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People of color missing in inflammatory bowel disease trials
LAS VEGAS – Clinical trials of treatments for inflammatory bowel disease (IBD) have disproportionately enrolled White people, researchers say.
These skewed demographics could result in researchers overlooking differences in how the disease and its treatments might affect other racial and ethnic groups, said Jellyana Peraza, MD, a chief resident at Albert Einstein College of Medicine, New York.
“The only way we can determine that therapies work differently in different populations is by including those populations in these clinical trials,” she said in an interview. “We think that diversity should be present, and that will answer some questions about the pathogenesis of the disease in general.”
Dr. Peraza presented the findings at the annual meeting of the American College of Gastroenterology.
Previous studies have found that, in trials of other conditions, such as cancer and cardiovascular disease, White people have been disproportionately represented. However, little research has been conducted regarding race and ethnicity in IBD trials.
To fill that gap, Dr. Peraza and colleagues analyzed data from completed trials through the U.S. National Library of Medicine’s registry, ClinicalTrials.gov, for the period from 2000 to 2020.
They found 22 trials conducted exclusively in the United States and 56 conducted in other countries that reported the race or ethnicity of participants; 54 trials did not include this information.
With regard to the prevalence of IBD in White people and Asian people, these populations were overrepresented in U.S. clinical trials. All other groups were underrepresented.
The researchers calculated the odds ratio of being included in an IBD clinical trial for each group. Compared with White people, all the other groups were less likely to be included except for Asian people, who were 85% more likely to be included. These ORs were all statistically significant (P < .03) except for Hispanic people (OR, 0.81; 95% confidence interval, 0.65-1.01; P = .06).
It’s not clear why Asian people are overrepresented, Dr. Peraza said. “Honestly, that was kind of surprising for us. We initially thought that could be related to where these studies were conducted, for example, if some of them were conducted on the West Coast, where maybe more Asian communities are located. However, we didn’t find any specific association between location and Asian representation.”
IBD is more prevalent among White people, although its prevalence is increasing among other groups, Dr. Peraza said. However, that is not reflected in the trials. In an analysis of data in 5-year increments, the researchers found that the participation of White and Hispanic people in IBD trials had not changed much, whereas the participation of Black people had declined, and the participation of Asian and Native American people had increased.
On the basis of work of other researchers, Dr. Peraza said that people of color are as willing to participate in trials as White people. “There is not so much a mistrust as a lack of education and a lack of access to the tertiary centers or the centers where these studies are conducted,” she said.
Clinical trial investigators should recruit more participants from community centers, and health care practitioners should talk about the trials with people in underrepresented groups, she said. “They should have the conversation with their patients about how these clinical trials can benefit the evolution of their diseases.”
One research center that is working hard to diversify its IBD trials is the Ohio State University IBD Center, Columbus, said Anita Afzali, MD, its medical director.
“We have a great team that works actively on the recruitment of all patients,” she said in an interview. “Oftentimes, it just takes a little bit of education and spending time with the patient on discussing what the options are for them.”
Some research indicates that Black people with IBD are more likely to have fistulizing disease, Dr. Afzali said. “However, it doesn’t come so much of their differences in phenotype that we’re seeing but more so the differences in access to care and getting the appropriate therapy in a timely way.”
Dr. Peraza and Dr. Afzali disclosed no relevant financial relationships.
AGA applauds researchers who are working to raise our awareness of health disparities in digestive diseases. AGA is committed to addressing this important societal issue head on. Learn more about AGA’s commitment through the AGA Equity Project.
A version of this article first appeared on Medscape.com.
LAS VEGAS – Clinical trials of treatments for inflammatory bowel disease (IBD) have disproportionately enrolled White people, researchers say.
These skewed demographics could result in researchers overlooking differences in how the disease and its treatments might affect other racial and ethnic groups, said Jellyana Peraza, MD, a chief resident at Albert Einstein College of Medicine, New York.
“The only way we can determine that therapies work differently in different populations is by including those populations in these clinical trials,” she said in an interview. “We think that diversity should be present, and that will answer some questions about the pathogenesis of the disease in general.”
Dr. Peraza presented the findings at the annual meeting of the American College of Gastroenterology.
Previous studies have found that, in trials of other conditions, such as cancer and cardiovascular disease, White people have been disproportionately represented. However, little research has been conducted regarding race and ethnicity in IBD trials.
To fill that gap, Dr. Peraza and colleagues analyzed data from completed trials through the U.S. National Library of Medicine’s registry, ClinicalTrials.gov, for the period from 2000 to 2020.
They found 22 trials conducted exclusively in the United States and 56 conducted in other countries that reported the race or ethnicity of participants; 54 trials did not include this information.
With regard to the prevalence of IBD in White people and Asian people, these populations were overrepresented in U.S. clinical trials. All other groups were underrepresented.
The researchers calculated the odds ratio of being included in an IBD clinical trial for each group. Compared with White people, all the other groups were less likely to be included except for Asian people, who were 85% more likely to be included. These ORs were all statistically significant (P < .03) except for Hispanic people (OR, 0.81; 95% confidence interval, 0.65-1.01; P = .06).
It’s not clear why Asian people are overrepresented, Dr. Peraza said. “Honestly, that was kind of surprising for us. We initially thought that could be related to where these studies were conducted, for example, if some of them were conducted on the West Coast, where maybe more Asian communities are located. However, we didn’t find any specific association between location and Asian representation.”
IBD is more prevalent among White people, although its prevalence is increasing among other groups, Dr. Peraza said. However, that is not reflected in the trials. In an analysis of data in 5-year increments, the researchers found that the participation of White and Hispanic people in IBD trials had not changed much, whereas the participation of Black people had declined, and the participation of Asian and Native American people had increased.
On the basis of work of other researchers, Dr. Peraza said that people of color are as willing to participate in trials as White people. “There is not so much a mistrust as a lack of education and a lack of access to the tertiary centers or the centers where these studies are conducted,” she said.
Clinical trial investigators should recruit more participants from community centers, and health care practitioners should talk about the trials with people in underrepresented groups, she said. “They should have the conversation with their patients about how these clinical trials can benefit the evolution of their diseases.”
One research center that is working hard to diversify its IBD trials is the Ohio State University IBD Center, Columbus, said Anita Afzali, MD, its medical director.
“We have a great team that works actively on the recruitment of all patients,” she said in an interview. “Oftentimes, it just takes a little bit of education and spending time with the patient on discussing what the options are for them.”
Some research indicates that Black people with IBD are more likely to have fistulizing disease, Dr. Afzali said. “However, it doesn’t come so much of their differences in phenotype that we’re seeing but more so the differences in access to care and getting the appropriate therapy in a timely way.”
Dr. Peraza and Dr. Afzali disclosed no relevant financial relationships.
AGA applauds researchers who are working to raise our awareness of health disparities in digestive diseases. AGA is committed to addressing this important societal issue head on. Learn more about AGA’s commitment through the AGA Equity Project.
A version of this article first appeared on Medscape.com.
LAS VEGAS – Clinical trials of treatments for inflammatory bowel disease (IBD) have disproportionately enrolled White people, researchers say.
These skewed demographics could result in researchers overlooking differences in how the disease and its treatments might affect other racial and ethnic groups, said Jellyana Peraza, MD, a chief resident at Albert Einstein College of Medicine, New York.
“The only way we can determine that therapies work differently in different populations is by including those populations in these clinical trials,” she said in an interview. “We think that diversity should be present, and that will answer some questions about the pathogenesis of the disease in general.”
Dr. Peraza presented the findings at the annual meeting of the American College of Gastroenterology.
Previous studies have found that, in trials of other conditions, such as cancer and cardiovascular disease, White people have been disproportionately represented. However, little research has been conducted regarding race and ethnicity in IBD trials.
To fill that gap, Dr. Peraza and colleagues analyzed data from completed trials through the U.S. National Library of Medicine’s registry, ClinicalTrials.gov, for the period from 2000 to 2020.
They found 22 trials conducted exclusively in the United States and 56 conducted in other countries that reported the race or ethnicity of participants; 54 trials did not include this information.
With regard to the prevalence of IBD in White people and Asian people, these populations were overrepresented in U.S. clinical trials. All other groups were underrepresented.
The researchers calculated the odds ratio of being included in an IBD clinical trial for each group. Compared with White people, all the other groups were less likely to be included except for Asian people, who were 85% more likely to be included. These ORs were all statistically significant (P < .03) except for Hispanic people (OR, 0.81; 95% confidence interval, 0.65-1.01; P = .06).
It’s not clear why Asian people are overrepresented, Dr. Peraza said. “Honestly, that was kind of surprising for us. We initially thought that could be related to where these studies were conducted, for example, if some of them were conducted on the West Coast, where maybe more Asian communities are located. However, we didn’t find any specific association between location and Asian representation.”
IBD is more prevalent among White people, although its prevalence is increasing among other groups, Dr. Peraza said. However, that is not reflected in the trials. In an analysis of data in 5-year increments, the researchers found that the participation of White and Hispanic people in IBD trials had not changed much, whereas the participation of Black people had declined, and the participation of Asian and Native American people had increased.
On the basis of work of other researchers, Dr. Peraza said that people of color are as willing to participate in trials as White people. “There is not so much a mistrust as a lack of education and a lack of access to the tertiary centers or the centers where these studies are conducted,” she said.
Clinical trial investigators should recruit more participants from community centers, and health care practitioners should talk about the trials with people in underrepresented groups, she said. “They should have the conversation with their patients about how these clinical trials can benefit the evolution of their diseases.”
One research center that is working hard to diversify its IBD trials is the Ohio State University IBD Center, Columbus, said Anita Afzali, MD, its medical director.
“We have a great team that works actively on the recruitment of all patients,” she said in an interview. “Oftentimes, it just takes a little bit of education and spending time with the patient on discussing what the options are for them.”
Some research indicates that Black people with IBD are more likely to have fistulizing disease, Dr. Afzali said. “However, it doesn’t come so much of their differences in phenotype that we’re seeing but more so the differences in access to care and getting the appropriate therapy in a timely way.”
Dr. Peraza and Dr. Afzali disclosed no relevant financial relationships.
AGA applauds researchers who are working to raise our awareness of health disparities in digestive diseases. AGA is committed to addressing this important societal issue head on. Learn more about AGA’s commitment through the AGA Equity Project.
A version of this article first appeared on Medscape.com.
AT ACG 2021
Spin doctors
The 1992 presidential election fell during my last year of medical school. I remember watching the three-way debates over at a friend’s apartment.
After each one they’d cut to representatives of each candidate, and for the first time I heard the phrase “spin” or “spin doctors” referring to those who put a very selective angle on their candidates performance, no matter how bad it may have been, to make it sound like something amazingly awesome. This trend, driven now by the Internet and the 24/7 news cycle, has only accelerated over time.
Recently, I’ve been reading slides, press releases, and preliminary reports for the many agents that are seeking to cure Alzheimer’s disease. A desperately needed effort if ever there was one.
Yet, I get the same feeling I did in 1992. It seems like a lot of the statements are more selective than real: a carefully worded attempt to emphasize the good points and minimize the bad. Granted that’s the nature of many things, but here, in a world of a few percentage points, it seems more conspicuous than usual.
After all, even a non–statistically significant improvement of 1%-2% can look really good if you use the right graph style or comparison scale.
When I read such articles now, I find myself wondering if the drug really works or if the spin doctors have gotten so good at making even the most minuscule numbers look impressive that I can’t tell the difference. In theory many of these drugs should work, but, in Alzheimer’s disease “should” and “does” haven’t matched up particularly well to date.
To be clear, I’m not cheering for these drugs to fail. On the contrary, if one showed overwhelming evidence of benefit (as opposed to having to be spun to look good), I’d be thrilled. Along with the patients and their support circles, it’s their doctors who watch the sad downhill slide of dementia, with the patients dying long before their bodies do. I would be thrilled to be able to offer them something that had clearly meaningful benefit with a decent safety profile.
But, barring more solid data,
I hope I’m wrong.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
The 1992 presidential election fell during my last year of medical school. I remember watching the three-way debates over at a friend’s apartment.
After each one they’d cut to representatives of each candidate, and for the first time I heard the phrase “spin” or “spin doctors” referring to those who put a very selective angle on their candidates performance, no matter how bad it may have been, to make it sound like something amazingly awesome. This trend, driven now by the Internet and the 24/7 news cycle, has only accelerated over time.
Recently, I’ve been reading slides, press releases, and preliminary reports for the many agents that are seeking to cure Alzheimer’s disease. A desperately needed effort if ever there was one.
Yet, I get the same feeling I did in 1992. It seems like a lot of the statements are more selective than real: a carefully worded attempt to emphasize the good points and minimize the bad. Granted that’s the nature of many things, but here, in a world of a few percentage points, it seems more conspicuous than usual.
After all, even a non–statistically significant improvement of 1%-2% can look really good if you use the right graph style or comparison scale.
When I read such articles now, I find myself wondering if the drug really works or if the spin doctors have gotten so good at making even the most minuscule numbers look impressive that I can’t tell the difference. In theory many of these drugs should work, but, in Alzheimer’s disease “should” and “does” haven’t matched up particularly well to date.
To be clear, I’m not cheering for these drugs to fail. On the contrary, if one showed overwhelming evidence of benefit (as opposed to having to be spun to look good), I’d be thrilled. Along with the patients and their support circles, it’s their doctors who watch the sad downhill slide of dementia, with the patients dying long before their bodies do. I would be thrilled to be able to offer them something that had clearly meaningful benefit with a decent safety profile.
But, barring more solid data,
I hope I’m wrong.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
The 1992 presidential election fell during my last year of medical school. I remember watching the three-way debates over at a friend’s apartment.
After each one they’d cut to representatives of each candidate, and for the first time I heard the phrase “spin” or “spin doctors” referring to those who put a very selective angle on their candidates performance, no matter how bad it may have been, to make it sound like something amazingly awesome. This trend, driven now by the Internet and the 24/7 news cycle, has only accelerated over time.
Recently, I’ve been reading slides, press releases, and preliminary reports for the many agents that are seeking to cure Alzheimer’s disease. A desperately needed effort if ever there was one.
Yet, I get the same feeling I did in 1992. It seems like a lot of the statements are more selective than real: a carefully worded attempt to emphasize the good points and minimize the bad. Granted that’s the nature of many things, but here, in a world of a few percentage points, it seems more conspicuous than usual.
After all, even a non–statistically significant improvement of 1%-2% can look really good if you use the right graph style or comparison scale.
When I read such articles now, I find myself wondering if the drug really works or if the spin doctors have gotten so good at making even the most minuscule numbers look impressive that I can’t tell the difference. In theory many of these drugs should work, but, in Alzheimer’s disease “should” and “does” haven’t matched up particularly well to date.
To be clear, I’m not cheering for these drugs to fail. On the contrary, if one showed overwhelming evidence of benefit (as opposed to having to be spun to look good), I’d be thrilled. Along with the patients and their support circles, it’s their doctors who watch the sad downhill slide of dementia, with the patients dying long before their bodies do. I would be thrilled to be able to offer them something that had clearly meaningful benefit with a decent safety profile.
But, barring more solid data,
I hope I’m wrong.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
The third generation of therapeutic innovation and the future of psychopharmacology
The field of psychiatric therapeutics is now experiencing its third generation of progress. No sooner had the pace of innovation in psychiatry and psychopharmacology hit the doldrums a few years ago, following the dwindling of the second generation of progress, than the current third generation of new drug development in psychopharmacology was born.
That is, the first generation of discovery of psychiatric medications in the 1960s and 1970s ushered in the first known psychotropic drugs, such as the tricyclic antidepressants, as well as major and minor tranquilizers, such as chlorpromazine and benzodiazepines, only to fizzle out in the 1980s. By the 1990s, the second generation of innovation in psychopharmacology was in full swing, with the “new” serotonin selective reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors for depression, and the “atypical” antipsychotics for schizophrenia. However, soon after the turn of the century, pessimism for psychiatric therapeutics crept in again, and “big Pharma” abandoned their psychopharmacology programs in favor of other therapeutic areas. Surprisingly, the current “green shoots” of new ideas sprouting in our field today have not come from traditional big Pharma returning to psychiatry, but largely from small, innovative companies. These new entrepreneurial small pharmas and biotechs have found several new therapeutic targets. Furthermore, current innovation in psychopharmacology is increasingly following a paradigm shift away from DSM-5 disorders and instead to domains or symptoms of psychopathology that cut across numerous psychiatric conditions (transdiagnostic model).
So, what are the new therapeutic mechanisms of this current third generation of innovation in psychopharmacology? Not all of these can be discussed here, but 2 examples of new approaches to psychosis deserve special mention because, for the first time in 70 years, they turn away from blocking postsynaptic dopamine D2 receptors to treat psychosis and instead stimulate receptors in other neurotransmitter systems that are linked to dopamine neurons in a network “upstream.” That is, trace amine-associated receptor 1 (TAAR1) agonists target the pre-synaptic dopamine neuron, where dopamine synthesis and release are too high in psychosis, and cause dopamine synthesis to be reduced so that blockade of postsynaptic dopamine receptors is no longer necessary (Table 1 and Figure 1).1 Similarly, muscarinic cholinergic 1 and 4 receptor agonists target excitatory cholinergic neurons upstream, and turn down their stimulation of dopamine neurons, thereby reducing dopamine release so that postsynaptic blockade of dopamine receptors is also not necessary to treat psychosis with this mechanism (Table 1 and Figure 2).1 A similar mechanism of reducing upstream stimulation of dopamine release by serotonin has led to demonstration of antipsychotic actions of blocking this stimulation at serotonin 2A receptors (Table 2), and multiple approaches to enhancing deficient glutamate actions upstream are also under investigation for the treatment of psychosis. 1
Another major area of innovation in psychopharmacology worthy of emphasis is the rapid induction of neurogenesis that is associated with rapid reduction in the symptoms of depression, even when many conventional treatments have failed. Blockade of N-methyl-
that may hypothetically drive rapid recovery from depression.1 Proof of this concept was first shown with intravenous ketamine, and then intranasal esketamine, and now the oral NMDA antagonists dextromethorphan (combined with either bupropion or quinidine) and esmethadone (Table 1).1 Interestingly, this same mechanism may lead to a novel treatment of agitation in Alzheimer’s dementia as well.1
Continue to: Yet another mechanism...
Yet another mechanism of potentially rapid onset antidepressant action is that of the novel agents known as neuroactive steroids that have a novel action at gamma aminobutyric acid A (GABA-A) receptors that are not sensitive to benzodiazepines (as well as those that are) (Table 1 and Figure 3).1 Finally, psychedelic drugs that target serotonin receptors such as psilocybin and 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) seem to also have rapid onset of both neurogenesis and antidepressant action.
The future of psychopharmacology is clearly going to be amazing.
1. Stahl SM. Stahl’s Essential Psychopharmacology. 5th ed. Cambridge University Press; 2021.
The field of psychiatric therapeutics is now experiencing its third generation of progress. No sooner had the pace of innovation in psychiatry and psychopharmacology hit the doldrums a few years ago, following the dwindling of the second generation of progress, than the current third generation of new drug development in psychopharmacology was born.
That is, the first generation of discovery of psychiatric medications in the 1960s and 1970s ushered in the first known psychotropic drugs, such as the tricyclic antidepressants, as well as major and minor tranquilizers, such as chlorpromazine and benzodiazepines, only to fizzle out in the 1980s. By the 1990s, the second generation of innovation in psychopharmacology was in full swing, with the “new” serotonin selective reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors for depression, and the “atypical” antipsychotics for schizophrenia. However, soon after the turn of the century, pessimism for psychiatric therapeutics crept in again, and “big Pharma” abandoned their psychopharmacology programs in favor of other therapeutic areas. Surprisingly, the current “green shoots” of new ideas sprouting in our field today have not come from traditional big Pharma returning to psychiatry, but largely from small, innovative companies. These new entrepreneurial small pharmas and biotechs have found several new therapeutic targets. Furthermore, current innovation in psychopharmacology is increasingly following a paradigm shift away from DSM-5 disorders and instead to domains or symptoms of psychopathology that cut across numerous psychiatric conditions (transdiagnostic model).
So, what are the new therapeutic mechanisms of this current third generation of innovation in psychopharmacology? Not all of these can be discussed here, but 2 examples of new approaches to psychosis deserve special mention because, for the first time in 70 years, they turn away from blocking postsynaptic dopamine D2 receptors to treat psychosis and instead stimulate receptors in other neurotransmitter systems that are linked to dopamine neurons in a network “upstream.” That is, trace amine-associated receptor 1 (TAAR1) agonists target the pre-synaptic dopamine neuron, where dopamine synthesis and release are too high in psychosis, and cause dopamine synthesis to be reduced so that blockade of postsynaptic dopamine receptors is no longer necessary (Table 1 and Figure 1).1 Similarly, muscarinic cholinergic 1 and 4 receptor agonists target excitatory cholinergic neurons upstream, and turn down their stimulation of dopamine neurons, thereby reducing dopamine release so that postsynaptic blockade of dopamine receptors is also not necessary to treat psychosis with this mechanism (Table 1 and Figure 2).1 A similar mechanism of reducing upstream stimulation of dopamine release by serotonin has led to demonstration of antipsychotic actions of blocking this stimulation at serotonin 2A receptors (Table 2), and multiple approaches to enhancing deficient glutamate actions upstream are also under investigation for the treatment of psychosis. 1
Another major area of innovation in psychopharmacology worthy of emphasis is the rapid induction of neurogenesis that is associated with rapid reduction in the symptoms of depression, even when many conventional treatments have failed. Blockade of N-methyl-
that may hypothetically drive rapid recovery from depression.1 Proof of this concept was first shown with intravenous ketamine, and then intranasal esketamine, and now the oral NMDA antagonists dextromethorphan (combined with either bupropion or quinidine) and esmethadone (Table 1).1 Interestingly, this same mechanism may lead to a novel treatment of agitation in Alzheimer’s dementia as well.1
Continue to: Yet another mechanism...
Yet another mechanism of potentially rapid onset antidepressant action is that of the novel agents known as neuroactive steroids that have a novel action at gamma aminobutyric acid A (GABA-A) receptors that are not sensitive to benzodiazepines (as well as those that are) (Table 1 and Figure 3).1 Finally, psychedelic drugs that target serotonin receptors such as psilocybin and 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) seem to also have rapid onset of both neurogenesis and antidepressant action.
The future of psychopharmacology is clearly going to be amazing.
The field of psychiatric therapeutics is now experiencing its third generation of progress. No sooner had the pace of innovation in psychiatry and psychopharmacology hit the doldrums a few years ago, following the dwindling of the second generation of progress, than the current third generation of new drug development in psychopharmacology was born.
That is, the first generation of discovery of psychiatric medications in the 1960s and 1970s ushered in the first known psychotropic drugs, such as the tricyclic antidepressants, as well as major and minor tranquilizers, such as chlorpromazine and benzodiazepines, only to fizzle out in the 1980s. By the 1990s, the second generation of innovation in psychopharmacology was in full swing, with the “new” serotonin selective reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors for depression, and the “atypical” antipsychotics for schizophrenia. However, soon after the turn of the century, pessimism for psychiatric therapeutics crept in again, and “big Pharma” abandoned their psychopharmacology programs in favor of other therapeutic areas. Surprisingly, the current “green shoots” of new ideas sprouting in our field today have not come from traditional big Pharma returning to psychiatry, but largely from small, innovative companies. These new entrepreneurial small pharmas and biotechs have found several new therapeutic targets. Furthermore, current innovation in psychopharmacology is increasingly following a paradigm shift away from DSM-5 disorders and instead to domains or symptoms of psychopathology that cut across numerous psychiatric conditions (transdiagnostic model).
So, what are the new therapeutic mechanisms of this current third generation of innovation in psychopharmacology? Not all of these can be discussed here, but 2 examples of new approaches to psychosis deserve special mention because, for the first time in 70 years, they turn away from blocking postsynaptic dopamine D2 receptors to treat psychosis and instead stimulate receptors in other neurotransmitter systems that are linked to dopamine neurons in a network “upstream.” That is, trace amine-associated receptor 1 (TAAR1) agonists target the pre-synaptic dopamine neuron, where dopamine synthesis and release are too high in psychosis, and cause dopamine synthesis to be reduced so that blockade of postsynaptic dopamine receptors is no longer necessary (Table 1 and Figure 1).1 Similarly, muscarinic cholinergic 1 and 4 receptor agonists target excitatory cholinergic neurons upstream, and turn down their stimulation of dopamine neurons, thereby reducing dopamine release so that postsynaptic blockade of dopamine receptors is also not necessary to treat psychosis with this mechanism (Table 1 and Figure 2).1 A similar mechanism of reducing upstream stimulation of dopamine release by serotonin has led to demonstration of antipsychotic actions of blocking this stimulation at serotonin 2A receptors (Table 2), and multiple approaches to enhancing deficient glutamate actions upstream are also under investigation for the treatment of psychosis. 1
Another major area of innovation in psychopharmacology worthy of emphasis is the rapid induction of neurogenesis that is associated with rapid reduction in the symptoms of depression, even when many conventional treatments have failed. Blockade of N-methyl-
that may hypothetically drive rapid recovery from depression.1 Proof of this concept was first shown with intravenous ketamine, and then intranasal esketamine, and now the oral NMDA antagonists dextromethorphan (combined with either bupropion or quinidine) and esmethadone (Table 1).1 Interestingly, this same mechanism may lead to a novel treatment of agitation in Alzheimer’s dementia as well.1
Continue to: Yet another mechanism...
Yet another mechanism of potentially rapid onset antidepressant action is that of the novel agents known as neuroactive steroids that have a novel action at gamma aminobutyric acid A (GABA-A) receptors that are not sensitive to benzodiazepines (as well as those that are) (Table 1 and Figure 3).1 Finally, psychedelic drugs that target serotonin receptors such as psilocybin and 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) seem to also have rapid onset of both neurogenesis and antidepressant action.
The future of psychopharmacology is clearly going to be amazing.
1. Stahl SM. Stahl’s Essential Psychopharmacology. 5th ed. Cambridge University Press; 2021.
1. Stahl SM. Stahl’s Essential Psychopharmacology. 5th ed. Cambridge University Press; 2021.
Congress OKs Veterans Affairs Expansive New Maternal Care Program
It’s called the Momnibus—the Black Maternal Health Momnibus Act of 2021 (HR 959) with 12 bills addressing “every dimension of the maternal health crisis in America.” The first bill in the Momnibus to pass Congress is the Protecting Moms Who Served act, which sets up a $15 million maternal care program within the US Department of Veterans Affairs (VA). “There has never been a comprehensive evaluation of how our nation’s growing maternal mortality crisis is impacting our women veterans, even though they may be at higher risk due to their service,” said Sen. Tammy Duckworth (D-IL), a co-sponsor of the Momnibus. The bill has passed Congress and awaits President Biden’s signature.
Rep. Lauren Underwood (D-IL) along with Rep. Alma Adams (D- NC-12), Sen. Cory Booker D-NJ), and members of the Black Maternal Health Caucus reintroduced the bill (first introduced last year). According to Rep. Underwood, the act would codify and strengthen the VA maternity care coordination programs. It also will require the US Government Accountability Office to report the deaths of pregnant and postpartum veterans and to focus on any racial or ethnic disparities. The bill passed overwhelmingly, 414 to 9 and awaits President Biden’s signature.
The Momnibus’s cute name represents a very serious purpose. “Maternal mortality has historically been used as a key indicator of the health of a population,” say researchers from National Vital Statistics Reports. But American mothers are dying at the highest rate in the developed world, and the numbers have been rising dramatically. Between 1987, when the Centers for Disease Control and Prevention (CDC) launched the Pregnancy Mortality Surveillance System in 2017, the latest year for available data, the number of reported pregnancy-related deaths in the United States rose steadily from 7.2 deaths per 100,000 live births to 17.3 per 100,000.
The maternal morbidity crisis is particularly stark among certain groups of women. Black women are acutely at risk, dying at 3 to 4 times the rate of White women (41.7 deaths per 100,000 live births), and one-third higher than the next highest risk group, Native American women (28.3 deaths per 100,000 live births).
But just how accurate have the data been? The study published in National Vital Statistics Report found that using a checkbox for “cause of death” specifying maternal death identified more than triple the number of maternal deaths. Without the checkbox item, maternal mortality rates in 2015 and 2016 would have been reported as 8.7 deaths per 100,000 live births, compared with 8.9 in 2002. With the checkbox, the rate would be reported as 20.9 per 100,000 live births in 2015 and 21.8/100,000 in 2016.
The CDC states that the reasons for the rising numbers are unclear; advances in identification have improved over time, for one. But by and large, the women are dying of preventable causes, such as hypertension, diabetes mellitus, and chronic heart disease. Nearly 60% of maternal deaths are deemed preventable.
Black and other minority women, though, may be dying of biases. Researchers from Beth Israel and Harvard cite studies that have found racial and ethnic disparities in obstetric care delivery. Non-Hispanic Blacks women, Hispanic women, and Asian women, for instance, have lower odds of labor induction when compared with that of White women. The odds of receiving an episiotomy are lower in non-Hispanic Black and Hispanic women. The Listening to Mothers survey III found that 24% of participants perceived discrimination during birth hospitalization, predominantly among Black or Hispanic women and uninsured women.
A maternal health equity advocacy group, 4Kira4Moms, was founded by the husband of Kira Johnson who died of hemorrhage following a routine scheduled cesarean section. In the recovery room, her catheter began turning pink with blood. For 10 hours, her husband said, he and her family begged the medical staff for help but were told his wife was not a priority. Thus, the Momnibus also contains the Kira Johnson Act, which will establish funding for community-based groups to provide Black pregnant women with more support.
Among other changes, the Momnibus will:
- Make critical investments in social determinants of health that influence maternal health outcomes, such as housing, transportation, and nutrition;
- Provide funding to community-based organizations that are working to improve maternal health outcomes and promote equity;
- Comprehensively study the unique maternal health risks facing pregnant and postpartum veterans and support VA maternity care coordination programs;
- Support mothers with mental health conditions and substance use disorders; and
- Promote innovative payment models to incentivize high-quality maternity care and nonclinical perinatal support
A variety of recent bills in Congress address maternal health. The Mothers and Offspring Mortality and Morbidity Awareness (MOMMA) Act, for instance, also would specifically address maternal health disparities by improving data collection and reporting, improving maternal care, and advancing respectful, equitable care. It also would extend Medicaid and the Children’s Health Insurance Program coverage. Katie Shea Barrett, MPH, executive director of March for Moms, a coalition of families, health care practitioners, policy makers, and partners advocating for mothers’ and families’ health, notes in an essay for thehill.com that Medicaid coverage ends about 60 days postpartum, although half of the maternal deaths happen between 42 days and 1 year postpartum.
She writes: “[W]e have to directly address the disproportionate impact of maternal mortality on women of color by training providers in offering care that is culturally competent and free of implicit bias. Health systems must be aware and respectful of cultural norms when providing care and be mindful of buying into stereotypes based on race, ethnicity, and even underlying medical conditions like diabetes, which often lead to perceived discrimination and perpetuate systems of injustice.”
In April, Vice President Kamala Harris called for sweeping action to curb racial inequities in pregnancy and childbirth. In an email Q&A with STAT, she said, “With every day that goes by and every woman who dies, the need for action grows more urgent.”
It’s called the Momnibus—the Black Maternal Health Momnibus Act of 2021 (HR 959) with 12 bills addressing “every dimension of the maternal health crisis in America.” The first bill in the Momnibus to pass Congress is the Protecting Moms Who Served act, which sets up a $15 million maternal care program within the US Department of Veterans Affairs (VA). “There has never been a comprehensive evaluation of how our nation’s growing maternal mortality crisis is impacting our women veterans, even though they may be at higher risk due to their service,” said Sen. Tammy Duckworth (D-IL), a co-sponsor of the Momnibus. The bill has passed Congress and awaits President Biden’s signature.
Rep. Lauren Underwood (D-IL) along with Rep. Alma Adams (D- NC-12), Sen. Cory Booker D-NJ), and members of the Black Maternal Health Caucus reintroduced the bill (first introduced last year). According to Rep. Underwood, the act would codify and strengthen the VA maternity care coordination programs. It also will require the US Government Accountability Office to report the deaths of pregnant and postpartum veterans and to focus on any racial or ethnic disparities. The bill passed overwhelmingly, 414 to 9 and awaits President Biden’s signature.
The Momnibus’s cute name represents a very serious purpose. “Maternal mortality has historically been used as a key indicator of the health of a population,” say researchers from National Vital Statistics Reports. But American mothers are dying at the highest rate in the developed world, and the numbers have been rising dramatically. Between 1987, when the Centers for Disease Control and Prevention (CDC) launched the Pregnancy Mortality Surveillance System in 2017, the latest year for available data, the number of reported pregnancy-related deaths in the United States rose steadily from 7.2 deaths per 100,000 live births to 17.3 per 100,000.
The maternal morbidity crisis is particularly stark among certain groups of women. Black women are acutely at risk, dying at 3 to 4 times the rate of White women (41.7 deaths per 100,000 live births), and one-third higher than the next highest risk group, Native American women (28.3 deaths per 100,000 live births).
But just how accurate have the data been? The study published in National Vital Statistics Report found that using a checkbox for “cause of death” specifying maternal death identified more than triple the number of maternal deaths. Without the checkbox item, maternal mortality rates in 2015 and 2016 would have been reported as 8.7 deaths per 100,000 live births, compared with 8.9 in 2002. With the checkbox, the rate would be reported as 20.9 per 100,000 live births in 2015 and 21.8/100,000 in 2016.
The CDC states that the reasons for the rising numbers are unclear; advances in identification have improved over time, for one. But by and large, the women are dying of preventable causes, such as hypertension, diabetes mellitus, and chronic heart disease. Nearly 60% of maternal deaths are deemed preventable.
Black and other minority women, though, may be dying of biases. Researchers from Beth Israel and Harvard cite studies that have found racial and ethnic disparities in obstetric care delivery. Non-Hispanic Blacks women, Hispanic women, and Asian women, for instance, have lower odds of labor induction when compared with that of White women. The odds of receiving an episiotomy are lower in non-Hispanic Black and Hispanic women. The Listening to Mothers survey III found that 24% of participants perceived discrimination during birth hospitalization, predominantly among Black or Hispanic women and uninsured women.
A maternal health equity advocacy group, 4Kira4Moms, was founded by the husband of Kira Johnson who died of hemorrhage following a routine scheduled cesarean section. In the recovery room, her catheter began turning pink with blood. For 10 hours, her husband said, he and her family begged the medical staff for help but were told his wife was not a priority. Thus, the Momnibus also contains the Kira Johnson Act, which will establish funding for community-based groups to provide Black pregnant women with more support.
Among other changes, the Momnibus will:
- Make critical investments in social determinants of health that influence maternal health outcomes, such as housing, transportation, and nutrition;
- Provide funding to community-based organizations that are working to improve maternal health outcomes and promote equity;
- Comprehensively study the unique maternal health risks facing pregnant and postpartum veterans and support VA maternity care coordination programs;
- Support mothers with mental health conditions and substance use disorders; and
- Promote innovative payment models to incentivize high-quality maternity care and nonclinical perinatal support
A variety of recent bills in Congress address maternal health. The Mothers and Offspring Mortality and Morbidity Awareness (MOMMA) Act, for instance, also would specifically address maternal health disparities by improving data collection and reporting, improving maternal care, and advancing respectful, equitable care. It also would extend Medicaid and the Children’s Health Insurance Program coverage. Katie Shea Barrett, MPH, executive director of March for Moms, a coalition of families, health care practitioners, policy makers, and partners advocating for mothers’ and families’ health, notes in an essay for thehill.com that Medicaid coverage ends about 60 days postpartum, although half of the maternal deaths happen between 42 days and 1 year postpartum.
She writes: “[W]e have to directly address the disproportionate impact of maternal mortality on women of color by training providers in offering care that is culturally competent and free of implicit bias. Health systems must be aware and respectful of cultural norms when providing care and be mindful of buying into stereotypes based on race, ethnicity, and even underlying medical conditions like diabetes, which often lead to perceived discrimination and perpetuate systems of injustice.”
In April, Vice President Kamala Harris called for sweeping action to curb racial inequities in pregnancy and childbirth. In an email Q&A with STAT, she said, “With every day that goes by and every woman who dies, the need for action grows more urgent.”
It’s called the Momnibus—the Black Maternal Health Momnibus Act of 2021 (HR 959) with 12 bills addressing “every dimension of the maternal health crisis in America.” The first bill in the Momnibus to pass Congress is the Protecting Moms Who Served act, which sets up a $15 million maternal care program within the US Department of Veterans Affairs (VA). “There has never been a comprehensive evaluation of how our nation’s growing maternal mortality crisis is impacting our women veterans, even though they may be at higher risk due to their service,” said Sen. Tammy Duckworth (D-IL), a co-sponsor of the Momnibus. The bill has passed Congress and awaits President Biden’s signature.
Rep. Lauren Underwood (D-IL) along with Rep. Alma Adams (D- NC-12), Sen. Cory Booker D-NJ), and members of the Black Maternal Health Caucus reintroduced the bill (first introduced last year). According to Rep. Underwood, the act would codify and strengthen the VA maternity care coordination programs. It also will require the US Government Accountability Office to report the deaths of pregnant and postpartum veterans and to focus on any racial or ethnic disparities. The bill passed overwhelmingly, 414 to 9 and awaits President Biden’s signature.
The Momnibus’s cute name represents a very serious purpose. “Maternal mortality has historically been used as a key indicator of the health of a population,” say researchers from National Vital Statistics Reports. But American mothers are dying at the highest rate in the developed world, and the numbers have been rising dramatically. Between 1987, when the Centers for Disease Control and Prevention (CDC) launched the Pregnancy Mortality Surveillance System in 2017, the latest year for available data, the number of reported pregnancy-related deaths in the United States rose steadily from 7.2 deaths per 100,000 live births to 17.3 per 100,000.
The maternal morbidity crisis is particularly stark among certain groups of women. Black women are acutely at risk, dying at 3 to 4 times the rate of White women (41.7 deaths per 100,000 live births), and one-third higher than the next highest risk group, Native American women (28.3 deaths per 100,000 live births).
But just how accurate have the data been? The study published in National Vital Statistics Report found that using a checkbox for “cause of death” specifying maternal death identified more than triple the number of maternal deaths. Without the checkbox item, maternal mortality rates in 2015 and 2016 would have been reported as 8.7 deaths per 100,000 live births, compared with 8.9 in 2002. With the checkbox, the rate would be reported as 20.9 per 100,000 live births in 2015 and 21.8/100,000 in 2016.
The CDC states that the reasons for the rising numbers are unclear; advances in identification have improved over time, for one. But by and large, the women are dying of preventable causes, such as hypertension, diabetes mellitus, and chronic heart disease. Nearly 60% of maternal deaths are deemed preventable.
Black and other minority women, though, may be dying of biases. Researchers from Beth Israel and Harvard cite studies that have found racial and ethnic disparities in obstetric care delivery. Non-Hispanic Blacks women, Hispanic women, and Asian women, for instance, have lower odds of labor induction when compared with that of White women. The odds of receiving an episiotomy are lower in non-Hispanic Black and Hispanic women. The Listening to Mothers survey III found that 24% of participants perceived discrimination during birth hospitalization, predominantly among Black or Hispanic women and uninsured women.
A maternal health equity advocacy group, 4Kira4Moms, was founded by the husband of Kira Johnson who died of hemorrhage following a routine scheduled cesarean section. In the recovery room, her catheter began turning pink with blood. For 10 hours, her husband said, he and her family begged the medical staff for help but were told his wife was not a priority. Thus, the Momnibus also contains the Kira Johnson Act, which will establish funding for community-based groups to provide Black pregnant women with more support.
Among other changes, the Momnibus will:
- Make critical investments in social determinants of health that influence maternal health outcomes, such as housing, transportation, and nutrition;
- Provide funding to community-based organizations that are working to improve maternal health outcomes and promote equity;
- Comprehensively study the unique maternal health risks facing pregnant and postpartum veterans and support VA maternity care coordination programs;
- Support mothers with mental health conditions and substance use disorders; and
- Promote innovative payment models to incentivize high-quality maternity care and nonclinical perinatal support
A variety of recent bills in Congress address maternal health. The Mothers and Offspring Mortality and Morbidity Awareness (MOMMA) Act, for instance, also would specifically address maternal health disparities by improving data collection and reporting, improving maternal care, and advancing respectful, equitable care. It also would extend Medicaid and the Children’s Health Insurance Program coverage. Katie Shea Barrett, MPH, executive director of March for Moms, a coalition of families, health care practitioners, policy makers, and partners advocating for mothers’ and families’ health, notes in an essay for thehill.com that Medicaid coverage ends about 60 days postpartum, although half of the maternal deaths happen between 42 days and 1 year postpartum.
She writes: “[W]e have to directly address the disproportionate impact of maternal mortality on women of color by training providers in offering care that is culturally competent and free of implicit bias. Health systems must be aware and respectful of cultural norms when providing care and be mindful of buying into stereotypes based on race, ethnicity, and even underlying medical conditions like diabetes, which often lead to perceived discrimination and perpetuate systems of injustice.”
In April, Vice President Kamala Harris called for sweeping action to curb racial inequities in pregnancy and childbirth. In an email Q&A with STAT, she said, “With every day that goes by and every woman who dies, the need for action grows more urgent.”
Did prior authorization refusals lead to this patient’s death?
Ramy Sedhom, MD, a medical oncologist and a palliative care physician at Penn Medicine Princeton Health in Plainsboro, N.J., will always wonder if prior authorization refusals led to his patient’s death.
The patient had advanced gastric cancer and the insurer initially denied a PET scan to rule out metastatic disease. When the scan was eventually allowed, it revealed that the cancer had spread.
Standard treatment would have been difficult for the patient, an older individual with comorbidities. But Dr. Sedhom knew that a European study had reported equal efficacy and fewer side effects with a reduced chemotherapy regimen, and he thought that was the best approach in this situation.
The insurer disagreed with Dr. Sedhom’s decision and, while the two argued, the patient’s symptoms worsened. He was admitted to the hospital, where he experienced a decline in function, common for older patients. “Long story short, he was never able to seek treatment and then transitioned to hospice,” Dr. Sedhom said. “It was one of those situations where there was a 3- to 4-week delay in what should have been standard care.”
. Nearly 4 years after major organizations — American Hospital Association, America’s Health Insurance Plans, American Medical Association, Blue Cross Blue Shield Association, and others — signed a consensus statement agreeing to improve the prior authorization process, physicians say little progress has been made.
Indeed, 83% of physicians say that the number of prior authorizations required for prescription medications and medical services has increased over the last 5 years, according to survey results released earlier this year.
“It’s decidedly worse — there’s no question about it,” said Andrew R. Spector, MD, a neurologist and sleep medicine specialist at Duke Health in Durham, N.C. “Drugs that I used to get without prior authorizations now require them.”
When Vignesh I. Doraiswamy, MD, an internal medicine hospitalist at the Ohio State University Wexner Medical Center in Columbus, discharged a patient with Clostridioides difficile infection, he followed clinical guidelines to prescribe vancomycin for 10 to 14 days. “And the insurance company said, ‘Well, yeah, we only authorize about 5 days,’ which just makes no sense,” Dr. Doraiswamy said. “There’s nowhere in any literature that says 5 days is sufficient. What worries me is that is the standard of care we are supposed to give and yet we are unable to.”
Yash B. Jobanputra, MD, a cardiology fellow at Saint Vincent Hospital in Worcester, Mass., laments that prior authorization is used in situations that simply do not make common sense. During his residency, a woman who had tested positive for the BRCA gene mutation with a strong family history of breast cancer needed a breast ultrasound and an MRI scan every 6 months to 1 year. Despite the documentation that she was at extremely high risk for developing breast cancer, he had to go through prior authorization every time she was due for new images.
“I had to call the insurance company, they would put me on hold, I would wait to speak to a physician — and the end response would be, ‘Yeah, this is what needs to be done,’” he said. “But having established her positive status once should be enough really. I shouldn’t have to go through the circus all over again.”
Prior authorization is also being used for routine diagnostics, such as a Holter monitor for patients complaining of heart palpitations. “Depending on the insurance, for some patients we can give it to them in the clinic right away,” Dr. Jobanputra said. “Whereas some others we have to wait until we get prior authorization from the insurance company and the patient has to come back again to the hospital to get the monitor. That is a delay in patient care.”
The delays also extend to emergency care, Dr. Doraiswamy said. He cites the example of a heart attack patient who needed an emergency heart catheterization but ran into a prior authorization delay. “I just said, ‘Try your best not to get stressed’ which is not easy for a patient finding out their stay wasn’t covered when they had just been through a heart attack,” he said. “Then I spent 20 to 30 minutes — most of it on hold — to answer the question ‘Why did this patient need to get admitted?’ “
Physicians feel disrespected because that type of prior authorization hassle is just busywork. “Rarely is a valid stay that was initially denied, not eventually accepted,” Dr. Doraiswamy said. “But why couldn’t they have just seen that the guy had a heart attack and he obviously needed to be in the hospital?”
For Dr. Spector, the Duke Health sleep medicine specialist, prior authorization is not just a speed bump, it’s a full stop. Insurers have started mandating a multiple sleep latency test (MSLT) to confirm narcolepsy before covering medication to treat the condition. “We know that the MSLT is very often wrong,” he said. “There are a lot of times we’re dealing with patients with narcolepsy who simply don’t meet the testing criteria that the insurance requires, and payers will not accept our clinical judgment.”
In his view, the prior authorization landscape is worsening — and not only because a “faulty test” is being used to deny treatment. “The appeal process is worse,” Dr. Spector said. “I used to be able to get on the phone and do a peer-to-peer review with a physician who I could reason with… but that doesn’t happen anymore. There is virtually no way to bypass these blanket rules.”
Other survey findings also stand in direct contradiction of the 2018 consensus agreement:
A large majority (87%) of physicians report that prior authorization interferes with continuity of care, even though the industry groups agreed that patients should be protected from treatment disruption when there is a formulary or treatment-coverage change.
Despite a consensus to encourage transparency and easy accessibility of prior authorization requirements, 68% of physicians reported that it is difficult to determine whether a prescription medication requires prior authorization, and 58% report that it’s difficult for medical services.
Phone and fax are the most commonly used methods for completing prior authorizations, despite agreement that electronic prior authorization, using existing national standard transactions, should be accelerated. Fewer than one quarter of physicians said that their electronic health record system supports electronic prior authorization for prescription medications.
Dr. Spector wants to see legislation that forces insurers to live up to some of the tenets of the 2018 consensus statement. In September, a new Texas law went into effect, exempting physicians from prior authorization if, during the previous six months, 90% of their treatments met an insurer›s medical necessity criteria. In January, the recently approved Prior Authorization Reform Act in Illinois will reduce the number of services subject to prior authorization, mandate a prior authorization decision within 5 days, and set disciplinary measures for health plans that do not comply, among other things.
“What gives me hope is that at least somewhere in the country, somebody is doing something,” Dr. Spector said. “And if it goes well, maybe other insurers will adopt it. I’m really hoping they demonstrate that the money they can save on the administration of all the appeals and prior authorization paperwork can actually go into caring for patients.”
In addition to state-level action, reform may also be advancing at the federal level. In October, a bill was introduced in the U.S. Senate that mirrors a prior authorization reform bill introduced in the House of Representatives last May. Both bills have broad bipartisan support; the House bill has more than 235 co-sponsors.
In an interview with this news organization, Rep. Ami Bera, MD, (D-CA) said it is “very realistic” that the bill will become law during this session of Congress. “We do think this bill will get marked up in committee and hopefully we can get it to the floor either as a stand-alone bill where we know we have the votes to pass it or as part of a larger legislative package,” he said.
If approved, the Improving Seniors’ Timely Access to Care Act of 2021 would require that Medicare Advantage plans minimize the use of prior authorization for routinely approved services; require real-time decisions for certain requests; report the extent of their use of prior authorization and their rate of approvals or denials, among other things; and establish an electronic prior authorization system.
Medicare Advantage plans are private insurers that are regulated by the Centers for Medicare & Medicaid Services (CMS), which will create the specific rules and penalties associated with the reforms, if they become law. “One would presume that a condition of being a Medicare Advantage plan is that you’re going to have to comply with these new regulations,” said Katie Orrico, senior vice president of health policy and advocacy for the American Association of Neurological Surgeons and Congress of Neurological Surgeons (AANS/CNS). “So they will have some amount of teeth in the form of a mandate.”
The AANS and CNS are part of the Regulatory Relief Coalition, a group of 14 national physician specialty organizations. Winning prior authorization reform in the Medicare Advantage plans is part of its bigger strategy. “If those commercial plans have to follow a set of rules and processes for Medicare, then why not just expand those same processes to all other parts of their business?” Ms. Orrico said.
Despite his frustration with their prior authorization processes, Dr. Doraiswamy, the Ohio State hospitalist, agrees that working to improve insurers’ practices is the best way forward. “It’s so easy to make them look like these evil, giant conglomerations that exist solely to suck money and not care about anyone’s health, but I don’t know if that’s necessarily the case,” he said. “We really have to figure out how best to work with insurance companies to make sure that, while they are profit-generating institutions, that [profit] shouldn’t come at the cost of patient care.”
A version of this article first appeared on Medscape.com.
Ramy Sedhom, MD, a medical oncologist and a palliative care physician at Penn Medicine Princeton Health in Plainsboro, N.J., will always wonder if prior authorization refusals led to his patient’s death.
The patient had advanced gastric cancer and the insurer initially denied a PET scan to rule out metastatic disease. When the scan was eventually allowed, it revealed that the cancer had spread.
Standard treatment would have been difficult for the patient, an older individual with comorbidities. But Dr. Sedhom knew that a European study had reported equal efficacy and fewer side effects with a reduced chemotherapy regimen, and he thought that was the best approach in this situation.
The insurer disagreed with Dr. Sedhom’s decision and, while the two argued, the patient’s symptoms worsened. He was admitted to the hospital, where he experienced a decline in function, common for older patients. “Long story short, he was never able to seek treatment and then transitioned to hospice,” Dr. Sedhom said. “It was one of those situations where there was a 3- to 4-week delay in what should have been standard care.”
. Nearly 4 years after major organizations — American Hospital Association, America’s Health Insurance Plans, American Medical Association, Blue Cross Blue Shield Association, and others — signed a consensus statement agreeing to improve the prior authorization process, physicians say little progress has been made.
Indeed, 83% of physicians say that the number of prior authorizations required for prescription medications and medical services has increased over the last 5 years, according to survey results released earlier this year.
“It’s decidedly worse — there’s no question about it,” said Andrew R. Spector, MD, a neurologist and sleep medicine specialist at Duke Health in Durham, N.C. “Drugs that I used to get without prior authorizations now require them.”
When Vignesh I. Doraiswamy, MD, an internal medicine hospitalist at the Ohio State University Wexner Medical Center in Columbus, discharged a patient with Clostridioides difficile infection, he followed clinical guidelines to prescribe vancomycin for 10 to 14 days. “And the insurance company said, ‘Well, yeah, we only authorize about 5 days,’ which just makes no sense,” Dr. Doraiswamy said. “There’s nowhere in any literature that says 5 days is sufficient. What worries me is that is the standard of care we are supposed to give and yet we are unable to.”
Yash B. Jobanputra, MD, a cardiology fellow at Saint Vincent Hospital in Worcester, Mass., laments that prior authorization is used in situations that simply do not make common sense. During his residency, a woman who had tested positive for the BRCA gene mutation with a strong family history of breast cancer needed a breast ultrasound and an MRI scan every 6 months to 1 year. Despite the documentation that she was at extremely high risk for developing breast cancer, he had to go through prior authorization every time she was due for new images.
“I had to call the insurance company, they would put me on hold, I would wait to speak to a physician — and the end response would be, ‘Yeah, this is what needs to be done,’” he said. “But having established her positive status once should be enough really. I shouldn’t have to go through the circus all over again.”
Prior authorization is also being used for routine diagnostics, such as a Holter monitor for patients complaining of heart palpitations. “Depending on the insurance, for some patients we can give it to them in the clinic right away,” Dr. Jobanputra said. “Whereas some others we have to wait until we get prior authorization from the insurance company and the patient has to come back again to the hospital to get the monitor. That is a delay in patient care.”
The delays also extend to emergency care, Dr. Doraiswamy said. He cites the example of a heart attack patient who needed an emergency heart catheterization but ran into a prior authorization delay. “I just said, ‘Try your best not to get stressed’ which is not easy for a patient finding out their stay wasn’t covered when they had just been through a heart attack,” he said. “Then I spent 20 to 30 minutes — most of it on hold — to answer the question ‘Why did this patient need to get admitted?’ “
Physicians feel disrespected because that type of prior authorization hassle is just busywork. “Rarely is a valid stay that was initially denied, not eventually accepted,” Dr. Doraiswamy said. “But why couldn’t they have just seen that the guy had a heart attack and he obviously needed to be in the hospital?”
For Dr. Spector, the Duke Health sleep medicine specialist, prior authorization is not just a speed bump, it’s a full stop. Insurers have started mandating a multiple sleep latency test (MSLT) to confirm narcolepsy before covering medication to treat the condition. “We know that the MSLT is very often wrong,” he said. “There are a lot of times we’re dealing with patients with narcolepsy who simply don’t meet the testing criteria that the insurance requires, and payers will not accept our clinical judgment.”
In his view, the prior authorization landscape is worsening — and not only because a “faulty test” is being used to deny treatment. “The appeal process is worse,” Dr. Spector said. “I used to be able to get on the phone and do a peer-to-peer review with a physician who I could reason with… but that doesn’t happen anymore. There is virtually no way to bypass these blanket rules.”
Other survey findings also stand in direct contradiction of the 2018 consensus agreement:
A large majority (87%) of physicians report that prior authorization interferes with continuity of care, even though the industry groups agreed that patients should be protected from treatment disruption when there is a formulary or treatment-coverage change.
Despite a consensus to encourage transparency and easy accessibility of prior authorization requirements, 68% of physicians reported that it is difficult to determine whether a prescription medication requires prior authorization, and 58% report that it’s difficult for medical services.
Phone and fax are the most commonly used methods for completing prior authorizations, despite agreement that electronic prior authorization, using existing national standard transactions, should be accelerated. Fewer than one quarter of physicians said that their electronic health record system supports electronic prior authorization for prescription medications.
Dr. Spector wants to see legislation that forces insurers to live up to some of the tenets of the 2018 consensus statement. In September, a new Texas law went into effect, exempting physicians from prior authorization if, during the previous six months, 90% of their treatments met an insurer›s medical necessity criteria. In January, the recently approved Prior Authorization Reform Act in Illinois will reduce the number of services subject to prior authorization, mandate a prior authorization decision within 5 days, and set disciplinary measures for health plans that do not comply, among other things.
“What gives me hope is that at least somewhere in the country, somebody is doing something,” Dr. Spector said. “And if it goes well, maybe other insurers will adopt it. I’m really hoping they demonstrate that the money they can save on the administration of all the appeals and prior authorization paperwork can actually go into caring for patients.”
In addition to state-level action, reform may also be advancing at the federal level. In October, a bill was introduced in the U.S. Senate that mirrors a prior authorization reform bill introduced in the House of Representatives last May. Both bills have broad bipartisan support; the House bill has more than 235 co-sponsors.
In an interview with this news organization, Rep. Ami Bera, MD, (D-CA) said it is “very realistic” that the bill will become law during this session of Congress. “We do think this bill will get marked up in committee and hopefully we can get it to the floor either as a stand-alone bill where we know we have the votes to pass it or as part of a larger legislative package,” he said.
If approved, the Improving Seniors’ Timely Access to Care Act of 2021 would require that Medicare Advantage plans minimize the use of prior authorization for routinely approved services; require real-time decisions for certain requests; report the extent of their use of prior authorization and their rate of approvals or denials, among other things; and establish an electronic prior authorization system.
Medicare Advantage plans are private insurers that are regulated by the Centers for Medicare & Medicaid Services (CMS), which will create the specific rules and penalties associated with the reforms, if they become law. “One would presume that a condition of being a Medicare Advantage plan is that you’re going to have to comply with these new regulations,” said Katie Orrico, senior vice president of health policy and advocacy for the American Association of Neurological Surgeons and Congress of Neurological Surgeons (AANS/CNS). “So they will have some amount of teeth in the form of a mandate.”
The AANS and CNS are part of the Regulatory Relief Coalition, a group of 14 national physician specialty organizations. Winning prior authorization reform in the Medicare Advantage plans is part of its bigger strategy. “If those commercial plans have to follow a set of rules and processes for Medicare, then why not just expand those same processes to all other parts of their business?” Ms. Orrico said.
Despite his frustration with their prior authorization processes, Dr. Doraiswamy, the Ohio State hospitalist, agrees that working to improve insurers’ practices is the best way forward. “It’s so easy to make them look like these evil, giant conglomerations that exist solely to suck money and not care about anyone’s health, but I don’t know if that’s necessarily the case,” he said. “We really have to figure out how best to work with insurance companies to make sure that, while they are profit-generating institutions, that [profit] shouldn’t come at the cost of patient care.”
A version of this article first appeared on Medscape.com.
Ramy Sedhom, MD, a medical oncologist and a palliative care physician at Penn Medicine Princeton Health in Plainsboro, N.J., will always wonder if prior authorization refusals led to his patient’s death.
The patient had advanced gastric cancer and the insurer initially denied a PET scan to rule out metastatic disease. When the scan was eventually allowed, it revealed that the cancer had spread.
Standard treatment would have been difficult for the patient, an older individual with comorbidities. But Dr. Sedhom knew that a European study had reported equal efficacy and fewer side effects with a reduced chemotherapy regimen, and he thought that was the best approach in this situation.
The insurer disagreed with Dr. Sedhom’s decision and, while the two argued, the patient’s symptoms worsened. He was admitted to the hospital, where he experienced a decline in function, common for older patients. “Long story short, he was never able to seek treatment and then transitioned to hospice,” Dr. Sedhom said. “It was one of those situations where there was a 3- to 4-week delay in what should have been standard care.”
. Nearly 4 years after major organizations — American Hospital Association, America’s Health Insurance Plans, American Medical Association, Blue Cross Blue Shield Association, and others — signed a consensus statement agreeing to improve the prior authorization process, physicians say little progress has been made.
Indeed, 83% of physicians say that the number of prior authorizations required for prescription medications and medical services has increased over the last 5 years, according to survey results released earlier this year.
“It’s decidedly worse — there’s no question about it,” said Andrew R. Spector, MD, a neurologist and sleep medicine specialist at Duke Health in Durham, N.C. “Drugs that I used to get without prior authorizations now require them.”
When Vignesh I. Doraiswamy, MD, an internal medicine hospitalist at the Ohio State University Wexner Medical Center in Columbus, discharged a patient with Clostridioides difficile infection, he followed clinical guidelines to prescribe vancomycin for 10 to 14 days. “And the insurance company said, ‘Well, yeah, we only authorize about 5 days,’ which just makes no sense,” Dr. Doraiswamy said. “There’s nowhere in any literature that says 5 days is sufficient. What worries me is that is the standard of care we are supposed to give and yet we are unable to.”
Yash B. Jobanputra, MD, a cardiology fellow at Saint Vincent Hospital in Worcester, Mass., laments that prior authorization is used in situations that simply do not make common sense. During his residency, a woman who had tested positive for the BRCA gene mutation with a strong family history of breast cancer needed a breast ultrasound and an MRI scan every 6 months to 1 year. Despite the documentation that she was at extremely high risk for developing breast cancer, he had to go through prior authorization every time she was due for new images.
“I had to call the insurance company, they would put me on hold, I would wait to speak to a physician — and the end response would be, ‘Yeah, this is what needs to be done,’” he said. “But having established her positive status once should be enough really. I shouldn’t have to go through the circus all over again.”
Prior authorization is also being used for routine diagnostics, such as a Holter monitor for patients complaining of heart palpitations. “Depending on the insurance, for some patients we can give it to them in the clinic right away,” Dr. Jobanputra said. “Whereas some others we have to wait until we get prior authorization from the insurance company and the patient has to come back again to the hospital to get the monitor. That is a delay in patient care.”
The delays also extend to emergency care, Dr. Doraiswamy said. He cites the example of a heart attack patient who needed an emergency heart catheterization but ran into a prior authorization delay. “I just said, ‘Try your best not to get stressed’ which is not easy for a patient finding out their stay wasn’t covered when they had just been through a heart attack,” he said. “Then I spent 20 to 30 minutes — most of it on hold — to answer the question ‘Why did this patient need to get admitted?’ “
Physicians feel disrespected because that type of prior authorization hassle is just busywork. “Rarely is a valid stay that was initially denied, not eventually accepted,” Dr. Doraiswamy said. “But why couldn’t they have just seen that the guy had a heart attack and he obviously needed to be in the hospital?”
For Dr. Spector, the Duke Health sleep medicine specialist, prior authorization is not just a speed bump, it’s a full stop. Insurers have started mandating a multiple sleep latency test (MSLT) to confirm narcolepsy before covering medication to treat the condition. “We know that the MSLT is very often wrong,” he said. “There are a lot of times we’re dealing with patients with narcolepsy who simply don’t meet the testing criteria that the insurance requires, and payers will not accept our clinical judgment.”
In his view, the prior authorization landscape is worsening — and not only because a “faulty test” is being used to deny treatment. “The appeal process is worse,” Dr. Spector said. “I used to be able to get on the phone and do a peer-to-peer review with a physician who I could reason with… but that doesn’t happen anymore. There is virtually no way to bypass these blanket rules.”
Other survey findings also stand in direct contradiction of the 2018 consensus agreement:
A large majority (87%) of physicians report that prior authorization interferes with continuity of care, even though the industry groups agreed that patients should be protected from treatment disruption when there is a formulary or treatment-coverage change.
Despite a consensus to encourage transparency and easy accessibility of prior authorization requirements, 68% of physicians reported that it is difficult to determine whether a prescription medication requires prior authorization, and 58% report that it’s difficult for medical services.
Phone and fax are the most commonly used methods for completing prior authorizations, despite agreement that electronic prior authorization, using existing national standard transactions, should be accelerated. Fewer than one quarter of physicians said that their electronic health record system supports electronic prior authorization for prescription medications.
Dr. Spector wants to see legislation that forces insurers to live up to some of the tenets of the 2018 consensus statement. In September, a new Texas law went into effect, exempting physicians from prior authorization if, during the previous six months, 90% of their treatments met an insurer›s medical necessity criteria. In January, the recently approved Prior Authorization Reform Act in Illinois will reduce the number of services subject to prior authorization, mandate a prior authorization decision within 5 days, and set disciplinary measures for health plans that do not comply, among other things.
“What gives me hope is that at least somewhere in the country, somebody is doing something,” Dr. Spector said. “And if it goes well, maybe other insurers will adopt it. I’m really hoping they demonstrate that the money they can save on the administration of all the appeals and prior authorization paperwork can actually go into caring for patients.”
In addition to state-level action, reform may also be advancing at the federal level. In October, a bill was introduced in the U.S. Senate that mirrors a prior authorization reform bill introduced in the House of Representatives last May. Both bills have broad bipartisan support; the House bill has more than 235 co-sponsors.
In an interview with this news organization, Rep. Ami Bera, MD, (D-CA) said it is “very realistic” that the bill will become law during this session of Congress. “We do think this bill will get marked up in committee and hopefully we can get it to the floor either as a stand-alone bill where we know we have the votes to pass it or as part of a larger legislative package,” he said.
If approved, the Improving Seniors’ Timely Access to Care Act of 2021 would require that Medicare Advantage plans minimize the use of prior authorization for routinely approved services; require real-time decisions for certain requests; report the extent of their use of prior authorization and their rate of approvals or denials, among other things; and establish an electronic prior authorization system.
Medicare Advantage plans are private insurers that are regulated by the Centers for Medicare & Medicaid Services (CMS), which will create the specific rules and penalties associated with the reforms, if they become law. “One would presume that a condition of being a Medicare Advantage plan is that you’re going to have to comply with these new regulations,” said Katie Orrico, senior vice president of health policy and advocacy for the American Association of Neurological Surgeons and Congress of Neurological Surgeons (AANS/CNS). “So they will have some amount of teeth in the form of a mandate.”
The AANS and CNS are part of the Regulatory Relief Coalition, a group of 14 national physician specialty organizations. Winning prior authorization reform in the Medicare Advantage plans is part of its bigger strategy. “If those commercial plans have to follow a set of rules and processes for Medicare, then why not just expand those same processes to all other parts of their business?” Ms. Orrico said.
Despite his frustration with their prior authorization processes, Dr. Doraiswamy, the Ohio State hospitalist, agrees that working to improve insurers’ practices is the best way forward. “It’s so easy to make them look like these evil, giant conglomerations that exist solely to suck money and not care about anyone’s health, but I don’t know if that’s necessarily the case,” he said. “We really have to figure out how best to work with insurance companies to make sure that, while they are profit-generating institutions, that [profit] shouldn’t come at the cost of patient care.”
A version of this article first appeared on Medscape.com.
Whole-food exclusion diet effective for adult Crohn’s disease
The Crohn’s disease exclusion diet (CDED), with or without partial enteral nutrition (PEN), effectively induced and maintained remission in adults with mild to moderate, biologic-naive CD, a randomized Israeli pilot study found.
The authors, led by Henit Yanai, MD, MBA, chief of the IBD Center at Rabin Medical Center in Petah Tikva, Israel, also suggested that dietary monotherapy might lead to durable endoscopic remission.
The study, published in The Lancet Gastroenterology & Hepatology, found about 60% of patients on CDED achieved clinical remission by week 6 without adding medications.
Furthermore, 80% of patients in remission at week 6 maintained clinical remission at week 24 on dietary monotherapy alone, allowing more than 50% of the intention-to-treat (ITT) population to achieve sustained remission at 6 months.
Dietary therapy resulted in a significant and progressive reduction in inflammatory markers such as C-reactive protein and fecal calprotectin. The benefit extended to mucosal healing, with 35% of the ITT population achieving endoscopic remission at 24 weeks.
Dr. Yanai explained the clinical context in which her group designed the study. “There were preliminary data regarding the efficacy of the dietary strategy for the induction of remission of mild CD in the pediatric population,” she said in an interview. “Additionally, there was an anecdotal experience in adults who reported benefits. Facing this and the lack of attractive alternatives for mild CD, we decided to examine the effectiveness of this therapeutic strategy in adults.”
Given the costs and side effects of medical treatment, interest in dietary monotherapy for IBD has been growing. As Dr. Yanai said, the CDED, a whole-foods regimen, plus PEN, has been found to help children with CD.
The CDED excludes proinflammatory food components associated with intestinal microbial dysbiosis, altered innate immunity, and impaired gut barrier function.
It involves increased consumption of fruits and vegetables, high-quality lean protein, complex carbohydrates, healthy oils, and fiber, while decreasing intake of inflammation-driving components such as animal and saturated vegetable fats, wheat, and dairy, as well as food additives such as emulsifiers, maltodextrin, and sulfites.
“The realization that exclusive enteral nutrition, which is based on liquid formulas, is effective for inducting remission in children PEN, which is a combination of liquid formulas and food, was less effective, led to the hypothesis that the mechanism might be the exclusion of dietary components that may lead to inflammation,” Dr. Yanai said. This theory, she added, derived from animal models showing that specific dietary components potentially drive inflammation.
The only current guideline-recommended nutritional therapy for remission induction is exclusive enteral nutrition (EEN) in pediatric CD.
The study
The open-label pilot trial led by Dr. Yanai, conducted at three medical centers, enrolled biologic-naive adults ages 18-55 with uncomplicated mild to moderate CD, with a disease duration of no more than 5 years. They had active disease on imaging and elevated C-reactive protein or fecal calprotectin.
During the period January 2017 to May 2020, eligible patients were randomly assigned 1 to 1 to CDED plus PEN enteral (n = 20) or CDED alone (n = 24) for 24 weeks. The primary endpoint was clinical remission, defined as a Harvey–Bradshaw Index score of less than 5 at week 6, an outcome was assessed in the ITT population, which consisted of those who used dietary therapy for at least 48 hours.
At week 6, 13 (68%) of 19 remaining patients in the CDED-plus-PEN group and 12 (57%) of 21 patients in the CDED-alone group had achieved clinical remission (P = .4618).
Among the 25 patients in remission 6 weeks out, 20 (80%) remained in sustained remission at week 24: 12 in the CDED-plus-PEN group and 8 in the CDED-alone group.
Moreover, 14 (35%) of 40 patients were in endoscopic remission at week 24: 8 on CDED plus PEN and 6 on CDED alone.
“CDED with or without partial enteral nutrition was effective for induction and maintenance of remission in adults with mild to moderate biologic-naive Crohn’s disease and might lead to endoscopic remission,” the authors wrote, adding that CDED for mild to moderate active disease should be assessed in a powered randomized controlled trial.
Compliance and adherence are obstacles to dietary therapies. Data for adults using exclusive enteral nutrition are conflicting, with poor compliance postulated to drive an inadequate response in some studies.
“Like every dietary treatment, adherence is challenging,” Dr. Yanai said. “However, when patients feel that it helps them, they have more incentive to follow the diet in the long run, and also once they quit and fare worse, they can go back and follow the first stage of CDED.”
She and her colleagues stressed the need for adequately powered randomized trials and recommended that the personalization of therapeutic diets in the future should take into account the need to deliver energy tailored to the nutritional and therapeutic goals of the patient.
Diets alone are not therapy
In an accompanying editorial, Alexa N. Sasson, MD, an IBD fellow at Massachusetts General Hospital and T.H. Chan Harvard School of Public Health, both in Boston, called diet “a promising and potentially modifiable risk factor with mounting evidence supporting its therapeutic benefit.”
She concurred that the Israeli findings indicate that CDED with or without PEN appears effective for inducing and maintaining remission in this cohort of patients. “Assessment of composite diets such as the CDED is important since they can be incorporated into daily life. The relative efficacy of each of the included and excluded foods, however, is not clear,” she wrote.
She cautioned, however, that dietary therapy does not constitute maintenance therapy and its effects are not sustained after the reintroduction of whole foods. “Identification of sustainable dietary interventions for the prevention and treatment of IBD is increasingly a focus of research,” she wrote.
Dr. Sasson agreed that dietary therapy for CD should be centered on patient interests, goals, and disease states. “Adjunctive dietary measures might be considered in all interested patients as a method of improving gastrointestinal-related symptoms and quality of life, with the potential to achieve a higher and more sustained level of remission,” she wrote.
Both the authors and the commentator agreed on the need for larger randomized trials with long-term follow-up to guide treatment decisions and identify patients who might benefit from dietary intervention.
This study was funded by the Azrieli Foundation and Nestlé Health Science. Dr. Yanai reported financial relationships with Pfizer, AbbVie, Ferring, Janssen, Neopharm, Pfizer, and Takeda. Several coauthors disclosed financial ties to multiple private-sector companies. Dr. Sasson had no competing interests to declare.
This article was updated Dec. 1, 2021.
The Crohn’s disease exclusion diet (CDED), with or without partial enteral nutrition (PEN), effectively induced and maintained remission in adults with mild to moderate, biologic-naive CD, a randomized Israeli pilot study found.
The authors, led by Henit Yanai, MD, MBA, chief of the IBD Center at Rabin Medical Center in Petah Tikva, Israel, also suggested that dietary monotherapy might lead to durable endoscopic remission.
The study, published in The Lancet Gastroenterology & Hepatology, found about 60% of patients on CDED achieved clinical remission by week 6 without adding medications.
Furthermore, 80% of patients in remission at week 6 maintained clinical remission at week 24 on dietary monotherapy alone, allowing more than 50% of the intention-to-treat (ITT) population to achieve sustained remission at 6 months.
Dietary therapy resulted in a significant and progressive reduction in inflammatory markers such as C-reactive protein and fecal calprotectin. The benefit extended to mucosal healing, with 35% of the ITT population achieving endoscopic remission at 24 weeks.
Dr. Yanai explained the clinical context in which her group designed the study. “There were preliminary data regarding the efficacy of the dietary strategy for the induction of remission of mild CD in the pediatric population,” she said in an interview. “Additionally, there was an anecdotal experience in adults who reported benefits. Facing this and the lack of attractive alternatives for mild CD, we decided to examine the effectiveness of this therapeutic strategy in adults.”
Given the costs and side effects of medical treatment, interest in dietary monotherapy for IBD has been growing. As Dr. Yanai said, the CDED, a whole-foods regimen, plus PEN, has been found to help children with CD.
The CDED excludes proinflammatory food components associated with intestinal microbial dysbiosis, altered innate immunity, and impaired gut barrier function.
It involves increased consumption of fruits and vegetables, high-quality lean protein, complex carbohydrates, healthy oils, and fiber, while decreasing intake of inflammation-driving components such as animal and saturated vegetable fats, wheat, and dairy, as well as food additives such as emulsifiers, maltodextrin, and sulfites.
“The realization that exclusive enteral nutrition, which is based on liquid formulas, is effective for inducting remission in children PEN, which is a combination of liquid formulas and food, was less effective, led to the hypothesis that the mechanism might be the exclusion of dietary components that may lead to inflammation,” Dr. Yanai said. This theory, she added, derived from animal models showing that specific dietary components potentially drive inflammation.
The only current guideline-recommended nutritional therapy for remission induction is exclusive enteral nutrition (EEN) in pediatric CD.
The study
The open-label pilot trial led by Dr. Yanai, conducted at three medical centers, enrolled biologic-naive adults ages 18-55 with uncomplicated mild to moderate CD, with a disease duration of no more than 5 years. They had active disease on imaging and elevated C-reactive protein or fecal calprotectin.
During the period January 2017 to May 2020, eligible patients were randomly assigned 1 to 1 to CDED plus PEN enteral (n = 20) or CDED alone (n = 24) for 24 weeks. The primary endpoint was clinical remission, defined as a Harvey–Bradshaw Index score of less than 5 at week 6, an outcome was assessed in the ITT population, which consisted of those who used dietary therapy for at least 48 hours.
At week 6, 13 (68%) of 19 remaining patients in the CDED-plus-PEN group and 12 (57%) of 21 patients in the CDED-alone group had achieved clinical remission (P = .4618).
Among the 25 patients in remission 6 weeks out, 20 (80%) remained in sustained remission at week 24: 12 in the CDED-plus-PEN group and 8 in the CDED-alone group.
Moreover, 14 (35%) of 40 patients were in endoscopic remission at week 24: 8 on CDED plus PEN and 6 on CDED alone.
“CDED with or without partial enteral nutrition was effective for induction and maintenance of remission in adults with mild to moderate biologic-naive Crohn’s disease and might lead to endoscopic remission,” the authors wrote, adding that CDED for mild to moderate active disease should be assessed in a powered randomized controlled trial.
Compliance and adherence are obstacles to dietary therapies. Data for adults using exclusive enteral nutrition are conflicting, with poor compliance postulated to drive an inadequate response in some studies.
“Like every dietary treatment, adherence is challenging,” Dr. Yanai said. “However, when patients feel that it helps them, they have more incentive to follow the diet in the long run, and also once they quit and fare worse, they can go back and follow the first stage of CDED.”
She and her colleagues stressed the need for adequately powered randomized trials and recommended that the personalization of therapeutic diets in the future should take into account the need to deliver energy tailored to the nutritional and therapeutic goals of the patient.
Diets alone are not therapy
In an accompanying editorial, Alexa N. Sasson, MD, an IBD fellow at Massachusetts General Hospital and T.H. Chan Harvard School of Public Health, both in Boston, called diet “a promising and potentially modifiable risk factor with mounting evidence supporting its therapeutic benefit.”
She concurred that the Israeli findings indicate that CDED with or without PEN appears effective for inducing and maintaining remission in this cohort of patients. “Assessment of composite diets such as the CDED is important since they can be incorporated into daily life. The relative efficacy of each of the included and excluded foods, however, is not clear,” she wrote.
She cautioned, however, that dietary therapy does not constitute maintenance therapy and its effects are not sustained after the reintroduction of whole foods. “Identification of sustainable dietary interventions for the prevention and treatment of IBD is increasingly a focus of research,” she wrote.
Dr. Sasson agreed that dietary therapy for CD should be centered on patient interests, goals, and disease states. “Adjunctive dietary measures might be considered in all interested patients as a method of improving gastrointestinal-related symptoms and quality of life, with the potential to achieve a higher and more sustained level of remission,” she wrote.
Both the authors and the commentator agreed on the need for larger randomized trials with long-term follow-up to guide treatment decisions and identify patients who might benefit from dietary intervention.
This study was funded by the Azrieli Foundation and Nestlé Health Science. Dr. Yanai reported financial relationships with Pfizer, AbbVie, Ferring, Janssen, Neopharm, Pfizer, and Takeda. Several coauthors disclosed financial ties to multiple private-sector companies. Dr. Sasson had no competing interests to declare.
This article was updated Dec. 1, 2021.
The Crohn’s disease exclusion diet (CDED), with or without partial enteral nutrition (PEN), effectively induced and maintained remission in adults with mild to moderate, biologic-naive CD, a randomized Israeli pilot study found.
The authors, led by Henit Yanai, MD, MBA, chief of the IBD Center at Rabin Medical Center in Petah Tikva, Israel, also suggested that dietary monotherapy might lead to durable endoscopic remission.
The study, published in The Lancet Gastroenterology & Hepatology, found about 60% of patients on CDED achieved clinical remission by week 6 without adding medications.
Furthermore, 80% of patients in remission at week 6 maintained clinical remission at week 24 on dietary monotherapy alone, allowing more than 50% of the intention-to-treat (ITT) population to achieve sustained remission at 6 months.
Dietary therapy resulted in a significant and progressive reduction in inflammatory markers such as C-reactive protein and fecal calprotectin. The benefit extended to mucosal healing, with 35% of the ITT population achieving endoscopic remission at 24 weeks.
Dr. Yanai explained the clinical context in which her group designed the study. “There were preliminary data regarding the efficacy of the dietary strategy for the induction of remission of mild CD in the pediatric population,” she said in an interview. “Additionally, there was an anecdotal experience in adults who reported benefits. Facing this and the lack of attractive alternatives for mild CD, we decided to examine the effectiveness of this therapeutic strategy in adults.”
Given the costs and side effects of medical treatment, interest in dietary monotherapy for IBD has been growing. As Dr. Yanai said, the CDED, a whole-foods regimen, plus PEN, has been found to help children with CD.
The CDED excludes proinflammatory food components associated with intestinal microbial dysbiosis, altered innate immunity, and impaired gut barrier function.
It involves increased consumption of fruits and vegetables, high-quality lean protein, complex carbohydrates, healthy oils, and fiber, while decreasing intake of inflammation-driving components such as animal and saturated vegetable fats, wheat, and dairy, as well as food additives such as emulsifiers, maltodextrin, and sulfites.
“The realization that exclusive enteral nutrition, which is based on liquid formulas, is effective for inducting remission in children PEN, which is a combination of liquid formulas and food, was less effective, led to the hypothesis that the mechanism might be the exclusion of dietary components that may lead to inflammation,” Dr. Yanai said. This theory, she added, derived from animal models showing that specific dietary components potentially drive inflammation.
The only current guideline-recommended nutritional therapy for remission induction is exclusive enteral nutrition (EEN) in pediatric CD.
The study
The open-label pilot trial led by Dr. Yanai, conducted at three medical centers, enrolled biologic-naive adults ages 18-55 with uncomplicated mild to moderate CD, with a disease duration of no more than 5 years. They had active disease on imaging and elevated C-reactive protein or fecal calprotectin.
During the period January 2017 to May 2020, eligible patients were randomly assigned 1 to 1 to CDED plus PEN enteral (n = 20) or CDED alone (n = 24) for 24 weeks. The primary endpoint was clinical remission, defined as a Harvey–Bradshaw Index score of less than 5 at week 6, an outcome was assessed in the ITT population, which consisted of those who used dietary therapy for at least 48 hours.
At week 6, 13 (68%) of 19 remaining patients in the CDED-plus-PEN group and 12 (57%) of 21 patients in the CDED-alone group had achieved clinical remission (P = .4618).
Among the 25 patients in remission 6 weeks out, 20 (80%) remained in sustained remission at week 24: 12 in the CDED-plus-PEN group and 8 in the CDED-alone group.
Moreover, 14 (35%) of 40 patients were in endoscopic remission at week 24: 8 on CDED plus PEN and 6 on CDED alone.
“CDED with or without partial enteral nutrition was effective for induction and maintenance of remission in adults with mild to moderate biologic-naive Crohn’s disease and might lead to endoscopic remission,” the authors wrote, adding that CDED for mild to moderate active disease should be assessed in a powered randomized controlled trial.
Compliance and adherence are obstacles to dietary therapies. Data for adults using exclusive enteral nutrition are conflicting, with poor compliance postulated to drive an inadequate response in some studies.
“Like every dietary treatment, adherence is challenging,” Dr. Yanai said. “However, when patients feel that it helps them, they have more incentive to follow the diet in the long run, and also once they quit and fare worse, they can go back and follow the first stage of CDED.”
She and her colleagues stressed the need for adequately powered randomized trials and recommended that the personalization of therapeutic diets in the future should take into account the need to deliver energy tailored to the nutritional and therapeutic goals of the patient.
Diets alone are not therapy
In an accompanying editorial, Alexa N. Sasson, MD, an IBD fellow at Massachusetts General Hospital and T.H. Chan Harvard School of Public Health, both in Boston, called diet “a promising and potentially modifiable risk factor with mounting evidence supporting its therapeutic benefit.”
She concurred that the Israeli findings indicate that CDED with or without PEN appears effective for inducing and maintaining remission in this cohort of patients. “Assessment of composite diets such as the CDED is important since they can be incorporated into daily life. The relative efficacy of each of the included and excluded foods, however, is not clear,” she wrote.
She cautioned, however, that dietary therapy does not constitute maintenance therapy and its effects are not sustained after the reintroduction of whole foods. “Identification of sustainable dietary interventions for the prevention and treatment of IBD is increasingly a focus of research,” she wrote.
Dr. Sasson agreed that dietary therapy for CD should be centered on patient interests, goals, and disease states. “Adjunctive dietary measures might be considered in all interested patients as a method of improving gastrointestinal-related symptoms and quality of life, with the potential to achieve a higher and more sustained level of remission,” she wrote.
Both the authors and the commentator agreed on the need for larger randomized trials with long-term follow-up to guide treatment decisions and identify patients who might benefit from dietary intervention.
This study was funded by the Azrieli Foundation and Nestlé Health Science. Dr. Yanai reported financial relationships with Pfizer, AbbVie, Ferring, Janssen, Neopharm, Pfizer, and Takeda. Several coauthors disclosed financial ties to multiple private-sector companies. Dr. Sasson had no competing interests to declare.
This article was updated Dec. 1, 2021.
FROM LANCET GASTROENTEROLOGY & HEPATOLOGY
Multiple Sclerosis: Treatment & Management
Does vitamin D benefit only those who are deficient?
, suggests a new large-scale analysis.
Data on more than 380,000 participants gathered from 35 studies showed that, overall, there is no significant relationship between 25(OH)D concentrations, a clinical indicator of vitamin D status, and the incidence of coronary heart disease (CHD), stroke, or all-cause death, in a Mendelian randomization analysis.
However, Stephen Burgess, PhD, and colleagues showed that, in vitamin D–deficient individuals, each 10 nmol/L increase in 25(OH)D concentrations reduced the risk of all-cause mortality by 31%.
The research, published in The Lancet Diabetes & Endocrinology, also suggests there was a nonsignificant link between 25(OH)D concentrations and stroke and CHD, but again, only in vitamin D deficient individuals.
In an accompanying editorial, Guillaume Butler-Laporte, MD, and J. Brent Richards, MD, praise the researchers on their study methodology.
They add that the results “could have important public health and clinical consequences” and will “allow clinicians to better weigh the potential benefits of supplementation against its risk,” such as financial cost, “for better patient care – particularly among those with frank vitamin D deficiency.”
They continue: “Given that vitamin D deficiency is relatively common and vitamin D supplementation is safe, the rationale exists to test the effect of vitamin D supplementation in those with deficiency in large-scale randomized controlled trials.”
However, Dr. Butler-Laporte and Dr. Richards, of the Lady Davis Institute, Jewish General Hospital, Montreal, also note the study has several limitations, including the fact that the lifetime exposure to lower vitamin D levels captured by Mendelian randomization may result in larger effect sizes than in conventional trials.
Prior RCTS underpowered to detect effects of vitamin D supplements
“There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality, including mechanisms linking low vitamin D status with hyperparathyroidism and low serum calcium and phosphate,” write Dr. Burgess of the MRC Biostatistics Unit, University of Cambridge (England), and coauthors.
They also highlight that vitamin D is “further implicated in endothelial cell function” and affects the transcription of genes linked to cell division and apoptosis, providing “potential mechanisms implicating vitamin D for cancer.”
The researchers note that, while epidemiologic studies have “consistently” found a link between 25(OH)D levels and increased risk of cardiovascular disease, all-cause mortality, and other chronic diseases, several large trials of vitamin D supplementation have reported “null results.”
They argue, however, that many of these trials have recruited individuals “irrespective of baseline 25(OH)D concentration” and have been underpowered to detect the effects of supplementation.
To overcome these limitations, the team gathered data from the UK Biobank, the European Prospective Investigation Into Cancer and Nutrition Cardiovascular Disease (EPIC-CVD) study, 31 studies from the Vitamin D Studies Collaboration (VitDSC), and two Copenhagen population-based studies.
They first performed an observational study that included 384,721 individuals from the UK Biobank and 26,336 from EPIC-CVD who had a valid 25(OH)D measurement and no previously known cardiovascular disease at baseline.
Researchers also included 67,992 participants from the VitDSC studies who did not have previously known cardiovascular disease. They analyzed 25(OH)D concentrations, conventional cardiovascular risk factors, and major incident cardiovascular morbidity and mortality using individual participant data.
The results showed that, at low 25(OH)D concentrations, there was an inverse association between 25(OH)D and incident CHD, stroke, and all-cause mortality.
Next, the team conducted a Mendelian randomization analysis on 333,002 individuals from the UK Biobank and 26,336 from EPIC-CVD who were of European ancestry and had both a valid 25(OH)D measurement and genetic data that passed quality-control steps.
Information on 31,362 participants in the Copenhagen population-based studies was also included, giving a total of 386,406 individuals, of whom 33,546 had CHD, 18,166 had a stroke, and 27,885 died.
The mean age of participants ranged from 54.8 to 57.5 years, and between 53.4% and 55.4% were female.
Up to 7% of study participants were vitamin D deficient
The 25(OH)D analysis indicated that 3.9% of UK Biobank and 3.7% of Copenhagen study participants were deficient, compared with 6.9% in EPIC-CVD.
Across the full range of 25(OH)D concentrations, there was no significant association between genetically predicted 25(OH)D levels and CHD, stroke, or all-cause mortality.
However, restricting the analysis to individuals deemed vitamin D deficient (25[OH]D concentration < 25 nmol/L) revealed there was “strong evidence” for an inverse association with all-cause mortality, at an odds ratio per 10 nmol/L increase in genetically predicted 25(OH)D concentration of 0.69 (P < .0001), the team notes.
There were also nonsignificant associations between being in the deficient stratum and CHD, at an odds ratio of 0.89 (P = .14), and stroke, at an odds ratio of 0.85 (P = .09).
Further analysis suggests the association between 25(OH)D concentrations and all-cause mortality has a “clear threshold shape,” the researchers say, with evidence of an inverse association at concentrations below 40 nmol/L and null associations above that threshold.
They acknowledge, however, that their study has several potential limitations, including the assumption in their Mendelian randomization that the “only causal pathway from the genetic variants to the outcome is via 25(OH)D concentrations.”
Moreover, the genetic variants may affect 25(OH)D concentrations in a different way from “dietary supplementation or other clinical interventions.”
They also concede that their study was limited to middle-aged participants of European ancestries, which means the findings “might not be applicable to other populations.”
The study was funded by the British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. Dr. Burgess has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.
A version of this article first appeared on Medscape.com.
, suggests a new large-scale analysis.
Data on more than 380,000 participants gathered from 35 studies showed that, overall, there is no significant relationship between 25(OH)D concentrations, a clinical indicator of vitamin D status, and the incidence of coronary heart disease (CHD), stroke, or all-cause death, in a Mendelian randomization analysis.
However, Stephen Burgess, PhD, and colleagues showed that, in vitamin D–deficient individuals, each 10 nmol/L increase in 25(OH)D concentrations reduced the risk of all-cause mortality by 31%.
The research, published in The Lancet Diabetes & Endocrinology, also suggests there was a nonsignificant link between 25(OH)D concentrations and stroke and CHD, but again, only in vitamin D deficient individuals.
In an accompanying editorial, Guillaume Butler-Laporte, MD, and J. Brent Richards, MD, praise the researchers on their study methodology.
They add that the results “could have important public health and clinical consequences” and will “allow clinicians to better weigh the potential benefits of supplementation against its risk,” such as financial cost, “for better patient care – particularly among those with frank vitamin D deficiency.”
They continue: “Given that vitamin D deficiency is relatively common and vitamin D supplementation is safe, the rationale exists to test the effect of vitamin D supplementation in those with deficiency in large-scale randomized controlled trials.”
However, Dr. Butler-Laporte and Dr. Richards, of the Lady Davis Institute, Jewish General Hospital, Montreal, also note the study has several limitations, including the fact that the lifetime exposure to lower vitamin D levels captured by Mendelian randomization may result in larger effect sizes than in conventional trials.
Prior RCTS underpowered to detect effects of vitamin D supplements
“There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality, including mechanisms linking low vitamin D status with hyperparathyroidism and low serum calcium and phosphate,” write Dr. Burgess of the MRC Biostatistics Unit, University of Cambridge (England), and coauthors.
They also highlight that vitamin D is “further implicated in endothelial cell function” and affects the transcription of genes linked to cell division and apoptosis, providing “potential mechanisms implicating vitamin D for cancer.”
The researchers note that, while epidemiologic studies have “consistently” found a link between 25(OH)D levels and increased risk of cardiovascular disease, all-cause mortality, and other chronic diseases, several large trials of vitamin D supplementation have reported “null results.”
They argue, however, that many of these trials have recruited individuals “irrespective of baseline 25(OH)D concentration” and have been underpowered to detect the effects of supplementation.
To overcome these limitations, the team gathered data from the UK Biobank, the European Prospective Investigation Into Cancer and Nutrition Cardiovascular Disease (EPIC-CVD) study, 31 studies from the Vitamin D Studies Collaboration (VitDSC), and two Copenhagen population-based studies.
They first performed an observational study that included 384,721 individuals from the UK Biobank and 26,336 from EPIC-CVD who had a valid 25(OH)D measurement and no previously known cardiovascular disease at baseline.
Researchers also included 67,992 participants from the VitDSC studies who did not have previously known cardiovascular disease. They analyzed 25(OH)D concentrations, conventional cardiovascular risk factors, and major incident cardiovascular morbidity and mortality using individual participant data.
The results showed that, at low 25(OH)D concentrations, there was an inverse association between 25(OH)D and incident CHD, stroke, and all-cause mortality.
Next, the team conducted a Mendelian randomization analysis on 333,002 individuals from the UK Biobank and 26,336 from EPIC-CVD who were of European ancestry and had both a valid 25(OH)D measurement and genetic data that passed quality-control steps.
Information on 31,362 participants in the Copenhagen population-based studies was also included, giving a total of 386,406 individuals, of whom 33,546 had CHD, 18,166 had a stroke, and 27,885 died.
The mean age of participants ranged from 54.8 to 57.5 years, and between 53.4% and 55.4% were female.
Up to 7% of study participants were vitamin D deficient
The 25(OH)D analysis indicated that 3.9% of UK Biobank and 3.7% of Copenhagen study participants were deficient, compared with 6.9% in EPIC-CVD.
Across the full range of 25(OH)D concentrations, there was no significant association between genetically predicted 25(OH)D levels and CHD, stroke, or all-cause mortality.
However, restricting the analysis to individuals deemed vitamin D deficient (25[OH]D concentration < 25 nmol/L) revealed there was “strong evidence” for an inverse association with all-cause mortality, at an odds ratio per 10 nmol/L increase in genetically predicted 25(OH)D concentration of 0.69 (P < .0001), the team notes.
There were also nonsignificant associations between being in the deficient stratum and CHD, at an odds ratio of 0.89 (P = .14), and stroke, at an odds ratio of 0.85 (P = .09).
Further analysis suggests the association between 25(OH)D concentrations and all-cause mortality has a “clear threshold shape,” the researchers say, with evidence of an inverse association at concentrations below 40 nmol/L and null associations above that threshold.
They acknowledge, however, that their study has several potential limitations, including the assumption in their Mendelian randomization that the “only causal pathway from the genetic variants to the outcome is via 25(OH)D concentrations.”
Moreover, the genetic variants may affect 25(OH)D concentrations in a different way from “dietary supplementation or other clinical interventions.”
They also concede that their study was limited to middle-aged participants of European ancestries, which means the findings “might not be applicable to other populations.”
The study was funded by the British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. Dr. Burgess has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.
A version of this article first appeared on Medscape.com.
, suggests a new large-scale analysis.
Data on more than 380,000 participants gathered from 35 studies showed that, overall, there is no significant relationship between 25(OH)D concentrations, a clinical indicator of vitamin D status, and the incidence of coronary heart disease (CHD), stroke, or all-cause death, in a Mendelian randomization analysis.
However, Stephen Burgess, PhD, and colleagues showed that, in vitamin D–deficient individuals, each 10 nmol/L increase in 25(OH)D concentrations reduced the risk of all-cause mortality by 31%.
The research, published in The Lancet Diabetes & Endocrinology, also suggests there was a nonsignificant link between 25(OH)D concentrations and stroke and CHD, but again, only in vitamin D deficient individuals.
In an accompanying editorial, Guillaume Butler-Laporte, MD, and J. Brent Richards, MD, praise the researchers on their study methodology.
They add that the results “could have important public health and clinical consequences” and will “allow clinicians to better weigh the potential benefits of supplementation against its risk,” such as financial cost, “for better patient care – particularly among those with frank vitamin D deficiency.”
They continue: “Given that vitamin D deficiency is relatively common and vitamin D supplementation is safe, the rationale exists to test the effect of vitamin D supplementation in those with deficiency in large-scale randomized controlled trials.”
However, Dr. Butler-Laporte and Dr. Richards, of the Lady Davis Institute, Jewish General Hospital, Montreal, also note the study has several limitations, including the fact that the lifetime exposure to lower vitamin D levels captured by Mendelian randomization may result in larger effect sizes than in conventional trials.
Prior RCTS underpowered to detect effects of vitamin D supplements
“There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality, including mechanisms linking low vitamin D status with hyperparathyroidism and low serum calcium and phosphate,” write Dr. Burgess of the MRC Biostatistics Unit, University of Cambridge (England), and coauthors.
They also highlight that vitamin D is “further implicated in endothelial cell function” and affects the transcription of genes linked to cell division and apoptosis, providing “potential mechanisms implicating vitamin D for cancer.”
The researchers note that, while epidemiologic studies have “consistently” found a link between 25(OH)D levels and increased risk of cardiovascular disease, all-cause mortality, and other chronic diseases, several large trials of vitamin D supplementation have reported “null results.”
They argue, however, that many of these trials have recruited individuals “irrespective of baseline 25(OH)D concentration” and have been underpowered to detect the effects of supplementation.
To overcome these limitations, the team gathered data from the UK Biobank, the European Prospective Investigation Into Cancer and Nutrition Cardiovascular Disease (EPIC-CVD) study, 31 studies from the Vitamin D Studies Collaboration (VitDSC), and two Copenhagen population-based studies.
They first performed an observational study that included 384,721 individuals from the UK Biobank and 26,336 from EPIC-CVD who had a valid 25(OH)D measurement and no previously known cardiovascular disease at baseline.
Researchers also included 67,992 participants from the VitDSC studies who did not have previously known cardiovascular disease. They analyzed 25(OH)D concentrations, conventional cardiovascular risk factors, and major incident cardiovascular morbidity and mortality using individual participant data.
The results showed that, at low 25(OH)D concentrations, there was an inverse association between 25(OH)D and incident CHD, stroke, and all-cause mortality.
Next, the team conducted a Mendelian randomization analysis on 333,002 individuals from the UK Biobank and 26,336 from EPIC-CVD who were of European ancestry and had both a valid 25(OH)D measurement and genetic data that passed quality-control steps.
Information on 31,362 participants in the Copenhagen population-based studies was also included, giving a total of 386,406 individuals, of whom 33,546 had CHD, 18,166 had a stroke, and 27,885 died.
The mean age of participants ranged from 54.8 to 57.5 years, and between 53.4% and 55.4% were female.
Up to 7% of study participants were vitamin D deficient
The 25(OH)D analysis indicated that 3.9% of UK Biobank and 3.7% of Copenhagen study participants were deficient, compared with 6.9% in EPIC-CVD.
Across the full range of 25(OH)D concentrations, there was no significant association between genetically predicted 25(OH)D levels and CHD, stroke, or all-cause mortality.
However, restricting the analysis to individuals deemed vitamin D deficient (25[OH]D concentration < 25 nmol/L) revealed there was “strong evidence” for an inverse association with all-cause mortality, at an odds ratio per 10 nmol/L increase in genetically predicted 25(OH)D concentration of 0.69 (P < .0001), the team notes.
There were also nonsignificant associations between being in the deficient stratum and CHD, at an odds ratio of 0.89 (P = .14), and stroke, at an odds ratio of 0.85 (P = .09).
Further analysis suggests the association between 25(OH)D concentrations and all-cause mortality has a “clear threshold shape,” the researchers say, with evidence of an inverse association at concentrations below 40 nmol/L and null associations above that threshold.
They acknowledge, however, that their study has several potential limitations, including the assumption in their Mendelian randomization that the “only causal pathway from the genetic variants to the outcome is via 25(OH)D concentrations.”
Moreover, the genetic variants may affect 25(OH)D concentrations in a different way from “dietary supplementation or other clinical interventions.”
They also concede that their study was limited to middle-aged participants of European ancestries, which means the findings “might not be applicable to other populations.”
The study was funded by the British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. Dr. Burgess has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.
A version of this article first appeared on Medscape.com.
FDA approves first drug for treatment of resistant cytomegalovirus infection
The Food and Drug Administration has approved the first treatment for posttransplant cytomegalovirus (CMV) that is resistant to other drugs.
There are an estimated 200,000 adult transplants every year globally. CMV, a type of herpes virus, is one of the most common infections in transplant patients, occurring in 16%-56% of solid organ transplant recipients and 30%-70% of hematopoietic stem cell transplant recipients, according to Takeda Pharmaceutical Company Limited, the company that manufactures Livtencity. For immunosuppressed transplant patients, CMV infection can lead to complications that include loss of the transplanted or organ or even death.
“Cytomegalovirus infections that are resistant or do not respond to available drugs are of even greater concern,” John Farley, MD, MPH, the director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Today’s approval helps meet a significant unmet medical need by providing a treatment option for this patient population.”
Livtencity, which is taken orally, works by preventing the activity of the enzyme responsible for virus replication. The approval, announced Nov. 23, was based on a phase 3 clinical trial that compared Livtencity with conventional antiviral treatments in the achievement of CMV DNA concentration levels below what is measurable in transplant patients with CMV infection that is refractory or treatment-resistant. After 8 weeks, of the 235 patients who received Livtencity, 56% achieved this primary endpoint, compared with 24% of the 117 patients who received conventional antiviral treatments, the press release says.
The most reported adverse reactions of Livtencity were taste disturbance, nausea, diarrhea, vomiting, and fatigue.
“We are grateful for the contributions of the patients and clinicians who participated in our clinical trials, as well as the dedication of our scientists and researchers,” Ramona Sequeira, president of the Takeda’s U.S. Business Unit and Global Portfolio Commercialization, said in a statement. “People undergoing transplants have a lengthy and complex health care journey; with the approval of this treatment, we’re proud to offer these individuals a new oral antiviral to fight CMV infection and disease.”
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved the first treatment for posttransplant cytomegalovirus (CMV) that is resistant to other drugs.
There are an estimated 200,000 adult transplants every year globally. CMV, a type of herpes virus, is one of the most common infections in transplant patients, occurring in 16%-56% of solid organ transplant recipients and 30%-70% of hematopoietic stem cell transplant recipients, according to Takeda Pharmaceutical Company Limited, the company that manufactures Livtencity. For immunosuppressed transplant patients, CMV infection can lead to complications that include loss of the transplanted or organ or even death.
“Cytomegalovirus infections that are resistant or do not respond to available drugs are of even greater concern,” John Farley, MD, MPH, the director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Today’s approval helps meet a significant unmet medical need by providing a treatment option for this patient population.”
Livtencity, which is taken orally, works by preventing the activity of the enzyme responsible for virus replication. The approval, announced Nov. 23, was based on a phase 3 clinical trial that compared Livtencity with conventional antiviral treatments in the achievement of CMV DNA concentration levels below what is measurable in transplant patients with CMV infection that is refractory or treatment-resistant. After 8 weeks, of the 235 patients who received Livtencity, 56% achieved this primary endpoint, compared with 24% of the 117 patients who received conventional antiviral treatments, the press release says.
The most reported adverse reactions of Livtencity were taste disturbance, nausea, diarrhea, vomiting, and fatigue.
“We are grateful for the contributions of the patients and clinicians who participated in our clinical trials, as well as the dedication of our scientists and researchers,” Ramona Sequeira, president of the Takeda’s U.S. Business Unit and Global Portfolio Commercialization, said in a statement. “People undergoing transplants have a lengthy and complex health care journey; with the approval of this treatment, we’re proud to offer these individuals a new oral antiviral to fight CMV infection and disease.”
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved the first treatment for posttransplant cytomegalovirus (CMV) that is resistant to other drugs.
There are an estimated 200,000 adult transplants every year globally. CMV, a type of herpes virus, is one of the most common infections in transplant patients, occurring in 16%-56% of solid organ transplant recipients and 30%-70% of hematopoietic stem cell transplant recipients, according to Takeda Pharmaceutical Company Limited, the company that manufactures Livtencity. For immunosuppressed transplant patients, CMV infection can lead to complications that include loss of the transplanted or organ or even death.
“Cytomegalovirus infections that are resistant or do not respond to available drugs are of even greater concern,” John Farley, MD, MPH, the director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Today’s approval helps meet a significant unmet medical need by providing a treatment option for this patient population.”
Livtencity, which is taken orally, works by preventing the activity of the enzyme responsible for virus replication. The approval, announced Nov. 23, was based on a phase 3 clinical trial that compared Livtencity with conventional antiviral treatments in the achievement of CMV DNA concentration levels below what is measurable in transplant patients with CMV infection that is refractory or treatment-resistant. After 8 weeks, of the 235 patients who received Livtencity, 56% achieved this primary endpoint, compared with 24% of the 117 patients who received conventional antiviral treatments, the press release says.
The most reported adverse reactions of Livtencity were taste disturbance, nausea, diarrhea, vomiting, and fatigue.
“We are grateful for the contributions of the patients and clinicians who participated in our clinical trials, as well as the dedication of our scientists and researchers,” Ramona Sequeira, president of the Takeda’s U.S. Business Unit and Global Portfolio Commercialization, said in a statement. “People undergoing transplants have a lengthy and complex health care journey; with the approval of this treatment, we’re proud to offer these individuals a new oral antiviral to fight CMV infection and disease.”
A version of this article first appeared on Medscape.com.
Multiple Lesions With Recurrent Bleeding
The Diagnosis: Nevoid Basal Cell Carcinoma Syndrome
Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a rare autosomal-dominant disorder that increases the risk for developing various carcinomas and affects multiple organ systems. Nevoid basal cell carcinoma syndrome is estimated at 1 per 40,000 to 60,000 individuals with no sexual predilection.1,2 Pathogenesis of NBCCS occurs through molecular alterations in the dormant hedgehog signaling pathway, causing constitutive signaling activity and a loss of function in the tumor suppressor patched 1 gene, PTCH1. As a result, the inhibition of smoothened oncogenes is released, Gli proteins are activated, and the hedgehog signaling pathway is no longer quiescent.2 Additional loss of function in the suppressor of fused homolog protein, a negative regulator of the hedgehog pathway, allows for further tumor proliferation. The crucial role these genes play in the hedgehog signaling pathway and their mutation association with NBCCS allows for molecular confirmation in the diagnosis of NBCCS. Allelic losses at the PTCH1 gene site are thought to occur in approximately 70% of NBCCS patients.2
Diagnosis of NBCCS is based on genetic testing to examine pathogenic gene variants, notably in the PTCH1 gene, and identification of characteristic clinical findings.2 Diagnosis of NBCCS requires either 2 minor suggestive criteria and 1 major suggestive criterion, 2 major suggestive criteria and 1 minor suggestive criterion, or 1 major suggestive criterion with molecular confirmation. The presence of basal cell carcinomas (BCCs) before 20 years of age or an excessive numbers of BCCs, keratocystic odontogenic tumors (KOTs), palmar or plantar pitting, and first-degree relatives with NBCCS are classified as major suggestive criteria.2 Nevoid basal cell carcinoma syndrome patients typically have BCCs that crust, ulcerate, or bleed. Minor suggestive criteria for NBCCS are rib abnormalities, skeletal malformations, macrocephaly, cleft lip or palate, and desmoplastic medulloblastoma.2-4 Suppressor of fused homolog protein mutations may increase the risk for desmoplastic medulloblastoma in NBCCS patients. Our patient had 4 of the major suggestive criteria, including a history of KOTs, multiple BCCs, first-degree relatives with NBCCS, and palmar or plantar pitting (bottom quiz image), while having 1 minor suggestive criterion of frontal bossing.
Patients with NBCCS have high phenotypic variability, as their skin carcinomas do not have the classic features of pearly surfaces or corkscrew telangiectasia that typically are associated with BCCs.1 Basal cell carcinomas in NBCCS-affected individuals usually are indistinguishable from sporadic lesions that arise in sun-exposed areas, making NBCCS difficult to diagnose. These sporadic lesions often are misdiagnosed as psoriatic or eczematous lesions, and additional subsequent examination is required. The findings of multiple papules and plaques spanning the body as well as lesions with rolled borders and ulcerated bases, indicative of BCCs, aid dermatologists in distinguishing benign lesions from those of NBCCS.1
Additional differential diagnoses are required to distinguish NBCCS from other similar inherited skin disorders that are characterized by BCCs. The presence of multiple incidental BCCs early in life remains a histopathologic clue for NBCCS diagnosis, as opposed to Rombo syndrome, in which BCCs often develop in adulthood.2,4 In addition, although both Bazex syndrome and Muir-Torre syndrome are characterized by the early onset of BCCs, the lack of skeletal abnormalities and palmar and plantar pitting distinguish these entities from NBCCS.2,4 Furthermore, though psoriasis also can present on the scalp, clinical presentation often includes well-demarcated and symmetric plaques that are erythematous and silvery, all of which were not present in our patient and typically are not seen in NBCCS.5
The recommended treatment of NBCCS is vismodegib, a specific oncogene inhibitor. This medication suppresses the hedgehog signaling pathway by inhibiting smoothened oncogenes and downstream target molecules, thereby decreasing tumor proliferation.6 In doing so, vismodegib inhibits the development of new BCCs while reducing the burden of present ones. Additionally, vismodegib appears to effectively treat KOTs. If successful, this medication may be able to suppress KOTs in patients with NBCCS and thus facilitate surgery.6 Additional hedgehog inhibitors include patidegib, sonidegib, and itraconazole. Patidegib gel 2% currently is in phase 3 clinical trials for evaluation of efficacy and safety in treatment of NBCCS. Sonidegib is approved for the treatment of locally advanced BCCs in the United States and the European Union and for both locally advanced BCCs and metastatic BCCs in Switzerland and Australia.7 Further research is needed before recommending antifungal itraconazole for NBCCS clinical use.8 Other medications for localized areas include topical application of 5-fluorouracil and imiquimod.2
- Sangehra R, Grewal P. Gorlin syndrome presentation and the importance of differential diagnosis of skin cancer: a case report. J Pharm Pharm Sci. 2018;21:222-224.
- Bresler S, Padwa B, Granter S. Nevoid basal cell carcinoma syndrome (Gorlin syndrome). Head Neck Pathol. 2016;10:119-124.
- Fujii K, Miyashita T. Gorlin syndrome (nevoid basal cell carcinoma syndrome): update and literature review. Pediatr Int. 2014;56:667-674.
- Evans G, Farndon P. Nevoid basal cell carcinoma syndrome. GeneReviews [Internet]. University of Washington; 1993-2020.
- Kim WB, Jerome D, Yeung J. Diagnosis and management of psoriasis. Can Fam Physician. 2017;63:278-285.
- Booms P, Harth M, Sader R, et al. Vismodegib hedgehog-signaling inhibition and treatment of basal cell carcinomas as well as keratocystic odontogenic tumors in Gorlin syndrome. Ann Maxillofac Surg. 2015;5:14-19.
- Gutzmer R, Soloon J. Hedgehog pathway inhibition for the treatment of basal cell carcinoma. Target Oncol. 2019;14:253-267.
- Leavitt E, Lask G, Martin S. Sonic hedgehog pathway inhibition in the treatment of advanced basal cell carcinoma. Curr Treat Options Oncol. 2019;20:84.
The Diagnosis: Nevoid Basal Cell Carcinoma Syndrome
Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a rare autosomal-dominant disorder that increases the risk for developing various carcinomas and affects multiple organ systems. Nevoid basal cell carcinoma syndrome is estimated at 1 per 40,000 to 60,000 individuals with no sexual predilection.1,2 Pathogenesis of NBCCS occurs through molecular alterations in the dormant hedgehog signaling pathway, causing constitutive signaling activity and a loss of function in the tumor suppressor patched 1 gene, PTCH1. As a result, the inhibition of smoothened oncogenes is released, Gli proteins are activated, and the hedgehog signaling pathway is no longer quiescent.2 Additional loss of function in the suppressor of fused homolog protein, a negative regulator of the hedgehog pathway, allows for further tumor proliferation. The crucial role these genes play in the hedgehog signaling pathway and their mutation association with NBCCS allows for molecular confirmation in the diagnosis of NBCCS. Allelic losses at the PTCH1 gene site are thought to occur in approximately 70% of NBCCS patients.2
Diagnosis of NBCCS is based on genetic testing to examine pathogenic gene variants, notably in the PTCH1 gene, and identification of characteristic clinical findings.2 Diagnosis of NBCCS requires either 2 minor suggestive criteria and 1 major suggestive criterion, 2 major suggestive criteria and 1 minor suggestive criterion, or 1 major suggestive criterion with molecular confirmation. The presence of basal cell carcinomas (BCCs) before 20 years of age or an excessive numbers of BCCs, keratocystic odontogenic tumors (KOTs), palmar or plantar pitting, and first-degree relatives with NBCCS are classified as major suggestive criteria.2 Nevoid basal cell carcinoma syndrome patients typically have BCCs that crust, ulcerate, or bleed. Minor suggestive criteria for NBCCS are rib abnormalities, skeletal malformations, macrocephaly, cleft lip or palate, and desmoplastic medulloblastoma.2-4 Suppressor of fused homolog protein mutations may increase the risk for desmoplastic medulloblastoma in NBCCS patients. Our patient had 4 of the major suggestive criteria, including a history of KOTs, multiple BCCs, first-degree relatives with NBCCS, and palmar or plantar pitting (bottom quiz image), while having 1 minor suggestive criterion of frontal bossing.
Patients with NBCCS have high phenotypic variability, as their skin carcinomas do not have the classic features of pearly surfaces or corkscrew telangiectasia that typically are associated with BCCs.1 Basal cell carcinomas in NBCCS-affected individuals usually are indistinguishable from sporadic lesions that arise in sun-exposed areas, making NBCCS difficult to diagnose. These sporadic lesions often are misdiagnosed as psoriatic or eczematous lesions, and additional subsequent examination is required. The findings of multiple papules and plaques spanning the body as well as lesions with rolled borders and ulcerated bases, indicative of BCCs, aid dermatologists in distinguishing benign lesions from those of NBCCS.1
Additional differential diagnoses are required to distinguish NBCCS from other similar inherited skin disorders that are characterized by BCCs. The presence of multiple incidental BCCs early in life remains a histopathologic clue for NBCCS diagnosis, as opposed to Rombo syndrome, in which BCCs often develop in adulthood.2,4 In addition, although both Bazex syndrome and Muir-Torre syndrome are characterized by the early onset of BCCs, the lack of skeletal abnormalities and palmar and plantar pitting distinguish these entities from NBCCS.2,4 Furthermore, though psoriasis also can present on the scalp, clinical presentation often includes well-demarcated and symmetric plaques that are erythematous and silvery, all of which were not present in our patient and typically are not seen in NBCCS.5
The recommended treatment of NBCCS is vismodegib, a specific oncogene inhibitor. This medication suppresses the hedgehog signaling pathway by inhibiting smoothened oncogenes and downstream target molecules, thereby decreasing tumor proliferation.6 In doing so, vismodegib inhibits the development of new BCCs while reducing the burden of present ones. Additionally, vismodegib appears to effectively treat KOTs. If successful, this medication may be able to suppress KOTs in patients with NBCCS and thus facilitate surgery.6 Additional hedgehog inhibitors include patidegib, sonidegib, and itraconazole. Patidegib gel 2% currently is in phase 3 clinical trials for evaluation of efficacy and safety in treatment of NBCCS. Sonidegib is approved for the treatment of locally advanced BCCs in the United States and the European Union and for both locally advanced BCCs and metastatic BCCs in Switzerland and Australia.7 Further research is needed before recommending antifungal itraconazole for NBCCS clinical use.8 Other medications for localized areas include topical application of 5-fluorouracil and imiquimod.2
The Diagnosis: Nevoid Basal Cell Carcinoma Syndrome
Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a rare autosomal-dominant disorder that increases the risk for developing various carcinomas and affects multiple organ systems. Nevoid basal cell carcinoma syndrome is estimated at 1 per 40,000 to 60,000 individuals with no sexual predilection.1,2 Pathogenesis of NBCCS occurs through molecular alterations in the dormant hedgehog signaling pathway, causing constitutive signaling activity and a loss of function in the tumor suppressor patched 1 gene, PTCH1. As a result, the inhibition of smoothened oncogenes is released, Gli proteins are activated, and the hedgehog signaling pathway is no longer quiescent.2 Additional loss of function in the suppressor of fused homolog protein, a negative regulator of the hedgehog pathway, allows for further tumor proliferation. The crucial role these genes play in the hedgehog signaling pathway and their mutation association with NBCCS allows for molecular confirmation in the diagnosis of NBCCS. Allelic losses at the PTCH1 gene site are thought to occur in approximately 70% of NBCCS patients.2
Diagnosis of NBCCS is based on genetic testing to examine pathogenic gene variants, notably in the PTCH1 gene, and identification of characteristic clinical findings.2 Diagnosis of NBCCS requires either 2 minor suggestive criteria and 1 major suggestive criterion, 2 major suggestive criteria and 1 minor suggestive criterion, or 1 major suggestive criterion with molecular confirmation. The presence of basal cell carcinomas (BCCs) before 20 years of age or an excessive numbers of BCCs, keratocystic odontogenic tumors (KOTs), palmar or plantar pitting, and first-degree relatives with NBCCS are classified as major suggestive criteria.2 Nevoid basal cell carcinoma syndrome patients typically have BCCs that crust, ulcerate, or bleed. Minor suggestive criteria for NBCCS are rib abnormalities, skeletal malformations, macrocephaly, cleft lip or palate, and desmoplastic medulloblastoma.2-4 Suppressor of fused homolog protein mutations may increase the risk for desmoplastic medulloblastoma in NBCCS patients. Our patient had 4 of the major suggestive criteria, including a history of KOTs, multiple BCCs, first-degree relatives with NBCCS, and palmar or plantar pitting (bottom quiz image), while having 1 minor suggestive criterion of frontal bossing.
Patients with NBCCS have high phenotypic variability, as their skin carcinomas do not have the classic features of pearly surfaces or corkscrew telangiectasia that typically are associated with BCCs.1 Basal cell carcinomas in NBCCS-affected individuals usually are indistinguishable from sporadic lesions that arise in sun-exposed areas, making NBCCS difficult to diagnose. These sporadic lesions often are misdiagnosed as psoriatic or eczematous lesions, and additional subsequent examination is required. The findings of multiple papules and plaques spanning the body as well as lesions with rolled borders and ulcerated bases, indicative of BCCs, aid dermatologists in distinguishing benign lesions from those of NBCCS.1
Additional differential diagnoses are required to distinguish NBCCS from other similar inherited skin disorders that are characterized by BCCs. The presence of multiple incidental BCCs early in life remains a histopathologic clue for NBCCS diagnosis, as opposed to Rombo syndrome, in which BCCs often develop in adulthood.2,4 In addition, although both Bazex syndrome and Muir-Torre syndrome are characterized by the early onset of BCCs, the lack of skeletal abnormalities and palmar and plantar pitting distinguish these entities from NBCCS.2,4 Furthermore, though psoriasis also can present on the scalp, clinical presentation often includes well-demarcated and symmetric plaques that are erythematous and silvery, all of which were not present in our patient and typically are not seen in NBCCS.5
The recommended treatment of NBCCS is vismodegib, a specific oncogene inhibitor. This medication suppresses the hedgehog signaling pathway by inhibiting smoothened oncogenes and downstream target molecules, thereby decreasing tumor proliferation.6 In doing so, vismodegib inhibits the development of new BCCs while reducing the burden of present ones. Additionally, vismodegib appears to effectively treat KOTs. If successful, this medication may be able to suppress KOTs in patients with NBCCS and thus facilitate surgery.6 Additional hedgehog inhibitors include patidegib, sonidegib, and itraconazole. Patidegib gel 2% currently is in phase 3 clinical trials for evaluation of efficacy and safety in treatment of NBCCS. Sonidegib is approved for the treatment of locally advanced BCCs in the United States and the European Union and for both locally advanced BCCs and metastatic BCCs in Switzerland and Australia.7 Further research is needed before recommending antifungal itraconazole for NBCCS clinical use.8 Other medications for localized areas include topical application of 5-fluorouracil and imiquimod.2
- Sangehra R, Grewal P. Gorlin syndrome presentation and the importance of differential diagnosis of skin cancer: a case report. J Pharm Pharm Sci. 2018;21:222-224.
- Bresler S, Padwa B, Granter S. Nevoid basal cell carcinoma syndrome (Gorlin syndrome). Head Neck Pathol. 2016;10:119-124.
- Fujii K, Miyashita T. Gorlin syndrome (nevoid basal cell carcinoma syndrome): update and literature review. Pediatr Int. 2014;56:667-674.
- Evans G, Farndon P. Nevoid basal cell carcinoma syndrome. GeneReviews [Internet]. University of Washington; 1993-2020.
- Kim WB, Jerome D, Yeung J. Diagnosis and management of psoriasis. Can Fam Physician. 2017;63:278-285.
- Booms P, Harth M, Sader R, et al. Vismodegib hedgehog-signaling inhibition and treatment of basal cell carcinomas as well as keratocystic odontogenic tumors in Gorlin syndrome. Ann Maxillofac Surg. 2015;5:14-19.
- Gutzmer R, Soloon J. Hedgehog pathway inhibition for the treatment of basal cell carcinoma. Target Oncol. 2019;14:253-267.
- Leavitt E, Lask G, Martin S. Sonic hedgehog pathway inhibition in the treatment of advanced basal cell carcinoma. Curr Treat Options Oncol. 2019;20:84.
- Sangehra R, Grewal P. Gorlin syndrome presentation and the importance of differential diagnosis of skin cancer: a case report. J Pharm Pharm Sci. 2018;21:222-224.
- Bresler S, Padwa B, Granter S. Nevoid basal cell carcinoma syndrome (Gorlin syndrome). Head Neck Pathol. 2016;10:119-124.
- Fujii K, Miyashita T. Gorlin syndrome (nevoid basal cell carcinoma syndrome): update and literature review. Pediatr Int. 2014;56:667-674.
- Evans G, Farndon P. Nevoid basal cell carcinoma syndrome. GeneReviews [Internet]. University of Washington; 1993-2020.
- Kim WB, Jerome D, Yeung J. Diagnosis and management of psoriasis. Can Fam Physician. 2017;63:278-285.
- Booms P, Harth M, Sader R, et al. Vismodegib hedgehog-signaling inhibition and treatment of basal cell carcinomas as well as keratocystic odontogenic tumors in Gorlin syndrome. Ann Maxillofac Surg. 2015;5:14-19.
- Gutzmer R, Soloon J. Hedgehog pathway inhibition for the treatment of basal cell carcinoma. Target Oncol. 2019;14:253-267.
- Leavitt E, Lask G, Martin S. Sonic hedgehog pathway inhibition in the treatment of advanced basal cell carcinoma. Curr Treat Options Oncol. 2019;20:84.
A 63-year-old man with frontal bossing and a history of jaw cysts presented with numerous lesions on the scalp, trunk, and legs with recurrent bleeding. Both of his siblings had similar findings. Many lesions had been present for at least 40 years. Physical examination revealed a large, irregular, atrophic, hyperpigmented plaque on the central scalp with multiple translucent hyperpigmented papules at the periphery (top). Similar papules and plaques were present at the temples, around the waist, and on the distal lower extremities, leading to surgical excision of the largest leg lesions. In addition, there were many pinpoint pits on both palms (bottom). A biopsy was submitted for review, which confirmed basal cell carcinomas on the scalp.
