects of vitamin D and n-3 supplementation on incident cancer and cardiovascular disease, also showed that 5 years of vitamin D supplementation was associated with a 22% reduction in risk for confirmed autoimmune diseases, and 5 years of n-3 FA supplementation was associated with an 18% reduction in confirmed and probable incident autoimmune diseases.

Now, investigators Karen H. Costenbader, MD, MPH, of Brigham & Women’s Hospital in Boston, Massachusetts, and colleagues reported that among 21,592 participants in VITAL who agreed to be followed for an additional 2 years after discontinuation, the protection against autoimmune diseases from daily vitamin D (cholecalciferol; 2000 IU/d) was no longer statistically significant, but the benefits of daily marine n-3 FAs (1 g/d as a fish-oil capsule containing 460 mg of eicosapentaenoic acid and 380 mg of docosahexaenoic acid) remained significant.

“VITAL observational extension results suggest that vitamin D supplementation should be given on a continuous basis for long-term prevention of [autoimmune diseases]. The beneficial effects of n-3 fatty acids, however, may be prolonged for at least 2 years after discontinuation,” they wrote in an article published in Arthritis & Rheumatology.

Dr. Costenbader told this news organization that the results of the observational extension study suggest that the benefits of vitamin D “wear off more quickly, and it should be continued for a longer period of time or indefinitely, rather than only for 5 years.”

In addition to the disparity in the duration of the protective effect, the investigators also saw differences in the effects across different autoimmune diseases.

“The protective effect of vitamin D seemed strongest for psoriasis, while for omega-3 fatty acids, the protective effects were strongest for rheumatoid arthritis and inflammatory bowel disease,” she said.
 

Mixed Effects

In an interview with this news organization, Janet Funk, MD, MS, vice chair of research in the Department of Medicine and professor in the School of Nutritional Science and Wellness at the University of Arizona, Tucson, Arizona, who was not involved in the study, saidthat the results suggest that while each supplement may offer protection against autoimmune diseases, the effects are inconsistent and may not apply to all patients.

“I think the VITAL extension results suggest that either supplement (or both together) may have benefits in reducing risk of autoimmune diseases, including possible persistent effects posttreatment, but that these effects are nuanced (ie, only in normal weight post-vitamin D treatment) and possibly not uniform across all autoimmune diseases (including possible adverse effects for some — eg, inverse association between prior omega-3 and psoriasis and tendency for increased autoimmune thyroid disease for vitamin D), although the study was not powered sufficiently to draw disease-specific conclusions,” she said.

In an editorial accompanying the study, rheumatologist Joel M. Kremer, MD, of Albany Medical College and the Corrona Research Foundation in Delray Beach, Florida, wrote that “[T]he studies by Dr. Costenbader, et al. have shed new light on the possibility that dietary supplements of n-3 FA [fatty acid] may prevent the onset of [autoimmune disease]. The sustained benefits they describe for as long as 2 years after the supplements are discontinued are consistent with the chronicity of FA species in cellular plasma membranes where they serve as substrates for a diverse array of salient metabolic and inflammatory pathways.”
 

VITAL Then

To test whether vitamin D or marine-derived long-chain n-3 FA supplementation could protect against autoimmune disease over time, Dr. Costenbader and colleagues piggybacked an ancillary study onto the VITAL trial, which had primary outcomes of cancer and cardiovascular disease incidence.

A total of 25,871 participants were enrolled, including 12,786 men aged 50 and older and 13,085 women aged 55 and older. The study had a 2 × 2 factorial design, with patients randomly assigned to vitamin D 2000 IU/d or placebo and then further randomized to either 1 g/d n-3 FAs or placebo in both the vitamin D and placebo primary randomization arms.

In multivariate analysis adjusted for age, sex, race, and other supplement arm, vitamin D alone was associated with a hazard ratio (HR) of 0.68 (P = .02) for incident autoimmune disease, n-3 alone was associated with a nonsignificant HR of 0.74, and the combination was associated with an HR of 0.69 (P = .03). However, when probable incident autoimmune disease cases were included, the effect of n-3 became significant, with an HR of 0.82.
 

VITAL Now

In the current analysis, Dr. Costenbader and colleagues reported observational data on 21,592 VITAL participants, a sample representing 83.5% of those who were initially randomized, and 87.9% of those who were alive and could be contacted at the end of the study.

As in the initial trial, the investigators used annual questionnaires to assess incident autoimmune diseases during the randomized follow-up. Participants were asked about new-onset, doctor-diagnosed rheumatoid arthritis, polymyalgia rheumatica, psoriasis, autoimmune thyroid disease, and inflammatory bowel disease. Participants could also write in any other new autoimmune disease diagnoses.

There were 236 new cases of confirmed autoimmune disease that occurred since the initial publication of the trial results, as well as 65 probable cases identified during the median 5.3 years of the randomized portion, and 42 probable cases diagnosed during the 2-year observational phase.

The investigators found that after the 2-year observation period, 255 participants initially randomized to receive vitamin D had a newly developed confirmed autoimmune disease, compared with 259 of those initially randomized to a vitamin D placebo. This translated into a nonsignificant HR of 0.98.

Adding probable autoimmune cases to the confirmed cases made little difference, resulting in a nonsignificant adjusted HR of 0.95.

In contrast, there were 234 confirmed autoimmune disease cases among patients initially assigned to n-3, compared with 280 among patients randomized to the n-3 placebo, translating into a statistically significant HR of 0.83 for new-onset autoimmune disease with n-3.

Dr. Costenbader and colleagues acknowledged that the study was limited by the use of doses intended to prevent cancer or cardiovascular disease and that higher doses intended for high-risk or nutritionally deficient populations might reveal larger effects of supplementation. In addition, they noted the difficulty of identifying the timing and onset of incident disease, and that the small number of cases that occurred during the 2-year observational period precluded detailed analyses of individual autoimmune diseases.

The study was funded by grants from the National Institutes of Health. Dr. Costenbader, Dr. Funk, and Dr. Kremer reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Two years after the end of a randomized trial that showed a benefit of daily vitamin D and omega-3 fatty acid (n-3 FA) supplementation for reducing risk for autoimmune diseases, the salubrious effects of daily vitamin D appear to have waned after the supplement was discontinued, while the protection from n-3 lived on for at least 2 additional years.

As previously reported, the randomized VITAL, which was designed primarily to study the effects of vitamin D and n-3 supplementation on incident cancer and cardiovascular disease, also showed that 5 years of vitamin D supplementation was associated with a 22% reduction in risk for confirmed autoimmune diseases, and 5 years of n-3 FA supplementation was associated with an 18% reduction in confirmed and probable incident autoimmune diseases.

Now, investigators Karen H. Costenbader, MD, MPH, of Brigham & Women’s Hospital in Boston, Massachusetts, and colleagues reported that among 21,592 participants in VITAL who agreed to be followed for an additional 2 years after discontinuation, the protection against autoimmune diseases from daily vitamin D (cholecalciferol; 2000 IU/d) was no longer statistically significant, but the benefits of daily marine n-3 FAs (1 g/d as a fish-oil capsule containing 460 mg of eicosapentaenoic acid and 380 mg of docosahexaenoic acid) remained significant.

“VITAL observational extension results suggest that vitamin D supplementation should be given on a continuous basis for long-term prevention of [autoimmune diseases]. The beneficial effects of n-3 fatty acids, however, may be prolonged for at least 2 years after discontinuation,” they wrote in an article published in Arthritis & Rheumatology.

Dr. Costenbader told this news organization that the results of the observational extension study suggest that the benefits of vitamin D “wear off more quickly, and it should be continued for a longer period of time or indefinitely, rather than only for 5 years.”

In addition to the disparity in the duration of the protective effect, the investigators also saw differences in the effects across different autoimmune diseases.

“The protective effect of vitamin D seemed strongest for psoriasis, while for omega-3 fatty acids, the protective effects were strongest for rheumatoid arthritis and inflammatory bowel disease,” she said.
 

Mixed Effects

In an interview with this news organization, Janet Funk, MD, MS, vice chair of research in the Department of Medicine and professor in the School of Nutritional Science and Wellness at the University of Arizona, Tucson, Arizona, who was not involved in the study, saidthat the results suggest that while each supplement may offer protection against autoimmune diseases, the effects are inconsistent and may not apply to all patients.

“I think the VITAL extension results suggest that either supplement (or both together) may have benefits in reducing risk of autoimmune diseases, including possible persistent effects posttreatment, but that these effects are nuanced (ie, only in normal weight post-vitamin D treatment) and possibly not uniform across all autoimmune diseases (including possible adverse effects for some — eg, inverse association between prior omega-3 and psoriasis and tendency for increased autoimmune thyroid disease for vitamin D), although the study was not powered sufficiently to draw disease-specific conclusions,” she said.

In an editorial accompanying the study, rheumatologist Joel M. Kremer, MD, of Albany Medical College and the Corrona Research Foundation in Delray Beach, Florida, wrote that “[T]he studies by Dr. Costenbader, et al. have shed new light on the possibility that dietary supplements of n-3 FA [fatty acid] may prevent the onset of [autoimmune disease]. The sustained benefits they describe for as long as 2 years after the supplements are discontinued are consistent with the chronicity of FA species in cellular plasma membranes where they serve as substrates for a diverse array of salient metabolic and inflammatory pathways.”
 

VITAL Then

To test whether vitamin D or marine-derived long-chain n-3 FA supplementation could protect against autoimmune disease over time, Dr. Costenbader and colleagues piggybacked an ancillary study onto the VITAL trial, which had primary outcomes of cancer and cardiovascular disease incidence.

A total of 25,871 participants were enrolled, including 12,786 men aged 50 and older and 13,085 women aged 55 and older. The study had a 2 × 2 factorial design, with patients randomly assigned to vitamin D 2000 IU/d or placebo and then further randomized to either 1 g/d n-3 FAs or placebo in both the vitamin D and placebo primary randomization arms.

In multivariate analysis adjusted for age, sex, race, and other supplement arm, vitamin D alone was associated with a hazard ratio (HR) of 0.68 (P = .02) for incident autoimmune disease, n-3 alone was associated with a nonsignificant HR of 0.74, and the combination was associated with an HR of 0.69 (P = .03). However, when probable incident autoimmune disease cases were included, the effect of n-3 became significant, with an HR of 0.82.
 

VITAL Now

In the current analysis, Dr. Costenbader and colleagues reported observational data on 21,592 VITAL participants, a sample representing 83.5% of those who were initially randomized, and 87.9% of those who were alive and could be contacted at the end of the study.

As in the initial trial, the investigators used annual questionnaires to assess incident autoimmune diseases during the randomized follow-up. Participants were asked about new-onset, doctor-diagnosed rheumatoid arthritis, polymyalgia rheumatica, psoriasis, autoimmune thyroid disease, and inflammatory bowel disease. Participants could also write in any other new autoimmune disease diagnoses.

There were 236 new cases of confirmed autoimmune disease that occurred since the initial publication of the trial results, as well as 65 probable cases identified during the median 5.3 years of the randomized portion, and 42 probable cases diagnosed during the 2-year observational phase.

The investigators found that after the 2-year observation period, 255 participants initially randomized to receive vitamin D had a newly developed confirmed autoimmune disease, compared with 259 of those initially randomized to a vitamin D placebo. This translated into a nonsignificant HR of 0.98.

Adding probable autoimmune cases to the confirmed cases made little difference, resulting in a nonsignificant adjusted HR of 0.95.

In contrast, there were 234 confirmed autoimmune disease cases among patients initially assigned to n-3, compared with 280 among patients randomized to the n-3 placebo, translating into a statistically significant HR of 0.83 for new-onset autoimmune disease with n-3.

Dr. Costenbader and colleagues acknowledged that the study was limited by the use of doses intended to prevent cancer or cardiovascular disease and that higher doses intended for high-risk or nutritionally deficient populations might reveal larger effects of supplementation. In addition, they noted the difficulty of identifying the timing and onset of incident disease, and that the small number of cases that occurred during the 2-year observational period precluded detailed analyses of individual autoimmune diseases.

The study was funded by grants from the National Institutes of Health. Dr. Costenbader, Dr. Funk, and Dr. Kremer reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Two years after the end of a randomized trial that showed a benefit of daily vitamin D and omega-3 fatty acid (n-3 FA) supplementation for reducing risk for autoimmune diseases, the salubrious effects of daily vitamin D appear to have waned after the supplement was discontinued, while the protection from n-3 lived on for at least 2 additional years.

As previously reported, the randomized VITAL, which was designed primarily to study the effects of vitamin D and n-3 supplementation on incident cancer and cardiovascular disease, also showed that 5 years of vitamin D supplementation was associated with a 22% reduction in risk for confirmed autoimmune diseases, and 5 years of n-3 FA supplementation was associated with an 18% reduction in confirmed and probable incident autoimmune diseases.

Now, investigators Karen H. Costenbader, MD, MPH, of Brigham & Women’s Hospital in Boston, Massachusetts, and colleagues reported that among 21,592 participants in VITAL who agreed to be followed for an additional 2 years after discontinuation, the protection against autoimmune diseases from daily vitamin D (cholecalciferol; 2000 IU/d) was no longer statistically significant, but the benefits of daily marine n-3 FAs (1 g/d as a fish-oil capsule containing 460 mg of eicosapentaenoic acid and 380 mg of docosahexaenoic acid) remained significant.

“VITAL observational extension results suggest that vitamin D supplementation should be given on a continuous basis for long-term prevention of [autoimmune diseases]. The beneficial effects of n-3 fatty acids, however, may be prolonged for at least 2 years after discontinuation,” they wrote in an article published in Arthritis & Rheumatology.

Dr. Costenbader told this news organization that the results of the observational extension study suggest that the benefits of vitamin D “wear off more quickly, and it should be continued for a longer period of time or indefinitely, rather than only for 5 years.”

In addition to the disparity in the duration of the protective effect, the investigators also saw differences in the effects across different autoimmune diseases.

“The protective effect of vitamin D seemed strongest for psoriasis, while for omega-3 fatty acids, the protective effects were strongest for rheumatoid arthritis and inflammatory bowel disease,” she said.
 

Mixed Effects

In an interview with this news organization, Janet Funk, MD, MS, vice chair of research in the Department of Medicine and professor in the School of Nutritional Science and Wellness at the University of Arizona, Tucson, Arizona, who was not involved in the study, saidthat the results suggest that while each supplement may offer protection against autoimmune diseases, the effects are inconsistent and may not apply to all patients.

“I think the VITAL extension results suggest that either supplement (or both together) may have benefits in reducing risk of autoimmune diseases, including possible persistent effects posttreatment, but that these effects are nuanced (ie, only in normal weight post-vitamin D treatment) and possibly not uniform across all autoimmune diseases (including possible adverse effects for some — eg, inverse association between prior omega-3 and psoriasis and tendency for increased autoimmune thyroid disease for vitamin D), although the study was not powered sufficiently to draw disease-specific conclusions,” she said.

In an editorial accompanying the study, rheumatologist Joel M. Kremer, MD, of Albany Medical College and the Corrona Research Foundation in Delray Beach, Florida, wrote that “[T]he studies by Dr. Costenbader, et al. have shed new light on the possibility that dietary supplements of n-3 FA [fatty acid] may prevent the onset of [autoimmune disease]. The sustained benefits they describe for as long as 2 years after the supplements are discontinued are consistent with the chronicity of FA species in cellular plasma membranes where they serve as substrates for a diverse array of salient metabolic and inflammatory pathways.”
 

VITAL Then

To test whether vitamin D or marine-derived long-chain n-3 FA supplementation could protect against autoimmune disease over time, Dr. Costenbader and colleagues piggybacked an ancillary study onto the VITAL trial, which had primary outcomes of cancer and cardiovascular disease incidence.

A total of 25,871 participants were enrolled, including 12,786 men aged 50 and older and 13,085 women aged 55 and older. The study had a 2 × 2 factorial design, with patients randomly assigned to vitamin D 2000 IU/d or placebo and then further randomized to either 1 g/d n-3 FAs or placebo in both the vitamin D and placebo primary randomization arms.

In multivariate analysis adjusted for age, sex, race, and other supplement arm, vitamin D alone was associated with a hazard ratio (HR) of 0.68 (P = .02) for incident autoimmune disease, n-3 alone was associated with a nonsignificant HR of 0.74, and the combination was associated with an HR of 0.69 (P = .03). However, when probable incident autoimmune disease cases were included, the effect of n-3 became significant, with an HR of 0.82.
 

VITAL Now

In the current analysis, Dr. Costenbader and colleagues reported observational data on 21,592 VITAL participants, a sample representing 83.5% of those who were initially randomized, and 87.9% of those who were alive and could be contacted at the end of the study.

As in the initial trial, the investigators used annual questionnaires to assess incident autoimmune diseases during the randomized follow-up. Participants were asked about new-onset, doctor-diagnosed rheumatoid arthritis, polymyalgia rheumatica, psoriasis, autoimmune thyroid disease, and inflammatory bowel disease. Participants could also write in any other new autoimmune disease diagnoses.

There were 236 new cases of confirmed autoimmune disease that occurred since the initial publication of the trial results, as well as 65 probable cases identified during the median 5.3 years of the randomized portion, and 42 probable cases diagnosed during the 2-year observational phase.

The investigators found that after the 2-year observation period, 255 participants initially randomized to receive vitamin D had a newly developed confirmed autoimmune disease, compared with 259 of those initially randomized to a vitamin D placebo. This translated into a nonsignificant HR of 0.98.

Adding probable autoimmune cases to the confirmed cases made little difference, resulting in a nonsignificant adjusted HR of 0.95.

In contrast, there were 234 confirmed autoimmune disease cases among patients initially assigned to n-3, compared with 280 among patients randomized to the n-3 placebo, translating into a statistically significant HR of 0.83 for new-onset autoimmune disease with n-3.

Dr. Costenbader and colleagues acknowledged that the study was limited by the use of doses intended to prevent cancer or cardiovascular disease and that higher doses intended for high-risk or nutritionally deficient populations might reveal larger effects of supplementation. In addition, they noted the difficulty of identifying the timing and onset of incident disease, and that the small number of cases that occurred during the 2-year observational period precluded detailed analyses of individual autoimmune diseases.

The study was funded by grants from the National Institutes of Health. Dr. Costenbader, Dr. Funk, and Dr. Kremer reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed despite treatment with novel hormonal therapy had a slight but statistically significant improvement in progression-free survival (PFS) with a combination of a targeted agent and immunotherapy compared with a second-line novel hormonal therapy.

The combination of the tyrosine kinase inhibitor (TKI), cabozantinib (Cabometyx), and the immune checkpoint inhibitor (ICI), atezolizumab (Tecentriq), was associated with a median PFS of 6.3 months vs 4.2 months for patients assigned to second hormonal therapy with either abiraterone (Zytiga) and prednisone, or enzalutamide (Xtandi) in the CONTACT-02 trial, Neeraj Agarwal, MD, reported at the ASCO Genitourinary Cancers Symposium. 

“CONTACT 2 is the first phase 3 trial of the TKI/ICI combination to show statistically significant improvement in PFS in patients with mCRPC,” said Dr. Agarwal, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

­­The data support the combination of cabozantinib and atezolizumab as a potential new treatment option for patients with mCRPC that has progressed on novel hormonal therapy, he said.
 

Study Design Questioned

That opinion, however, was not shared by Kim N. Chi, MD, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant.

Dr. Chi acknowledged that the study results as presented were positive, but also pointed to several limitations, including the small difference between the treatment groups in radiographic progression-free survival (rPFS).

“I would say the rPFS benefit is modest, and in the absence of other improvements the difference in the median rPFS is equivalent from one scan to the next in the scanning cycle. I would argue about the clinical significance of that,” he said.

He also noted that there was no improvement in the investigational arm in patient-reported outcomes, and that pain progression and quality-of-life deterioration occurred within 2 to 4 months, which is “quite quick.”

Additionally, he questioned the choice of an androgen receptor pathway inhibitor (ARPI) switch as the control arm of the study.

“I’d also argue that ARPI switch is not the best standard of care for this patient population with measurable disease and 40% visceral metastases; there are better options,” he said.

For example, in phase 3 trials, docetaxel and cabazitaxel (Jevtana) have consistently demonstrated radiographic PFS of 8 to 9 months. In addition, lutetium-177–PSMA-617, a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the tumor microenvironment, has also been shown to have PFS and overall survival benefits, he said.

“Irrespective of regulatory decisions, I personally could not recommend this at this time, given the data that we’ve seen and the better options that are available for this patient population,” Dr. Chi said.
 

Real-World Practice

“Kim Chi offered a pretty fair critique and summary of the control arm, but in real world practice, ARPI switch, from abi [abiraterone] to enza [enzalutamide] or enza to abi continues to be used in routine clinical practice for various reasons,” Xin Gao, MD, a genitourinary oncologist at Mass General Cancer Center in Boston, said in an interview.

“There are patients who can’t tolerate chemotherapy or don’t want chemotherapy, and we do know also that there are patients who can benefit from an ARPI switch, especially some patients with more indolent disease,” said Dr. Gao, who attended the presentation but was not involved in the study.

He noted that some patients being switched from abiraterone to enzalutamide have clinical responses, and that the ARPIs are generally more tolerable than chemotherapy.

In addition, CONTACT-02 is one of a series of trials in which ARPI switch was used as the control arm, and many of these trials were initiated before there were data confirming the superior efficacy of some newer therapeutic options, Dr. Gao noted.

He agreed, however that there is growing evidence to show that ARPI switch may not be the optimal choice for patients with more measurable disease, especially visceral metastases, and other more aggressive forms of mCRPC.
 

CONTACT-02 Details

Investigators in the phase 3 study screened 866 men with mCRPC and after stratification by liver metastases, prior docetaxel use for castration-sensitive prostate cancer, and disease stage for which the first novel hormonal therapy was given. About 500 patients (507) were randomized to receive either oral cabozantinib 40 mg daily plus intravenous atezolizumab 1200 mg every 3 weeks or second hormonal therapy with either abiraterone 1000 mg with oral prednisone 5 mg twice daily, or oral enzalutamide 160 mg daily.

After a median follow-up of 14.3 months in the PFS intention-to-treat population, the median ­PFS by blinded central review was 6.3 months with cabozantinib/atezolizumab and 4.2 months with second hormonal therapy. This translated into a hazard ratio of 0.64 (P = .0002). The results were similar for a PFS analysis according to Prostate Cancer Working Group 3 criteria.

The combination was also associated with modest improvements in PFS in prespecified subgroups, including patients who had liver or bone metastases and those who had previously received docetaxel.

There were no significant differences in overall survival at the time of data cutoff. Overall survival data were not mature and will be reported at a later date.

Disease control rates, a composite of complete and partial responses and stable disease, were 73% with the combination and 55% with second hormonal therapy (P value not shown).
 

Safety Data

The safety analysis indicated that patients found the ARPI switch easier to tolerate than the combination.

Adverse events leading to dose reductions occurred in 40% of patients on the combination, vs 3% of patients on second hormonal therapy, and treatment-related adverse events leading to discontinuation occurred in 13% and 2%, respectively.

Grade 3 or 4 adverse events occurred in 48% of patients assigned to the combination vs. 23% of patients assigned to the ARPI switch.

In all, 8% of patients on the combination and 12% on second hormonal therapy died on study, but none of the deaths were deemed to be treatment related.­­

CONTACT-02 was sponsored by Exelixis in partnerships with Ipsen and Takeda.

Dr. Agarwal disclosed institutional research funding from Exelixis, Roche, Takeda, and others, and travel expenses from Pfizer. Dr. Chi disclosed honoraria, a consulting/advisory role and institutional research funding with Roche and others. Dr. Gao has served as a consultant or advisor to several companies, not including the sponsors of the study, and has served as principal investigator at his institution, which has received research funding from Exelixis, Takeda, and others.

Men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed despite treatment with novel hormonal therapy had a slight but statistically significant improvement in progression-free survival (PFS) with a combination of a targeted agent and immunotherapy compared with a second-line novel hormonal therapy.

The combination of the tyrosine kinase inhibitor (TKI), cabozantinib (Cabometyx), and the immune checkpoint inhibitor (ICI), atezolizumab (Tecentriq), was associated with a median PFS of 6.3 months vs 4.2 months for patients assigned to second hormonal therapy with either abiraterone (Zytiga) and prednisone, or enzalutamide (Xtandi) in the CONTACT-02 trial, Neeraj Agarwal, MD, reported at the ASCO Genitourinary Cancers Symposium. 

“CONTACT 2 is the first phase 3 trial of the TKI/ICI combination to show statistically significant improvement in PFS in patients with mCRPC,” said Dr. Agarwal, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

­­The data support the combination of cabozantinib and atezolizumab as a potential new treatment option for patients with mCRPC that has progressed on novel hormonal therapy, he said.
 

Study Design Questioned

That opinion, however, was not shared by Kim N. Chi, MD, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant.

Dr. Chi acknowledged that the study results as presented were positive, but also pointed to several limitations, including the small difference between the treatment groups in radiographic progression-free survival (rPFS).

“I would say the rPFS benefit is modest, and in the absence of other improvements the difference in the median rPFS is equivalent from one scan to the next in the scanning cycle. I would argue about the clinical significance of that,” he said.

He also noted that there was no improvement in the investigational arm in patient-reported outcomes, and that pain progression and quality-of-life deterioration occurred within 2 to 4 months, which is “quite quick.”

Additionally, he questioned the choice of an androgen receptor pathway inhibitor (ARPI) switch as the control arm of the study.

“I’d also argue that ARPI switch is not the best standard of care for this patient population with measurable disease and 40% visceral metastases; there are better options,” he said.

For example, in phase 3 trials, docetaxel and cabazitaxel (Jevtana) have consistently demonstrated radiographic PFS of 8 to 9 months. In addition, lutetium-177–PSMA-617, a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the tumor microenvironment, has also been shown to have PFS and overall survival benefits, he said.

“Irrespective of regulatory decisions, I personally could not recommend this at this time, given the data that we’ve seen and the better options that are available for this patient population,” Dr. Chi said.
 

Real-World Practice

“Kim Chi offered a pretty fair critique and summary of the control arm, but in real world practice, ARPI switch, from abi [abiraterone] to enza [enzalutamide] or enza to abi continues to be used in routine clinical practice for various reasons,” Xin Gao, MD, a genitourinary oncologist at Mass General Cancer Center in Boston, said in an interview.

“There are patients who can’t tolerate chemotherapy or don’t want chemotherapy, and we do know also that there are patients who can benefit from an ARPI switch, especially some patients with more indolent disease,” said Dr. Gao, who attended the presentation but was not involved in the study.

He noted that some patients being switched from abiraterone to enzalutamide have clinical responses, and that the ARPIs are generally more tolerable than chemotherapy.

In addition, CONTACT-02 is one of a series of trials in which ARPI switch was used as the control arm, and many of these trials were initiated before there were data confirming the superior efficacy of some newer therapeutic options, Dr. Gao noted.

He agreed, however that there is growing evidence to show that ARPI switch may not be the optimal choice for patients with more measurable disease, especially visceral metastases, and other more aggressive forms of mCRPC.
 

CONTACT-02 Details

Investigators in the phase 3 study screened 866 men with mCRPC and after stratification by liver metastases, prior docetaxel use for castration-sensitive prostate cancer, and disease stage for which the first novel hormonal therapy was given. About 500 patients (507) were randomized to receive either oral cabozantinib 40 mg daily plus intravenous atezolizumab 1200 mg every 3 weeks or second hormonal therapy with either abiraterone 1000 mg with oral prednisone 5 mg twice daily, or oral enzalutamide 160 mg daily.

After a median follow-up of 14.3 months in the PFS intention-to-treat population, the median ­PFS by blinded central review was 6.3 months with cabozantinib/atezolizumab and 4.2 months with second hormonal therapy. This translated into a hazard ratio of 0.64 (P = .0002). The results were similar for a PFS analysis according to Prostate Cancer Working Group 3 criteria.

The combination was also associated with modest improvements in PFS in prespecified subgroups, including patients who had liver or bone metastases and those who had previously received docetaxel.

There were no significant differences in overall survival at the time of data cutoff. Overall survival data were not mature and will be reported at a later date.

Disease control rates, a composite of complete and partial responses and stable disease, were 73% with the combination and 55% with second hormonal therapy (P value not shown).
 

Safety Data

The safety analysis indicated that patients found the ARPI switch easier to tolerate than the combination.

Adverse events leading to dose reductions occurred in 40% of patients on the combination, vs 3% of patients on second hormonal therapy, and treatment-related adverse events leading to discontinuation occurred in 13% and 2%, respectively.

Grade 3 or 4 adverse events occurred in 48% of patients assigned to the combination vs. 23% of patients assigned to the ARPI switch.

In all, 8% of patients on the combination and 12% on second hormonal therapy died on study, but none of the deaths were deemed to be treatment related.­­

CONTACT-02 was sponsored by Exelixis in partnerships with Ipsen and Takeda.

Dr. Agarwal disclosed institutional research funding from Exelixis, Roche, Takeda, and others, and travel expenses from Pfizer. Dr. Chi disclosed honoraria, a consulting/advisory role and institutional research funding with Roche and others. Dr. Gao has served as a consultant or advisor to several companies, not including the sponsors of the study, and has served as principal investigator at his institution, which has received research funding from Exelixis, Takeda, and others.

Men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed despite treatment with novel hormonal therapy had a slight but statistically significant improvement in progression-free survival (PFS) with a combination of a targeted agent and immunotherapy compared with a second-line novel hormonal therapy.

The combination of the tyrosine kinase inhibitor (TKI), cabozantinib (Cabometyx), and the immune checkpoint inhibitor (ICI), atezolizumab (Tecentriq), was associated with a median PFS of 6.3 months vs 4.2 months for patients assigned to second hormonal therapy with either abiraterone (Zytiga) and prednisone, or enzalutamide (Xtandi) in the CONTACT-02 trial, Neeraj Agarwal, MD, reported at the ASCO Genitourinary Cancers Symposium. 

“CONTACT 2 is the first phase 3 trial of the TKI/ICI combination to show statistically significant improvement in PFS in patients with mCRPC,” said Dr. Agarwal, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

­­The data support the combination of cabozantinib and atezolizumab as a potential new treatment option for patients with mCRPC that has progressed on novel hormonal therapy, he said.
 

Study Design Questioned

That opinion, however, was not shared by Kim N. Chi, MD, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant.

Dr. Chi acknowledged that the study results as presented were positive, but also pointed to several limitations, including the small difference between the treatment groups in radiographic progression-free survival (rPFS).

“I would say the rPFS benefit is modest, and in the absence of other improvements the difference in the median rPFS is equivalent from one scan to the next in the scanning cycle. I would argue about the clinical significance of that,” he said.

He also noted that there was no improvement in the investigational arm in patient-reported outcomes, and that pain progression and quality-of-life deterioration occurred within 2 to 4 months, which is “quite quick.”

Additionally, he questioned the choice of an androgen receptor pathway inhibitor (ARPI) switch as the control arm of the study.

“I’d also argue that ARPI switch is not the best standard of care for this patient population with measurable disease and 40% visceral metastases; there are better options,” he said.

For example, in phase 3 trials, docetaxel and cabazitaxel (Jevtana) have consistently demonstrated radiographic PFS of 8 to 9 months. In addition, lutetium-177–PSMA-617, a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the tumor microenvironment, has also been shown to have PFS and overall survival benefits, he said.

“Irrespective of regulatory decisions, I personally could not recommend this at this time, given the data that we’ve seen and the better options that are available for this patient population,” Dr. Chi said.
 

Real-World Practice

“Kim Chi offered a pretty fair critique and summary of the control arm, but in real world practice, ARPI switch, from abi [abiraterone] to enza [enzalutamide] or enza to abi continues to be used in routine clinical practice for various reasons,” Xin Gao, MD, a genitourinary oncologist at Mass General Cancer Center in Boston, said in an interview.

“There are patients who can’t tolerate chemotherapy or don’t want chemotherapy, and we do know also that there are patients who can benefit from an ARPI switch, especially some patients with more indolent disease,” said Dr. Gao, who attended the presentation but was not involved in the study.

He noted that some patients being switched from abiraterone to enzalutamide have clinical responses, and that the ARPIs are generally more tolerable than chemotherapy.

In addition, CONTACT-02 is one of a series of trials in which ARPI switch was used as the control arm, and many of these trials were initiated before there were data confirming the superior efficacy of some newer therapeutic options, Dr. Gao noted.

He agreed, however that there is growing evidence to show that ARPI switch may not be the optimal choice for patients with more measurable disease, especially visceral metastases, and other more aggressive forms of mCRPC.
 

CONTACT-02 Details

Investigators in the phase 3 study screened 866 men with mCRPC and after stratification by liver metastases, prior docetaxel use for castration-sensitive prostate cancer, and disease stage for which the first novel hormonal therapy was given. About 500 patients (507) were randomized to receive either oral cabozantinib 40 mg daily plus intravenous atezolizumab 1200 mg every 3 weeks or second hormonal therapy with either abiraterone 1000 mg with oral prednisone 5 mg twice daily, or oral enzalutamide 160 mg daily.

After a median follow-up of 14.3 months in the PFS intention-to-treat population, the median ­PFS by blinded central review was 6.3 months with cabozantinib/atezolizumab and 4.2 months with second hormonal therapy. This translated into a hazard ratio of 0.64 (P = .0002). The results were similar for a PFS analysis according to Prostate Cancer Working Group 3 criteria.

The combination was also associated with modest improvements in PFS in prespecified subgroups, including patients who had liver or bone metastases and those who had previously received docetaxel.

There were no significant differences in overall survival at the time of data cutoff. Overall survival data were not mature and will be reported at a later date.

Disease control rates, a composite of complete and partial responses and stable disease, were 73% with the combination and 55% with second hormonal therapy (P value not shown).
 

Safety Data

The safety analysis indicated that patients found the ARPI switch easier to tolerate than the combination.

Adverse events leading to dose reductions occurred in 40% of patients on the combination, vs 3% of patients on second hormonal therapy, and treatment-related adverse events leading to discontinuation occurred in 13% and 2%, respectively.

Grade 3 or 4 adverse events occurred in 48% of patients assigned to the combination vs. 23% of patients assigned to the ARPI switch.

In all, 8% of patients on the combination and 12% on second hormonal therapy died on study, but none of the deaths were deemed to be treatment related.­­

CONTACT-02 was sponsored by Exelixis in partnerships with Ipsen and Takeda.

Dr. Agarwal disclosed institutional research funding from Exelixis, Roche, Takeda, and others, and travel expenses from Pfizer. Dr. Chi disclosed honoraria, a consulting/advisory role and institutional research funding with Roche and others. Dr. Gao has served as a consultant or advisor to several companies, not including the sponsors of the study, and has served as principal investigator at his institution, which has received research funding from Exelixis, Takeda, and others.

Two drugs delivered in combination are better than one after the other for the first-line treatment of men with metastatic castration-resistant prostate cancer bearing homologous recombination-repair mutations.

That’s the conclusion of investigators in the phase 2 BRCAAway trial, which compared a combination of abiraterone (Zytiga) and prednisone plus olaparib (Lynparza) against sequential therapy with the same agents.

At the time of data cutoff, median progression-free survival (PFS), the primary endpoint, was 39 months for patients randomized to the combination, compared with 8.4 months for those assigned to abiraterone/prednisone, and 14 months for those assigned to olaparib monotherapy, reported Maha Hussain, MD, of the Robert H. Lurie Comprehensive Cancer Center in Chicago.

“In patients with metastatic castration-resistant prostate cancer [mCRPC] and BRCA1/2 or ATM alterations, abiraterone and prednisone plus olaparib was well tolerated and resulted in better progression-free survival and response rates vs. single-agent olaparib or abiraterone/prednisone,” she said in an oral abstract presentation at the ASCO Genitourinary Cancers Symposium.

Although the study allowed crossover between the single-agent arms at the time of progression, only a few patients made the switch. Nonetheless, in these patients the PFS with the frontline combination was superior to that of sequential therapy, she noted.
 

Study Rationale and Design

Germline or somatic mutations in genes encoding for homologous recombination-repair occur in about 20% of men with mCRPC. Olaparib, a PARP1 (poly-adp ribose polymerase-1) inhibitor, interacts with androgen signaling, and preclinical studies have shown that castration-resistant prostate tumor cells have increased PARP1 activity. In addition, PARP1 has been shown preclinically to synergize with androgen receptor pathway inhibitors (ARPIs) such as abiraterone, Dr. Hussain explained.

The BRCAAway trial was designed to test whether co-targeting the androgen receptor and PARP1 could result in higher and more durable responses than current frontline therapies in patients with mCRPC with DNA-damage response mutations.

Patients with mCRPC with no prior exposure to either a PARP1 inhibitor, androgen receptor inhibitor, or mCRPC-directed chemotherapy underwent next-generation sequencing and germline testing of tumor tissues, and those patients found to have inactivating BRCA1/2 and/or ATM alterations were randomized on a 1:1:1 basis to either abiraterone 1000 mg daily plus prednisone 5 mg twice daily (19 patients); olaparib 300 mg twice daily (21 patients); or to the combination (21 patients).

The primary endpoint was radiographic PFS according to RECIST 1.1 criteria, Prostate Cancer Working Group 3 criteria, clinical assessment, or death.

As noted, the median PFS was 8.4 months with abiraterone/prednisone, 14 months with olaparib, and 39 months with the combination.

Secondary endpoints also favored the combination therapy arm, with objective response rates of 22%, 14%, and 33%, respectively; PSA response rates of 61%, 67% and 95%; and undetectable PSA response rates of 17%, 14%, and 33%.

A total of 8 of 19 patients on abiraterone were crossed over to olaparib, and 8 of 21 initially assigned to olaparib were crossed over to abiraterone. In these patients the median PFS from crossover was 8.3 and 7.2 months, respectively. In each crossover group the median PFS from the time of randomization was 16 months.

There were no grade 4 adverse events or treatment-related deaths reported in any of the study arms, and “essentially when you look at the adverse events, they pretty much are consistent with what you would expect to see with these particular agents,” Dr. Hussain said.

“Overall the patients were tolerating the treatment well,” she added.
 

Practice Changing with Caveats

Kim N. Chi, MD, FRCPC, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant, said that the strengths of the study included an olaparib monotherapy arm — something that was missing from phase 3 trials — that provides insights into how PARP inhibitors perform in this population. He also applauded the inclusion of clinical assessment as a primary endpoint, noting that “this is what we do in routine practice, and therefore, the generalizability of the trial becomes more evident.”

The crossover design provides important information about whether an upfront combination or a sequential therapy approach is more effective, as well, he added.

He pointed out, however, that the trial was limited by small sample size and by its “horse race” design rather than as a comparison trial.

“So how does the BRCAAway trial change our practice? Despite the limitations, I think it does support an upfront PARP inhibitor-ARPI combination as firstline therapy for HRR gene-mutated metastatic CRPC. These data suggest synergy, and most importantly, there is no loss of opportunity [for more effective therapies]. However, the limitations of the trial will not end this debate today,” he said.

The trial was funded by AstraZeneca. Both Dr. Hussain and Dr. Chi disclosed honoraria, consulting/advising, and institutional research funding from AstraZeneca and others.

Two drugs delivered in combination are better than one after the other for the first-line treatment of men with metastatic castration-resistant prostate cancer bearing homologous recombination-repair mutations.

That’s the conclusion of investigators in the phase 2 BRCAAway trial, which compared a combination of abiraterone (Zytiga) and prednisone plus olaparib (Lynparza) against sequential therapy with the same agents.

At the time of data cutoff, median progression-free survival (PFS), the primary endpoint, was 39 months for patients randomized to the combination, compared with 8.4 months for those assigned to abiraterone/prednisone, and 14 months for those assigned to olaparib monotherapy, reported Maha Hussain, MD, of the Robert H. Lurie Comprehensive Cancer Center in Chicago.

“In patients with metastatic castration-resistant prostate cancer [mCRPC] and BRCA1/2 or ATM alterations, abiraterone and prednisone plus olaparib was well tolerated and resulted in better progression-free survival and response rates vs. single-agent olaparib or abiraterone/prednisone,” she said in an oral abstract presentation at the ASCO Genitourinary Cancers Symposium.

Although the study allowed crossover between the single-agent arms at the time of progression, only a few patients made the switch. Nonetheless, in these patients the PFS with the frontline combination was superior to that of sequential therapy, she noted.
 

Study Rationale and Design

Germline or somatic mutations in genes encoding for homologous recombination-repair occur in about 20% of men with mCRPC. Olaparib, a PARP1 (poly-adp ribose polymerase-1) inhibitor, interacts with androgen signaling, and preclinical studies have shown that castration-resistant prostate tumor cells have increased PARP1 activity. In addition, PARP1 has been shown preclinically to synergize with androgen receptor pathway inhibitors (ARPIs) such as abiraterone, Dr. Hussain explained.

The BRCAAway trial was designed to test whether co-targeting the androgen receptor and PARP1 could result in higher and more durable responses than current frontline therapies in patients with mCRPC with DNA-damage response mutations.

Patients with mCRPC with no prior exposure to either a PARP1 inhibitor, androgen receptor inhibitor, or mCRPC-directed chemotherapy underwent next-generation sequencing and germline testing of tumor tissues, and those patients found to have inactivating BRCA1/2 and/or ATM alterations were randomized on a 1:1:1 basis to either abiraterone 1000 mg daily plus prednisone 5 mg twice daily (19 patients); olaparib 300 mg twice daily (21 patients); or to the combination (21 patients).

The primary endpoint was radiographic PFS according to RECIST 1.1 criteria, Prostate Cancer Working Group 3 criteria, clinical assessment, or death.

As noted, the median PFS was 8.4 months with abiraterone/prednisone, 14 months with olaparib, and 39 months with the combination.

Secondary endpoints also favored the combination therapy arm, with objective response rates of 22%, 14%, and 33%, respectively; PSA response rates of 61%, 67% and 95%; and undetectable PSA response rates of 17%, 14%, and 33%.

A total of 8 of 19 patients on abiraterone were crossed over to olaparib, and 8 of 21 initially assigned to olaparib were crossed over to abiraterone. In these patients the median PFS from crossover was 8.3 and 7.2 months, respectively. In each crossover group the median PFS from the time of randomization was 16 months.

There were no grade 4 adverse events or treatment-related deaths reported in any of the study arms, and “essentially when you look at the adverse events, they pretty much are consistent with what you would expect to see with these particular agents,” Dr. Hussain said.

“Overall the patients were tolerating the treatment well,” she added.
 

Practice Changing with Caveats

Kim N. Chi, MD, FRCPC, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant, said that the strengths of the study included an olaparib monotherapy arm — something that was missing from phase 3 trials — that provides insights into how PARP inhibitors perform in this population. He also applauded the inclusion of clinical assessment as a primary endpoint, noting that “this is what we do in routine practice, and therefore, the generalizability of the trial becomes more evident.”

The crossover design provides important information about whether an upfront combination or a sequential therapy approach is more effective, as well, he added.

He pointed out, however, that the trial was limited by small sample size and by its “horse race” design rather than as a comparison trial.

“So how does the BRCAAway trial change our practice? Despite the limitations, I think it does support an upfront PARP inhibitor-ARPI combination as firstline therapy for HRR gene-mutated metastatic CRPC. These data suggest synergy, and most importantly, there is no loss of opportunity [for more effective therapies]. However, the limitations of the trial will not end this debate today,” he said.

The trial was funded by AstraZeneca. Both Dr. Hussain and Dr. Chi disclosed honoraria, consulting/advising, and institutional research funding from AstraZeneca and others.

Two drugs delivered in combination are better than one after the other for the first-line treatment of men with metastatic castration-resistant prostate cancer bearing homologous recombination-repair mutations.

That’s the conclusion of investigators in the phase 2 BRCAAway trial, which compared a combination of abiraterone (Zytiga) and prednisone plus olaparib (Lynparza) against sequential therapy with the same agents.

At the time of data cutoff, median progression-free survival (PFS), the primary endpoint, was 39 months for patients randomized to the combination, compared with 8.4 months for those assigned to abiraterone/prednisone, and 14 months for those assigned to olaparib monotherapy, reported Maha Hussain, MD, of the Robert H. Lurie Comprehensive Cancer Center in Chicago.

“In patients with metastatic castration-resistant prostate cancer [mCRPC] and BRCA1/2 or ATM alterations, abiraterone and prednisone plus olaparib was well tolerated and resulted in better progression-free survival and response rates vs. single-agent olaparib or abiraterone/prednisone,” she said in an oral abstract presentation at the ASCO Genitourinary Cancers Symposium.

Although the study allowed crossover between the single-agent arms at the time of progression, only a few patients made the switch. Nonetheless, in these patients the PFS with the frontline combination was superior to that of sequential therapy, she noted.
 

Study Rationale and Design

Germline or somatic mutations in genes encoding for homologous recombination-repair occur in about 20% of men with mCRPC. Olaparib, a PARP1 (poly-adp ribose polymerase-1) inhibitor, interacts with androgen signaling, and preclinical studies have shown that castration-resistant prostate tumor cells have increased PARP1 activity. In addition, PARP1 has been shown preclinically to synergize with androgen receptor pathway inhibitors (ARPIs) such as abiraterone, Dr. Hussain explained.

The BRCAAway trial was designed to test whether co-targeting the androgen receptor and PARP1 could result in higher and more durable responses than current frontline therapies in patients with mCRPC with DNA-damage response mutations.

Patients with mCRPC with no prior exposure to either a PARP1 inhibitor, androgen receptor inhibitor, or mCRPC-directed chemotherapy underwent next-generation sequencing and germline testing of tumor tissues, and those patients found to have inactivating BRCA1/2 and/or ATM alterations were randomized on a 1:1:1 basis to either abiraterone 1000 mg daily plus prednisone 5 mg twice daily (19 patients); olaparib 300 mg twice daily (21 patients); or to the combination (21 patients).

The primary endpoint was radiographic PFS according to RECIST 1.1 criteria, Prostate Cancer Working Group 3 criteria, clinical assessment, or death.

As noted, the median PFS was 8.4 months with abiraterone/prednisone, 14 months with olaparib, and 39 months with the combination.

Secondary endpoints also favored the combination therapy arm, with objective response rates of 22%, 14%, and 33%, respectively; PSA response rates of 61%, 67% and 95%; and undetectable PSA response rates of 17%, 14%, and 33%.

A total of 8 of 19 patients on abiraterone were crossed over to olaparib, and 8 of 21 initially assigned to olaparib were crossed over to abiraterone. In these patients the median PFS from crossover was 8.3 and 7.2 months, respectively. In each crossover group the median PFS from the time of randomization was 16 months.

There were no grade 4 adverse events or treatment-related deaths reported in any of the study arms, and “essentially when you look at the adverse events, they pretty much are consistent with what you would expect to see with these particular agents,” Dr. Hussain said.

“Overall the patients were tolerating the treatment well,” she added.
 

Practice Changing with Caveats

Kim N. Chi, MD, FRCPC, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant, said that the strengths of the study included an olaparib monotherapy arm — something that was missing from phase 3 trials — that provides insights into how PARP inhibitors perform in this population. He also applauded the inclusion of clinical assessment as a primary endpoint, noting that “this is what we do in routine practice, and therefore, the generalizability of the trial becomes more evident.”

The crossover design provides important information about whether an upfront combination or a sequential therapy approach is more effective, as well, he added.

He pointed out, however, that the trial was limited by small sample size and by its “horse race” design rather than as a comparison trial.

“So how does the BRCAAway trial change our practice? Despite the limitations, I think it does support an upfront PARP inhibitor-ARPI combination as firstline therapy for HRR gene-mutated metastatic CRPC. These data suggest synergy, and most importantly, there is no loss of opportunity [for more effective therapies]. However, the limitations of the trial will not end this debate today,” he said.

The trial was funded by AstraZeneca. Both Dr. Hussain and Dr. Chi disclosed honoraria, consulting/advising, and institutional research funding from AstraZeneca and others.