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Benralizumab hits target for eosinophilic granulomatosis with polyangiitis
(EGPA), based on data from 140 individuals.
The unpublished topline results of the phase 3 MANDARA study were shared in a press release from benralizumab’s manufacturer, AstraZeneca. More detailed findings are scheduled to be presented at a future medical meeting, according to the company.
EGPA, although rare, can damage multiple organs including the heart, lungs, gastrointestinal tract, skin, and nerves, and can be fatal if left untreated, but treatment options are limited, and mepolizumab, an anti-interleukin (IL)-5 monoclonal antibody, is the only currently approved treatment.
In the study, adults with EGPA were randomized to a single 30-mg subcutaneous injection of benralizumab or three separate 100-mg subcutaneous injections of mepolizumab once every 4 weeks. The primary endpoint was remission rates after 36 and 48 weeks of treatment. Remission was defined as a Birmingham Vasculitis Activity Score of 0 and use of 4 mg/day or less of oral corticosteroids.
At 36 weeks and 48 weeks, remission rates for benralizumab were noninferior to mepolizumab. According to Clinicaltrials.gov, the study is scheduled to last for 52 weeks to compare the remission rates with the two treatments, and collect data from an extension that allows each patient at least 1 year of treatment in an open-label format.
Benralizumab, also a monoclonal antibody, differs in action from mepolizumab by binding directly to the IL-5 receptor alpha on eosinophils.
“This trial demonstrates that a biologic medicine given in a single monthly injection could help patients achieve remission rates comparable to the current standard of care, adding to the importance of benralizumab as a potential treatment option for eosinophilic granulomatosis with polyangiitis,” Michael Wechsler, MD, principal investigator on the MANDARA study, said in the press release.
The safety and tolerability of benralizumab in the MANDARA study were consistent with drug’s known profile, according to the company.
Benralizumab is currently approved as an add-on maintenance treatment for severe eosinophilic asthma in the United States, the European Union, and Japan, among other countries, and for self-administration in the United States, the European Union, and other countries, according to the company.
Benralizumab also is in development for other eosinophilic diseases, including chronic obstructive pulmonary disease, chronic rhinosinusitis with nasal polyps, and hypereosinophilic syndrome, and received an Orphan Drug Designation from the U.S. Food and Drug Administration in 2018, according to the company.
(EGPA), based on data from 140 individuals.
The unpublished topline results of the phase 3 MANDARA study were shared in a press release from benralizumab’s manufacturer, AstraZeneca. More detailed findings are scheduled to be presented at a future medical meeting, according to the company.
EGPA, although rare, can damage multiple organs including the heart, lungs, gastrointestinal tract, skin, and nerves, and can be fatal if left untreated, but treatment options are limited, and mepolizumab, an anti-interleukin (IL)-5 monoclonal antibody, is the only currently approved treatment.
In the study, adults with EGPA were randomized to a single 30-mg subcutaneous injection of benralizumab or three separate 100-mg subcutaneous injections of mepolizumab once every 4 weeks. The primary endpoint was remission rates after 36 and 48 weeks of treatment. Remission was defined as a Birmingham Vasculitis Activity Score of 0 and use of 4 mg/day or less of oral corticosteroids.
At 36 weeks and 48 weeks, remission rates for benralizumab were noninferior to mepolizumab. According to Clinicaltrials.gov, the study is scheduled to last for 52 weeks to compare the remission rates with the two treatments, and collect data from an extension that allows each patient at least 1 year of treatment in an open-label format.
Benralizumab, also a monoclonal antibody, differs in action from mepolizumab by binding directly to the IL-5 receptor alpha on eosinophils.
“This trial demonstrates that a biologic medicine given in a single monthly injection could help patients achieve remission rates comparable to the current standard of care, adding to the importance of benralizumab as a potential treatment option for eosinophilic granulomatosis with polyangiitis,” Michael Wechsler, MD, principal investigator on the MANDARA study, said in the press release.
The safety and tolerability of benralizumab in the MANDARA study were consistent with drug’s known profile, according to the company.
Benralizumab is currently approved as an add-on maintenance treatment for severe eosinophilic asthma in the United States, the European Union, and Japan, among other countries, and for self-administration in the United States, the European Union, and other countries, according to the company.
Benralizumab also is in development for other eosinophilic diseases, including chronic obstructive pulmonary disease, chronic rhinosinusitis with nasal polyps, and hypereosinophilic syndrome, and received an Orphan Drug Designation from the U.S. Food and Drug Administration in 2018, according to the company.
(EGPA), based on data from 140 individuals.
The unpublished topline results of the phase 3 MANDARA study were shared in a press release from benralizumab’s manufacturer, AstraZeneca. More detailed findings are scheduled to be presented at a future medical meeting, according to the company.
EGPA, although rare, can damage multiple organs including the heart, lungs, gastrointestinal tract, skin, and nerves, and can be fatal if left untreated, but treatment options are limited, and mepolizumab, an anti-interleukin (IL)-5 monoclonal antibody, is the only currently approved treatment.
In the study, adults with EGPA were randomized to a single 30-mg subcutaneous injection of benralizumab or three separate 100-mg subcutaneous injections of mepolizumab once every 4 weeks. The primary endpoint was remission rates after 36 and 48 weeks of treatment. Remission was defined as a Birmingham Vasculitis Activity Score of 0 and use of 4 mg/day or less of oral corticosteroids.
At 36 weeks and 48 weeks, remission rates for benralizumab were noninferior to mepolizumab. According to Clinicaltrials.gov, the study is scheduled to last for 52 weeks to compare the remission rates with the two treatments, and collect data from an extension that allows each patient at least 1 year of treatment in an open-label format.
Benralizumab, also a monoclonal antibody, differs in action from mepolizumab by binding directly to the IL-5 receptor alpha on eosinophils.
“This trial demonstrates that a biologic medicine given in a single monthly injection could help patients achieve remission rates comparable to the current standard of care, adding to the importance of benralizumab as a potential treatment option for eosinophilic granulomatosis with polyangiitis,” Michael Wechsler, MD, principal investigator on the MANDARA study, said in the press release.
The safety and tolerability of benralizumab in the MANDARA study were consistent with drug’s known profile, according to the company.
Benralizumab is currently approved as an add-on maintenance treatment for severe eosinophilic asthma in the United States, the European Union, and Japan, among other countries, and for self-administration in the United States, the European Union, and other countries, according to the company.
Benralizumab also is in development for other eosinophilic diseases, including chronic obstructive pulmonary disease, chronic rhinosinusitis with nasal polyps, and hypereosinophilic syndrome, and received an Orphan Drug Designation from the U.S. Food and Drug Administration in 2018, according to the company.
Disenfranchised grief: What it looks like, where it goes
What happens to grief when those around you don’t understand it? Where does it go? How do you process it?
Disenfranchised grief, when someone or society more generally doesn’t see a loss as worthy of mourning, can deprive people of experiencing or processing their sadness. This grief, which may be triggered by the death of an ex-spouse, a pet, a failed adoption, can be painful and long-lasting.
Suzanne Cole, MD: ‘I didn’t feel the right to grieve’
During the COVID-19 pandemic, my little sister unexpectedly died. Though she was not one of the nearly 7 million people who died of the virus, in 2021 she became another type of statistic: one of the 109,699 people in the United State who died from a drug overdose. Hers was from fentanyl laced with methamphetamines.
Her death unraveled me. I felt deep guilt that I could not pull her from the sweeping current that had wrenched her from mainstream society into the underbelly of sex work and toward the solace of mind-altering drugs.
But I did not feel the right to grieve for her as I have grieved for other loved ones who were not blamed for their exit from this world. My sister was living a sordid life on the fringes of society. My grief felt invalid, undeserved. Yet, in the eyes of other “upstanding citizens,” her life was not as worth grieving – or so I thought. I tucked my sorrow into a small corner of my soul so no one would see, and I carried on.
To this day, the shame I feel robbed me of the ability to freely talk about her or share the searing pain I feel. Tears still prick my eyes when I think of her, but I have become adept at swallowing them, shaking off the waves of grief as though nothing happened. Even now, I cannot shake the pervasive feeling that my silent tears don’t deserve to be wept.
Don S. Dizon, MD: Working through tragedy
As a medical student, I worked with an outpatient physician as part of a third-year rotation. When we met, the first thing that struck me was how disheveled he looked. His clothes were wrinkled, and his pants were baggy. He took cigarette breaks, which I found disturbing.
But I quickly came to admire him. Despite my first impression, he was the type of doctor I aspired to be. He didn’t need to look at a patient’s chart to recall who they were. He just knew them. He greeted patients warmly, asked about their family. He even remembered the special occasions his patients had mentioned since their past visit. He epitomized empathy and connectedness.
Spending one day in clinic brought to light the challenges of forming such bonds with patients. A man came into the cancer clinic reporting chest pain and was triaged to an exam room. Soon after, the patient was found unresponsive on the floor. Nurses were yelling for help, and the doctor ran in and started CPR while minutes ticked by waiting for an ambulance that could take him to the ED.
By the time help arrived, the patient was blue.
He had died in the clinic in the middle of the day, as the waiting room filled. After the body was taken away, the doctor went into the bathroom. About 20 minutes later, he came out, eyes bloodshot, and continued with the rest of his day, ensuring each patient was seen and cared for.
As a medical student, it hit me how hard it must be to see something so tragic like the end of a life and then continue with your day as if nothing had happened. This is an experience of grief I later came to know well after nearly 30 years treating patients with advanced cancers: compartmentalizing it and carrying on.
A space for grieving: The Schwartz Center Rounds
Disenfranchised grief, the grief that is hard to share and often seems wrong to feel in the first place, can be triggered in many situations. Losing a person others don’t believe deserve to be grieved, such as an abusive partner or someone who committed a crime; losing someone you cared for in a professional role; a loss experienced in a breakup or same-sex partnership, if that relationship was not accepted by one’s family; loss from infertility, miscarriage, stillbirth, or failed adoption; loss that may be taboo or stigmatized, such as deaths via suicide or abortion; and loss of a job, home, or possession that you treasure.
Many of us have had similar situations or will, and the feeling that no one understands the need to mourn can be paralyzing and alienating. In the early days, intense, crushing feelings can cause intrusive, distracting thoughts, and over time, that grief can linger and find a permanent place in our minds.
More and more, though, we are being given opportunities to reflect on these sad moments.
The Schwartz Rounds are an example of such an opportunity. In these rounds, we gather to talk about the experience of caring for people, not the science of medicine.
During one particularly powerful rounds, I spoke to my colleagues about my initial meeting with a patient who was very sick. I detailed the experience of telling her children and her at that initial consult how I thought she was dying and that I did not recommend therapy. I remember how they cried. And I remembered how powerless I felt.
As I recalled that memory during Schwartz Rounds, I could not stop from crying. The unfairness of being a physician meeting someone for the first time and having to tell them such bad news overwhelmed me.
Even more poignant, I had the chance to reconnect with this woman’s children, who were present that day, not as audience members but as participants. Their presence may have brought my emotions to the surface more strongly. In that moment, I could show them the feelings I had bottled up for the sake of professionalism. Ultimately, I felt relieved, freer somehow, as if this burden my soul was carrying had been lifted.
Although we are both grateful for forums like this, these opportunities to share and express the grief we may have hidden away are not as common as they should be.
As physicians, we may express grief by shedding tears at the bedside of a patient nearing the end of life or through the anxiety we feel when our patient suffers a severe reaction to treatment. But we tend to put it away, to go on with our day, because there are others to be seen and cared for and more work to be done. Somehow, we move forward, shedding tears in one room and celebrating victories in another.
We need to create more spaces to express and feel grief, so we don’t get lost in it. Because understanding how grief impacts us, as people and as providers, is one of the most important realizations we can make as we go about our time-honored profession as healers.
Dr. Dizon is the director of women’s cancers at Lifespan Cancer Institute, director of medical oncology at Rhode Island Hospital, and a professor of medicine at Brown University, all in Providence. He reported conflicts of interest with Regeneron, AstraZeneca, Clovis, Bristol-Myers Squibb, and Kazia.
A version of this article first appeared on Medscape.com.
What happens to grief when those around you don’t understand it? Where does it go? How do you process it?
Disenfranchised grief, when someone or society more generally doesn’t see a loss as worthy of mourning, can deprive people of experiencing or processing their sadness. This grief, which may be triggered by the death of an ex-spouse, a pet, a failed adoption, can be painful and long-lasting.
Suzanne Cole, MD: ‘I didn’t feel the right to grieve’
During the COVID-19 pandemic, my little sister unexpectedly died. Though she was not one of the nearly 7 million people who died of the virus, in 2021 she became another type of statistic: one of the 109,699 people in the United State who died from a drug overdose. Hers was from fentanyl laced with methamphetamines.
Her death unraveled me. I felt deep guilt that I could not pull her from the sweeping current that had wrenched her from mainstream society into the underbelly of sex work and toward the solace of mind-altering drugs.
But I did not feel the right to grieve for her as I have grieved for other loved ones who were not blamed for their exit from this world. My sister was living a sordid life on the fringes of society. My grief felt invalid, undeserved. Yet, in the eyes of other “upstanding citizens,” her life was not as worth grieving – or so I thought. I tucked my sorrow into a small corner of my soul so no one would see, and I carried on.
To this day, the shame I feel robbed me of the ability to freely talk about her or share the searing pain I feel. Tears still prick my eyes when I think of her, but I have become adept at swallowing them, shaking off the waves of grief as though nothing happened. Even now, I cannot shake the pervasive feeling that my silent tears don’t deserve to be wept.
Don S. Dizon, MD: Working through tragedy
As a medical student, I worked with an outpatient physician as part of a third-year rotation. When we met, the first thing that struck me was how disheveled he looked. His clothes were wrinkled, and his pants were baggy. He took cigarette breaks, which I found disturbing.
But I quickly came to admire him. Despite my first impression, he was the type of doctor I aspired to be. He didn’t need to look at a patient’s chart to recall who they were. He just knew them. He greeted patients warmly, asked about their family. He even remembered the special occasions his patients had mentioned since their past visit. He epitomized empathy and connectedness.
Spending one day in clinic brought to light the challenges of forming such bonds with patients. A man came into the cancer clinic reporting chest pain and was triaged to an exam room. Soon after, the patient was found unresponsive on the floor. Nurses were yelling for help, and the doctor ran in and started CPR while minutes ticked by waiting for an ambulance that could take him to the ED.
By the time help arrived, the patient was blue.
He had died in the clinic in the middle of the day, as the waiting room filled. After the body was taken away, the doctor went into the bathroom. About 20 minutes later, he came out, eyes bloodshot, and continued with the rest of his day, ensuring each patient was seen and cared for.
As a medical student, it hit me how hard it must be to see something so tragic like the end of a life and then continue with your day as if nothing had happened. This is an experience of grief I later came to know well after nearly 30 years treating patients with advanced cancers: compartmentalizing it and carrying on.
A space for grieving: The Schwartz Center Rounds
Disenfranchised grief, the grief that is hard to share and often seems wrong to feel in the first place, can be triggered in many situations. Losing a person others don’t believe deserve to be grieved, such as an abusive partner or someone who committed a crime; losing someone you cared for in a professional role; a loss experienced in a breakup or same-sex partnership, if that relationship was not accepted by one’s family; loss from infertility, miscarriage, stillbirth, or failed adoption; loss that may be taboo or stigmatized, such as deaths via suicide or abortion; and loss of a job, home, or possession that you treasure.
Many of us have had similar situations or will, and the feeling that no one understands the need to mourn can be paralyzing and alienating. In the early days, intense, crushing feelings can cause intrusive, distracting thoughts, and over time, that grief can linger and find a permanent place in our minds.
More and more, though, we are being given opportunities to reflect on these sad moments.
The Schwartz Rounds are an example of such an opportunity. In these rounds, we gather to talk about the experience of caring for people, not the science of medicine.
During one particularly powerful rounds, I spoke to my colleagues about my initial meeting with a patient who was very sick. I detailed the experience of telling her children and her at that initial consult how I thought she was dying and that I did not recommend therapy. I remember how they cried. And I remembered how powerless I felt.
As I recalled that memory during Schwartz Rounds, I could not stop from crying. The unfairness of being a physician meeting someone for the first time and having to tell them such bad news overwhelmed me.
Even more poignant, I had the chance to reconnect with this woman’s children, who were present that day, not as audience members but as participants. Their presence may have brought my emotions to the surface more strongly. In that moment, I could show them the feelings I had bottled up for the sake of professionalism. Ultimately, I felt relieved, freer somehow, as if this burden my soul was carrying had been lifted.
Although we are both grateful for forums like this, these opportunities to share and express the grief we may have hidden away are not as common as they should be.
As physicians, we may express grief by shedding tears at the bedside of a patient nearing the end of life or through the anxiety we feel when our patient suffers a severe reaction to treatment. But we tend to put it away, to go on with our day, because there are others to be seen and cared for and more work to be done. Somehow, we move forward, shedding tears in one room and celebrating victories in another.
We need to create more spaces to express and feel grief, so we don’t get lost in it. Because understanding how grief impacts us, as people and as providers, is one of the most important realizations we can make as we go about our time-honored profession as healers.
Dr. Dizon is the director of women’s cancers at Lifespan Cancer Institute, director of medical oncology at Rhode Island Hospital, and a professor of medicine at Brown University, all in Providence. He reported conflicts of interest with Regeneron, AstraZeneca, Clovis, Bristol-Myers Squibb, and Kazia.
A version of this article first appeared on Medscape.com.
What happens to grief when those around you don’t understand it? Where does it go? How do you process it?
Disenfranchised grief, when someone or society more generally doesn’t see a loss as worthy of mourning, can deprive people of experiencing or processing their sadness. This grief, which may be triggered by the death of an ex-spouse, a pet, a failed adoption, can be painful and long-lasting.
Suzanne Cole, MD: ‘I didn’t feel the right to grieve’
During the COVID-19 pandemic, my little sister unexpectedly died. Though she was not one of the nearly 7 million people who died of the virus, in 2021 she became another type of statistic: one of the 109,699 people in the United State who died from a drug overdose. Hers was from fentanyl laced with methamphetamines.
Her death unraveled me. I felt deep guilt that I could not pull her from the sweeping current that had wrenched her from mainstream society into the underbelly of sex work and toward the solace of mind-altering drugs.
But I did not feel the right to grieve for her as I have grieved for other loved ones who were not blamed for their exit from this world. My sister was living a sordid life on the fringes of society. My grief felt invalid, undeserved. Yet, in the eyes of other “upstanding citizens,” her life was not as worth grieving – or so I thought. I tucked my sorrow into a small corner of my soul so no one would see, and I carried on.
To this day, the shame I feel robbed me of the ability to freely talk about her or share the searing pain I feel. Tears still prick my eyes when I think of her, but I have become adept at swallowing them, shaking off the waves of grief as though nothing happened. Even now, I cannot shake the pervasive feeling that my silent tears don’t deserve to be wept.
Don S. Dizon, MD: Working through tragedy
As a medical student, I worked with an outpatient physician as part of a third-year rotation. When we met, the first thing that struck me was how disheveled he looked. His clothes were wrinkled, and his pants were baggy. He took cigarette breaks, which I found disturbing.
But I quickly came to admire him. Despite my first impression, he was the type of doctor I aspired to be. He didn’t need to look at a patient’s chart to recall who they were. He just knew them. He greeted patients warmly, asked about their family. He even remembered the special occasions his patients had mentioned since their past visit. He epitomized empathy and connectedness.
Spending one day in clinic brought to light the challenges of forming such bonds with patients. A man came into the cancer clinic reporting chest pain and was triaged to an exam room. Soon after, the patient was found unresponsive on the floor. Nurses were yelling for help, and the doctor ran in and started CPR while minutes ticked by waiting for an ambulance that could take him to the ED.
By the time help arrived, the patient was blue.
He had died in the clinic in the middle of the day, as the waiting room filled. After the body was taken away, the doctor went into the bathroom. About 20 minutes later, he came out, eyes bloodshot, and continued with the rest of his day, ensuring each patient was seen and cared for.
As a medical student, it hit me how hard it must be to see something so tragic like the end of a life and then continue with your day as if nothing had happened. This is an experience of grief I later came to know well after nearly 30 years treating patients with advanced cancers: compartmentalizing it and carrying on.
A space for grieving: The Schwartz Center Rounds
Disenfranchised grief, the grief that is hard to share and often seems wrong to feel in the first place, can be triggered in many situations. Losing a person others don’t believe deserve to be grieved, such as an abusive partner or someone who committed a crime; losing someone you cared for in a professional role; a loss experienced in a breakup or same-sex partnership, if that relationship was not accepted by one’s family; loss from infertility, miscarriage, stillbirth, or failed adoption; loss that may be taboo or stigmatized, such as deaths via suicide or abortion; and loss of a job, home, or possession that you treasure.
Many of us have had similar situations or will, and the feeling that no one understands the need to mourn can be paralyzing and alienating. In the early days, intense, crushing feelings can cause intrusive, distracting thoughts, and over time, that grief can linger and find a permanent place in our minds.
More and more, though, we are being given opportunities to reflect on these sad moments.
The Schwartz Rounds are an example of such an opportunity. In these rounds, we gather to talk about the experience of caring for people, not the science of medicine.
During one particularly powerful rounds, I spoke to my colleagues about my initial meeting with a patient who was very sick. I detailed the experience of telling her children and her at that initial consult how I thought she was dying and that I did not recommend therapy. I remember how they cried. And I remembered how powerless I felt.
As I recalled that memory during Schwartz Rounds, I could not stop from crying. The unfairness of being a physician meeting someone for the first time and having to tell them such bad news overwhelmed me.
Even more poignant, I had the chance to reconnect with this woman’s children, who were present that day, not as audience members but as participants. Their presence may have brought my emotions to the surface more strongly. In that moment, I could show them the feelings I had bottled up for the sake of professionalism. Ultimately, I felt relieved, freer somehow, as if this burden my soul was carrying had been lifted.
Although we are both grateful for forums like this, these opportunities to share and express the grief we may have hidden away are not as common as they should be.
As physicians, we may express grief by shedding tears at the bedside of a patient nearing the end of life or through the anxiety we feel when our patient suffers a severe reaction to treatment. But we tend to put it away, to go on with our day, because there are others to be seen and cared for and more work to be done. Somehow, we move forward, shedding tears in one room and celebrating victories in another.
We need to create more spaces to express and feel grief, so we don’t get lost in it. Because understanding how grief impacts us, as people and as providers, is one of the most important realizations we can make as we go about our time-honored profession as healers.
Dr. Dizon is the director of women’s cancers at Lifespan Cancer Institute, director of medical oncology at Rhode Island Hospital, and a professor of medicine at Brown University, all in Providence. He reported conflicts of interest with Regeneron, AstraZeneca, Clovis, Bristol-Myers Squibb, and Kazia.
A version of this article first appeared on Medscape.com.
Sedentary lifestyle tied to increased dementia risk
The study of nearly 50,000 adults in the UK Biobank shows that dementia risk increased 8% with 10 hours of sedentary time and 63% with 12 hours. That’s particularly concerning because Americans spend an average of 9.5 hours a day sitting.
Sleep wasn’t factored into the sedentary time and how someone accumulated the 10 hours – either in one continuous block or broken up throughout the day – was irrelevant.
“Our analysis cannot determine whether there is a causal link, so prescriptive conclusions are not really possible; however. I think it is very reasonable to conclude that sitting less and moving more may help reduce risk of dementia,” lead investigator David Raichlen, PhD, professor of biological sciences and anthropology, University of Southern California, Los Angeles, said in an interview.
The findings were published online in JAMA.
A surprising find?
The study is a retrospective analysis of prospectively collected data from the UK Biobank of 49,841 adults aged 60 years or older who wore an accelerometer on their wrists 24 hours a day for a week. Participants had no history of dementia when they wore the movement monitoring device.
Investigators used machine-based learning to determine sedentary time based on readings from the accelerometers. Sleep was not included as sedentary behavior.
Over a mean follow-up of 6.72 years, 414 participants were diagnosed with dementia.
Investigators found that dementia risk rises by 8% at 10 hours a day (adjusted hazard ratio, 1.08; P < .001) and 63% at 12 hours a day (aHR, 1.63; P < .001), compared with 9.27 hours a day. Those who logged 15 hours of sedentary behavior a day had more than triple the dementia risk (aHR, 3.21; P < .001).
Although previous studies had found that breaking up sedentary periods with short bursts of activity help offset some negative health effects of sitting, that wasn’t the case here. Dementia risk was elevated whether participants were sedentary for 10 uninterrupted hours or multiple sedentary periods that totaled 10 hours over the whole day.
“This was surprising,” Dr. Raichlen said. “We expected to find that patterns of sedentary behavior would play a role in risk of dementia, but once you take into account the daily volume of time spent sedentary, how you get there doesn’t seem to matter as much.”
The study did not examine how participants spent sedentary time, but an earlier study by Dr. Raichlen found that watching TV was associated with a greater risk of dementia in older adults, compared with working on a computer.
More research welcome
Dr. Raichlen noted that the number of dementia cases in the study is low and that the view of sedentary behavior is based on 1 week of accelerometer readings. A longitudinal study is needed to determine if the findings last over a longer time period.
In a comment, Claire Sexton, DPhil, senior director of scientific programs and outreach for the Alzheimer’s Association, says that earlier studies reported an association between sedentary time and dementia, so these results aren’t “particularly surprising.”
“However, reports that did not find an association have also been published, so additional research on possible associations is welcome,” she said.
It’s also important to note that this observational study doesn’t establish a causal relationship between inactivity and cognitive function, which Dr. Sexton said means the influence of other dementia risk factors that are also exacerbated by sedentary behavior can’t be ruled out.
“Although results remained significant after adjusting for several of these factors, further research is required to better understand the various elements that may influence the observed relationship,” noted Dr. Sexton, who was not part of the study. “Reverse causality – that changes in the brain related to dementia are causing the sedentary behavior – cannot be ruled out.”
The study was funded by the National Institutes of Health, the state of Arizona, the Arizona Department of Health Services, and the McKnight Brain Research Foundation. Dr. Raichlen and Dr. Sexton report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The study of nearly 50,000 adults in the UK Biobank shows that dementia risk increased 8% with 10 hours of sedentary time and 63% with 12 hours. That’s particularly concerning because Americans spend an average of 9.5 hours a day sitting.
Sleep wasn’t factored into the sedentary time and how someone accumulated the 10 hours – either in one continuous block or broken up throughout the day – was irrelevant.
“Our analysis cannot determine whether there is a causal link, so prescriptive conclusions are not really possible; however. I think it is very reasonable to conclude that sitting less and moving more may help reduce risk of dementia,” lead investigator David Raichlen, PhD, professor of biological sciences and anthropology, University of Southern California, Los Angeles, said in an interview.
The findings were published online in JAMA.
A surprising find?
The study is a retrospective analysis of prospectively collected data from the UK Biobank of 49,841 adults aged 60 years or older who wore an accelerometer on their wrists 24 hours a day for a week. Participants had no history of dementia when they wore the movement monitoring device.
Investigators used machine-based learning to determine sedentary time based on readings from the accelerometers. Sleep was not included as sedentary behavior.
Over a mean follow-up of 6.72 years, 414 participants were diagnosed with dementia.
Investigators found that dementia risk rises by 8% at 10 hours a day (adjusted hazard ratio, 1.08; P < .001) and 63% at 12 hours a day (aHR, 1.63; P < .001), compared with 9.27 hours a day. Those who logged 15 hours of sedentary behavior a day had more than triple the dementia risk (aHR, 3.21; P < .001).
Although previous studies had found that breaking up sedentary periods with short bursts of activity help offset some negative health effects of sitting, that wasn’t the case here. Dementia risk was elevated whether participants were sedentary for 10 uninterrupted hours or multiple sedentary periods that totaled 10 hours over the whole day.
“This was surprising,” Dr. Raichlen said. “We expected to find that patterns of sedentary behavior would play a role in risk of dementia, but once you take into account the daily volume of time spent sedentary, how you get there doesn’t seem to matter as much.”
The study did not examine how participants spent sedentary time, but an earlier study by Dr. Raichlen found that watching TV was associated with a greater risk of dementia in older adults, compared with working on a computer.
More research welcome
Dr. Raichlen noted that the number of dementia cases in the study is low and that the view of sedentary behavior is based on 1 week of accelerometer readings. A longitudinal study is needed to determine if the findings last over a longer time period.
In a comment, Claire Sexton, DPhil, senior director of scientific programs and outreach for the Alzheimer’s Association, says that earlier studies reported an association between sedentary time and dementia, so these results aren’t “particularly surprising.”
“However, reports that did not find an association have also been published, so additional research on possible associations is welcome,” she said.
It’s also important to note that this observational study doesn’t establish a causal relationship between inactivity and cognitive function, which Dr. Sexton said means the influence of other dementia risk factors that are also exacerbated by sedentary behavior can’t be ruled out.
“Although results remained significant after adjusting for several of these factors, further research is required to better understand the various elements that may influence the observed relationship,” noted Dr. Sexton, who was not part of the study. “Reverse causality – that changes in the brain related to dementia are causing the sedentary behavior – cannot be ruled out.”
The study was funded by the National Institutes of Health, the state of Arizona, the Arizona Department of Health Services, and the McKnight Brain Research Foundation. Dr. Raichlen and Dr. Sexton report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The study of nearly 50,000 adults in the UK Biobank shows that dementia risk increased 8% with 10 hours of sedentary time and 63% with 12 hours. That’s particularly concerning because Americans spend an average of 9.5 hours a day sitting.
Sleep wasn’t factored into the sedentary time and how someone accumulated the 10 hours – either in one continuous block or broken up throughout the day – was irrelevant.
“Our analysis cannot determine whether there is a causal link, so prescriptive conclusions are not really possible; however. I think it is very reasonable to conclude that sitting less and moving more may help reduce risk of dementia,” lead investigator David Raichlen, PhD, professor of biological sciences and anthropology, University of Southern California, Los Angeles, said in an interview.
The findings were published online in JAMA.
A surprising find?
The study is a retrospective analysis of prospectively collected data from the UK Biobank of 49,841 adults aged 60 years or older who wore an accelerometer on their wrists 24 hours a day for a week. Participants had no history of dementia when they wore the movement monitoring device.
Investigators used machine-based learning to determine sedentary time based on readings from the accelerometers. Sleep was not included as sedentary behavior.
Over a mean follow-up of 6.72 years, 414 participants were diagnosed with dementia.
Investigators found that dementia risk rises by 8% at 10 hours a day (adjusted hazard ratio, 1.08; P < .001) and 63% at 12 hours a day (aHR, 1.63; P < .001), compared with 9.27 hours a day. Those who logged 15 hours of sedentary behavior a day had more than triple the dementia risk (aHR, 3.21; P < .001).
Although previous studies had found that breaking up sedentary periods with short bursts of activity help offset some negative health effects of sitting, that wasn’t the case here. Dementia risk was elevated whether participants were sedentary for 10 uninterrupted hours or multiple sedentary periods that totaled 10 hours over the whole day.
“This was surprising,” Dr. Raichlen said. “We expected to find that patterns of sedentary behavior would play a role in risk of dementia, but once you take into account the daily volume of time spent sedentary, how you get there doesn’t seem to matter as much.”
The study did not examine how participants spent sedentary time, but an earlier study by Dr. Raichlen found that watching TV was associated with a greater risk of dementia in older adults, compared with working on a computer.
More research welcome
Dr. Raichlen noted that the number of dementia cases in the study is low and that the view of sedentary behavior is based on 1 week of accelerometer readings. A longitudinal study is needed to determine if the findings last over a longer time period.
In a comment, Claire Sexton, DPhil, senior director of scientific programs and outreach for the Alzheimer’s Association, says that earlier studies reported an association between sedentary time and dementia, so these results aren’t “particularly surprising.”
“However, reports that did not find an association have also been published, so additional research on possible associations is welcome,” she said.
It’s also important to note that this observational study doesn’t establish a causal relationship between inactivity and cognitive function, which Dr. Sexton said means the influence of other dementia risk factors that are also exacerbated by sedentary behavior can’t be ruled out.
“Although results remained significant after adjusting for several of these factors, further research is required to better understand the various elements that may influence the observed relationship,” noted Dr. Sexton, who was not part of the study. “Reverse causality – that changes in the brain related to dementia are causing the sedentary behavior – cannot be ruled out.”
The study was funded by the National Institutes of Health, the state of Arizona, the Arizona Department of Health Services, and the McKnight Brain Research Foundation. Dr. Raichlen and Dr. Sexton report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA
Service dogs help veterans with PTSD lead better lives
When Ryan (not his real name), 37, returned home from two deployments with the 101st Airborne Division in Iraq from 2005 to 2008, he began withdrawing from social situations and experienced chronic anxiety. Nights brought no respite – his sleep was interrupted by punishing nightmares.
“I had every calling card of a veteran in distress,” he said in an interview. When his wife told him she thought he may have posttraumatic stress disorder (PTSD), he shrugged it off. “I wasn’t automatically going to accept [the diagnosis] because as an infantry veteran, we’re big tough guys. We don’t need help with anything.”
The dogs, mostly recruited from rescue organizations, receive 5-7 months of specialized training to assist the veterans.
Life-changing help
While Ryan was skeptical about the program and whether it would work for him, he agreed to try it. After working with Bullet, a cream-colored golden retriever, he realized his life was improving.
“I stopped self-medicating, started advocating for myself, and became more comfortable socializing in public.” In his 3 years with Bullet, Ryan was able to work on his marriage, advance his career, and become a homeowner.
“The dreams I never thought were attainable started coming to fruition, and I was happy and comfortable for the first time in as long as I could remember.”
Unfortunately, Bullet died from a rare heart condition after a few years, and when that happened, NWBB immediately began working with Ryan to find him a new dog to fill the void left by Bullet.
Soon, Ryan began working with Twitch, who, like Bullet, knew when Ryan was becoming anxious, angry, or depressed before he did, he said.
“These dogs pick up on PTSD symptoms and come over and press themselves against you, push their faces into yours, and give you those big puppy dog eyes as if to say, ‘I got you. Everything is going to be okay.’ ”
The same thing happened when Ryan had night terrors and nightmares. “These dogs wake you up, and again, you’re greeted with this sweet puppy dog face.”
NWBB founder and CEO Shannon Walker, who has been training dogs for 25 years and whose father served in the U.S. Air Force in the 1950s, leads a 5-week training course for the veterans and their “battle buddies” so that the veterans can learn how to bond with and benefit from their new service dogs.
Finding the perfect match
Veterans are paired with trained service dogs based on their lifestyle and personality. For instance, a Vietnam veteran who is having trouble walking may be paired with a calm dog while a younger veteran who runs each morning is paired with a more active dog.
NWBB operates on funds from private donors and nonprofit organizations that make it financially feasible for the veterans to travel to Washington State and stay for the time required to train with their service dogs.
“Our service dogs are there in the midnight hour when no one else is,” she said. “Our veterans are fighting internal battles that no one else sees but the dogs. The dogs alert on their adrenaline and bring them back to the moment of now, interrupting suicidal ideations, panic attacks, and night terrors.”
Joshua Morganstein, MD, chair of the American Psychiatric Association’s Committee on the Psychiatric Dimensions of Disaster, said in an interview that “PTSD can be devastating for service members and veterans and is often associated with comorbid mental health conditions, such as anxiety and substance use.”
He noted that for many people, dogs and other animals can be an important source of physical, emotional, and psychological comfort.
“Programs like the Northwest Battle Buddies are important for us to study and better understand the extent to which trained animals are able to help alleviate the symptoms of PTSD and associated disorders and, perhaps most importantly, enhance the ability of service members and veterans to function and live in ways that feel healthy and productive to them,” said Dr. Morganstein.
He added that the concept of a “battle buddy” is a term pioneered by the U.S. Army in 2002 and describes a “formal, rather than ad hoc, system of peer support in which service members are assigned buddies.
“Buddies look out for each other, encourage self-care and self-advocacy and, when needed, help their buddy to seek help. Buddies remind us that someone is looking out for us and there is someone we look out for as well, both of which are protective during difficult times,” he said.
A version of this article first appeared on Medscape.com.
When Ryan (not his real name), 37, returned home from two deployments with the 101st Airborne Division in Iraq from 2005 to 2008, he began withdrawing from social situations and experienced chronic anxiety. Nights brought no respite – his sleep was interrupted by punishing nightmares.
“I had every calling card of a veteran in distress,” he said in an interview. When his wife told him she thought he may have posttraumatic stress disorder (PTSD), he shrugged it off. “I wasn’t automatically going to accept [the diagnosis] because as an infantry veteran, we’re big tough guys. We don’t need help with anything.”
The dogs, mostly recruited from rescue organizations, receive 5-7 months of specialized training to assist the veterans.
Life-changing help
While Ryan was skeptical about the program and whether it would work for him, he agreed to try it. After working with Bullet, a cream-colored golden retriever, he realized his life was improving.
“I stopped self-medicating, started advocating for myself, and became more comfortable socializing in public.” In his 3 years with Bullet, Ryan was able to work on his marriage, advance his career, and become a homeowner.
“The dreams I never thought were attainable started coming to fruition, and I was happy and comfortable for the first time in as long as I could remember.”
Unfortunately, Bullet died from a rare heart condition after a few years, and when that happened, NWBB immediately began working with Ryan to find him a new dog to fill the void left by Bullet.
Soon, Ryan began working with Twitch, who, like Bullet, knew when Ryan was becoming anxious, angry, or depressed before he did, he said.
“These dogs pick up on PTSD symptoms and come over and press themselves against you, push their faces into yours, and give you those big puppy dog eyes as if to say, ‘I got you. Everything is going to be okay.’ ”
The same thing happened when Ryan had night terrors and nightmares. “These dogs wake you up, and again, you’re greeted with this sweet puppy dog face.”
NWBB founder and CEO Shannon Walker, who has been training dogs for 25 years and whose father served in the U.S. Air Force in the 1950s, leads a 5-week training course for the veterans and their “battle buddies” so that the veterans can learn how to bond with and benefit from their new service dogs.
Finding the perfect match
Veterans are paired with trained service dogs based on their lifestyle and personality. For instance, a Vietnam veteran who is having trouble walking may be paired with a calm dog while a younger veteran who runs each morning is paired with a more active dog.
NWBB operates on funds from private donors and nonprofit organizations that make it financially feasible for the veterans to travel to Washington State and stay for the time required to train with their service dogs.
“Our service dogs are there in the midnight hour when no one else is,” she said. “Our veterans are fighting internal battles that no one else sees but the dogs. The dogs alert on their adrenaline and bring them back to the moment of now, interrupting suicidal ideations, panic attacks, and night terrors.”
Joshua Morganstein, MD, chair of the American Psychiatric Association’s Committee on the Psychiatric Dimensions of Disaster, said in an interview that “PTSD can be devastating for service members and veterans and is often associated with comorbid mental health conditions, such as anxiety and substance use.”
He noted that for many people, dogs and other animals can be an important source of physical, emotional, and psychological comfort.
“Programs like the Northwest Battle Buddies are important for us to study and better understand the extent to which trained animals are able to help alleviate the symptoms of PTSD and associated disorders and, perhaps most importantly, enhance the ability of service members and veterans to function and live in ways that feel healthy and productive to them,” said Dr. Morganstein.
He added that the concept of a “battle buddy” is a term pioneered by the U.S. Army in 2002 and describes a “formal, rather than ad hoc, system of peer support in which service members are assigned buddies.
“Buddies look out for each other, encourage self-care and self-advocacy and, when needed, help their buddy to seek help. Buddies remind us that someone is looking out for us and there is someone we look out for as well, both of which are protective during difficult times,” he said.
A version of this article first appeared on Medscape.com.
When Ryan (not his real name), 37, returned home from two deployments with the 101st Airborne Division in Iraq from 2005 to 2008, he began withdrawing from social situations and experienced chronic anxiety. Nights brought no respite – his sleep was interrupted by punishing nightmares.
“I had every calling card of a veteran in distress,” he said in an interview. When his wife told him she thought he may have posttraumatic stress disorder (PTSD), he shrugged it off. “I wasn’t automatically going to accept [the diagnosis] because as an infantry veteran, we’re big tough guys. We don’t need help with anything.”
The dogs, mostly recruited from rescue organizations, receive 5-7 months of specialized training to assist the veterans.
Life-changing help
While Ryan was skeptical about the program and whether it would work for him, he agreed to try it. After working with Bullet, a cream-colored golden retriever, he realized his life was improving.
“I stopped self-medicating, started advocating for myself, and became more comfortable socializing in public.” In his 3 years with Bullet, Ryan was able to work on his marriage, advance his career, and become a homeowner.
“The dreams I never thought were attainable started coming to fruition, and I was happy and comfortable for the first time in as long as I could remember.”
Unfortunately, Bullet died from a rare heart condition after a few years, and when that happened, NWBB immediately began working with Ryan to find him a new dog to fill the void left by Bullet.
Soon, Ryan began working with Twitch, who, like Bullet, knew when Ryan was becoming anxious, angry, or depressed before he did, he said.
“These dogs pick up on PTSD symptoms and come over and press themselves against you, push their faces into yours, and give you those big puppy dog eyes as if to say, ‘I got you. Everything is going to be okay.’ ”
The same thing happened when Ryan had night terrors and nightmares. “These dogs wake you up, and again, you’re greeted with this sweet puppy dog face.”
NWBB founder and CEO Shannon Walker, who has been training dogs for 25 years and whose father served in the U.S. Air Force in the 1950s, leads a 5-week training course for the veterans and their “battle buddies” so that the veterans can learn how to bond with and benefit from their new service dogs.
Finding the perfect match
Veterans are paired with trained service dogs based on their lifestyle and personality. For instance, a Vietnam veteran who is having trouble walking may be paired with a calm dog while a younger veteran who runs each morning is paired with a more active dog.
NWBB operates on funds from private donors and nonprofit organizations that make it financially feasible for the veterans to travel to Washington State and stay for the time required to train with their service dogs.
“Our service dogs are there in the midnight hour when no one else is,” she said. “Our veterans are fighting internal battles that no one else sees but the dogs. The dogs alert on their adrenaline and bring them back to the moment of now, interrupting suicidal ideations, panic attacks, and night terrors.”
Joshua Morganstein, MD, chair of the American Psychiatric Association’s Committee on the Psychiatric Dimensions of Disaster, said in an interview that “PTSD can be devastating for service members and veterans and is often associated with comorbid mental health conditions, such as anxiety and substance use.”
He noted that for many people, dogs and other animals can be an important source of physical, emotional, and psychological comfort.
“Programs like the Northwest Battle Buddies are important for us to study and better understand the extent to which trained animals are able to help alleviate the symptoms of PTSD and associated disorders and, perhaps most importantly, enhance the ability of service members and veterans to function and live in ways that feel healthy and productive to them,” said Dr. Morganstein.
He added that the concept of a “battle buddy” is a term pioneered by the U.S. Army in 2002 and describes a “formal, rather than ad hoc, system of peer support in which service members are assigned buddies.
“Buddies look out for each other, encourage self-care and self-advocacy and, when needed, help their buddy to seek help. Buddies remind us that someone is looking out for us and there is someone we look out for as well, both of which are protective during difficult times,” he said.
A version of this article first appeared on Medscape.com.
Early glucocorticoid bridging in RA supported by meta-analysis, but concerns remain
In a new salvo in the dispute over the wisdom of early “bridging” treatment with glucocorticoids in rheumatoid arthritis, Dutch researchers suggested in a new meta-analysis that the American College of Rheumatology guideline is too cautious.
The report, published in Annals of the Rheumatic Diseases, examined three randomized trials of bridging versus nonbridging. The findings “emphasize the benefits of bridging therapy and shows that bridgers are not using more glucocorticoids after their intended bridging period, compared with nonbridgers, during a 2-year follow-up,” study coauthor Sytske Anne Bergstra, PhD, a postdoctoral researcher at Leiden (the Netherlands) University Medical Center, said in an interview.
However, an American researcher who helped create the 2021 ACR guideline is unmoved by the new report. “This publication didn’t do anything to assuage my concerns,” Joel Kremer, MD, founder and president of the Corrona Research Foundation and professor of medicine emeritus at Albany (N.Y.) Medical College, said in an interview.
At issue is whether patients with early RA should be temporarily treated with glucocorticoids in order to provide rapid relief. The ACR’s 2021 guideline on the treatment of RA says short-term glucocorticoids should not be “systematically prescribed” but notes that they are still “frequently necessary to alleviate symptoms” before disease-modifying therapies are given. The guideline adds that “these recommendations were made in recognition of the frequent difficulty tapering glucocorticoids, leading to undesirable prolonged use and the increasing evidence of the negative impact of glucocorticoids on long-term patient outcomes, including risk for infection, osteoporosis, and cardiovascular disease, in RA and other rheumatic diseases.”
For its part, the European Alliance of Associations for Rheumatology’s 2022 recommendations state that short-term glucocorticoids “should be considered when initiating or changing [disease-modifying antirheumatic drugs], in different dose regimens and routes of administration, but should be tapered and discontinued as rapidly as clinically feasible.”
Members of the Dutch team behind the new meta-analysis have been supporters of “bridging” therapy. For the new report, they analyzed three studies, including one led by a member of the team. Each study had at least one arm that randomized patients with RA to glucocorticoid bridging. Patients also took disease-modifying antirheumatic drugs (DMARDs).
There were 252 patients in study arms that started with bridging (mean age, 52 years; 68% female) and 373 other patients (mean age, 53 years; 67% female).
The researchers found that glucocorticoid use was higher in the bridgers at 12 months (odds ratio, 3.27; 95% confidence interval, 1.06-10.08), but the excess risk at 18 months (OR, 1.60; 95% CI, 0.46-5.60) and 24 months (OR, 1.70; 95% CI, 0.58-4.97) dipped below statistical significance. Also, they reported that “bridgers improved more rapidly (P < .001) in the first 6 months and the bridgers required significantly fewer changes in DMARDs (incidence rate ratio, 0.59; 95% CI, 0.38-0.94).”
“Based on our results, combined with two earlier publications [here and here], we show that most patients included in clinical trials with protocolized tapering schedules are able to stop glucocorticoids after bridging,” Dr. Bergstra said. “We also confirm the well-known short-term clinical effects and show that patients using glucocorticoid bridging require fewer DMARD changes. For a re-evaluation of the ACR guideline, this evidence should be combined with the extensive evidence showing short- as well as long-term clinical benefits of glucocorticoid bridging but also with evidence on potential side effects at different doses.”
She added that “implementing predefined tapering protocols may help clinicians and patients to stop glucocorticoids after bridging.” As for limitations, “patients included in these trials may differ from patients in clinical practice. We cannot be sure whether these results can be generalized to the full patient population.”
Dr. Kremer, a coauthor of the ACR guideline, pointed out that the patients who took glucocorticoids early were much more likely to be on them at 12 months.
By definition, “bridging” is temporary, he said, a brief period to help patients tolerate RA until DMARDs kick in. But in the studies, many of the patients clearly took the drugs for extended periods of time. In those cases, “it not a bridge,” and the risk is that “you’re treating people with a lifelong disease with doses of glucocorticoids that have been shown in multiple studies to be dangerous.”
He added that, while the excess likelihood of these patients staying on the drugs at 18 or 24 months wasn’t deemed to be statistically significant in the meta-analysis, the confidence intervals were unusually wide. That raises questions about whether some of the patients actually stay on the drugs.
Dr. Kremer said it can still be appropriate to give glucocorticoids to patients in distress, although it’s crucial in those cases to take the patients off them as soon as possible. It’s best, though, to not prescribe them at all. “If you can avoid it,” he said, “definitely avoid it.”
The study was conducted without outside funding. Dr. Bergstra reported receiving grant funding from Pfizer, and some of the other study authors reported various relationships with industry. Dr. Kremer had no relevant disclosures.
In a new salvo in the dispute over the wisdom of early “bridging” treatment with glucocorticoids in rheumatoid arthritis, Dutch researchers suggested in a new meta-analysis that the American College of Rheumatology guideline is too cautious.
The report, published in Annals of the Rheumatic Diseases, examined three randomized trials of bridging versus nonbridging. The findings “emphasize the benefits of bridging therapy and shows that bridgers are not using more glucocorticoids after their intended bridging period, compared with nonbridgers, during a 2-year follow-up,” study coauthor Sytske Anne Bergstra, PhD, a postdoctoral researcher at Leiden (the Netherlands) University Medical Center, said in an interview.
However, an American researcher who helped create the 2021 ACR guideline is unmoved by the new report. “This publication didn’t do anything to assuage my concerns,” Joel Kremer, MD, founder and president of the Corrona Research Foundation and professor of medicine emeritus at Albany (N.Y.) Medical College, said in an interview.
At issue is whether patients with early RA should be temporarily treated with glucocorticoids in order to provide rapid relief. The ACR’s 2021 guideline on the treatment of RA says short-term glucocorticoids should not be “systematically prescribed” but notes that they are still “frequently necessary to alleviate symptoms” before disease-modifying therapies are given. The guideline adds that “these recommendations were made in recognition of the frequent difficulty tapering glucocorticoids, leading to undesirable prolonged use and the increasing evidence of the negative impact of glucocorticoids on long-term patient outcomes, including risk for infection, osteoporosis, and cardiovascular disease, in RA and other rheumatic diseases.”
For its part, the European Alliance of Associations for Rheumatology’s 2022 recommendations state that short-term glucocorticoids “should be considered when initiating or changing [disease-modifying antirheumatic drugs], in different dose regimens and routes of administration, but should be tapered and discontinued as rapidly as clinically feasible.”
Members of the Dutch team behind the new meta-analysis have been supporters of “bridging” therapy. For the new report, they analyzed three studies, including one led by a member of the team. Each study had at least one arm that randomized patients with RA to glucocorticoid bridging. Patients also took disease-modifying antirheumatic drugs (DMARDs).
There were 252 patients in study arms that started with bridging (mean age, 52 years; 68% female) and 373 other patients (mean age, 53 years; 67% female).
The researchers found that glucocorticoid use was higher in the bridgers at 12 months (odds ratio, 3.27; 95% confidence interval, 1.06-10.08), but the excess risk at 18 months (OR, 1.60; 95% CI, 0.46-5.60) and 24 months (OR, 1.70; 95% CI, 0.58-4.97) dipped below statistical significance. Also, they reported that “bridgers improved more rapidly (P < .001) in the first 6 months and the bridgers required significantly fewer changes in DMARDs (incidence rate ratio, 0.59; 95% CI, 0.38-0.94).”
“Based on our results, combined with two earlier publications [here and here], we show that most patients included in clinical trials with protocolized tapering schedules are able to stop glucocorticoids after bridging,” Dr. Bergstra said. “We also confirm the well-known short-term clinical effects and show that patients using glucocorticoid bridging require fewer DMARD changes. For a re-evaluation of the ACR guideline, this evidence should be combined with the extensive evidence showing short- as well as long-term clinical benefits of glucocorticoid bridging but also with evidence on potential side effects at different doses.”
She added that “implementing predefined tapering protocols may help clinicians and patients to stop glucocorticoids after bridging.” As for limitations, “patients included in these trials may differ from patients in clinical practice. We cannot be sure whether these results can be generalized to the full patient population.”
Dr. Kremer, a coauthor of the ACR guideline, pointed out that the patients who took glucocorticoids early were much more likely to be on them at 12 months.
By definition, “bridging” is temporary, he said, a brief period to help patients tolerate RA until DMARDs kick in. But in the studies, many of the patients clearly took the drugs for extended periods of time. In those cases, “it not a bridge,” and the risk is that “you’re treating people with a lifelong disease with doses of glucocorticoids that have been shown in multiple studies to be dangerous.”
He added that, while the excess likelihood of these patients staying on the drugs at 18 or 24 months wasn’t deemed to be statistically significant in the meta-analysis, the confidence intervals were unusually wide. That raises questions about whether some of the patients actually stay on the drugs.
Dr. Kremer said it can still be appropriate to give glucocorticoids to patients in distress, although it’s crucial in those cases to take the patients off them as soon as possible. It’s best, though, to not prescribe them at all. “If you can avoid it,” he said, “definitely avoid it.”
The study was conducted without outside funding. Dr. Bergstra reported receiving grant funding from Pfizer, and some of the other study authors reported various relationships with industry. Dr. Kremer had no relevant disclosures.
In a new salvo in the dispute over the wisdom of early “bridging” treatment with glucocorticoids in rheumatoid arthritis, Dutch researchers suggested in a new meta-analysis that the American College of Rheumatology guideline is too cautious.
The report, published in Annals of the Rheumatic Diseases, examined three randomized trials of bridging versus nonbridging. The findings “emphasize the benefits of bridging therapy and shows that bridgers are not using more glucocorticoids after their intended bridging period, compared with nonbridgers, during a 2-year follow-up,” study coauthor Sytske Anne Bergstra, PhD, a postdoctoral researcher at Leiden (the Netherlands) University Medical Center, said in an interview.
However, an American researcher who helped create the 2021 ACR guideline is unmoved by the new report. “This publication didn’t do anything to assuage my concerns,” Joel Kremer, MD, founder and president of the Corrona Research Foundation and professor of medicine emeritus at Albany (N.Y.) Medical College, said in an interview.
At issue is whether patients with early RA should be temporarily treated with glucocorticoids in order to provide rapid relief. The ACR’s 2021 guideline on the treatment of RA says short-term glucocorticoids should not be “systematically prescribed” but notes that they are still “frequently necessary to alleviate symptoms” before disease-modifying therapies are given. The guideline adds that “these recommendations were made in recognition of the frequent difficulty tapering glucocorticoids, leading to undesirable prolonged use and the increasing evidence of the negative impact of glucocorticoids on long-term patient outcomes, including risk for infection, osteoporosis, and cardiovascular disease, in RA and other rheumatic diseases.”
For its part, the European Alliance of Associations for Rheumatology’s 2022 recommendations state that short-term glucocorticoids “should be considered when initiating or changing [disease-modifying antirheumatic drugs], in different dose regimens and routes of administration, but should be tapered and discontinued as rapidly as clinically feasible.”
Members of the Dutch team behind the new meta-analysis have been supporters of “bridging” therapy. For the new report, they analyzed three studies, including one led by a member of the team. Each study had at least one arm that randomized patients with RA to glucocorticoid bridging. Patients also took disease-modifying antirheumatic drugs (DMARDs).
There were 252 patients in study arms that started with bridging (mean age, 52 years; 68% female) and 373 other patients (mean age, 53 years; 67% female).
The researchers found that glucocorticoid use was higher in the bridgers at 12 months (odds ratio, 3.27; 95% confidence interval, 1.06-10.08), but the excess risk at 18 months (OR, 1.60; 95% CI, 0.46-5.60) and 24 months (OR, 1.70; 95% CI, 0.58-4.97) dipped below statistical significance. Also, they reported that “bridgers improved more rapidly (P < .001) in the first 6 months and the bridgers required significantly fewer changes in DMARDs (incidence rate ratio, 0.59; 95% CI, 0.38-0.94).”
“Based on our results, combined with two earlier publications [here and here], we show that most patients included in clinical trials with protocolized tapering schedules are able to stop glucocorticoids after bridging,” Dr. Bergstra said. “We also confirm the well-known short-term clinical effects and show that patients using glucocorticoid bridging require fewer DMARD changes. For a re-evaluation of the ACR guideline, this evidence should be combined with the extensive evidence showing short- as well as long-term clinical benefits of glucocorticoid bridging but also with evidence on potential side effects at different doses.”
She added that “implementing predefined tapering protocols may help clinicians and patients to stop glucocorticoids after bridging.” As for limitations, “patients included in these trials may differ from patients in clinical practice. We cannot be sure whether these results can be generalized to the full patient population.”
Dr. Kremer, a coauthor of the ACR guideline, pointed out that the patients who took glucocorticoids early were much more likely to be on them at 12 months.
By definition, “bridging” is temporary, he said, a brief period to help patients tolerate RA until DMARDs kick in. But in the studies, many of the patients clearly took the drugs for extended periods of time. In those cases, “it not a bridge,” and the risk is that “you’re treating people with a lifelong disease with doses of glucocorticoids that have been shown in multiple studies to be dangerous.”
He added that, while the excess likelihood of these patients staying on the drugs at 18 or 24 months wasn’t deemed to be statistically significant in the meta-analysis, the confidence intervals were unusually wide. That raises questions about whether some of the patients actually stay on the drugs.
Dr. Kremer said it can still be appropriate to give glucocorticoids to patients in distress, although it’s crucial in those cases to take the patients off them as soon as possible. It’s best, though, to not prescribe them at all. “If you can avoid it,” he said, “definitely avoid it.”
The study was conducted without outside funding. Dr. Bergstra reported receiving grant funding from Pfizer, and some of the other study authors reported various relationships with industry. Dr. Kremer had no relevant disclosures.
FROM ANNALS OF THE RHEUMATIC DISEASES
Commentary: Looking at CGRP medications for migraine, September 2023
The calcitonin gene-related peptide (CGRP) antagonist class of medications has changed the face of migraine treatment — and there are now both acute and preventive options that are available in oral and injectable formulations. The gepant subclass of CGRP antagonists are small-molecule medications, in contrast to the CGRP monoclonal antibodies. Atogepant was developed as the first oral migraine-specific preventive medication, and the initial trials allowed for an initial approval by the US Food and Drug Administration for episodic migraine alone. The study by Pozo-Rosich and colleagues extended the patient population to patients with chronic migraine.
This was an international, multicenter, randomized controlled study of two dosages of atogepant (30 mg twice daily and 60 mg daily) compared with placebo over 12 weeks. The primary endpoint was change in mean monthly migraine days. There was a safety population as well that received a single dose of medication. Nearly 800 participants were enrolled equally into these three groups, and the authors used a modified intention-to-treat format that included all participants with at least 1 month of e-diary data and took at least one dose of the study medication.
The baseline number of mean monthly migraine days in this chronic migraine population was 18.6 days per month. After 12 weeks, the three groups showed decreases of 7.5, 6.1, and 5.1 days per month, which was statistically significant for the two intervention groups. The most common side effects were constipation and nausea, with up to 10% of the study population experiencing some gastrointestinal symptoms. Weight loss of 7% of body weight was also noticed in the two intervention groups.
This study describes the benefit of atogepant extending beyond the indication of episodic migraine. This chronic migraine population showed significant benefit in the decrease of mean monthly migraine days per month after 12 weeks. One additional benefit is weight loss even after 12 weeks. Compared with the monoclonal antibody class of CGRP antagonist, this medication appears to be approximately equally effective, with the additional benefit of weight loss. Because many preventive medications for migraine may be associated with weight gain — particularly the antidepressant and potentially the antihypertensive classes of medications — this can be a differentiating factor when choosing an appropriate preventive medication for your patients with chronic migraine.
CGRP is a known inflammatory modulator that also plays a significant role in the propagation of migraine. CGRP blockade has been associated, in some studies, with upper respiratory tract infection symptoms, raising the question of whether blocking CGRP chronically may increase the risk for infection. A prior study revealed that CGRP levels were decreased in patients with severe COVID-19, and another study did not find significant differences in COVID-19 disease, progression, or severity among migraine patients on CGRP antagonists. Wang and colleagues specifically sought to determine any potential association or risk between the use of CGRP antagonist medications and COVID.
This retrospective cohort study was performed in the US Veterans Affairs (VA) hospital system. It analyzed the electronic medical records of veterans diagnosed with migraine between January and May 2022. The participants' exposure to CGRP medications and the 30-day odds of hospitalization, as well as use of mechanical ventilation, were calculated. CGRP prescriptions were identified using outpatient pharmacy records for erenumab, fremanezumab (225 mg/1.5 mL), and galcanezumab (120 mg/mL), which were the only CGRP medications available at that point in the VA system. The primary outcome was cumulative incidence of SARS-CoV-2 infection; occurrences of SARS-CoV-2 infection were obtained from the VA COVID-19 Shared Data Resource. Secondary analysis of the clinical outcomes was performed among patients with a positive SARS-CoV-2 test result.
This analysis revealed that CGRP monoclonal antibody use was not associated with risk for COVID-19, and among participants who tested positive for COVID-19, there were no significant differences in hospitalization, oxygen supplementation, mechanical ventilation, or COVID-19–related death between those who were receiving CGRP medications and those who were not. Although another prior study implied that CGRP blockade may decrease the risk for severe disease related to a cytokine storm, those results were only in vitro, and no results from human or animal trials have replicated these data. There is, therefore, no contraindication to using CGRP antagonist medications in people at high risk for development of COVID-19.
Many patients with migraine are recommended specific treatments for the prevention of migraine attacks and for the acute treatment of their attacks. Very few studies have investigated specific combinations of acute and preventive treatments. Although logically, there should be no contraindication to most treatment combinations, there may be some additional synergistic benefit to the combination of specific classes of medications. We have previously discussed a synergy between the CGRP antagonist class and onabotulinumtoxinA (Botox) for the prevention of chronic migraine; Manack Adams and colleagues sought to quantify the efficacy of ubrogepant when the patients were also administered botulinum toxin.
The joint American Academy of Neurology/American Headache Society consensus statement recommends starting preventive medication for anyone with migraine who experiences > 4-5 days of headache per month. It also recommends a migraine-specific acute treatment for anyone who experiences migraine attacks. Botulinum toxin is approved by the US Food and Drug Administration for the prevention of chronic migraine at a dose of 155 units injected every 3 months; ubrogepant is a CGRP oral small-molecule antagonist that is approved for the acute treatment of migraine.
This study investigated the effectiveness of ubrogepant, with a primary endpoint of meaningful pain relief and return to normal function 2 and 4 hours after an initial dose of 50 or 100 mg. Meaningful pain relief was defined as answering "yes" to a question about whether the patient experienced meaningful pain relief. This has been a pre-reported endpoint in other acute migraine treatment trials. Return to normal function was defined as the time point where the patient could perform their daily activities on the basis of a functional disability scale. Achieving normal function was classified as either remaining free of disability or by reporting functional disability before taking ubrogepant and then indicating a return to normal function at 2 and 4 hours post-dose.
A total of 134 patients were enrolled, taking both ubrogepant and botulinum toxin; patients were included if they were treated with ubrogepant at least once. Meaningful pain relief was achieved in 53.3% of patients at 2 hours and in 76.2% of patients at 4 hours post-dose. Return to normal function was achieved by 30.1% of patients at 2 hours and by 52.1% of patients at 4 hours post-dose. Both meaningful pain relief and return to normal function were seen to be statistically significant and stable across up to 10 attacks per person.
Headache treatment providers typically need to consider different classes of medications for prevention and acute treatment. A growing body of evidence describes a synergy between the CGRP class of medications and botulinum toxin. This appears to be true both when CGRP antagonists are used preventively and, in this case, when they are used for acute events. This certainly would be a safe and effective choice in many instances for many patients.
The calcitonin gene-related peptide (CGRP) antagonist class of medications has changed the face of migraine treatment — and there are now both acute and preventive options that are available in oral and injectable formulations. The gepant subclass of CGRP antagonists are small-molecule medications, in contrast to the CGRP monoclonal antibodies. Atogepant was developed as the first oral migraine-specific preventive medication, and the initial trials allowed for an initial approval by the US Food and Drug Administration for episodic migraine alone. The study by Pozo-Rosich and colleagues extended the patient population to patients with chronic migraine.
This was an international, multicenter, randomized controlled study of two dosages of atogepant (30 mg twice daily and 60 mg daily) compared with placebo over 12 weeks. The primary endpoint was change in mean monthly migraine days. There was a safety population as well that received a single dose of medication. Nearly 800 participants were enrolled equally into these three groups, and the authors used a modified intention-to-treat format that included all participants with at least 1 month of e-diary data and took at least one dose of the study medication.
The baseline number of mean monthly migraine days in this chronic migraine population was 18.6 days per month. After 12 weeks, the three groups showed decreases of 7.5, 6.1, and 5.1 days per month, which was statistically significant for the two intervention groups. The most common side effects were constipation and nausea, with up to 10% of the study population experiencing some gastrointestinal symptoms. Weight loss of 7% of body weight was also noticed in the two intervention groups.
This study describes the benefit of atogepant extending beyond the indication of episodic migraine. This chronic migraine population showed significant benefit in the decrease of mean monthly migraine days per month after 12 weeks. One additional benefit is weight loss even after 12 weeks. Compared with the monoclonal antibody class of CGRP antagonist, this medication appears to be approximately equally effective, with the additional benefit of weight loss. Because many preventive medications for migraine may be associated with weight gain — particularly the antidepressant and potentially the antihypertensive classes of medications — this can be a differentiating factor when choosing an appropriate preventive medication for your patients with chronic migraine.
CGRP is a known inflammatory modulator that also plays a significant role in the propagation of migraine. CGRP blockade has been associated, in some studies, with upper respiratory tract infection symptoms, raising the question of whether blocking CGRP chronically may increase the risk for infection. A prior study revealed that CGRP levels were decreased in patients with severe COVID-19, and another study did not find significant differences in COVID-19 disease, progression, or severity among migraine patients on CGRP antagonists. Wang and colleagues specifically sought to determine any potential association or risk between the use of CGRP antagonist medications and COVID.
This retrospective cohort study was performed in the US Veterans Affairs (VA) hospital system. It analyzed the electronic medical records of veterans diagnosed with migraine between January and May 2022. The participants' exposure to CGRP medications and the 30-day odds of hospitalization, as well as use of mechanical ventilation, were calculated. CGRP prescriptions were identified using outpatient pharmacy records for erenumab, fremanezumab (225 mg/1.5 mL), and galcanezumab (120 mg/mL), which were the only CGRP medications available at that point in the VA system. The primary outcome was cumulative incidence of SARS-CoV-2 infection; occurrences of SARS-CoV-2 infection were obtained from the VA COVID-19 Shared Data Resource. Secondary analysis of the clinical outcomes was performed among patients with a positive SARS-CoV-2 test result.
This analysis revealed that CGRP monoclonal antibody use was not associated with risk for COVID-19, and among participants who tested positive for COVID-19, there were no significant differences in hospitalization, oxygen supplementation, mechanical ventilation, or COVID-19–related death between those who were receiving CGRP medications and those who were not. Although another prior study implied that CGRP blockade may decrease the risk for severe disease related to a cytokine storm, those results were only in vitro, and no results from human or animal trials have replicated these data. There is, therefore, no contraindication to using CGRP antagonist medications in people at high risk for development of COVID-19.
Many patients with migraine are recommended specific treatments for the prevention of migraine attacks and for the acute treatment of their attacks. Very few studies have investigated specific combinations of acute and preventive treatments. Although logically, there should be no contraindication to most treatment combinations, there may be some additional synergistic benefit to the combination of specific classes of medications. We have previously discussed a synergy between the CGRP antagonist class and onabotulinumtoxinA (Botox) for the prevention of chronic migraine; Manack Adams and colleagues sought to quantify the efficacy of ubrogepant when the patients were also administered botulinum toxin.
The joint American Academy of Neurology/American Headache Society consensus statement recommends starting preventive medication for anyone with migraine who experiences > 4-5 days of headache per month. It also recommends a migraine-specific acute treatment for anyone who experiences migraine attacks. Botulinum toxin is approved by the US Food and Drug Administration for the prevention of chronic migraine at a dose of 155 units injected every 3 months; ubrogepant is a CGRP oral small-molecule antagonist that is approved for the acute treatment of migraine.
This study investigated the effectiveness of ubrogepant, with a primary endpoint of meaningful pain relief and return to normal function 2 and 4 hours after an initial dose of 50 or 100 mg. Meaningful pain relief was defined as answering "yes" to a question about whether the patient experienced meaningful pain relief. This has been a pre-reported endpoint in other acute migraine treatment trials. Return to normal function was defined as the time point where the patient could perform their daily activities on the basis of a functional disability scale. Achieving normal function was classified as either remaining free of disability or by reporting functional disability before taking ubrogepant and then indicating a return to normal function at 2 and 4 hours post-dose.
A total of 134 patients were enrolled, taking both ubrogepant and botulinum toxin; patients were included if they were treated with ubrogepant at least once. Meaningful pain relief was achieved in 53.3% of patients at 2 hours and in 76.2% of patients at 4 hours post-dose. Return to normal function was achieved by 30.1% of patients at 2 hours and by 52.1% of patients at 4 hours post-dose. Both meaningful pain relief and return to normal function were seen to be statistically significant and stable across up to 10 attacks per person.
Headache treatment providers typically need to consider different classes of medications for prevention and acute treatment. A growing body of evidence describes a synergy between the CGRP class of medications and botulinum toxin. This appears to be true both when CGRP antagonists are used preventively and, in this case, when they are used for acute events. This certainly would be a safe and effective choice in many instances for many patients.
The calcitonin gene-related peptide (CGRP) antagonist class of medications has changed the face of migraine treatment — and there are now both acute and preventive options that are available in oral and injectable formulations. The gepant subclass of CGRP antagonists are small-molecule medications, in contrast to the CGRP monoclonal antibodies. Atogepant was developed as the first oral migraine-specific preventive medication, and the initial trials allowed for an initial approval by the US Food and Drug Administration for episodic migraine alone. The study by Pozo-Rosich and colleagues extended the patient population to patients with chronic migraine.
This was an international, multicenter, randomized controlled study of two dosages of atogepant (30 mg twice daily and 60 mg daily) compared with placebo over 12 weeks. The primary endpoint was change in mean monthly migraine days. There was a safety population as well that received a single dose of medication. Nearly 800 participants were enrolled equally into these three groups, and the authors used a modified intention-to-treat format that included all participants with at least 1 month of e-diary data and took at least one dose of the study medication.
The baseline number of mean monthly migraine days in this chronic migraine population was 18.6 days per month. After 12 weeks, the three groups showed decreases of 7.5, 6.1, and 5.1 days per month, which was statistically significant for the two intervention groups. The most common side effects were constipation and nausea, with up to 10% of the study population experiencing some gastrointestinal symptoms. Weight loss of 7% of body weight was also noticed in the two intervention groups.
This study describes the benefit of atogepant extending beyond the indication of episodic migraine. This chronic migraine population showed significant benefit in the decrease of mean monthly migraine days per month after 12 weeks. One additional benefit is weight loss even after 12 weeks. Compared with the monoclonal antibody class of CGRP antagonist, this medication appears to be approximately equally effective, with the additional benefit of weight loss. Because many preventive medications for migraine may be associated with weight gain — particularly the antidepressant and potentially the antihypertensive classes of medications — this can be a differentiating factor when choosing an appropriate preventive medication for your patients with chronic migraine.
CGRP is a known inflammatory modulator that also plays a significant role in the propagation of migraine. CGRP blockade has been associated, in some studies, with upper respiratory tract infection symptoms, raising the question of whether blocking CGRP chronically may increase the risk for infection. A prior study revealed that CGRP levels were decreased in patients with severe COVID-19, and another study did not find significant differences in COVID-19 disease, progression, or severity among migraine patients on CGRP antagonists. Wang and colleagues specifically sought to determine any potential association or risk between the use of CGRP antagonist medications and COVID.
This retrospective cohort study was performed in the US Veterans Affairs (VA) hospital system. It analyzed the electronic medical records of veterans diagnosed with migraine between January and May 2022. The participants' exposure to CGRP medications and the 30-day odds of hospitalization, as well as use of mechanical ventilation, were calculated. CGRP prescriptions were identified using outpatient pharmacy records for erenumab, fremanezumab (225 mg/1.5 mL), and galcanezumab (120 mg/mL), which were the only CGRP medications available at that point in the VA system. The primary outcome was cumulative incidence of SARS-CoV-2 infection; occurrences of SARS-CoV-2 infection were obtained from the VA COVID-19 Shared Data Resource. Secondary analysis of the clinical outcomes was performed among patients with a positive SARS-CoV-2 test result.
This analysis revealed that CGRP monoclonal antibody use was not associated with risk for COVID-19, and among participants who tested positive for COVID-19, there were no significant differences in hospitalization, oxygen supplementation, mechanical ventilation, or COVID-19–related death between those who were receiving CGRP medications and those who were not. Although another prior study implied that CGRP blockade may decrease the risk for severe disease related to a cytokine storm, those results were only in vitro, and no results from human or animal trials have replicated these data. There is, therefore, no contraindication to using CGRP antagonist medications in people at high risk for development of COVID-19.
Many patients with migraine are recommended specific treatments for the prevention of migraine attacks and for the acute treatment of their attacks. Very few studies have investigated specific combinations of acute and preventive treatments. Although logically, there should be no contraindication to most treatment combinations, there may be some additional synergistic benefit to the combination of specific classes of medications. We have previously discussed a synergy between the CGRP antagonist class and onabotulinumtoxinA (Botox) for the prevention of chronic migraine; Manack Adams and colleagues sought to quantify the efficacy of ubrogepant when the patients were also administered botulinum toxin.
The joint American Academy of Neurology/American Headache Society consensus statement recommends starting preventive medication for anyone with migraine who experiences > 4-5 days of headache per month. It also recommends a migraine-specific acute treatment for anyone who experiences migraine attacks. Botulinum toxin is approved by the US Food and Drug Administration for the prevention of chronic migraine at a dose of 155 units injected every 3 months; ubrogepant is a CGRP oral small-molecule antagonist that is approved for the acute treatment of migraine.
This study investigated the effectiveness of ubrogepant, with a primary endpoint of meaningful pain relief and return to normal function 2 and 4 hours after an initial dose of 50 or 100 mg. Meaningful pain relief was defined as answering "yes" to a question about whether the patient experienced meaningful pain relief. This has been a pre-reported endpoint in other acute migraine treatment trials. Return to normal function was defined as the time point where the patient could perform their daily activities on the basis of a functional disability scale. Achieving normal function was classified as either remaining free of disability or by reporting functional disability before taking ubrogepant and then indicating a return to normal function at 2 and 4 hours post-dose.
A total of 134 patients were enrolled, taking both ubrogepant and botulinum toxin; patients were included if they were treated with ubrogepant at least once. Meaningful pain relief was achieved in 53.3% of patients at 2 hours and in 76.2% of patients at 4 hours post-dose. Return to normal function was achieved by 30.1% of patients at 2 hours and by 52.1% of patients at 4 hours post-dose. Both meaningful pain relief and return to normal function were seen to be statistically significant and stable across up to 10 attacks per person.
Headache treatment providers typically need to consider different classes of medications for prevention and acute treatment. A growing body of evidence describes a synergy between the CGRP class of medications and botulinum toxin. This appears to be true both when CGRP antagonists are used preventively and, in this case, when they are used for acute events. This certainly would be a safe and effective choice in many instances for many patients.
Transient Skin Rippling in an Infant
The Diagnosis: Infantile Transient Smooth Muscle Contraction of the Skin
A diagnosis of infantile transient smooth muscle contraction of the skin (ITSMC) was made based on our patient’s clinical presentation and eliminating the diagnoses in the differential. No treatment ultimately was indicated, as episodes became less frequent over time.
The term infantile transient smooth muscle contraction of the skin was first proposed in 2013 by Torrelo et al,1 who described 9 newborns with episodic skin rippling occasionally associated with exposure to cold or friction. The authors postulated that ITSMC was the result of a transient contraction of the arrector pili smooth muscle fibers of the skin, secondary to autonomic immaturity, primitive reflexes, or smooth muscle hypersensitivity.1 Since this first description, ITSMC has remained a rarely reported and poorly understood phenomenon with rare identified cases in the literature.2,3 Clinical history and examination of infants with intermittent transient skin rippling help to distinguish ITSMC from other diagnoses without the need for biopsy, which is particularly undesirable in the pediatric population.
Congenital smooth muscle hamartoma is a benign proliferation of mature smooth muscle that also can arise from the arrector pili muscles.4 In contrast to ITSMC, a hamartoma does not clear; rather, it persists and grows proportionally with the child and is associated with overlying hyperpigmentation and hypertrichosis. The transient nature of ITSMC may be worrisome for mastocytoma; however, this condition presents as erythematous, yellow, red, or brown macules, papules, plaques, or nodules with a positive Darier sign.5 Although the differential diagnosis includes the shagreen patch characteristic of tuberous sclerosis, this irregular plaque typically is located on the lower back with overlying peau d’orange skin changes, and our patient lacked other features indicative of this condition.6 Becker nevus also remains a consideration in patients with rippled skin, but this entity typically becomes more notable at puberty and is associated with hyperpigmentation and hypertrichosis and is a type of smooth muscle hamartoma.4
Our case highlighted the unusual presentation of ITSMC, a condition that can easily go unrecognized, leading to unnecessary referrals and concern. Familiarity with this benign diagnosis is essential to inform prognosis and guide management.
- Torrelo A, Moreno S, Castro C, et al. Infantile transient smooth muscle contraction of the skin. J Am Acad Dermatol. 2013;69:498-500. doi:10.1016/j.jaad.2013.04.029
- Theodosiou G, Belfrage E, Berggård K, et al. Infantile transient smooth muscle contraction of the skin: a case report and literature review. Eur J Dermatol. 2021;31:260-261. doi:10.1684/ejd.2021.3996
- Topham C, Deacon DC, Bowen A, et al. More than goosebumps: a case of marked skin dimpling in an infant. Pediatr Dermatol. 2019;36:E71-E72. doi:10.1111/pde.13791
- Raboudi A, Litaiem N. Congenital smooth muscle hamartoma. StatPearls. StatPearls Publishing; 2022.
- Leung AKC, Lam JM, Leong KF. Childhood solitary cutaneous mastocytoma: clinical manifestations, diagnosis, evaluation, and management. Curr Pediatr Rev. 2019;15:42-46. doi:10.2174/1573396315666 181120163952
- Bongiorno MA, Nathan N, Oyerinde O, et al. Clinical characteristics of connective tissue nevi in tuberous sclerosis complex with special emphasis on shagreen patches. JAMA Dermatol. 2017;153:660-665. doi:10.1001/jamadermatol.2017.0298
The Diagnosis: Infantile Transient Smooth Muscle Contraction of the Skin
A diagnosis of infantile transient smooth muscle contraction of the skin (ITSMC) was made based on our patient’s clinical presentation and eliminating the diagnoses in the differential. No treatment ultimately was indicated, as episodes became less frequent over time.
The term infantile transient smooth muscle contraction of the skin was first proposed in 2013 by Torrelo et al,1 who described 9 newborns with episodic skin rippling occasionally associated with exposure to cold or friction. The authors postulated that ITSMC was the result of a transient contraction of the arrector pili smooth muscle fibers of the skin, secondary to autonomic immaturity, primitive reflexes, or smooth muscle hypersensitivity.1 Since this first description, ITSMC has remained a rarely reported and poorly understood phenomenon with rare identified cases in the literature.2,3 Clinical history and examination of infants with intermittent transient skin rippling help to distinguish ITSMC from other diagnoses without the need for biopsy, which is particularly undesirable in the pediatric population.
Congenital smooth muscle hamartoma is a benign proliferation of mature smooth muscle that also can arise from the arrector pili muscles.4 In contrast to ITSMC, a hamartoma does not clear; rather, it persists and grows proportionally with the child and is associated with overlying hyperpigmentation and hypertrichosis. The transient nature of ITSMC may be worrisome for mastocytoma; however, this condition presents as erythematous, yellow, red, or brown macules, papules, plaques, or nodules with a positive Darier sign.5 Although the differential diagnosis includes the shagreen patch characteristic of tuberous sclerosis, this irregular plaque typically is located on the lower back with overlying peau d’orange skin changes, and our patient lacked other features indicative of this condition.6 Becker nevus also remains a consideration in patients with rippled skin, but this entity typically becomes more notable at puberty and is associated with hyperpigmentation and hypertrichosis and is a type of smooth muscle hamartoma.4
Our case highlighted the unusual presentation of ITSMC, a condition that can easily go unrecognized, leading to unnecessary referrals and concern. Familiarity with this benign diagnosis is essential to inform prognosis and guide management.
The Diagnosis: Infantile Transient Smooth Muscle Contraction of the Skin
A diagnosis of infantile transient smooth muscle contraction of the skin (ITSMC) was made based on our patient’s clinical presentation and eliminating the diagnoses in the differential. No treatment ultimately was indicated, as episodes became less frequent over time.
The term infantile transient smooth muscle contraction of the skin was first proposed in 2013 by Torrelo et al,1 who described 9 newborns with episodic skin rippling occasionally associated with exposure to cold or friction. The authors postulated that ITSMC was the result of a transient contraction of the arrector pili smooth muscle fibers of the skin, secondary to autonomic immaturity, primitive reflexes, or smooth muscle hypersensitivity.1 Since this first description, ITSMC has remained a rarely reported and poorly understood phenomenon with rare identified cases in the literature.2,3 Clinical history and examination of infants with intermittent transient skin rippling help to distinguish ITSMC from other diagnoses without the need for biopsy, which is particularly undesirable in the pediatric population.
Congenital smooth muscle hamartoma is a benign proliferation of mature smooth muscle that also can arise from the arrector pili muscles.4 In contrast to ITSMC, a hamartoma does not clear; rather, it persists and grows proportionally with the child and is associated with overlying hyperpigmentation and hypertrichosis. The transient nature of ITSMC may be worrisome for mastocytoma; however, this condition presents as erythematous, yellow, red, or brown macules, papules, plaques, or nodules with a positive Darier sign.5 Although the differential diagnosis includes the shagreen patch characteristic of tuberous sclerosis, this irregular plaque typically is located on the lower back with overlying peau d’orange skin changes, and our patient lacked other features indicative of this condition.6 Becker nevus also remains a consideration in patients with rippled skin, but this entity typically becomes more notable at puberty and is associated with hyperpigmentation and hypertrichosis and is a type of smooth muscle hamartoma.4
Our case highlighted the unusual presentation of ITSMC, a condition that can easily go unrecognized, leading to unnecessary referrals and concern. Familiarity with this benign diagnosis is essential to inform prognosis and guide management.
- Torrelo A, Moreno S, Castro C, et al. Infantile transient smooth muscle contraction of the skin. J Am Acad Dermatol. 2013;69:498-500. doi:10.1016/j.jaad.2013.04.029
- Theodosiou G, Belfrage E, Berggård K, et al. Infantile transient smooth muscle contraction of the skin: a case report and literature review. Eur J Dermatol. 2021;31:260-261. doi:10.1684/ejd.2021.3996
- Topham C, Deacon DC, Bowen A, et al. More than goosebumps: a case of marked skin dimpling in an infant. Pediatr Dermatol. 2019;36:E71-E72. doi:10.1111/pde.13791
- Raboudi A, Litaiem N. Congenital smooth muscle hamartoma. StatPearls. StatPearls Publishing; 2022.
- Leung AKC, Lam JM, Leong KF. Childhood solitary cutaneous mastocytoma: clinical manifestations, diagnosis, evaluation, and management. Curr Pediatr Rev. 2019;15:42-46. doi:10.2174/1573396315666 181120163952
- Bongiorno MA, Nathan N, Oyerinde O, et al. Clinical characteristics of connective tissue nevi in tuberous sclerosis complex with special emphasis on shagreen patches. JAMA Dermatol. 2017;153:660-665. doi:10.1001/jamadermatol.2017.0298
- Torrelo A, Moreno S, Castro C, et al. Infantile transient smooth muscle contraction of the skin. J Am Acad Dermatol. 2013;69:498-500. doi:10.1016/j.jaad.2013.04.029
- Theodosiou G, Belfrage E, Berggård K, et al. Infantile transient smooth muscle contraction of the skin: a case report and literature review. Eur J Dermatol. 2021;31:260-261. doi:10.1684/ejd.2021.3996
- Topham C, Deacon DC, Bowen A, et al. More than goosebumps: a case of marked skin dimpling in an infant. Pediatr Dermatol. 2019;36:E71-E72. doi:10.1111/pde.13791
- Raboudi A, Litaiem N. Congenital smooth muscle hamartoma. StatPearls. StatPearls Publishing; 2022.
- Leung AKC, Lam JM, Leong KF. Childhood solitary cutaneous mastocytoma: clinical manifestations, diagnosis, evaluation, and management. Curr Pediatr Rev. 2019;15:42-46. doi:10.2174/1573396315666 181120163952
- Bongiorno MA, Nathan N, Oyerinde O, et al. Clinical characteristics of connective tissue nevi in tuberous sclerosis complex with special emphasis on shagreen patches. JAMA Dermatol. 2017;153:660-665. doi:10.1001/jamadermatol.2017.0298
A healthy, full-term, 5-month-old infant boy presented to dermatology for evaluation of an intermittent, asymptomatic, rippled skin texture of the left thigh that resolved completely between flares. The parents noted fewer than 10 intermittent flares prior to the initial presentation at 5 months. Physical examination of the patient’s skin revealed no epidermal abnormalities, dermatographism, or subcutaneous nodules, and there was no positive Darier sign. A subsequent flare at 9 months of age occurred concurrently with fevers up to 39.4 °C (103 °F), and a corresponding photograph (quiz image) provided by the parents due to the intermittent and transient nature of the condition demonstrated an ill-defined, raised, rippled plaque on the left lateral thigh.
ADCs show early promise in NSCLC
This has led to a burgeoning interest in solid tumors, with over 100 clinical trials in progress. Non–small cell lung cancer (NSCLC) is no exception. In 2022, the Food and Drug Administration approved trastuzumab DXd for pretreated NSCLC patients with HER2-mutant tumors. Two others have lung cancer breakthrough therapy designations from the FDA, including patritumab deruxtecan (HER3-DXd) for EGFR-mutant NSCLC and telisotuzumab vedotin for NSCLC that overexpresses c-Met.
At the annual World Conference on Lung Cancer, researchers outlined some of the latest developments in ADCs targeting the antigens HER3, trophoblast cell-surface antigen 2 (TROP-2), and the B7-H3 immunoregulatory protein, as single agents or in combination with immunotherapy. Following the presentations, discussant Helena Linardou, MD, PhD, emphasized the need for pharmacogenomics to predict toxicity and studies to understand resistance mechanisms. “ADCs are a new, rapidly evolving class of therapeutics, and I think that we will all have to be prepared for the future that is coming,” said Dr. Linardou, who is director of the 4th oncology department and the Comprehensive Clinical Trials Center at Metropolitan Hospital in Athens.
Researchers presented four ADC clinical trial updates.
Patritumab deruxtecan
Patritumab deruxtecan (Daiichi Sankyo) links a HER3 antibody to the topoisomerase I inhibitor deruxtecan (HER3-DXd). In the open-label, phase 2 HERTHENA-Lung01 trial, it was tested in patients with NSCLC EGFR-activation mutations, which occurs in 14%-38% of NSCLC cases. There are few options for these patients following failure of EGFR tyrosine kinase inhibitor therapy.
The study included 225 patients previously treated with EGFR tyrosine kinase inhibitors and platinum-based chemotherapy who received 5.6 mg/kg of HER3-DXd every 3 weeks. Over a median follow-up of 13.1 months and a median treatment duration of 5.5 months), 29.8% had a confirmed overall response (95% confidence interval, 23.9%-36.2%) with a median duration of 6.4 months (95% CI, 4.9-7.8). The median progression-free survival was 5.5 months (95% CI, 5.1-5.9), and the median OS was 11.9 months (95% CI, 11.2-13.1). The researchers noted similar outcomes among patients with different mechanisms of EGFR TKI resistance. The frequency of adverse events was similar to previous studies, with drug-related adverse events linked to treatment discontinuation of 7.1% interstitial lung disease in 5.3%. Among 30 patients with brain metastases, the confirmed intracranial response rate was 33.3% (95% CI, 17.3%-52.8%).
The study was published simultaneously online in the Journal of Clinical Oncology. (Abstract)
Datopotamab deruxtecan
PD-1/PD-L1 inhibitors are the first-line therapy for metastatic NSCLC, but there are efforts to improve outcomes through combination therapy. Datopotamab deruxtecan (Dato-DXd, Daiichi Sankyo, AstraZeneca) is an ADC targeting TROP2, and it has been shown in preclinical studies to enhance tumor responses to PD-1/PD-L1 inhibitors. The ADC improved progression-free survival (PFS), compared with docetaxel, in previously treated advanced or metastatic NSCLC.
In an interim analysis of the phase 1b TROPION-Lung04 study, researchers reported results from the combination of Dato-DXd with durvalumab with or without carboplatin. The study included 38 patients, some of whom had previously undergone treatment with immune checkpoint inhibitors. Nineteen patients received the doublet, and 14 received the carboplatin triplet. Grade 3 or higher treatment-emergent adverse events occurred in 42.1% of the doublet group and 71.4% of the triplet group. Interstitial lung disease occurred in 15.8% and 7.1% of the two groups, respectively. The objective response rate was 50.0% in the doublet group and 76.9% in the triplet group. The disease control rate was 92.9% and 92.3%, respectively. Durable responses occurred in both the first-line setting and the overall population. (Abstract)
Sacituzumab govitecan
Another ADC being tested with PD-1/PD-L1 inhibitors is sacituzumab govitecan (Trodelvy, Gilead), which has already received FDA approval for metastatic triple-negative breast cancer, pretreated HR+/HER2- metastatic breast cancer, and metastatic urothelial cancer. Like datopotamab, sacituzumab targets TROP-2. Researchers reported preliminary results from the phase 2 EVOKE-02 study, in which the ADC was combined with pembrolizumab for the first-line treatment of metastatic NSCLC. The overall response rate was 56% (95% CI, 42%-69%). Among patients with PD-L1 tumor proportion score (TPS) ≥ 50%, the ORR was 69% (95% CI, 49%-85%) and 44% (95% CI, 26%-62%) among those with TPS < 50%. The disease control rate was 86% (95% CI, 68%-96%) and 78% (95% CI, 60%-91%), respectively. The most frequent treatment-emergent adverse events (TEAEs) were diarrhea, anemia, and asthenia, and 18% of patients discontinued the study drug because of TEAEs. (Abstract)
Ifinatamab deruxtecan
Ifinatamab deruxtecan (Daiichi Sankyo) targets the B7-H3 antigen, which is an immunoregulatory protein that is overexpressed in many tumors. In the DS7300-A-J101 study, it was tested in patients with advanced or metastatic solid tumors, without selection for B7-H3 expression. A subgroup analysis of 22 patients with small cell lung cancer (SCLC) showed an ORR of 52.4 (95% CI, 29.8-74.3), a complete response of 4.8%, and a partial response in 47.6%. The median PFS was 5.6 months (95% CI, 3.9-8.1) and median OS was 12.2 months (95% CI, 6.4-not applicable). The most common treatment-emergent adverse events were nausea (59.1%), fatigue (50.0%), anemia (27.3%), vomiting (27.3%), and decreased appetite (22.7%). (Abstract)
This has led to a burgeoning interest in solid tumors, with over 100 clinical trials in progress. Non–small cell lung cancer (NSCLC) is no exception. In 2022, the Food and Drug Administration approved trastuzumab DXd for pretreated NSCLC patients with HER2-mutant tumors. Two others have lung cancer breakthrough therapy designations from the FDA, including patritumab deruxtecan (HER3-DXd) for EGFR-mutant NSCLC and telisotuzumab vedotin for NSCLC that overexpresses c-Met.
At the annual World Conference on Lung Cancer, researchers outlined some of the latest developments in ADCs targeting the antigens HER3, trophoblast cell-surface antigen 2 (TROP-2), and the B7-H3 immunoregulatory protein, as single agents or in combination with immunotherapy. Following the presentations, discussant Helena Linardou, MD, PhD, emphasized the need for pharmacogenomics to predict toxicity and studies to understand resistance mechanisms. “ADCs are a new, rapidly evolving class of therapeutics, and I think that we will all have to be prepared for the future that is coming,” said Dr. Linardou, who is director of the 4th oncology department and the Comprehensive Clinical Trials Center at Metropolitan Hospital in Athens.
Researchers presented four ADC clinical trial updates.
Patritumab deruxtecan
Patritumab deruxtecan (Daiichi Sankyo) links a HER3 antibody to the topoisomerase I inhibitor deruxtecan (HER3-DXd). In the open-label, phase 2 HERTHENA-Lung01 trial, it was tested in patients with NSCLC EGFR-activation mutations, which occurs in 14%-38% of NSCLC cases. There are few options for these patients following failure of EGFR tyrosine kinase inhibitor therapy.
The study included 225 patients previously treated with EGFR tyrosine kinase inhibitors and platinum-based chemotherapy who received 5.6 mg/kg of HER3-DXd every 3 weeks. Over a median follow-up of 13.1 months and a median treatment duration of 5.5 months), 29.8% had a confirmed overall response (95% confidence interval, 23.9%-36.2%) with a median duration of 6.4 months (95% CI, 4.9-7.8). The median progression-free survival was 5.5 months (95% CI, 5.1-5.9), and the median OS was 11.9 months (95% CI, 11.2-13.1). The researchers noted similar outcomes among patients with different mechanisms of EGFR TKI resistance. The frequency of adverse events was similar to previous studies, with drug-related adverse events linked to treatment discontinuation of 7.1% interstitial lung disease in 5.3%. Among 30 patients with brain metastases, the confirmed intracranial response rate was 33.3% (95% CI, 17.3%-52.8%).
The study was published simultaneously online in the Journal of Clinical Oncology. (Abstract)
Datopotamab deruxtecan
PD-1/PD-L1 inhibitors are the first-line therapy for metastatic NSCLC, but there are efforts to improve outcomes through combination therapy. Datopotamab deruxtecan (Dato-DXd, Daiichi Sankyo, AstraZeneca) is an ADC targeting TROP2, and it has been shown in preclinical studies to enhance tumor responses to PD-1/PD-L1 inhibitors. The ADC improved progression-free survival (PFS), compared with docetaxel, in previously treated advanced or metastatic NSCLC.
In an interim analysis of the phase 1b TROPION-Lung04 study, researchers reported results from the combination of Dato-DXd with durvalumab with or without carboplatin. The study included 38 patients, some of whom had previously undergone treatment with immune checkpoint inhibitors. Nineteen patients received the doublet, and 14 received the carboplatin triplet. Grade 3 or higher treatment-emergent adverse events occurred in 42.1% of the doublet group and 71.4% of the triplet group. Interstitial lung disease occurred in 15.8% and 7.1% of the two groups, respectively. The objective response rate was 50.0% in the doublet group and 76.9% in the triplet group. The disease control rate was 92.9% and 92.3%, respectively. Durable responses occurred in both the first-line setting and the overall population. (Abstract)
Sacituzumab govitecan
Another ADC being tested with PD-1/PD-L1 inhibitors is sacituzumab govitecan (Trodelvy, Gilead), which has already received FDA approval for metastatic triple-negative breast cancer, pretreated HR+/HER2- metastatic breast cancer, and metastatic urothelial cancer. Like datopotamab, sacituzumab targets TROP-2. Researchers reported preliminary results from the phase 2 EVOKE-02 study, in which the ADC was combined with pembrolizumab for the first-line treatment of metastatic NSCLC. The overall response rate was 56% (95% CI, 42%-69%). Among patients with PD-L1 tumor proportion score (TPS) ≥ 50%, the ORR was 69% (95% CI, 49%-85%) and 44% (95% CI, 26%-62%) among those with TPS < 50%. The disease control rate was 86% (95% CI, 68%-96%) and 78% (95% CI, 60%-91%), respectively. The most frequent treatment-emergent adverse events (TEAEs) were diarrhea, anemia, and asthenia, and 18% of patients discontinued the study drug because of TEAEs. (Abstract)
Ifinatamab deruxtecan
Ifinatamab deruxtecan (Daiichi Sankyo) targets the B7-H3 antigen, which is an immunoregulatory protein that is overexpressed in many tumors. In the DS7300-A-J101 study, it was tested in patients with advanced or metastatic solid tumors, without selection for B7-H3 expression. A subgroup analysis of 22 patients with small cell lung cancer (SCLC) showed an ORR of 52.4 (95% CI, 29.8-74.3), a complete response of 4.8%, and a partial response in 47.6%. The median PFS was 5.6 months (95% CI, 3.9-8.1) and median OS was 12.2 months (95% CI, 6.4-not applicable). The most common treatment-emergent adverse events were nausea (59.1%), fatigue (50.0%), anemia (27.3%), vomiting (27.3%), and decreased appetite (22.7%). (Abstract)
This has led to a burgeoning interest in solid tumors, with over 100 clinical trials in progress. Non–small cell lung cancer (NSCLC) is no exception. In 2022, the Food and Drug Administration approved trastuzumab DXd for pretreated NSCLC patients with HER2-mutant tumors. Two others have lung cancer breakthrough therapy designations from the FDA, including patritumab deruxtecan (HER3-DXd) for EGFR-mutant NSCLC and telisotuzumab vedotin for NSCLC that overexpresses c-Met.
At the annual World Conference on Lung Cancer, researchers outlined some of the latest developments in ADCs targeting the antigens HER3, trophoblast cell-surface antigen 2 (TROP-2), and the B7-H3 immunoregulatory protein, as single agents or in combination with immunotherapy. Following the presentations, discussant Helena Linardou, MD, PhD, emphasized the need for pharmacogenomics to predict toxicity and studies to understand resistance mechanisms. “ADCs are a new, rapidly evolving class of therapeutics, and I think that we will all have to be prepared for the future that is coming,” said Dr. Linardou, who is director of the 4th oncology department and the Comprehensive Clinical Trials Center at Metropolitan Hospital in Athens.
Researchers presented four ADC clinical trial updates.
Patritumab deruxtecan
Patritumab deruxtecan (Daiichi Sankyo) links a HER3 antibody to the topoisomerase I inhibitor deruxtecan (HER3-DXd). In the open-label, phase 2 HERTHENA-Lung01 trial, it was tested in patients with NSCLC EGFR-activation mutations, which occurs in 14%-38% of NSCLC cases. There are few options for these patients following failure of EGFR tyrosine kinase inhibitor therapy.
The study included 225 patients previously treated with EGFR tyrosine kinase inhibitors and platinum-based chemotherapy who received 5.6 mg/kg of HER3-DXd every 3 weeks. Over a median follow-up of 13.1 months and a median treatment duration of 5.5 months), 29.8% had a confirmed overall response (95% confidence interval, 23.9%-36.2%) with a median duration of 6.4 months (95% CI, 4.9-7.8). The median progression-free survival was 5.5 months (95% CI, 5.1-5.9), and the median OS was 11.9 months (95% CI, 11.2-13.1). The researchers noted similar outcomes among patients with different mechanisms of EGFR TKI resistance. The frequency of adverse events was similar to previous studies, with drug-related adverse events linked to treatment discontinuation of 7.1% interstitial lung disease in 5.3%. Among 30 patients with brain metastases, the confirmed intracranial response rate was 33.3% (95% CI, 17.3%-52.8%).
The study was published simultaneously online in the Journal of Clinical Oncology. (Abstract)
Datopotamab deruxtecan
PD-1/PD-L1 inhibitors are the first-line therapy for metastatic NSCLC, but there are efforts to improve outcomes through combination therapy. Datopotamab deruxtecan (Dato-DXd, Daiichi Sankyo, AstraZeneca) is an ADC targeting TROP2, and it has been shown in preclinical studies to enhance tumor responses to PD-1/PD-L1 inhibitors. The ADC improved progression-free survival (PFS), compared with docetaxel, in previously treated advanced or metastatic NSCLC.
In an interim analysis of the phase 1b TROPION-Lung04 study, researchers reported results from the combination of Dato-DXd with durvalumab with or without carboplatin. The study included 38 patients, some of whom had previously undergone treatment with immune checkpoint inhibitors. Nineteen patients received the doublet, and 14 received the carboplatin triplet. Grade 3 or higher treatment-emergent adverse events occurred in 42.1% of the doublet group and 71.4% of the triplet group. Interstitial lung disease occurred in 15.8% and 7.1% of the two groups, respectively. The objective response rate was 50.0% in the doublet group and 76.9% in the triplet group. The disease control rate was 92.9% and 92.3%, respectively. Durable responses occurred in both the first-line setting and the overall population. (Abstract)
Sacituzumab govitecan
Another ADC being tested with PD-1/PD-L1 inhibitors is sacituzumab govitecan (Trodelvy, Gilead), which has already received FDA approval for metastatic triple-negative breast cancer, pretreated HR+/HER2- metastatic breast cancer, and metastatic urothelial cancer. Like datopotamab, sacituzumab targets TROP-2. Researchers reported preliminary results from the phase 2 EVOKE-02 study, in which the ADC was combined with pembrolizumab for the first-line treatment of metastatic NSCLC. The overall response rate was 56% (95% CI, 42%-69%). Among patients with PD-L1 tumor proportion score (TPS) ≥ 50%, the ORR was 69% (95% CI, 49%-85%) and 44% (95% CI, 26%-62%) among those with TPS < 50%. The disease control rate was 86% (95% CI, 68%-96%) and 78% (95% CI, 60%-91%), respectively. The most frequent treatment-emergent adverse events (TEAEs) were diarrhea, anemia, and asthenia, and 18% of patients discontinued the study drug because of TEAEs. (Abstract)
Ifinatamab deruxtecan
Ifinatamab deruxtecan (Daiichi Sankyo) targets the B7-H3 antigen, which is an immunoregulatory protein that is overexpressed in many tumors. In the DS7300-A-J101 study, it was tested in patients with advanced or metastatic solid tumors, without selection for B7-H3 expression. A subgroup analysis of 22 patients with small cell lung cancer (SCLC) showed an ORR of 52.4 (95% CI, 29.8-74.3), a complete response of 4.8%, and a partial response in 47.6%. The median PFS was 5.6 months (95% CI, 3.9-8.1) and median OS was 12.2 months (95% CI, 6.4-not applicable). The most common treatment-emergent adverse events were nausea (59.1%), fatigue (50.0%), anemia (27.3%), vomiting (27.3%), and decreased appetite (22.7%). (Abstract)
FROM WCLC 2023
Hydroxychloroquine blood level ‘sweet spot’ may maximize efficacy in lupus
A blood-level reference range of 750-1,200 ng/mL of hydroxychloroquine (HCQ) has been linked with 71% lower odds of active lupus, new research suggests.
Researchers, led by Shivani Garg, MD, assistant professor of rheumatology at the University of Wisconsin–Madison, also found that maintaining levels within that range lowered the odds for flares by 26% over 9 months of follow-up.
The findings, published in Arthritis Care & Research, could help clinicians personalize HCQ doses to maximize efficacy for each patient.
HCQ levels in whole blood and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) were measured during a baseline visit and again during a routine follow-up visit.
Among 158 baseline patient visits, 19% of the patients had active lupus. Researchers longitudinally followed 42 patients using convenience sampling, and among those patients, 7 (17%) had flares at the follow-up visit.
Michelle Petri, MD, MPH, director of the Johns Hopkins Lupus Center in Baltimore, called the findings that suggest upper and lower efficacy and safety boundaries “very important.”
The findings highlight that guidelines for dosing don’t match efficacy needs, said Dr. Petri, who was not involved with the study.
“HCQ dosing has been under threat by guidelines insisting that the dose should be < 5 mg/kg even though this does not correlate with efficacy,” she said. “Basically, if we dose too low, the patient loses efficacy. If we dose too high, the risk of retinopathy increases, so this paper hones down the sweet spot.”
A 2014 study identified a higher eye toxicity risk with HCQ doses > 5 mg/kg per day, and the American Academy of Ophthalmology followed with guidelines for HCQ retinopathy screening that recommended reducing HCQ to ≤ 5 mg/kg per day.
Dr. Petri said that the range Dr. Garg and colleagues identified corroborates findings in one of her team’s studies.
That paper showed that thrombotic events dropped by 69% in patients with average HCQ blood levels ≥ 1,068 ng/mL vs. those with levels < 648 ng/mL (relative risk, 0.31; 95% confidence interval, 0.11-0.86; P = .024).
Dr. Garg and colleagues write that current lupus treatment guidelines do not universally recommend blood level monitoring for HCQ “as different cut-points have been used to define therapeutic HCQ blood levels and an effective range of HCQ levels with upper and lower bounds for efficacy has not been extensively examined.”
When to start checking levels
Blood levels of HCQ can be checked for any patient, although 1-3 months after starting the medication may be best to get steady levels, Dr. Garg told this news organization.
Dr. Petri said that she recommends HCQ whole blood levels be checked routinely for maximum dosing efficacy “but also to identify patients who are missing so many doses that they are subtherapeutic.”
She noted that nonadherence is a major issue among patients with systemic lupus erythematosus, especially among those who are younger and newly diagnosed.
Dr. Garg and Dr. Petri both said that insurance does not automatically cover the costs of checking HCQ levels in the blood, which has been a consistent frustration in the field.
“Having more data validates the reason to do it,” Dr. Garg said.
She added that “HCQ blood levels are still not done routinely in all patients, and at times the test needs to be sent to outside laboratories.”
Importance for patients with CKD
Many patient factors can affect how the body absorbs HCQ, Dr. Garg said, so finding the right level that is safe and maximizes benefit individually is important.
The findings are particularly important for patients with chronic kidney disease (CKD) of stage 3 or higher, Dr. Garg said.
The authors write that because kidneys clear more than half of all HCQ, impaired kidney function could boost HCQ blood levels, risking toxicity.
“Our study found a sixfold higher odds of having supratherapeutic HCQ blood levels in patients with CKD stage ≥ 3,” they write.
Dr. Garg added that if blood levels cannot be analyzed in all patients, they could be prioritized in patients with CKD stage 3 or above because these patients are at “higher risk of being underdosed with arbitrary reductions in HCQ doses and carry higher risk of toxicity if HCQ doses are not adjusted.”
More research will uncover other high-risk groups who would benefit most from close monitoring of HCQ blood levels, she said.
The study was supported by an award from the University of Wisconsin–Madison, and by an award to the institution from the National Institutes of Health National Center for Advancing Translational Sciences. Dr. Garg and coauthors as well as Dr. Petri report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A blood-level reference range of 750-1,200 ng/mL of hydroxychloroquine (HCQ) has been linked with 71% lower odds of active lupus, new research suggests.
Researchers, led by Shivani Garg, MD, assistant professor of rheumatology at the University of Wisconsin–Madison, also found that maintaining levels within that range lowered the odds for flares by 26% over 9 months of follow-up.
The findings, published in Arthritis Care & Research, could help clinicians personalize HCQ doses to maximize efficacy for each patient.
HCQ levels in whole blood and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) were measured during a baseline visit and again during a routine follow-up visit.
Among 158 baseline patient visits, 19% of the patients had active lupus. Researchers longitudinally followed 42 patients using convenience sampling, and among those patients, 7 (17%) had flares at the follow-up visit.
Michelle Petri, MD, MPH, director of the Johns Hopkins Lupus Center in Baltimore, called the findings that suggest upper and lower efficacy and safety boundaries “very important.”
The findings highlight that guidelines for dosing don’t match efficacy needs, said Dr. Petri, who was not involved with the study.
“HCQ dosing has been under threat by guidelines insisting that the dose should be < 5 mg/kg even though this does not correlate with efficacy,” she said. “Basically, if we dose too low, the patient loses efficacy. If we dose too high, the risk of retinopathy increases, so this paper hones down the sweet spot.”
A 2014 study identified a higher eye toxicity risk with HCQ doses > 5 mg/kg per day, and the American Academy of Ophthalmology followed with guidelines for HCQ retinopathy screening that recommended reducing HCQ to ≤ 5 mg/kg per day.
Dr. Petri said that the range Dr. Garg and colleagues identified corroborates findings in one of her team’s studies.
That paper showed that thrombotic events dropped by 69% in patients with average HCQ blood levels ≥ 1,068 ng/mL vs. those with levels < 648 ng/mL (relative risk, 0.31; 95% confidence interval, 0.11-0.86; P = .024).
Dr. Garg and colleagues write that current lupus treatment guidelines do not universally recommend blood level monitoring for HCQ “as different cut-points have been used to define therapeutic HCQ blood levels and an effective range of HCQ levels with upper and lower bounds for efficacy has not been extensively examined.”
When to start checking levels
Blood levels of HCQ can be checked for any patient, although 1-3 months after starting the medication may be best to get steady levels, Dr. Garg told this news organization.
Dr. Petri said that she recommends HCQ whole blood levels be checked routinely for maximum dosing efficacy “but also to identify patients who are missing so many doses that they are subtherapeutic.”
She noted that nonadherence is a major issue among patients with systemic lupus erythematosus, especially among those who are younger and newly diagnosed.
Dr. Garg and Dr. Petri both said that insurance does not automatically cover the costs of checking HCQ levels in the blood, which has been a consistent frustration in the field.
“Having more data validates the reason to do it,” Dr. Garg said.
She added that “HCQ blood levels are still not done routinely in all patients, and at times the test needs to be sent to outside laboratories.”
Importance for patients with CKD
Many patient factors can affect how the body absorbs HCQ, Dr. Garg said, so finding the right level that is safe and maximizes benefit individually is important.
The findings are particularly important for patients with chronic kidney disease (CKD) of stage 3 or higher, Dr. Garg said.
The authors write that because kidneys clear more than half of all HCQ, impaired kidney function could boost HCQ blood levels, risking toxicity.
“Our study found a sixfold higher odds of having supratherapeutic HCQ blood levels in patients with CKD stage ≥ 3,” they write.
Dr. Garg added that if blood levels cannot be analyzed in all patients, they could be prioritized in patients with CKD stage 3 or above because these patients are at “higher risk of being underdosed with arbitrary reductions in HCQ doses and carry higher risk of toxicity if HCQ doses are not adjusted.”
More research will uncover other high-risk groups who would benefit most from close monitoring of HCQ blood levels, she said.
The study was supported by an award from the University of Wisconsin–Madison, and by an award to the institution from the National Institutes of Health National Center for Advancing Translational Sciences. Dr. Garg and coauthors as well as Dr. Petri report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A blood-level reference range of 750-1,200 ng/mL of hydroxychloroquine (HCQ) has been linked with 71% lower odds of active lupus, new research suggests.
Researchers, led by Shivani Garg, MD, assistant professor of rheumatology at the University of Wisconsin–Madison, also found that maintaining levels within that range lowered the odds for flares by 26% over 9 months of follow-up.
The findings, published in Arthritis Care & Research, could help clinicians personalize HCQ doses to maximize efficacy for each patient.
HCQ levels in whole blood and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) were measured during a baseline visit and again during a routine follow-up visit.
Among 158 baseline patient visits, 19% of the patients had active lupus. Researchers longitudinally followed 42 patients using convenience sampling, and among those patients, 7 (17%) had flares at the follow-up visit.
Michelle Petri, MD, MPH, director of the Johns Hopkins Lupus Center in Baltimore, called the findings that suggest upper and lower efficacy and safety boundaries “very important.”
The findings highlight that guidelines for dosing don’t match efficacy needs, said Dr. Petri, who was not involved with the study.
“HCQ dosing has been under threat by guidelines insisting that the dose should be < 5 mg/kg even though this does not correlate with efficacy,” she said. “Basically, if we dose too low, the patient loses efficacy. If we dose too high, the risk of retinopathy increases, so this paper hones down the sweet spot.”
A 2014 study identified a higher eye toxicity risk with HCQ doses > 5 mg/kg per day, and the American Academy of Ophthalmology followed with guidelines for HCQ retinopathy screening that recommended reducing HCQ to ≤ 5 mg/kg per day.
Dr. Petri said that the range Dr. Garg and colleagues identified corroborates findings in one of her team’s studies.
That paper showed that thrombotic events dropped by 69% in patients with average HCQ blood levels ≥ 1,068 ng/mL vs. those with levels < 648 ng/mL (relative risk, 0.31; 95% confidence interval, 0.11-0.86; P = .024).
Dr. Garg and colleagues write that current lupus treatment guidelines do not universally recommend blood level monitoring for HCQ “as different cut-points have been used to define therapeutic HCQ blood levels and an effective range of HCQ levels with upper and lower bounds for efficacy has not been extensively examined.”
When to start checking levels
Blood levels of HCQ can be checked for any patient, although 1-3 months after starting the medication may be best to get steady levels, Dr. Garg told this news organization.
Dr. Petri said that she recommends HCQ whole blood levels be checked routinely for maximum dosing efficacy “but also to identify patients who are missing so many doses that they are subtherapeutic.”
She noted that nonadherence is a major issue among patients with systemic lupus erythematosus, especially among those who are younger and newly diagnosed.
Dr. Garg and Dr. Petri both said that insurance does not automatically cover the costs of checking HCQ levels in the blood, which has been a consistent frustration in the field.
“Having more data validates the reason to do it,” Dr. Garg said.
She added that “HCQ blood levels are still not done routinely in all patients, and at times the test needs to be sent to outside laboratories.”
Importance for patients with CKD
Many patient factors can affect how the body absorbs HCQ, Dr. Garg said, so finding the right level that is safe and maximizes benefit individually is important.
The findings are particularly important for patients with chronic kidney disease (CKD) of stage 3 or higher, Dr. Garg said.
The authors write that because kidneys clear more than half of all HCQ, impaired kidney function could boost HCQ blood levels, risking toxicity.
“Our study found a sixfold higher odds of having supratherapeutic HCQ blood levels in patients with CKD stage ≥ 3,” they write.
Dr. Garg added that if blood levels cannot be analyzed in all patients, they could be prioritized in patients with CKD stage 3 or above because these patients are at “higher risk of being underdosed with arbitrary reductions in HCQ doses and carry higher risk of toxicity if HCQ doses are not adjusted.”
More research will uncover other high-risk groups who would benefit most from close monitoring of HCQ blood levels, she said.
The study was supported by an award from the University of Wisconsin–Madison, and by an award to the institution from the National Institutes of Health National Center for Advancing Translational Sciences. Dr. Garg and coauthors as well as Dr. Petri report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ARTHRITIS CARE & RESEARCH
Blueprint to curb postop opioids after pancreatic resection
TOPLINE:
Implementing a post-surgery protocol that has undergone incremental changes over time significantly reduced inpatient and discharge opioid volumes while maintaining pain control after pancreatic cancer surgery.
METHODOLOGY:
- To reduce opioid dependence, misuse, and diversion, Centers for Disease Control and Prevention guidelines emphasize strategies to minimize opioid prescribing for managing pain. Still, opioid prescribing following surgery remains common practice.
- In the current study,
- The study evaluated three sequential protocols implemented over a period of about 6 years, from 2016 to 2022.
- In the final version, a standardized three-drug nonopioid bundle (acetaminophen, celecoxib, and methocarbamol) was initiated intravenously in the recovery room, after which the patient was given oral agents on postoperative day 1.
- The primary outcome measure was inpatient and discharge opioid volume in oral morphine equivalents (OMEs) across the three pathways.
TAKEAWAY:
- Opioid use significantly decreased with each sequential pathway refinement.
- For inpatients, total OME decreased by more than 55% across the pathways from a median of 290 mg to 184 mg and finally to 129 mg (P < .001).
- Median discharge OME dropped from 150 mg to 25 mg and then to 0 mg across the pathways (P < .001).
- With the final version of the pathway, more than half of patients (52.5%) had opioid-free discharges, compared with only 7.2% in the first pathway. Pain scores remained stable at 3 or less; the number of postdischarge refill requests was unchanged.
IN PRACTICE:
“Our findings suggest that reduction of postoperative opioid dissemination through opioid-free discharge after pancreatectomy and other major cancer operations may be realistic and feasible by following this no-cost blueprint,” the authors concluded. In an accompanying editorial, Melissa Hogg, MD, from NorthShore University Health System in Evanston, Ill., said the “study inspired me to update our institution’s [early recovery after surgery] protocol to reduce and eliminate opioid prescriptions.”
SOURCE:
The study was led by Ching-Wei D. Tzeng, MD, of the University of Texas MD Anderson Cancer Center, Houston. It was published online in JAMA Surgery.
LIMITATIONS:
The study evaluated the opioid protocol at a single center, which may limit the generalizability of the findings. The researchers did not receive patient feedback on pain control expectations or postoperative quality of life.
DISCLOSURES:
Dr. Tzeng reported receiving consultant fees and a sponsored research agreement from PanTher outside the submitted work. Dr. Hogg reported receiving training and travel funds from Intuitive Money. No other disclosures or outside funding were reported.
A version of this article appeared on Medscape.com.
TOPLINE:
Implementing a post-surgery protocol that has undergone incremental changes over time significantly reduced inpatient and discharge opioid volumes while maintaining pain control after pancreatic cancer surgery.
METHODOLOGY:
- To reduce opioid dependence, misuse, and diversion, Centers for Disease Control and Prevention guidelines emphasize strategies to minimize opioid prescribing for managing pain. Still, opioid prescribing following surgery remains common practice.
- In the current study,
- The study evaluated three sequential protocols implemented over a period of about 6 years, from 2016 to 2022.
- In the final version, a standardized three-drug nonopioid bundle (acetaminophen, celecoxib, and methocarbamol) was initiated intravenously in the recovery room, after which the patient was given oral agents on postoperative day 1.
- The primary outcome measure was inpatient and discharge opioid volume in oral morphine equivalents (OMEs) across the three pathways.
TAKEAWAY:
- Opioid use significantly decreased with each sequential pathway refinement.
- For inpatients, total OME decreased by more than 55% across the pathways from a median of 290 mg to 184 mg and finally to 129 mg (P < .001).
- Median discharge OME dropped from 150 mg to 25 mg and then to 0 mg across the pathways (P < .001).
- With the final version of the pathway, more than half of patients (52.5%) had opioid-free discharges, compared with only 7.2% in the first pathway. Pain scores remained stable at 3 or less; the number of postdischarge refill requests was unchanged.
IN PRACTICE:
“Our findings suggest that reduction of postoperative opioid dissemination through opioid-free discharge after pancreatectomy and other major cancer operations may be realistic and feasible by following this no-cost blueprint,” the authors concluded. In an accompanying editorial, Melissa Hogg, MD, from NorthShore University Health System in Evanston, Ill., said the “study inspired me to update our institution’s [early recovery after surgery] protocol to reduce and eliminate opioid prescriptions.”
SOURCE:
The study was led by Ching-Wei D. Tzeng, MD, of the University of Texas MD Anderson Cancer Center, Houston. It was published online in JAMA Surgery.
LIMITATIONS:
The study evaluated the opioid protocol at a single center, which may limit the generalizability of the findings. The researchers did not receive patient feedback on pain control expectations or postoperative quality of life.
DISCLOSURES:
Dr. Tzeng reported receiving consultant fees and a sponsored research agreement from PanTher outside the submitted work. Dr. Hogg reported receiving training and travel funds from Intuitive Money. No other disclosures or outside funding were reported.
A version of this article appeared on Medscape.com.
TOPLINE:
Implementing a post-surgery protocol that has undergone incremental changes over time significantly reduced inpatient and discharge opioid volumes while maintaining pain control after pancreatic cancer surgery.
METHODOLOGY:
- To reduce opioid dependence, misuse, and diversion, Centers for Disease Control and Prevention guidelines emphasize strategies to minimize opioid prescribing for managing pain. Still, opioid prescribing following surgery remains common practice.
- In the current study,
- The study evaluated three sequential protocols implemented over a period of about 6 years, from 2016 to 2022.
- In the final version, a standardized three-drug nonopioid bundle (acetaminophen, celecoxib, and methocarbamol) was initiated intravenously in the recovery room, after which the patient was given oral agents on postoperative day 1.
- The primary outcome measure was inpatient and discharge opioid volume in oral morphine equivalents (OMEs) across the three pathways.
TAKEAWAY:
- Opioid use significantly decreased with each sequential pathway refinement.
- For inpatients, total OME decreased by more than 55% across the pathways from a median of 290 mg to 184 mg and finally to 129 mg (P < .001).
- Median discharge OME dropped from 150 mg to 25 mg and then to 0 mg across the pathways (P < .001).
- With the final version of the pathway, more than half of patients (52.5%) had opioid-free discharges, compared with only 7.2% in the first pathway. Pain scores remained stable at 3 or less; the number of postdischarge refill requests was unchanged.
IN PRACTICE:
“Our findings suggest that reduction of postoperative opioid dissemination through opioid-free discharge after pancreatectomy and other major cancer operations may be realistic and feasible by following this no-cost blueprint,” the authors concluded. In an accompanying editorial, Melissa Hogg, MD, from NorthShore University Health System in Evanston, Ill., said the “study inspired me to update our institution’s [early recovery after surgery] protocol to reduce and eliminate opioid prescriptions.”
SOURCE:
The study was led by Ching-Wei D. Tzeng, MD, of the University of Texas MD Anderson Cancer Center, Houston. It was published online in JAMA Surgery.
LIMITATIONS:
The study evaluated the opioid protocol at a single center, which may limit the generalizability of the findings. The researchers did not receive patient feedback on pain control expectations or postoperative quality of life.
DISCLOSURES:
Dr. Tzeng reported receiving consultant fees and a sponsored research agreement from PanTher outside the submitted work. Dr. Hogg reported receiving training and travel funds from Intuitive Money. No other disclosures or outside funding were reported.
A version of this article appeared on Medscape.com.
FROM JAMA SURGERY