Checkpoint inhibitor use as adjuvant therapy for patients with high-risk cutaneous squamous cell carcinoma (cSCC) may eventually overtake the use of cytotoxic chemotherapeutic agents, say the authors of a clinical review recently published in the journal Head and Neck.

The review, led by Jason G. Newman, MD, director of head and neck surgery at Penn Medicine, Philadelphia, includes evidence-based research findings from the last 10 years which describe the possible roles for adjuvant radiation, chemotherapy, immunotherapy, and/or targeted therapy in the management of high-risk cSCC.

Dr. Newman and colleagues wrote that more data – and high-quality data – are needed for physicians to determine with more confidence which adjuvant therapies would be best for specific patients with high-risk cSCC. But without that data, uncertainty in treatment decisions will persist.

“The requirements for and efficacy of adjuvant therapies in cutaneous squamous cell carcinoma are unclear, and the gap in evidence for practice decisions regarding adjuvant therapy in patients with high-risk cSCC has been apparent for more than a decade,” they wrote.

While surgical excision with clear margins of the primary cSCC lesion remains the standard of care, certain high-risk factors necessitate adjuvant therapy, the authors wrote. However, since the evidence consists of small retrospective studies with conflicting results, it is unclear which patients might benefit from adjuvant therapy. This review included recent and current trials in cutaneous SCC and the role of immune checkpoint inhibitors.

According to the review, adjuvant radiation therapy is usually considered with high-risk features, such as perineural invasion, lymph node metastasis and extracapsular/extranodal extension, if the patient is otherwise at high risk for metastasis or recurrence, or if further surgery is not possible.

The National Comprehensive Cancer Network, the American College of Radiology, and the American Society for Radiation Oncology do not recommend adjuvant radiation therapy for most patients with cSCC. However, adjuvant radiation therapy with or without systemic therapy may be considered in locally advanced disease, when further surgery is not an option, or if there is regional lymph node metastasis, but multidisciplinary consultation is recommended.

Regarding checkpoint inhibitors, the NCCN, ACR, and ASTRO do not recommend the use of systemic therapy for local disease amenable to surgery. Potential use of a checkpoint inhibitor with radiation therapy in a clinical trial is recommended for residual disease in locally advanced cSCC as palliative care when other options are not available. While the use of cemiplimab or pembrolizumab are preferred in regional recurrence when curative surgery and radiation therapy are not an option, a targeted therapy can be considered if this is not feasible.

“Given the current activity of checkpoint inhibition in this disease, enthusiasm for the addition of cytotoxic chemotherapeutic agents in the adjuvant setting may be on the decline,” the authors wrote. “Multidisciplinary approaches will most likely continue to be recommended in complicated cases, including those involving immunosuppression.”

The authors said that further study is needed on prognostic testing, such as gene expression profile testing or sentinel lymph node biopsy, as such testing early in disease could identify patients who would likely benefit from adjuvant therapy. They added that the need to identify patients at early stages of disease who are at high risk for metastasis continues to remain critical.

Checkpoint inhibitor use as adjuvant therapy for patients with high-risk cutaneous squamous cell carcinoma (cSCC) may eventually overtake the use of cytotoxic chemotherapeutic agents, say the authors of a clinical review recently published in the journal Head and Neck.

The review, led by Jason G. Newman, MD, director of head and neck surgery at Penn Medicine, Philadelphia, includes evidence-based research findings from the last 10 years which describe the possible roles for adjuvant radiation, chemotherapy, immunotherapy, and/or targeted therapy in the management of high-risk cSCC.

Dr. Newman and colleagues wrote that more data – and high-quality data – are needed for physicians to determine with more confidence which adjuvant therapies would be best for specific patients with high-risk cSCC. But without that data, uncertainty in treatment decisions will persist.

“The requirements for and efficacy of adjuvant therapies in cutaneous squamous cell carcinoma are unclear, and the gap in evidence for practice decisions regarding adjuvant therapy in patients with high-risk cSCC has been apparent for more than a decade,” they wrote.

While surgical excision with clear margins of the primary cSCC lesion remains the standard of care, certain high-risk factors necessitate adjuvant therapy, the authors wrote. However, since the evidence consists of small retrospective studies with conflicting results, it is unclear which patients might benefit from adjuvant therapy. This review included recent and current trials in cutaneous SCC and the role of immune checkpoint inhibitors.

According to the review, adjuvant radiation therapy is usually considered with high-risk features, such as perineural invasion, lymph node metastasis and extracapsular/extranodal extension, if the patient is otherwise at high risk for metastasis or recurrence, or if further surgery is not possible.

The National Comprehensive Cancer Network, the American College of Radiology, and the American Society for Radiation Oncology do not recommend adjuvant radiation therapy for most patients with cSCC. However, adjuvant radiation therapy with or without systemic therapy may be considered in locally advanced disease, when further surgery is not an option, or if there is regional lymph node metastasis, but multidisciplinary consultation is recommended.

Regarding checkpoint inhibitors, the NCCN, ACR, and ASTRO do not recommend the use of systemic therapy for local disease amenable to surgery. Potential use of a checkpoint inhibitor with radiation therapy in a clinical trial is recommended for residual disease in locally advanced cSCC as palliative care when other options are not available. While the use of cemiplimab or pembrolizumab are preferred in regional recurrence when curative surgery and radiation therapy are not an option, a targeted therapy can be considered if this is not feasible.

“Given the current activity of checkpoint inhibition in this disease, enthusiasm for the addition of cytotoxic chemotherapeutic agents in the adjuvant setting may be on the decline,” the authors wrote. “Multidisciplinary approaches will most likely continue to be recommended in complicated cases, including those involving immunosuppression.”

The authors said that further study is needed on prognostic testing, such as gene expression profile testing or sentinel lymph node biopsy, as such testing early in disease could identify patients who would likely benefit from adjuvant therapy. They added that the need to identify patients at early stages of disease who are at high risk for metastasis continues to remain critical.

Checkpoint inhibitor use as adjuvant therapy for patients with high-risk cutaneous squamous cell carcinoma (cSCC) may eventually overtake the use of cytotoxic chemotherapeutic agents, say the authors of a clinical review recently published in the journal Head and Neck.

The review, led by Jason G. Newman, MD, director of head and neck surgery at Penn Medicine, Philadelphia, includes evidence-based research findings from the last 10 years which describe the possible roles for adjuvant radiation, chemotherapy, immunotherapy, and/or targeted therapy in the management of high-risk cSCC.

Dr. Newman and colleagues wrote that more data – and high-quality data – are needed for physicians to determine with more confidence which adjuvant therapies would be best for specific patients with high-risk cSCC. But without that data, uncertainty in treatment decisions will persist.

“The requirements for and efficacy of adjuvant therapies in cutaneous squamous cell carcinoma are unclear, and the gap in evidence for practice decisions regarding adjuvant therapy in patients with high-risk cSCC has been apparent for more than a decade,” they wrote.

While surgical excision with clear margins of the primary cSCC lesion remains the standard of care, certain high-risk factors necessitate adjuvant therapy, the authors wrote. However, since the evidence consists of small retrospective studies with conflicting results, it is unclear which patients might benefit from adjuvant therapy. This review included recent and current trials in cutaneous SCC and the role of immune checkpoint inhibitors.

According to the review, adjuvant radiation therapy is usually considered with high-risk features, such as perineural invasion, lymph node metastasis and extracapsular/extranodal extension, if the patient is otherwise at high risk for metastasis or recurrence, or if further surgery is not possible.

The National Comprehensive Cancer Network, the American College of Radiology, and the American Society for Radiation Oncology do not recommend adjuvant radiation therapy for most patients with cSCC. However, adjuvant radiation therapy with or without systemic therapy may be considered in locally advanced disease, when further surgery is not an option, or if there is regional lymph node metastasis, but multidisciplinary consultation is recommended.

Regarding checkpoint inhibitors, the NCCN, ACR, and ASTRO do not recommend the use of systemic therapy for local disease amenable to surgery. Potential use of a checkpoint inhibitor with radiation therapy in a clinical trial is recommended for residual disease in locally advanced cSCC as palliative care when other options are not available. While the use of cemiplimab or pembrolizumab are preferred in regional recurrence when curative surgery and radiation therapy are not an option, a targeted therapy can be considered if this is not feasible.

“Given the current activity of checkpoint inhibition in this disease, enthusiasm for the addition of cytotoxic chemotherapeutic agents in the adjuvant setting may be on the decline,” the authors wrote. “Multidisciplinary approaches will most likely continue to be recommended in complicated cases, including those involving immunosuppression.”

The authors said that further study is needed on prognostic testing, such as gene expression profile testing or sentinel lymph node biopsy, as such testing early in disease could identify patients who would likely benefit from adjuvant therapy. They added that the need to identify patients at early stages of disease who are at high risk for metastasis continues to remain critical.

Fentanyl is now threatening overdoses in patients exposed to essentially any of the full array of recreational drugs – not just opioids – that are being sold illicitly, according to an overview of the problem presented at the virtual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

US DEA

“Fentanyl can now be found in cocaine and methamphetamine. At this point, there is really no way to predict what is in a [street] drug,” Edwin A. Salsitz, MD, said at the meeting, sponsored by Medscape Live. He is associate clinical professor of medicine who works in the division of chemical dependency at Mount Sinai Beth Israel Medical Center in New York.

As proof of the frequency with which fentanyl is now being used as an additive, most patients with a drug use disorder, regardless of their drug of choice, are testing positive for fentanyl at Dr. Salsitz’s center. Many of those with positive fentanyl tests are unaware that their drugs had been doctored with this agent.

Relative to drugs sold as an opioid, such as heroin or oxycodone, the fentanyl dose in nonopioid drugs is typically more modest, but Dr. Salsitz pointed out that those expecting cocaine or methamphetamine often “have no heroin tolerance, so they are more vulnerable” to the adverse effects of fentanyl, including an overdose.

Although opioid tolerance might improve the chances for surviving a fentanyl overdose, the toxicology of fentanyl is not the same as other opioids. Death from heroin is typically a result of respiratory depression, but the onset is relatively slow, providing a greater opportunity to administer a reversal agent, such as naloxone.

Fentanyl not only produces respiratory depression but skeletal muscle rigidity. The rapid onset of “wooden chest syndrome” can occur within minutes, making the opportunity for intervention much smaller, Dr. Salsitz said.

To illustrate the phenomenon, Dr. Salsitz recounted a case.

After an argument with his mother, a 26-year-old male with a long history of intravenous drug use went to his bedroom. His mother, responding to the sound of a loud thud, rushed to the bedroom to find her son on the floor with a needle still in his arm. Resuscitation efforts by the mother and by the emergency responders, who arrived quickly, failed.

“The speed of his death made it clear that it was fentanyl related, and the postmortem toxicology confirmed that the exposure involved both heroin and fentanyl,” Dr. Salsitz said.

After the first wave of deaths in the opioid epidemic, which was attributed to inappropriate use of prescription opioids, the second wave was driven by heroin. In that wave, patients who became addicted to prescription opioids but were having more difficulty gaining access to them, turned to far cheaper and readily available street heroin. The third wave, driven by fentanyl, began several years ago when sellers of heroin began adding this synthetic opioid, which is relatively cheap, to intensify the high.

It is not expected to end quickly. The fentanyl added to heroin was never a prescription version. Rather, Dr. Salsitz said, it is synthesized in laboratories in China, Mexico, and the United States. It is relatively easy to produce and compact, which makes it easy to transport.

Exacerbating the risks that fentanyl poses when added to street drugs, even more potent versions, such as carfentanil, are also being added to cocaine, methamphetamines, and other nonopioid illicit drugs. When compared on a per-milligram basis, fentanyl is about 100 times more potent than heroin, but carfentanil is about 100 times more potent than fentanyl, according to Dr. Salsitz.

When the third wave of deaths in the opioid epidemic began around 2013, prescriptions of fentanyl, like many other opioid-type therapies were declining. The “perfect storm” that initiated the opioid epidemic was a product of intense focus on pain control and a misperception that prescription opioids posed a low risk of abuse potential, Dr. Salsitz said. By the time fentanyl was driving opioid deaths, the risks of opioids were widely appreciated and their use for prescription analgesia was declining.

Citing several cases, Dr. Salsitz noted that only 20 years after clinicians were being successfully sued for not offering enough analgesia, they were now going to jail for prescribing these drugs too liberally.

According to Dr. Salsitz, the pendulum might now have swung too far in the other direction so that at least some patients are no longer receiving adequate pain control. While psychiatrists might not have a role in this issue, Dr. Salsitz did see a role for these specialists in protecting patients from the adverse consequences of using illicit drugs doctored with fentanyl.

Noting that individuals with psychiatric disorders are more likely than the general population to self-medicate with drugs purchased illegally, Dr. Salsitz encouraged psychiatrists “to get involved” in asking about drug use and counseling patients on the risks of fentanyl substitution or additives.

“The message is that no one knows what are in these drugs, anymore,” he said.

In addition to making patients aware that many street drugs are now contaminated with fentanyl, Dr. Salsitz provided some safety tips. He suggested instructing patients to take a low dose of any newly acquired drug to gauge its effect, to avoid taking drugs alone, and to avoid mixing drugs. He also recommended using rapid fentanyl test strips in order to detect fentanyl contamination.

Even for the many psychiatrists who do not feel comfortable managing addiction, Dr. Salsitz recommended a proactive approach to address the current threat.
 

Test strips as an intervention

The seriousness of fentanyl contamination of illicit drugs, including cocaine and methamphetamine, was corroborated by two investigators at the School of Public Health and the Albert Einstein Medical School of Brown University, Providence, R.I. Brandon D.L. Marshall, PhD, associate professor of epidemiology in the School of Public Health, called fentanyl-contaminated cannabis “extremely rare,” but he said that it is being found in counterfeit prescription pills as well as in crystal methamphetamine and in both crack and powder cocaine.

He also advocated the use of fentanyl test strips.

“Test strips are an efficient, inexpensive, and effective way to determine whether fentanyl or related analogs are present in illicit drugs,” he said, noting that he is involved in a trial designed to determine whether fentanyl test strips can reduce the risk of fatal and nonfatal overdoses.

In a pilot study conducted in Baltimore, 69% of the 103 participants engaged in harm reduction behavior after using a fentanyl test strip and receiving a positive result (Addict Behav. 2020;110:106529). It is notable that 86% of the participants had a least one positive result when using the strips. More than half were surprised by the result.

One of the findings from this study was “that the lasting benefit of fentanyl test strip distribution is the opportunity to engage in discussions around safety and relationship building with historically underserved communities,” said the lead author, Ju Nyeong Park, PhD, assistant professor of medicine and epidemiology at Brown University. She moved to Brown after performing this work at Johns Hopkins University, Baltimore.

Dr. Park noted that “many patients in the community already know that they are using drugs containing fentanyl,” but for those who are concerned and wish to avoid contaminated drugs, fentanyl test strips “are a quick screening tool.” However, while the strips are helpful, she cautioned that they cannot be considered a definitive tool for detecting harm in illicit drugs.

“There may also be other chemicals present in tested drugs that confer risk,” she said.

Medscape Live and this news organization are owned by the same parent company. Dr. Salsitz, Dr. Marshall, and Dr. Park reported no potential conflicts of interest.

Fentanyl is now threatening overdoses in patients exposed to essentially any of the full array of recreational drugs – not just opioids – that are being sold illicitly, according to an overview of the problem presented at the virtual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

US DEA

“Fentanyl can now be found in cocaine and methamphetamine. At this point, there is really no way to predict what is in a [street] drug,” Edwin A. Salsitz, MD, said at the meeting, sponsored by Medscape Live. He is associate clinical professor of medicine who works in the division of chemical dependency at Mount Sinai Beth Israel Medical Center in New York.

As proof of the frequency with which fentanyl is now being used as an additive, most patients with a drug use disorder, regardless of their drug of choice, are testing positive for fentanyl at Dr. Salsitz’s center. Many of those with positive fentanyl tests are unaware that their drugs had been doctored with this agent.

Relative to drugs sold as an opioid, such as heroin or oxycodone, the fentanyl dose in nonopioid drugs is typically more modest, but Dr. Salsitz pointed out that those expecting cocaine or methamphetamine often “have no heroin tolerance, so they are more vulnerable” to the adverse effects of fentanyl, including an overdose.

Although opioid tolerance might improve the chances for surviving a fentanyl overdose, the toxicology of fentanyl is not the same as other opioids. Death from heroin is typically a result of respiratory depression, but the onset is relatively slow, providing a greater opportunity to administer a reversal agent, such as naloxone.

Fentanyl not only produces respiratory depression but skeletal muscle rigidity. The rapid onset of “wooden chest syndrome” can occur within minutes, making the opportunity for intervention much smaller, Dr. Salsitz said.

To illustrate the phenomenon, Dr. Salsitz recounted a case.

After an argument with his mother, a 26-year-old male with a long history of intravenous drug use went to his bedroom. His mother, responding to the sound of a loud thud, rushed to the bedroom to find her son on the floor with a needle still in his arm. Resuscitation efforts by the mother and by the emergency responders, who arrived quickly, failed.

“The speed of his death made it clear that it was fentanyl related, and the postmortem toxicology confirmed that the exposure involved both heroin and fentanyl,” Dr. Salsitz said.

After the first wave of deaths in the opioid epidemic, which was attributed to inappropriate use of prescription opioids, the second wave was driven by heroin. In that wave, patients who became addicted to prescription opioids but were having more difficulty gaining access to them, turned to far cheaper and readily available street heroin. The third wave, driven by fentanyl, began several years ago when sellers of heroin began adding this synthetic opioid, which is relatively cheap, to intensify the high.

It is not expected to end quickly. The fentanyl added to heroin was never a prescription version. Rather, Dr. Salsitz said, it is synthesized in laboratories in China, Mexico, and the United States. It is relatively easy to produce and compact, which makes it easy to transport.

Exacerbating the risks that fentanyl poses when added to street drugs, even more potent versions, such as carfentanil, are also being added to cocaine, methamphetamines, and other nonopioid illicit drugs. When compared on a per-milligram basis, fentanyl is about 100 times more potent than heroin, but carfentanil is about 100 times more potent than fentanyl, according to Dr. Salsitz.

When the third wave of deaths in the opioid epidemic began around 2013, prescriptions of fentanyl, like many other opioid-type therapies were declining. The “perfect storm” that initiated the opioid epidemic was a product of intense focus on pain control and a misperception that prescription opioids posed a low risk of abuse potential, Dr. Salsitz said. By the time fentanyl was driving opioid deaths, the risks of opioids were widely appreciated and their use for prescription analgesia was declining.

Citing several cases, Dr. Salsitz noted that only 20 years after clinicians were being successfully sued for not offering enough analgesia, they were now going to jail for prescribing these drugs too liberally.

According to Dr. Salsitz, the pendulum might now have swung too far in the other direction so that at least some patients are no longer receiving adequate pain control. While psychiatrists might not have a role in this issue, Dr. Salsitz did see a role for these specialists in protecting patients from the adverse consequences of using illicit drugs doctored with fentanyl.

Noting that individuals with psychiatric disorders are more likely than the general population to self-medicate with drugs purchased illegally, Dr. Salsitz encouraged psychiatrists “to get involved” in asking about drug use and counseling patients on the risks of fentanyl substitution or additives.

“The message is that no one knows what are in these drugs, anymore,” he said.

In addition to making patients aware that many street drugs are now contaminated with fentanyl, Dr. Salsitz provided some safety tips. He suggested instructing patients to take a low dose of any newly acquired drug to gauge its effect, to avoid taking drugs alone, and to avoid mixing drugs. He also recommended using rapid fentanyl test strips in order to detect fentanyl contamination.

Even for the many psychiatrists who do not feel comfortable managing addiction, Dr. Salsitz recommended a proactive approach to address the current threat.
 

Test strips as an intervention

The seriousness of fentanyl contamination of illicit drugs, including cocaine and methamphetamine, was corroborated by two investigators at the School of Public Health and the Albert Einstein Medical School of Brown University, Providence, R.I. Brandon D.L. Marshall, PhD, associate professor of epidemiology in the School of Public Health, called fentanyl-contaminated cannabis “extremely rare,” but he said that it is being found in counterfeit prescription pills as well as in crystal methamphetamine and in both crack and powder cocaine.

He also advocated the use of fentanyl test strips.

“Test strips are an efficient, inexpensive, and effective way to determine whether fentanyl or related analogs are present in illicit drugs,” he said, noting that he is involved in a trial designed to determine whether fentanyl test strips can reduce the risk of fatal and nonfatal overdoses.

In a pilot study conducted in Baltimore, 69% of the 103 participants engaged in harm reduction behavior after using a fentanyl test strip and receiving a positive result (Addict Behav. 2020;110:106529). It is notable that 86% of the participants had a least one positive result when using the strips. More than half were surprised by the result.

One of the findings from this study was “that the lasting benefit of fentanyl test strip distribution is the opportunity to engage in discussions around safety and relationship building with historically underserved communities,” said the lead author, Ju Nyeong Park, PhD, assistant professor of medicine and epidemiology at Brown University. She moved to Brown after performing this work at Johns Hopkins University, Baltimore.

Dr. Park noted that “many patients in the community already know that they are using drugs containing fentanyl,” but for those who are concerned and wish to avoid contaminated drugs, fentanyl test strips “are a quick screening tool.” However, while the strips are helpful, she cautioned that they cannot be considered a definitive tool for detecting harm in illicit drugs.

“There may also be other chemicals present in tested drugs that confer risk,” she said.

Medscape Live and this news organization are owned by the same parent company. Dr. Salsitz, Dr. Marshall, and Dr. Park reported no potential conflicts of interest.

Fentanyl is now threatening overdoses in patients exposed to essentially any of the full array of recreational drugs – not just opioids – that are being sold illicitly, according to an overview of the problem presented at the virtual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

US DEA

“Fentanyl can now be found in cocaine and methamphetamine. At this point, there is really no way to predict what is in a [street] drug,” Edwin A. Salsitz, MD, said at the meeting, sponsored by Medscape Live. He is associate clinical professor of medicine who works in the division of chemical dependency at Mount Sinai Beth Israel Medical Center in New York.

As proof of the frequency with which fentanyl is now being used as an additive, most patients with a drug use disorder, regardless of their drug of choice, are testing positive for fentanyl at Dr. Salsitz’s center. Many of those with positive fentanyl tests are unaware that their drugs had been doctored with this agent.

Relative to drugs sold as an opioid, such as heroin or oxycodone, the fentanyl dose in nonopioid drugs is typically more modest, but Dr. Salsitz pointed out that those expecting cocaine or methamphetamine often “have no heroin tolerance, so they are more vulnerable” to the adverse effects of fentanyl, including an overdose.

Although opioid tolerance might improve the chances for surviving a fentanyl overdose, the toxicology of fentanyl is not the same as other opioids. Death from heroin is typically a result of respiratory depression, but the onset is relatively slow, providing a greater opportunity to administer a reversal agent, such as naloxone.

Fentanyl not only produces respiratory depression but skeletal muscle rigidity. The rapid onset of “wooden chest syndrome” can occur within minutes, making the opportunity for intervention much smaller, Dr. Salsitz said.

To illustrate the phenomenon, Dr. Salsitz recounted a case.

After an argument with his mother, a 26-year-old male with a long history of intravenous drug use went to his bedroom. His mother, responding to the sound of a loud thud, rushed to the bedroom to find her son on the floor with a needle still in his arm. Resuscitation efforts by the mother and by the emergency responders, who arrived quickly, failed.

“The speed of his death made it clear that it was fentanyl related, and the postmortem toxicology confirmed that the exposure involved both heroin and fentanyl,” Dr. Salsitz said.

After the first wave of deaths in the opioid epidemic, which was attributed to inappropriate use of prescription opioids, the second wave was driven by heroin. In that wave, patients who became addicted to prescription opioids but were having more difficulty gaining access to them, turned to far cheaper and readily available street heroin. The third wave, driven by fentanyl, began several years ago when sellers of heroin began adding this synthetic opioid, which is relatively cheap, to intensify the high.

It is not expected to end quickly. The fentanyl added to heroin was never a prescription version. Rather, Dr. Salsitz said, it is synthesized in laboratories in China, Mexico, and the United States. It is relatively easy to produce and compact, which makes it easy to transport.

Exacerbating the risks that fentanyl poses when added to street drugs, even more potent versions, such as carfentanil, are also being added to cocaine, methamphetamines, and other nonopioid illicit drugs. When compared on a per-milligram basis, fentanyl is about 100 times more potent than heroin, but carfentanil is about 100 times more potent than fentanyl, according to Dr. Salsitz.

When the third wave of deaths in the opioid epidemic began around 2013, prescriptions of fentanyl, like many other opioid-type therapies were declining. The “perfect storm” that initiated the opioid epidemic was a product of intense focus on pain control and a misperception that prescription opioids posed a low risk of abuse potential, Dr. Salsitz said. By the time fentanyl was driving opioid deaths, the risks of opioids were widely appreciated and their use for prescription analgesia was declining.

Citing several cases, Dr. Salsitz noted that only 20 years after clinicians were being successfully sued for not offering enough analgesia, they were now going to jail for prescribing these drugs too liberally.

According to Dr. Salsitz, the pendulum might now have swung too far in the other direction so that at least some patients are no longer receiving adequate pain control. While psychiatrists might not have a role in this issue, Dr. Salsitz did see a role for these specialists in protecting patients from the adverse consequences of using illicit drugs doctored with fentanyl.

Noting that individuals with psychiatric disorders are more likely than the general population to self-medicate with drugs purchased illegally, Dr. Salsitz encouraged psychiatrists “to get involved” in asking about drug use and counseling patients on the risks of fentanyl substitution or additives.

“The message is that no one knows what are in these drugs, anymore,” he said.

In addition to making patients aware that many street drugs are now contaminated with fentanyl, Dr. Salsitz provided some safety tips. He suggested instructing patients to take a low dose of any newly acquired drug to gauge its effect, to avoid taking drugs alone, and to avoid mixing drugs. He also recommended using rapid fentanyl test strips in order to detect fentanyl contamination.

Even for the many psychiatrists who do not feel comfortable managing addiction, Dr. Salsitz recommended a proactive approach to address the current threat.
 

Test strips as an intervention

The seriousness of fentanyl contamination of illicit drugs, including cocaine and methamphetamine, was corroborated by two investigators at the School of Public Health and the Albert Einstein Medical School of Brown University, Providence, R.I. Brandon D.L. Marshall, PhD, associate professor of epidemiology in the School of Public Health, called fentanyl-contaminated cannabis “extremely rare,” but he said that it is being found in counterfeit prescription pills as well as in crystal methamphetamine and in both crack and powder cocaine.

He also advocated the use of fentanyl test strips.

“Test strips are an efficient, inexpensive, and effective way to determine whether fentanyl or related analogs are present in illicit drugs,” he said, noting that he is involved in a trial designed to determine whether fentanyl test strips can reduce the risk of fatal and nonfatal overdoses.

In a pilot study conducted in Baltimore, 69% of the 103 participants engaged in harm reduction behavior after using a fentanyl test strip and receiving a positive result (Addict Behav. 2020;110:106529). It is notable that 86% of the participants had a least one positive result when using the strips. More than half were surprised by the result.

One of the findings from this study was “that the lasting benefit of fentanyl test strip distribution is the opportunity to engage in discussions around safety and relationship building with historically underserved communities,” said the lead author, Ju Nyeong Park, PhD, assistant professor of medicine and epidemiology at Brown University. She moved to Brown after performing this work at Johns Hopkins University, Baltimore.

Dr. Park noted that “many patients in the community already know that they are using drugs containing fentanyl,” but for those who are concerned and wish to avoid contaminated drugs, fentanyl test strips “are a quick screening tool.” However, while the strips are helpful, she cautioned that they cannot be considered a definitive tool for detecting harm in illicit drugs.

“There may also be other chemicals present in tested drugs that confer risk,” she said.

Medscape Live and this news organization are owned by the same parent company. Dr. Salsitz, Dr. Marshall, and Dr. Park reported no potential conflicts of interest.

In this modern age of health care where telemedicine rules, conversational agents (CAs) that use text messaging systems are becoming a major mode of communication.

Many people are familiar with voice-enabled agents, such as Apple’s Siri, Google Now, and Microsoft’s Cortana. However, CAs come in different forms of complexity, ranging from a short message service–based texting platform to an embodied conversational agent (ECA).

ECAs allow participants to interact with a physical or graphical figure that simulates a person in appearance, behavior, and dialect. These are essentially virtual humans, or avatars, who talk with participants. By taking greater advantage of these automated agents, some have projected there may be $11 billion in combined cost savings across a variety of business sectors by 2023.¹ The health care field is one sector in which CAs can play an important role. Because of their accessibility, CAs have the potential to improve mental health by combating health care inequities and stigma, encouraging disclosure from participants, and serving as companions during the COVID-19 pandemic.

CAs provide accessible health care for rural, low socioeconomic status (SES), and minority communities in a variety of advantageous ways. For example, one study found that long-term use of a text-based agent that combines motivational interviewing and cognitive-behavioral therapy (CBT) can support smoking cessation in adolescents of low SES.²

CAs can help vulnerable participants advocate for themselves and proactively maintain their mental health through access to health care resources. In specific cases, these agents equalize health care treatment for different populations. Even though some participants live in secluded areas or are blocked by barriers, these text-based agents can still provide self-help intervention for them at any time on an individual basis, regardless of their location or socioeconomic status. Furthermore, they serve as highly cost-effective mental health promotion tools for large populations, some of which might not otherwise be reached by mental health care.

In combating mental illnesses such as depression and anxiety, studies have found that CAs are great treatment tools. For example, participants in an experimental group who received a self-help program based on CBT from a text-based CA named Woebot experienced significantly reduced depression symptoms when compared to the control group of participants, who received only information from a self-help electronic book.³ As a result, CAs might prove successful in treating younger populations who find online tools more feasible and accessible. Often, this population self-identifies depressive and anxiety symptoms without consulting a health care professional. Thus, this tool would prove useful to those who are bothered by the stigma of seeing a mental health professional.

Virtual human–based CAs also encourage participants to disclose more information in a nonjudgmental manner, especially among people with diseases with stigma. CAs use neutral languages, which may be helpful when dealing with stigmatized issues such as HIV, family planning, and abortion care because this heightens confidentiality and privacy. When participants believe that the agent does not “judge” or evaluate their capabilities, this elicits more sensitive information from them. For example, one study found that military service members who believed that they were interacting with a computer rather than a human operator reported lower fear of self-disclosure, displayed more sadness, and were rated by observers as more willing to disclose posttraumatic stress disorder symptoms.⁴ Additional findings show that participants prefer CAs when topics are highly sensitive and more likely to evoke negative self-admissions.

In what we hope will soon be a post–COVID-19 landscape of medicine, CAs are fast being used on the front lines of health care technology. Empathetic CAs can combat adverse effects of social exclusion during these pressing times. Etsuko Ishii, a researcher affiliated with the Hong Kong University of Science and Technology, and associates demonstrated that a virtual CA was as effective as a COVID-19 companion because it uses natural language processing (NLP) and nonverbal facial expressions to give users the feeling that they are being treated with empathy.⁵ While minimizing the number of in-person interactions that could potentially spread COVID-19, these agents promote virtual companionship that mirrors natural conversations and provide emotional support with psychological safety as participants express their pent-up thoughts. Not only do these agents help recover mood quickly, but they also have the power to overcome geographic barriers, be constantly available, and alleviate the high demand for mental health care. As a result, CAs have the potential to facilitate better communication and sustain social interactions within the isolated environment the pandemic has created.

CAs can predict, detect, and determine treatment solutions for mental health conditions based on behavioral insights. These agents’ natural language processing also allows them to be powerful therapeutic agents that can serve different communities, particularly for populations with limited access to medical resources. As the use of CAs becomes more integrated into telemedicine, their utility will continue to grow as their proven versatility in many situations expands the boundaries of health care technology.
 

Ms. Wong, a medical student at New York Institute of Technology College of Osteopathic Medicine in Old Westbury, conducts research related to mental health care services. She disclosed writing a telemental health software platform called Orchid. Dr. Vo, a board-certified psychiatrist, is the medical director of telehealth for the department of child and adolescent psychiatry and behavioral sciences at Children’s Hospital of Philadelphia. She is a faculty member of the University of Pennsylvania, also in Philadelphia. Dr. Vo conducts digital health research focused on using automation and artificial intelligence for suicide risk screening and connecting patients to mental health care services. She disclosed serving as cofounder of Orchid.

References

1. Chatbots: Vendor opportunities & market forecasts 2020-2024. Juniper Research, 2020.

2. Simon P et al. On using chatbots to promote smoking cessation among adolescents of low socioeconomic status, Artificial Intelligence and Work: Association for the Advancement of Artificial Intelligence (AAAI) 2019 Fall Symposium, 2019.

3. Fitzpatrick KK et al. JMIR Mental Health. 2017;4(2):e19.

4. Lucas GM et al. Front Robot AI. 2017 Oct 12. doi: 10.3389/frobt.2017.00051.

5. Ishii E et al. ERICA: An empathetic android companion for COVID-19 quarantine. arXiv preprint arXiv:2106.02325.

In this modern age of health care where telemedicine rules, conversational agents (CAs) that use text messaging systems are becoming a major mode of communication.

Many people are familiar with voice-enabled agents, such as Apple’s Siri, Google Now, and Microsoft’s Cortana. However, CAs come in different forms of complexity, ranging from a short message service–based texting platform to an embodied conversational agent (ECA).

ECAs allow participants to interact with a physical or graphical figure that simulates a person in appearance, behavior, and dialect. These are essentially virtual humans, or avatars, who talk with participants. By taking greater advantage of these automated agents, some have projected there may be $11 billion in combined cost savings across a variety of business sectors by 2023.¹ The health care field is one sector in which CAs can play an important role. Because of their accessibility, CAs have the potential to improve mental health by combating health care inequities and stigma, encouraging disclosure from participants, and serving as companions during the COVID-19 pandemic.

CAs provide accessible health care for rural, low socioeconomic status (SES), and minority communities in a variety of advantageous ways. For example, one study found that long-term use of a text-based agent that combines motivational interviewing and cognitive-behavioral therapy (CBT) can support smoking cessation in adolescents of low SES.²

CAs can help vulnerable participants advocate for themselves and proactively maintain their mental health through access to health care resources. In specific cases, these agents equalize health care treatment for different populations. Even though some participants live in secluded areas or are blocked by barriers, these text-based agents can still provide self-help intervention for them at any time on an individual basis, regardless of their location or socioeconomic status. Furthermore, they serve as highly cost-effective mental health promotion tools for large populations, some of which might not otherwise be reached by mental health care.

In combating mental illnesses such as depression and anxiety, studies have found that CAs are great treatment tools. For example, participants in an experimental group who received a self-help program based on CBT from a text-based CA named Woebot experienced significantly reduced depression symptoms when compared to the control group of participants, who received only information from a self-help electronic book.³ As a result, CAs might prove successful in treating younger populations who find online tools more feasible and accessible. Often, this population self-identifies depressive and anxiety symptoms without consulting a health care professional. Thus, this tool would prove useful to those who are bothered by the stigma of seeing a mental health professional.

Virtual human–based CAs also encourage participants to disclose more information in a nonjudgmental manner, especially among people with diseases with stigma. CAs use neutral languages, which may be helpful when dealing with stigmatized issues such as HIV, family planning, and abortion care because this heightens confidentiality and privacy. When participants believe that the agent does not “judge” or evaluate their capabilities, this elicits more sensitive information from them. For example, one study found that military service members who believed that they were interacting with a computer rather than a human operator reported lower fear of self-disclosure, displayed more sadness, and were rated by observers as more willing to disclose posttraumatic stress disorder symptoms.⁴ Additional findings show that participants prefer CAs when topics are highly sensitive and more likely to evoke negative self-admissions.

In what we hope will soon be a post–COVID-19 landscape of medicine, CAs are fast being used on the front lines of health care technology. Empathetic CAs can combat adverse effects of social exclusion during these pressing times. Etsuko Ishii, a researcher affiliated with the Hong Kong University of Science and Technology, and associates demonstrated that a virtual CA was as effective as a COVID-19 companion because it uses natural language processing (NLP) and nonverbal facial expressions to give users the feeling that they are being treated with empathy.⁵ While minimizing the number of in-person interactions that could potentially spread COVID-19, these agents promote virtual companionship that mirrors natural conversations and provide emotional support with psychological safety as participants express their pent-up thoughts. Not only do these agents help recover mood quickly, but they also have the power to overcome geographic barriers, be constantly available, and alleviate the high demand for mental health care. As a result, CAs have the potential to facilitate better communication and sustain social interactions within the isolated environment the pandemic has created.

CAs can predict, detect, and determine treatment solutions for mental health conditions based on behavioral insights. These agents’ natural language processing also allows them to be powerful therapeutic agents that can serve different communities, particularly for populations with limited access to medical resources. As the use of CAs becomes more integrated into telemedicine, their utility will continue to grow as their proven versatility in many situations expands the boundaries of health care technology.
 

Ms. Wong, a medical student at New York Institute of Technology College of Osteopathic Medicine in Old Westbury, conducts research related to mental health care services. She disclosed writing a telemental health software platform called Orchid. Dr. Vo, a board-certified psychiatrist, is the medical director of telehealth for the department of child and adolescent psychiatry and behavioral sciences at Children’s Hospital of Philadelphia. She is a faculty member of the University of Pennsylvania, also in Philadelphia. Dr. Vo conducts digital health research focused on using automation and artificial intelligence for suicide risk screening and connecting patients to mental health care services. She disclosed serving as cofounder of Orchid.

References

1. Chatbots: Vendor opportunities & market forecasts 2020-2024. Juniper Research, 2020.

2. Simon P et al. On using chatbots to promote smoking cessation among adolescents of low socioeconomic status, Artificial Intelligence and Work: Association for the Advancement of Artificial Intelligence (AAAI) 2019 Fall Symposium, 2019.

3. Fitzpatrick KK et al. JMIR Mental Health. 2017;4(2):e19.

4. Lucas GM et al. Front Robot AI. 2017 Oct 12. doi: 10.3389/frobt.2017.00051.

5. Ishii E et al. ERICA: An empathetic android companion for COVID-19 quarantine. arXiv preprint arXiv:2106.02325.

In this modern age of health care where telemedicine rules, conversational agents (CAs) that use text messaging systems are becoming a major mode of communication.

Many people are familiar with voice-enabled agents, such as Apple’s Siri, Google Now, and Microsoft’s Cortana. However, CAs come in different forms of complexity, ranging from a short message service–based texting platform to an embodied conversational agent (ECA).

ECAs allow participants to interact with a physical or graphical figure that simulates a person in appearance, behavior, and dialect. These are essentially virtual humans, or avatars, who talk with participants. By taking greater advantage of these automated agents, some have projected there may be $11 billion in combined cost savings across a variety of business sectors by 2023.¹ The health care field is one sector in which CAs can play an important role. Because of their accessibility, CAs have the potential to improve mental health by combating health care inequities and stigma, encouraging disclosure from participants, and serving as companions during the COVID-19 pandemic.

CAs provide accessible health care for rural, low socioeconomic status (SES), and minority communities in a variety of advantageous ways. For example, one study found that long-term use of a text-based agent that combines motivational interviewing and cognitive-behavioral therapy (CBT) can support smoking cessation in adolescents of low SES.²

CAs can help vulnerable participants advocate for themselves and proactively maintain their mental health through access to health care resources. In specific cases, these agents equalize health care treatment for different populations. Even though some participants live in secluded areas or are blocked by barriers, these text-based agents can still provide self-help intervention for them at any time on an individual basis, regardless of their location or socioeconomic status. Furthermore, they serve as highly cost-effective mental health promotion tools for large populations, some of which might not otherwise be reached by mental health care.

In combating mental illnesses such as depression and anxiety, studies have found that CAs are great treatment tools. For example, participants in an experimental group who received a self-help program based on CBT from a text-based CA named Woebot experienced significantly reduced depression symptoms when compared to the control group of participants, who received only information from a self-help electronic book.³ As a result, CAs might prove successful in treating younger populations who find online tools more feasible and accessible. Often, this population self-identifies depressive and anxiety symptoms without consulting a health care professional. Thus, this tool would prove useful to those who are bothered by the stigma of seeing a mental health professional.

Virtual human–based CAs also encourage participants to disclose more information in a nonjudgmental manner, especially among people with diseases with stigma. CAs use neutral languages, which may be helpful when dealing with stigmatized issues such as HIV, family planning, and abortion care because this heightens confidentiality and privacy. When participants believe that the agent does not “judge” or evaluate their capabilities, this elicits more sensitive information from them. For example, one study found that military service members who believed that they were interacting with a computer rather than a human operator reported lower fear of self-disclosure, displayed more sadness, and were rated by observers as more willing to disclose posttraumatic stress disorder symptoms.⁴ Additional findings show that participants prefer CAs when topics are highly sensitive and more likely to evoke negative self-admissions.

In what we hope will soon be a post–COVID-19 landscape of medicine, CAs are fast being used on the front lines of health care technology. Empathetic CAs can combat adverse effects of social exclusion during these pressing times. Etsuko Ishii, a researcher affiliated with the Hong Kong University of Science and Technology, and associates demonstrated that a virtual CA was as effective as a COVID-19 companion because it uses natural language processing (NLP) and nonverbal facial expressions to give users the feeling that they are being treated with empathy.⁵ While minimizing the number of in-person interactions that could potentially spread COVID-19, these agents promote virtual companionship that mirrors natural conversations and provide emotional support with psychological safety as participants express their pent-up thoughts. Not only do these agents help recover mood quickly, but they also have the power to overcome geographic barriers, be constantly available, and alleviate the high demand for mental health care. As a result, CAs have the potential to facilitate better communication and sustain social interactions within the isolated environment the pandemic has created.

CAs can predict, detect, and determine treatment solutions for mental health conditions based on behavioral insights. These agents’ natural language processing also allows them to be powerful therapeutic agents that can serve different communities, particularly for populations with limited access to medical resources. As the use of CAs becomes more integrated into telemedicine, their utility will continue to grow as their proven versatility in many situations expands the boundaries of health care technology.
 

Ms. Wong, a medical student at New York Institute of Technology College of Osteopathic Medicine in Old Westbury, conducts research related to mental health care services. She disclosed writing a telemental health software platform called Orchid. Dr. Vo, a board-certified psychiatrist, is the medical director of telehealth for the department of child and adolescent psychiatry and behavioral sciences at Children’s Hospital of Philadelphia. She is a faculty member of the University of Pennsylvania, also in Philadelphia. Dr. Vo conducts digital health research focused on using automation and artificial intelligence for suicide risk screening and connecting patients to mental health care services. She disclosed serving as cofounder of Orchid.

References

1. Chatbots: Vendor opportunities & market forecasts 2020-2024. Juniper Research, 2020.

2. Simon P et al. On using chatbots to promote smoking cessation among adolescents of low socioeconomic status, Artificial Intelligence and Work: Association for the Advancement of Artificial Intelligence (AAAI) 2019 Fall Symposium, 2019.

3. Fitzpatrick KK et al. JMIR Mental Health. 2017;4(2):e19.

4. Lucas GM et al. Front Robot AI. 2017 Oct 12. doi: 10.3389/frobt.2017.00051.

5. Ishii E et al. ERICA: An empathetic android companion for COVID-19 quarantine. arXiv preprint arXiv:2106.02325.

Social media isn’t everyone’s cup of tea, but for those who want to become a significant influencer on Instagram, YouTube, TikTok, or other platforms, “you have to enjoy it,” Sandra Lee, MD, said during a virtual course on laser and aesthetic skin therapy.

“I admit that I’m somewhat obsessed with it. I kind of blame it on my work as a dermatologist, that I’m trying to grow my social media as well. It’s interesting to me, fascinating, and I want to understand it more. I think that’s the mindset you need to approach it with.”

Perhaps no other public figure in dermatology has enjoyed success in social media more than Dr. Lee, a board-certified dermatologist who practices in Upland, Calif. In the fall of 2014, she started using Instagram to provide followers a glimpse into her life as a dermatologist, everything from Mohs surgery and Botox to keloid removals and ear lobe repair surgeries. From this she formed her alter ego, “Dr. Pimple Popper,” and became a YouTube sensation, building 7.1 million subscribers over the course of a few years, amounting to 4.5 billion lifetime views. She also grew 12 million followers on TikTok, 4.4 million followers on Instagram, 3 million on Facebook, and more than 139,000 on Twitter. About 80% of her followers are women who range between 18 and 40 years of age.

During the meeting she offered five social media marketing tips for busy clinicians:

You have to ‘play’ to ‘win.’ Active participation in social media is required to develop followers. “You cannot delegate this content,” Dr. Lee said. “You can hire people to help you or leave the task to a social media-savvy medical assistant in your office, but the content should be your responsibility ultimately, because you are the physician,” she added. Not everyone chooses to participate in social media, but it’s also something not to shy away from out of intimidation. “There is some talent associated with it, but it takes a lot of persistence as well,” she said.

Patients come first. Protect them at all costs. Dr. Lee rarely posts the faces of patients she cares for unless they grant consent in advance. “I try to show the work that I do and the beauty of dermatology,” she said during the meeting, which was named “Laser & Aesthetic Skin Therapy: What’s the Truth?” and was sponsored by Harvard Medical School, Massachusetts General Hospital, and the Wellman Center for Photomedicine. She added that taking part in social media can help you improve communication skills by engaging with followers who like, share, or respond to the material posted. “When you look back at your posts objectively, you learn about yourself and how you relate to your patients,” she said. “It helps to hone my bedside manner and my skills as a dermatologist.”

Show that you are human. Many dermatologists and other “skin influencers” have established their presence on the Internet and may be direct competitors for patients, but that doesn’t mean you can’t establish your own identity. One way to stand out is by posting content related to your authentic self, such as a photo or video that shows you engaged in a hobby, dining at a favorite restaurant, or visiting a beloved vacation spot. “Your followers don’t want a robot, someone who thinks they’re amazing and can do everything,” said Dr. Lee, who stars in her own TV reality show on TLC. “Show that you have a funny side. You want them to fall in love with you and see a little bit of your world, whatever it might be. Charm the socks off of them.”

Entertain first, educate a close second. The main way you’re going to get people to follow and watch you is to provide some entertainment, “not at the expense of a patient or your practice, though,” she said. “Then you’re going to educate people. We dermatologists have something to teach the world because we are experts on skin, hair, and nails. You want to impart this knowledge in a way that captivates people.” It’s like the sense of accomplishment that comes from learning something new after reading a book or watching a movie, she explained. “You feel good about it, and you can take that knowledge with you somewhere else. I love it when kids come up to me and tell me they know what a lipoma is, what a cyst is, and what psoriasis is because they’ve seen my show, or because they follow me on social media. It’s wonderful because I can see that I’ve educated them.”

Be kind and don’t activate the trolls. Dr. Lee allows positivity and kindness to rule the day on her social media content. “This is what I try to relay to followers, but I also do not engage with the negativity,” she said. “Every now and then, there will be someone who tries to insult what you do or who insults you personally. If you engage with them, it almost invites them to do it more. It almost gives them the ability to fight with you. Try to stay above that; just put out goodness and kindness.”

Several years ago, YouTube and Instagram temporarily shut down Dr. Lee’s accounts because she posted graphic images of skin lesions and procedures – a practice that wasn’t so commonplace at the time. “Don’t just post a graphic image just to be graphic,” she advised. “Make sure it has an educational message associated with it. That will help to validate your content. Posting a warning sign that some images may be graphic could help, too.”

Dr. Lee reported having no relevant financial disclosures.

[email protected]

Social media isn’t everyone’s cup of tea, but for those who want to become a significant influencer on Instagram, YouTube, TikTok, or other platforms, “you have to enjoy it,” Sandra Lee, MD, said during a virtual course on laser and aesthetic skin therapy.

“I admit that I’m somewhat obsessed with it. I kind of blame it on my work as a dermatologist, that I’m trying to grow my social media as well. It’s interesting to me, fascinating, and I want to understand it more. I think that’s the mindset you need to approach it with.”

Perhaps no other public figure in dermatology has enjoyed success in social media more than Dr. Lee, a board-certified dermatologist who practices in Upland, Calif. In the fall of 2014, she started using Instagram to provide followers a glimpse into her life as a dermatologist, everything from Mohs surgery and Botox to keloid removals and ear lobe repair surgeries. From this she formed her alter ego, “Dr. Pimple Popper,” and became a YouTube sensation, building 7.1 million subscribers over the course of a few years, amounting to 4.5 billion lifetime views. She also grew 12 million followers on TikTok, 4.4 million followers on Instagram, 3 million on Facebook, and more than 139,000 on Twitter. About 80% of her followers are women who range between 18 and 40 years of age.

During the meeting she offered five social media marketing tips for busy clinicians:

You have to ‘play’ to ‘win.’ Active participation in social media is required to develop followers. “You cannot delegate this content,” Dr. Lee said. “You can hire people to help you or leave the task to a social media-savvy medical assistant in your office, but the content should be your responsibility ultimately, because you are the physician,” she added. Not everyone chooses to participate in social media, but it’s also something not to shy away from out of intimidation. “There is some talent associated with it, but it takes a lot of persistence as well,” she said.

Patients come first. Protect them at all costs. Dr. Lee rarely posts the faces of patients she cares for unless they grant consent in advance. “I try to show the work that I do and the beauty of dermatology,” she said during the meeting, which was named “Laser & Aesthetic Skin Therapy: What’s the Truth?” and was sponsored by Harvard Medical School, Massachusetts General Hospital, and the Wellman Center for Photomedicine. She added that taking part in social media can help you improve communication skills by engaging with followers who like, share, or respond to the material posted. “When you look back at your posts objectively, you learn about yourself and how you relate to your patients,” she said. “It helps to hone my bedside manner and my skills as a dermatologist.”

Show that you are human. Many dermatologists and other “skin influencers” have established their presence on the Internet and may be direct competitors for patients, but that doesn’t mean you can’t establish your own identity. One way to stand out is by posting content related to your authentic self, such as a photo or video that shows you engaged in a hobby, dining at a favorite restaurant, or visiting a beloved vacation spot. “Your followers don’t want a robot, someone who thinks they’re amazing and can do everything,” said Dr. Lee, who stars in her own TV reality show on TLC. “Show that you have a funny side. You want them to fall in love with you and see a little bit of your world, whatever it might be. Charm the socks off of them.”

Entertain first, educate a close second. The main way you’re going to get people to follow and watch you is to provide some entertainment, “not at the expense of a patient or your practice, though,” she said. “Then you’re going to educate people. We dermatologists have something to teach the world because we are experts on skin, hair, and nails. You want to impart this knowledge in a way that captivates people.” It’s like the sense of accomplishment that comes from learning something new after reading a book or watching a movie, she explained. “You feel good about it, and you can take that knowledge with you somewhere else. I love it when kids come up to me and tell me they know what a lipoma is, what a cyst is, and what psoriasis is because they’ve seen my show, or because they follow me on social media. It’s wonderful because I can see that I’ve educated them.”

Be kind and don’t activate the trolls. Dr. Lee allows positivity and kindness to rule the day on her social media content. “This is what I try to relay to followers, but I also do not engage with the negativity,” she said. “Every now and then, there will be someone who tries to insult what you do or who insults you personally. If you engage with them, it almost invites them to do it more. It almost gives them the ability to fight with you. Try to stay above that; just put out goodness and kindness.”

Several years ago, YouTube and Instagram temporarily shut down Dr. Lee’s accounts because she posted graphic images of skin lesions and procedures – a practice that wasn’t so commonplace at the time. “Don’t just post a graphic image just to be graphic,” she advised. “Make sure it has an educational message associated with it. That will help to validate your content. Posting a warning sign that some images may be graphic could help, too.”

Dr. Lee reported having no relevant financial disclosures.

[email protected]

Social media isn’t everyone’s cup of tea, but for those who want to become a significant influencer on Instagram, YouTube, TikTok, or other platforms, “you have to enjoy it,” Sandra Lee, MD, said during a virtual course on laser and aesthetic skin therapy.

“I admit that I’m somewhat obsessed with it. I kind of blame it on my work as a dermatologist, that I’m trying to grow my social media as well. It’s interesting to me, fascinating, and I want to understand it more. I think that’s the mindset you need to approach it with.”

Perhaps no other public figure in dermatology has enjoyed success in social media more than Dr. Lee, a board-certified dermatologist who practices in Upland, Calif. In the fall of 2014, she started using Instagram to provide followers a glimpse into her life as a dermatologist, everything from Mohs surgery and Botox to keloid removals and ear lobe repair surgeries. From this she formed her alter ego, “Dr. Pimple Popper,” and became a YouTube sensation, building 7.1 million subscribers over the course of a few years, amounting to 4.5 billion lifetime views. She also grew 12 million followers on TikTok, 4.4 million followers on Instagram, 3 million on Facebook, and more than 139,000 on Twitter. About 80% of her followers are women who range between 18 and 40 years of age.

During the meeting she offered five social media marketing tips for busy clinicians:

You have to ‘play’ to ‘win.’ Active participation in social media is required to develop followers. “You cannot delegate this content,” Dr. Lee said. “You can hire people to help you or leave the task to a social media-savvy medical assistant in your office, but the content should be your responsibility ultimately, because you are the physician,” she added. Not everyone chooses to participate in social media, but it’s also something not to shy away from out of intimidation. “There is some talent associated with it, but it takes a lot of persistence as well,” she said.

Patients come first. Protect them at all costs. Dr. Lee rarely posts the faces of patients she cares for unless they grant consent in advance. “I try to show the work that I do and the beauty of dermatology,” she said during the meeting, which was named “Laser & Aesthetic Skin Therapy: What’s the Truth?” and was sponsored by Harvard Medical School, Massachusetts General Hospital, and the Wellman Center for Photomedicine. She added that taking part in social media can help you improve communication skills by engaging with followers who like, share, or respond to the material posted. “When you look back at your posts objectively, you learn about yourself and how you relate to your patients,” she said. “It helps to hone my bedside manner and my skills as a dermatologist.”

Show that you are human. Many dermatologists and other “skin influencers” have established their presence on the Internet and may be direct competitors for patients, but that doesn’t mean you can’t establish your own identity. One way to stand out is by posting content related to your authentic self, such as a photo or video that shows you engaged in a hobby, dining at a favorite restaurant, or visiting a beloved vacation spot. “Your followers don’t want a robot, someone who thinks they’re amazing and can do everything,” said Dr. Lee, who stars in her own TV reality show on TLC. “Show that you have a funny side. You want them to fall in love with you and see a little bit of your world, whatever it might be. Charm the socks off of them.”

Entertain first, educate a close second. The main way you’re going to get people to follow and watch you is to provide some entertainment, “not at the expense of a patient or your practice, though,” she said. “Then you’re going to educate people. We dermatologists have something to teach the world because we are experts on skin, hair, and nails. You want to impart this knowledge in a way that captivates people.” It’s like the sense of accomplishment that comes from learning something new after reading a book or watching a movie, she explained. “You feel good about it, and you can take that knowledge with you somewhere else. I love it when kids come up to me and tell me they know what a lipoma is, what a cyst is, and what psoriasis is because they’ve seen my show, or because they follow me on social media. It’s wonderful because I can see that I’ve educated them.”

Be kind and don’t activate the trolls. Dr. Lee allows positivity and kindness to rule the day on her social media content. “This is what I try to relay to followers, but I also do not engage with the negativity,” she said. “Every now and then, there will be someone who tries to insult what you do or who insults you personally. If you engage with them, it almost invites them to do it more. It almost gives them the ability to fight with you. Try to stay above that; just put out goodness and kindness.”

Several years ago, YouTube and Instagram temporarily shut down Dr. Lee’s accounts because she posted graphic images of skin lesions and procedures – a practice that wasn’t so commonplace at the time. “Don’t just post a graphic image just to be graphic,” she advised. “Make sure it has an educational message associated with it. That will help to validate your content. Posting a warning sign that some images may be graphic could help, too.”

Dr. Lee reported having no relevant financial disclosures.

[email protected]

Trick-or-treaters may not be so easily tricked into loving sugar-free treats, thanks to taste buds hard-wired to seek calorie-containing sweets, a new study suggests.

Taste isn’t all about choosing peanut butter cups over jelly beans. Since earliest humanity, our sense of taste has helped us detect salty, sweet, sour, savory, and bitter so that we can choose foods high in energy and low in poisons.

But these new findings suggest that our taste buds have another hidden talent: identifying foods that don’t give us any energy at all.

Scientists suspected this ability after research in mice showed that their taste buds could distinguish between sugar and calorie-free artificial sweeteners.

To test this possibility in humans, scientists asked people to drink a series of clear beverages and identify whether they were plain water or sweetened. The goal was to compare how people responded to glucose – a natural caloric sweetener in fruits, honey, and table sugar – and sucralose, a calorie-free artificial sweetener.

All participants wore nose plugs, ensuring that they would use only their taste buds and not their sense of smell for detection.

As expected, people could easily tell plain water from sweetened drinks, whether with glucose or sucralose, confirming that taste buds detect sweetness.

In a twist, researchers then mixed in flavorless chemicals that block taste buds from picking up sweetness. With these drinks, people could no longer distinguish sucralose-sweetened beverages from plain water. But they could still tell when they had a beverage sweetened with glucose.

This finding indicates that two separate pathways underlie the mouth’s response to sugar, researchers report in PLOS One. The first pathway identifies sweet flavors, and the second one detects foods that contain energy that can be used for fuel.

Scientists might one day come up with calorie-free sweets that trick taste buds into detecting the presence of calories, enhancing their appeal. But in the lab studies, the participants had no visual cues or smell to guide their reactions, meaning how these other sensory inputs would affect treat perception isn’t known.

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

Trick-or-treaters may not be so easily tricked into loving sugar-free treats, thanks to taste buds hard-wired to seek calorie-containing sweets, a new study suggests.

Taste isn’t all about choosing peanut butter cups over jelly beans. Since earliest humanity, our sense of taste has helped us detect salty, sweet, sour, savory, and bitter so that we can choose foods high in energy and low in poisons.

But these new findings suggest that our taste buds have another hidden talent: identifying foods that don’t give us any energy at all.

Scientists suspected this ability after research in mice showed that their taste buds could distinguish between sugar and calorie-free artificial sweeteners.

To test this possibility in humans, scientists asked people to drink a series of clear beverages and identify whether they were plain water or sweetened. The goal was to compare how people responded to glucose – a natural caloric sweetener in fruits, honey, and table sugar – and sucralose, a calorie-free artificial sweetener.

All participants wore nose plugs, ensuring that they would use only their taste buds and not their sense of smell for detection.

As expected, people could easily tell plain water from sweetened drinks, whether with glucose or sucralose, confirming that taste buds detect sweetness.

In a twist, researchers then mixed in flavorless chemicals that block taste buds from picking up sweetness. With these drinks, people could no longer distinguish sucralose-sweetened beverages from plain water. But they could still tell when they had a beverage sweetened with glucose.

This finding indicates that two separate pathways underlie the mouth’s response to sugar, researchers report in PLOS One. The first pathway identifies sweet flavors, and the second one detects foods that contain energy that can be used for fuel.

Scientists might one day come up with calorie-free sweets that trick taste buds into detecting the presence of calories, enhancing their appeal. But in the lab studies, the participants had no visual cues or smell to guide their reactions, meaning how these other sensory inputs would affect treat perception isn’t known.

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

Trick-or-treaters may not be so easily tricked into loving sugar-free treats, thanks to taste buds hard-wired to seek calorie-containing sweets, a new study suggests.

Taste isn’t all about choosing peanut butter cups over jelly beans. Since earliest humanity, our sense of taste has helped us detect salty, sweet, sour, savory, and bitter so that we can choose foods high in energy and low in poisons.

But these new findings suggest that our taste buds have another hidden talent: identifying foods that don’t give us any energy at all.

Scientists suspected this ability after research in mice showed that their taste buds could distinguish between sugar and calorie-free artificial sweeteners.

To test this possibility in humans, scientists asked people to drink a series of clear beverages and identify whether they were plain water or sweetened. The goal was to compare how people responded to glucose – a natural caloric sweetener in fruits, honey, and table sugar – and sucralose, a calorie-free artificial sweetener.

All participants wore nose plugs, ensuring that they would use only their taste buds and not their sense of smell for detection.

As expected, people could easily tell plain water from sweetened drinks, whether with glucose or sucralose, confirming that taste buds detect sweetness.

In a twist, researchers then mixed in flavorless chemicals that block taste buds from picking up sweetness. With these drinks, people could no longer distinguish sucralose-sweetened beverages from plain water. But they could still tell when they had a beverage sweetened with glucose.

This finding indicates that two separate pathways underlie the mouth’s response to sugar, researchers report in PLOS One. The first pathway identifies sweet flavors, and the second one detects foods that contain energy that can be used for fuel.

Scientists might one day come up with calorie-free sweets that trick taste buds into detecting the presence of calories, enhancing their appeal. But in the lab studies, the participants had no visual cues or smell to guide their reactions, meaning how these other sensory inputs would affect treat perception isn’t known.

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

CHICAGO –Only 4% of patients with liver cancer who are awaiting transplant undergo external-beam radiotherapy (EBRT), even though this is a safe and effective bridging therapy. It is greatly underutilized compared to other liver-directed therapies, according to new findings.

“This highlights a real-world gap in the treatment armamentarium for hepatocellular carcinoma [HCC],” said Nima Nabavizadeh, MD, associate professor of radiation oncology and residency program director at the Oregon Health and Science University, Portland.

He was speaking at the annual meeting of the American Society for Radiation Oncology.

These new data suggest there is reluctance within transplant programs to utilize radiotherapy as a bridging therapy prior to liver transplant, said Hyun Kim, MD, chief, GI service, department of radiation oncology, Washington University and the Alvin J. Siteman Cancer Center, St. Louis.

“This is despite 10-year-old data from Princess Margaret and Toronto General Hospital showing that external-beam radiation is a safe and feasible bridging therapy,” he said. “More modern data from the same institutions indicate that patients bridged with stereotactic body radiotherapy ablative radiation doses delivered with high conformality have similar survival as patients bridged with radiofrequency ablation.”

Dr. Kim also noted that even after transplant, rates of intrahepatic recurrence can be as high as 10%. Approximately 60% of patients experience recurrence of any type within 3 years.

“Nonablative local therapies leave viable disease, which may permit metastatic progression while the patient awaits transplant,” he said in an interview. This new analysis highlights the need for well-designed clinical trials with modern endpoints to evaluate which bridging therapy is most beneficial for the patient, he added.

In this current “era of radiomics, deep learning, and liquid biopsies, we have unprecedented tools and responsibility to ensure that our practice continues to improve in a data-centric fashion and not remain paused in the paradigm of a previous era,” Dr. Kim said.
 

A leading cause of death worldwide

HCC is a leading cause of cancer death worldwide, and the incidence is rising within the United States. Transplant is often the best option for long-term survival for patients with localized HCC and advanced cirrhosis, Dr. Nabavizadeh told the meeting.

Because patients often have to wait months to over a year for a transplant, many patients receive liver-directed bridging therapy to prevent tumor growth or spread and to maintain their eligibility for transplant, he explained.

These bridging therapies include thermal ablation procedures, transarterial chemoembolization (TACE), and Y-90 radioembolization, as well as EBRT.

To investigate how these therapies were being used, Dr. Nabavizadeh and colleagues conducted a retrospective study in which they analyzed data from the United Network for Organ Sharing, a nonprofit organization that manages the only national liver transplant waiting list in the United States.

They identified patients on the transplant list who had applied for Model of End-Stage Liver Disease (MELD) exceptions so as to be prioritized on the waiting list.

A total of 18,447 HCC patients submitted MELD exception applications during the study period (October 2013 to June 2020). More than half of these patients (n = 11,171; 60.6%) received a transplant. After submitting the exception application, the median time for receiving a transplant was 7 months.

Of the total group, 15,759 patients (85.4%) received liver-directed therapy while waiting for the transplant, but only 658 patients (3.6% of the overall cohort) received EBRT, either alone or in combination with another therapy.

“The majority of patients received chemoembolization, and ERBT represents a very small percentage,” Dr. Nabavizadeh said.

During the study period, the use of transarterial chemoembolization decreased. It has largely been replaced by thermal ablation and Y-90 radioembolization. The analysis also showed that the use of EBRT had increased over the past several years, but its utilization still remained well below that of the other therapies.

TACE was the most utilized therapy. It was used for 39.6% of patients, followed by thermal ablation (12.8%) and radioembolization (8.7%). Almost a quarter of patients (22.2%) received a combination of non-EBRT therapies.

“We found that EBRT use significantly differed by region,” Dr. Nabavizadeh said. The highest usage (8.7%) was in Great Lakes states. In the Southeast, it was used for 1.7% patients.

No statistical differences were observed in clinicopathologic factors between the patients who received EBRT and those who did not.
 

Transplant is curative

Transplant is curative both for cancer and underlying cirrhosis, but patients may experience disease progression while waiting for transplant, noted Jessica Karen Wong, MD, assistant professor, department of radiation oncology, Fox Chase Cancer Center, Philadelphia, who was approached for comment.

“Radiation, specifically, stereotactic body radiation therapy, is a safe and effective bridging therapy but was only used in a small minority of eligible patients in this national database,” she said. “Although the use of radiation as bridging therapy is increasing over time, it continues to be underutilized. Increasing the use of radiation provides an opportunity to improve patient care for hepatocellular carcinoma patients awaiting a liver transplant.”

Dr. Nabavizadeh and Dr. Wong have disclosed no relevant financial relationships. Dr. Kim has received research funding and speaker honorarium from Varian and ViewRay.

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

CHICAGO –Only 4% of patients with liver cancer who are awaiting transplant undergo external-beam radiotherapy (EBRT), even though this is a safe and effective bridging therapy. It is greatly underutilized compared to other liver-directed therapies, according to new findings.

“This highlights a real-world gap in the treatment armamentarium for hepatocellular carcinoma [HCC],” said Nima Nabavizadeh, MD, associate professor of radiation oncology and residency program director at the Oregon Health and Science University, Portland.

He was speaking at the annual meeting of the American Society for Radiation Oncology.

These new data suggest there is reluctance within transplant programs to utilize radiotherapy as a bridging therapy prior to liver transplant, said Hyun Kim, MD, chief, GI service, department of radiation oncology, Washington University and the Alvin J. Siteman Cancer Center, St. Louis.

“This is despite 10-year-old data from Princess Margaret and Toronto General Hospital showing that external-beam radiation is a safe and feasible bridging therapy,” he said. “More modern data from the same institutions indicate that patients bridged with stereotactic body radiotherapy ablative radiation doses delivered with high conformality have similar survival as patients bridged with radiofrequency ablation.”

Dr. Kim also noted that even after transplant, rates of intrahepatic recurrence can be as high as 10%. Approximately 60% of patients experience recurrence of any type within 3 years.

“Nonablative local therapies leave viable disease, which may permit metastatic progression while the patient awaits transplant,” he said in an interview. This new analysis highlights the need for well-designed clinical trials with modern endpoints to evaluate which bridging therapy is most beneficial for the patient, he added.

In this current “era of radiomics, deep learning, and liquid biopsies, we have unprecedented tools and responsibility to ensure that our practice continues to improve in a data-centric fashion and not remain paused in the paradigm of a previous era,” Dr. Kim said.
 

A leading cause of death worldwide

HCC is a leading cause of cancer death worldwide, and the incidence is rising within the United States. Transplant is often the best option for long-term survival for patients with localized HCC and advanced cirrhosis, Dr. Nabavizadeh told the meeting.

Because patients often have to wait months to over a year for a transplant, many patients receive liver-directed bridging therapy to prevent tumor growth or spread and to maintain their eligibility for transplant, he explained.

These bridging therapies include thermal ablation procedures, transarterial chemoembolization (TACE), and Y-90 radioembolization, as well as EBRT.

To investigate how these therapies were being used, Dr. Nabavizadeh and colleagues conducted a retrospective study in which they analyzed data from the United Network for Organ Sharing, a nonprofit organization that manages the only national liver transplant waiting list in the United States.

They identified patients on the transplant list who had applied for Model of End-Stage Liver Disease (MELD) exceptions so as to be prioritized on the waiting list.

A total of 18,447 HCC patients submitted MELD exception applications during the study period (October 2013 to June 2020). More than half of these patients (n = 11,171; 60.6%) received a transplant. After submitting the exception application, the median time for receiving a transplant was 7 months.

Of the total group, 15,759 patients (85.4%) received liver-directed therapy while waiting for the transplant, but only 658 patients (3.6% of the overall cohort) received EBRT, either alone or in combination with another therapy.

“The majority of patients received chemoembolization, and ERBT represents a very small percentage,” Dr. Nabavizadeh said.

During the study period, the use of transarterial chemoembolization decreased. It has largely been replaced by thermal ablation and Y-90 radioembolization. The analysis also showed that the use of EBRT had increased over the past several years, but its utilization still remained well below that of the other therapies.

TACE was the most utilized therapy. It was used for 39.6% of patients, followed by thermal ablation (12.8%) and radioembolization (8.7%). Almost a quarter of patients (22.2%) received a combination of non-EBRT therapies.

“We found that EBRT use significantly differed by region,” Dr. Nabavizadeh said. The highest usage (8.7%) was in Great Lakes states. In the Southeast, it was used for 1.7% patients.

No statistical differences were observed in clinicopathologic factors between the patients who received EBRT and those who did not.
 

Transplant is curative

Transplant is curative both for cancer and underlying cirrhosis, but patients may experience disease progression while waiting for transplant, noted Jessica Karen Wong, MD, assistant professor, department of radiation oncology, Fox Chase Cancer Center, Philadelphia, who was approached for comment.

“Radiation, specifically, stereotactic body radiation therapy, is a safe and effective bridging therapy but was only used in a small minority of eligible patients in this national database,” she said. “Although the use of radiation as bridging therapy is increasing over time, it continues to be underutilized. Increasing the use of radiation provides an opportunity to improve patient care for hepatocellular carcinoma patients awaiting a liver transplant.”

Dr. Nabavizadeh and Dr. Wong have disclosed no relevant financial relationships. Dr. Kim has received research funding and speaker honorarium from Varian and ViewRay.

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

CHICAGO –Only 4% of patients with liver cancer who are awaiting transplant undergo external-beam radiotherapy (EBRT), even though this is a safe and effective bridging therapy. It is greatly underutilized compared to other liver-directed therapies, according to new findings.

“This highlights a real-world gap in the treatment armamentarium for hepatocellular carcinoma [HCC],” said Nima Nabavizadeh, MD, associate professor of radiation oncology and residency program director at the Oregon Health and Science University, Portland.

He was speaking at the annual meeting of the American Society for Radiation Oncology.

These new data suggest there is reluctance within transplant programs to utilize radiotherapy as a bridging therapy prior to liver transplant, said Hyun Kim, MD, chief, GI service, department of radiation oncology, Washington University and the Alvin J. Siteman Cancer Center, St. Louis.

“This is despite 10-year-old data from Princess Margaret and Toronto General Hospital showing that external-beam radiation is a safe and feasible bridging therapy,” he said. “More modern data from the same institutions indicate that patients bridged with stereotactic body radiotherapy ablative radiation doses delivered with high conformality have similar survival as patients bridged with radiofrequency ablation.”

Dr. Kim also noted that even after transplant, rates of intrahepatic recurrence can be as high as 10%. Approximately 60% of patients experience recurrence of any type within 3 years.

“Nonablative local therapies leave viable disease, which may permit metastatic progression while the patient awaits transplant,” he said in an interview. This new analysis highlights the need for well-designed clinical trials with modern endpoints to evaluate which bridging therapy is most beneficial for the patient, he added.

In this current “era of radiomics, deep learning, and liquid biopsies, we have unprecedented tools and responsibility to ensure that our practice continues to improve in a data-centric fashion and not remain paused in the paradigm of a previous era,” Dr. Kim said.
 

A leading cause of death worldwide

HCC is a leading cause of cancer death worldwide, and the incidence is rising within the United States. Transplant is often the best option for long-term survival for patients with localized HCC and advanced cirrhosis, Dr. Nabavizadeh told the meeting.

Because patients often have to wait months to over a year for a transplant, many patients receive liver-directed bridging therapy to prevent tumor growth or spread and to maintain their eligibility for transplant, he explained.

These bridging therapies include thermal ablation procedures, transarterial chemoembolization (TACE), and Y-90 radioembolization, as well as EBRT.

To investigate how these therapies were being used, Dr. Nabavizadeh and colleagues conducted a retrospective study in which they analyzed data from the United Network for Organ Sharing, a nonprofit organization that manages the only national liver transplant waiting list in the United States.

They identified patients on the transplant list who had applied for Model of End-Stage Liver Disease (MELD) exceptions so as to be prioritized on the waiting list.

A total of 18,447 HCC patients submitted MELD exception applications during the study period (October 2013 to June 2020). More than half of these patients (n = 11,171; 60.6%) received a transplant. After submitting the exception application, the median time for receiving a transplant was 7 months.

Of the total group, 15,759 patients (85.4%) received liver-directed therapy while waiting for the transplant, but only 658 patients (3.6% of the overall cohort) received EBRT, either alone or in combination with another therapy.

“The majority of patients received chemoembolization, and ERBT represents a very small percentage,” Dr. Nabavizadeh said.

During the study period, the use of transarterial chemoembolization decreased. It has largely been replaced by thermal ablation and Y-90 radioembolization. The analysis also showed that the use of EBRT had increased over the past several years, but its utilization still remained well below that of the other therapies.

TACE was the most utilized therapy. It was used for 39.6% of patients, followed by thermal ablation (12.8%) and radioembolization (8.7%). Almost a quarter of patients (22.2%) received a combination of non-EBRT therapies.

“We found that EBRT use significantly differed by region,” Dr. Nabavizadeh said. The highest usage (8.7%) was in Great Lakes states. In the Southeast, it was used for 1.7% patients.

No statistical differences were observed in clinicopathologic factors between the patients who received EBRT and those who did not.
 

Transplant is curative

Transplant is curative both for cancer and underlying cirrhosis, but patients may experience disease progression while waiting for transplant, noted Jessica Karen Wong, MD, assistant professor, department of radiation oncology, Fox Chase Cancer Center, Philadelphia, who was approached for comment.

“Radiation, specifically, stereotactic body radiation therapy, is a safe and effective bridging therapy but was only used in a small minority of eligible patients in this national database,” she said. “Although the use of radiation as bridging therapy is increasing over time, it continues to be underutilized. Increasing the use of radiation provides an opportunity to improve patient care for hepatocellular carcinoma patients awaiting a liver transplant.”

Dr. Nabavizadeh and Dr. Wong have disclosed no relevant financial relationships. Dr. Kim has received research funding and speaker honorarium from Varian and ViewRay.

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

Takeda Pharmaceuticals is now the latest pharmaceutical company to offer a value-based agreement on one of its new targeted therapies.

The rebate offer is for brigatinib (Alunbrig) which is approved for the treatment of adults with anaplastic lymphoma kinase positive (ALK+) metastatic non–small cell lung cancer (NSCLC) as detected by an FDA-approved test.

The move follows a rebate offer from Pfizer for crizotinib (Xalkori), which is also approved for ALK+ (as well as ROS1+) NSCLC, and also for ALK+ anaplastic large cell lymphoma

For its offer, Takeda has teamed up with Point32Health, the second-largest health plan in New England with about 2.3 million members. The new agreement will make brigatinib widely available to patients who may benefit from its use, say the companies.

If a patient is unable to remain on brigatinib for 3 months or longer because of effectiveness or tolerability, Takeda will refund a yet unspecified amount of money to Point32Health. Brigatinib’s list price is $17,000 for a month’s treatment.

“Given the importance of facilitating cutting-edge oncology treatment and also the reality that not all patients show a positive response, reimbursement for oncology treatments is an area that is prime for innovative financing approaches,” said Michael Sherman, MD, chief medical officer and executive vice president, Point32Health, in a statement. “Collaborating with Takeda to share risk makes this agreement a crucial milestone in bringing cost-effectiveness to cancer care.”

The Pfizer program for crizotinib is somewhat different. For one thing, Pfizer’s refund is offered to any patient who qualifies and not just those who are covered by a specific plan. Second, Takeda is thus far only refunding money to the insurer, whereas Pfizer will also reimburse patients for out-of-pocket expenses.

There is a similar approach that has been offered by Novartis for tisagenlecleucel (Kymriah), the CAR T-cell therapy that launched with a daunting price tag of $475,000. After receiving backlash over the cost, Novartis announced that if the drug does not work after the first month, patients pay nothing.

In addition, Italy has been using this system for several years. Pharmaceutical companies must refund money if the drug fails to work. In 2015, the state-run health care system collected 200 million euros ($220 million) in refunds.

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

Takeda Pharmaceuticals is now the latest pharmaceutical company to offer a value-based agreement on one of its new targeted therapies.

The rebate offer is for brigatinib (Alunbrig) which is approved for the treatment of adults with anaplastic lymphoma kinase positive (ALK+) metastatic non–small cell lung cancer (NSCLC) as detected by an FDA-approved test.

The move follows a rebate offer from Pfizer for crizotinib (Xalkori), which is also approved for ALK+ (as well as ROS1+) NSCLC, and also for ALK+ anaplastic large cell lymphoma

For its offer, Takeda has teamed up with Point32Health, the second-largest health plan in New England with about 2.3 million members. The new agreement will make brigatinib widely available to patients who may benefit from its use, say the companies.

If a patient is unable to remain on brigatinib for 3 months or longer because of effectiveness or tolerability, Takeda will refund a yet unspecified amount of money to Point32Health. Brigatinib’s list price is $17,000 for a month’s treatment.

“Given the importance of facilitating cutting-edge oncology treatment and also the reality that not all patients show a positive response, reimbursement for oncology treatments is an area that is prime for innovative financing approaches,” said Michael Sherman, MD, chief medical officer and executive vice president, Point32Health, in a statement. “Collaborating with Takeda to share risk makes this agreement a crucial milestone in bringing cost-effectiveness to cancer care.”

The Pfizer program for crizotinib is somewhat different. For one thing, Pfizer’s refund is offered to any patient who qualifies and not just those who are covered by a specific plan. Second, Takeda is thus far only refunding money to the insurer, whereas Pfizer will also reimburse patients for out-of-pocket expenses.

There is a similar approach that has been offered by Novartis for tisagenlecleucel (Kymriah), the CAR T-cell therapy that launched with a daunting price tag of $475,000. After receiving backlash over the cost, Novartis announced that if the drug does not work after the first month, patients pay nothing.

In addition, Italy has been using this system for several years. Pharmaceutical companies must refund money if the drug fails to work. In 2015, the state-run health care system collected 200 million euros ($220 million) in refunds.

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

Takeda Pharmaceuticals is now the latest pharmaceutical company to offer a value-based agreement on one of its new targeted therapies.

The rebate offer is for brigatinib (Alunbrig) which is approved for the treatment of adults with anaplastic lymphoma kinase positive (ALK+) metastatic non–small cell lung cancer (NSCLC) as detected by an FDA-approved test.

The move follows a rebate offer from Pfizer for crizotinib (Xalkori), which is also approved for ALK+ (as well as ROS1+) NSCLC, and also for ALK+ anaplastic large cell lymphoma

For its offer, Takeda has teamed up with Point32Health, the second-largest health plan in New England with about 2.3 million members. The new agreement will make brigatinib widely available to patients who may benefit from its use, say the companies.

If a patient is unable to remain on brigatinib for 3 months or longer because of effectiveness or tolerability, Takeda will refund a yet unspecified amount of money to Point32Health. Brigatinib’s list price is $17,000 for a month’s treatment.

“Given the importance of facilitating cutting-edge oncology treatment and also the reality that not all patients show a positive response, reimbursement for oncology treatments is an area that is prime for innovative financing approaches,” said Michael Sherman, MD, chief medical officer and executive vice president, Point32Health, in a statement. “Collaborating with Takeda to share risk makes this agreement a crucial milestone in bringing cost-effectiveness to cancer care.”

The Pfizer program for crizotinib is somewhat different. For one thing, Pfizer’s refund is offered to any patient who qualifies and not just those who are covered by a specific plan. Second, Takeda is thus far only refunding money to the insurer, whereas Pfizer will also reimburse patients for out-of-pocket expenses.

There is a similar approach that has been offered by Novartis for tisagenlecleucel (Kymriah), the CAR T-cell therapy that launched with a daunting price tag of $475,000. After receiving backlash over the cost, Novartis announced that if the drug does not work after the first month, patients pay nothing.

In addition, Italy has been using this system for several years. Pharmaceutical companies must refund money if the drug fails to work. In 2015, the state-run health care system collected 200 million euros ($220 million) in refunds.

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

Can treatment or removal of high-grade squamous intraepithelial lesions (HSIL) reduce the likelihood of developing anal cancer in people living with HIV (PLHIV)?

“In theory, looking for and treating high-grade disease (like we know works in the cervix) is a potential way to prevent anal cancer in high-risk individuals,” Joel Palefsky, MD, lead investigator of the Anal Cancer/HSIL Outcomes Research (ANCHOR) study and founder/director of the University of California, San Francisco’s Anal Neoplasia Clinic, told this news organization. “But we’ve never had any direct evidence that it worked,” he said.

Initial findings from ANCHOR – the first randomized trial to demonstrate that anal cancer can be prevented in high-risk, HIV-infected patients – promise to change that paradigm and may even portend a new standard of care.

Undoubtedly, this is welcome news for the HIV community, who are not only at increased risk for anal HSIL overall, but among whom anal cancer cases have been rising over the past decade. This is especially true for women who are expected to bear a large portion of overall burden of human papillomavirus (HPV)–associated anal squamous cell carcinoma over the next 10 to 20 years.

In the study, 4,446 PLHIV ages 35 and older with precursor anal HSIL were randomly assigned to topical (imiquimod intra-anally, perianally, or both, or fluorouracil) or ablative (infrared coagulation, hyfrecation/electrocautery) treatment, or active surveillance, and followed every 6 months for 5 years. The study population was broadly representative, including men who have sex with men (MSM), women, transgender people, and historically underrepresented minorities, a factor that reinforces the study’s importance in this specific population.

Because the primary endpoint was reached (that is, to determine if HSIL treatment and removal effectively reduces anal cancer incidence in HIV-infected men and women), the Data Safety Board halted accrual and recommended that participants in the surveillance group be offered treatment moving forward. While the investigators are currently working on publication of the results, the study is ongoing.

Still, the ANCHOR study, which is one of the largest malignancy screening studies conducted in PLHIV, has also highlighted significant challenges in how anal cancer is approached in general.

“Anal cancer has many similarities to cervical cancer, where screening for precancerous lesions and treatment have been shown to substantially reduce morbidity and mortality,” said Joseph Sparano, MD, a medical oncologist specializing in HIV and breast cancer at Icahn School of Medicine at Mount Sinai, New York. Dr. Sparano is chair and principal investigator of the AIDS Malignancy Consortium but was not involved in the ANCHOR study.

But, he explained in an interview, “it’s much more difficult and technically challenging to screen for and evaluate the anal canal histology,” noting that New York is currently the only U.S. state to recommend screening for anal dysplasia with high-resolution anoscopy in HIV-infected men and women.

Availability and access to high-resolution anoscopy is limited, said Robert Yarchoan, MD, chief of the HIV and AIDS Malignancy Branch at the National Cancer Institute’s Clinical Cancer Research Division and director of the Office of HIV and AIDS Malignancy (which, incidentally, cosponsored ANCHOR).

“There are relatively few people that do this at this time,” he added in an interview, pointing out that among those who do, most are obstetricians/gynecologists.

A bit of digging into ANCHOR’s backstory revealed that this was a point of contention at the study’s onset. While physicians participating in the study received extensive training in high-resolution anoscopy, ob/gyns were the fastest to achieve competency and/or had the most prior experience, namely because of their experience in cervical cancer screening in women.

But initial objections by the American Board of Obstetricians and Gynecologists (which at the time, insisted that its members only treat women and threatened to remove their certification if they participated in the research), almost threw a wrench into the study’s start, according to a report in The New York Times. While rational minds prevailed and the board reversed its earlier statements, lack of ample training in the procedure may signal future barriers to treatment.

Another challenge lies in how study findings might be applicable to other groups outside of the HIV/AIDS population, such as people with other forms of immunosuppression who have HSIL, or even healthy women or men who are at risk as a result of penetrative/nonpenetrative sexual or nonsexual (for example, vaginal discharge to the anus) contact.

Although he was unable to share specifics at this time, Dr. Palefsky said that when they designed the ANCHOR study, they were aware that “merely showing efficacy wouldn’t necessarily be sufficient for establishing a standard of care, where[as] other pieces of information undoubtedly would be considered by entities that make guidelines” (for example, an examination of adverse events, risks/benefits, and factors that influence quality of life).

“With that in mind, we are doing a quality-of-life study and, in fact, have [collaborated on], developed, and validated what I think is the first anal disease-specific, quality of life instrument,” Dr. Palefsky said. “The work is still ongoing because we did not complete enrollment in the study, but we are continuing it as part of the follow up.”

Study investigators have also collected samples for a biorepository of specimens that will hopefully facilitate a better understanding of the molecular events driving progression from precancer to cancer. “A lot of people with HIV have these high-grade lesions,” Dr. Palefsky said. “If we were able to identify who’s at highest risk of all of them, that would be very important, because we prefer not to treat everybody with high-grade disease,” he noted, adding that the “underlying hope is that the biomarkers we find in the setting will also be relevant for other HPV-related cancers,” especially in women.

Dr. Yarchoan concurred. “One of the challenges is going to be to digest this information and see how to use it to potentially address the growing problem of females with HIV,” he said.

Dr. Palefsky, Dr. Sparano, and Dr. Yarchoan have disclosed no relevant financial relationships.

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

Can treatment or removal of high-grade squamous intraepithelial lesions (HSIL) reduce the likelihood of developing anal cancer in people living with HIV (PLHIV)?

“In theory, looking for and treating high-grade disease (like we know works in the cervix) is a potential way to prevent anal cancer in high-risk individuals,” Joel Palefsky, MD, lead investigator of the Anal Cancer/HSIL Outcomes Research (ANCHOR) study and founder/director of the University of California, San Francisco’s Anal Neoplasia Clinic, told this news organization. “But we’ve never had any direct evidence that it worked,” he said.

Initial findings from ANCHOR – the first randomized trial to demonstrate that anal cancer can be prevented in high-risk, HIV-infected patients – promise to change that paradigm and may even portend a new standard of care.

Undoubtedly, this is welcome news for the HIV community, who are not only at increased risk for anal HSIL overall, but among whom anal cancer cases have been rising over the past decade. This is especially true for women who are expected to bear a large portion of overall burden of human papillomavirus (HPV)–associated anal squamous cell carcinoma over the next 10 to 20 years.

In the study, 4,446 PLHIV ages 35 and older with precursor anal HSIL were randomly assigned to topical (imiquimod intra-anally, perianally, or both, or fluorouracil) or ablative (infrared coagulation, hyfrecation/electrocautery) treatment, or active surveillance, and followed every 6 months for 5 years. The study population was broadly representative, including men who have sex with men (MSM), women, transgender people, and historically underrepresented minorities, a factor that reinforces the study’s importance in this specific population.

Because the primary endpoint was reached (that is, to determine if HSIL treatment and removal effectively reduces anal cancer incidence in HIV-infected men and women), the Data Safety Board halted accrual and recommended that participants in the surveillance group be offered treatment moving forward. While the investigators are currently working on publication of the results, the study is ongoing.

Still, the ANCHOR study, which is one of the largest malignancy screening studies conducted in PLHIV, has also highlighted significant challenges in how anal cancer is approached in general.

“Anal cancer has many similarities to cervical cancer, where screening for precancerous lesions and treatment have been shown to substantially reduce morbidity and mortality,” said Joseph Sparano, MD, a medical oncologist specializing in HIV and breast cancer at Icahn School of Medicine at Mount Sinai, New York. Dr. Sparano is chair and principal investigator of the AIDS Malignancy Consortium but was not involved in the ANCHOR study.

But, he explained in an interview, “it’s much more difficult and technically challenging to screen for and evaluate the anal canal histology,” noting that New York is currently the only U.S. state to recommend screening for anal dysplasia with high-resolution anoscopy in HIV-infected men and women.

Availability and access to high-resolution anoscopy is limited, said Robert Yarchoan, MD, chief of the HIV and AIDS Malignancy Branch at the National Cancer Institute’s Clinical Cancer Research Division and director of the Office of HIV and AIDS Malignancy (which, incidentally, cosponsored ANCHOR).

“There are relatively few people that do this at this time,” he added in an interview, pointing out that among those who do, most are obstetricians/gynecologists.

A bit of digging into ANCHOR’s backstory revealed that this was a point of contention at the study’s onset. While physicians participating in the study received extensive training in high-resolution anoscopy, ob/gyns were the fastest to achieve competency and/or had the most prior experience, namely because of their experience in cervical cancer screening in women.

But initial objections by the American Board of Obstetricians and Gynecologists (which at the time, insisted that its members only treat women and threatened to remove their certification if they participated in the research), almost threw a wrench into the study’s start, according to a report in The New York Times. While rational minds prevailed and the board reversed its earlier statements, lack of ample training in the procedure may signal future barriers to treatment.

Another challenge lies in how study findings might be applicable to other groups outside of the HIV/AIDS population, such as people with other forms of immunosuppression who have HSIL, or even healthy women or men who are at risk as a result of penetrative/nonpenetrative sexual or nonsexual (for example, vaginal discharge to the anus) contact.

Although he was unable to share specifics at this time, Dr. Palefsky said that when they designed the ANCHOR study, they were aware that “merely showing efficacy wouldn’t necessarily be sufficient for establishing a standard of care, where[as] other pieces of information undoubtedly would be considered by entities that make guidelines” (for example, an examination of adverse events, risks/benefits, and factors that influence quality of life).

“With that in mind, we are doing a quality-of-life study and, in fact, have [collaborated on], developed, and validated what I think is the first anal disease-specific, quality of life instrument,” Dr. Palefsky said. “The work is still ongoing because we did not complete enrollment in the study, but we are continuing it as part of the follow up.”

Study investigators have also collected samples for a biorepository of specimens that will hopefully facilitate a better understanding of the molecular events driving progression from precancer to cancer. “A lot of people with HIV have these high-grade lesions,” Dr. Palefsky said. “If we were able to identify who’s at highest risk of all of them, that would be very important, because we prefer not to treat everybody with high-grade disease,” he noted, adding that the “underlying hope is that the biomarkers we find in the setting will also be relevant for other HPV-related cancers,” especially in women.

Dr. Yarchoan concurred. “One of the challenges is going to be to digest this information and see how to use it to potentially address the growing problem of females with HIV,” he said.

Dr. Palefsky, Dr. Sparano, and Dr. Yarchoan have disclosed no relevant financial relationships.

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

Can treatment or removal of high-grade squamous intraepithelial lesions (HSIL) reduce the likelihood of developing anal cancer in people living with HIV (PLHIV)?

“In theory, looking for and treating high-grade disease (like we know works in the cervix) is a potential way to prevent anal cancer in high-risk individuals,” Joel Palefsky, MD, lead investigator of the Anal Cancer/HSIL Outcomes Research (ANCHOR) study and founder/director of the University of California, San Francisco’s Anal Neoplasia Clinic, told this news organization. “But we’ve never had any direct evidence that it worked,” he said.

Initial findings from ANCHOR – the first randomized trial to demonstrate that anal cancer can be prevented in high-risk, HIV-infected patients – promise to change that paradigm and may even portend a new standard of care.

Undoubtedly, this is welcome news for the HIV community, who are not only at increased risk for anal HSIL overall, but among whom anal cancer cases have been rising over the past decade. This is especially true for women who are expected to bear a large portion of overall burden of human papillomavirus (HPV)–associated anal squamous cell carcinoma over the next 10 to 20 years.

In the study, 4,446 PLHIV ages 35 and older with precursor anal HSIL were randomly assigned to topical (imiquimod intra-anally, perianally, or both, or fluorouracil) or ablative (infrared coagulation, hyfrecation/electrocautery) treatment, or active surveillance, and followed every 6 months for 5 years. The study population was broadly representative, including men who have sex with men (MSM), women, transgender people, and historically underrepresented minorities, a factor that reinforces the study’s importance in this specific population.

Because the primary endpoint was reached (that is, to determine if HSIL treatment and removal effectively reduces anal cancer incidence in HIV-infected men and women), the Data Safety Board halted accrual and recommended that participants in the surveillance group be offered treatment moving forward. While the investigators are currently working on publication of the results, the study is ongoing.

Still, the ANCHOR study, which is one of the largest malignancy screening studies conducted in PLHIV, has also highlighted significant challenges in how anal cancer is approached in general.

“Anal cancer has many similarities to cervical cancer, where screening for precancerous lesions and treatment have been shown to substantially reduce morbidity and mortality,” said Joseph Sparano, MD, a medical oncologist specializing in HIV and breast cancer at Icahn School of Medicine at Mount Sinai, New York. Dr. Sparano is chair and principal investigator of the AIDS Malignancy Consortium but was not involved in the ANCHOR study.

But, he explained in an interview, “it’s much more difficult and technically challenging to screen for and evaluate the anal canal histology,” noting that New York is currently the only U.S. state to recommend screening for anal dysplasia with high-resolution anoscopy in HIV-infected men and women.

Availability and access to high-resolution anoscopy is limited, said Robert Yarchoan, MD, chief of the HIV and AIDS Malignancy Branch at the National Cancer Institute’s Clinical Cancer Research Division and director of the Office of HIV and AIDS Malignancy (which, incidentally, cosponsored ANCHOR).

“There are relatively few people that do this at this time,” he added in an interview, pointing out that among those who do, most are obstetricians/gynecologists.

A bit of digging into ANCHOR’s backstory revealed that this was a point of contention at the study’s onset. While physicians participating in the study received extensive training in high-resolution anoscopy, ob/gyns were the fastest to achieve competency and/or had the most prior experience, namely because of their experience in cervical cancer screening in women.

But initial objections by the American Board of Obstetricians and Gynecologists (which at the time, insisted that its members only treat women and threatened to remove their certification if they participated in the research), almost threw a wrench into the study’s start, according to a report in The New York Times. While rational minds prevailed and the board reversed its earlier statements, lack of ample training in the procedure may signal future barriers to treatment.

Another challenge lies in how study findings might be applicable to other groups outside of the HIV/AIDS population, such as people with other forms of immunosuppression who have HSIL, or even healthy women or men who are at risk as a result of penetrative/nonpenetrative sexual or nonsexual (for example, vaginal discharge to the anus) contact.

Although he was unable to share specifics at this time, Dr. Palefsky said that when they designed the ANCHOR study, they were aware that “merely showing efficacy wouldn’t necessarily be sufficient for establishing a standard of care, where[as] other pieces of information undoubtedly would be considered by entities that make guidelines” (for example, an examination of adverse events, risks/benefits, and factors that influence quality of life).

“With that in mind, we are doing a quality-of-life study and, in fact, have [collaborated on], developed, and validated what I think is the first anal disease-specific, quality of life instrument,” Dr. Palefsky said. “The work is still ongoing because we did not complete enrollment in the study, but we are continuing it as part of the follow up.”

Study investigators have also collected samples for a biorepository of specimens that will hopefully facilitate a better understanding of the molecular events driving progression from precancer to cancer. “A lot of people with HIV have these high-grade lesions,” Dr. Palefsky said. “If we were able to identify who’s at highest risk of all of them, that would be very important, because we prefer not to treat everybody with high-grade disease,” he noted, adding that the “underlying hope is that the biomarkers we find in the setting will also be relevant for other HPV-related cancers,” especially in women.

Dr. Yarchoan concurred. “One of the challenges is going to be to digest this information and see how to use it to potentially address the growing problem of females with HIV,” he said.

Dr. Palefsky, Dr. Sparano, and Dr. Yarchoan have disclosed no relevant financial relationships.

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

For patients with moderate to severe asthma, blockade with itepekimab, a new human IgG4P monoclonal antibody against the upstream alarmin interleukin-33, led to a reduction in events that indicate loss of asthma control. Treatment with itepekimab also led to an improvement in lung function compared with placebo, according to results of a phase 2 trial.

However, findings for a subgroup of patients treated with itepekimab in combination with dupilumab, an anti–interleukin-4–receptor alpha subunit and IL-13 monoclonal antibody, were not favorable in comparison with placebo, noted M. E. Wechsler, MD, and colleagues in an article published online in the New England Journal of Medicine.
 

New target

Despite the demonstrated efficacy of available biologic therapies targeting IgE, interleukin-4, interleukin-13, and interleukin-5 for treating moderate to severe type 2 asthma, many patients with type 2 or non–type 2 asthma continue to have symptoms, exacerbations, and reduced lung function. New therapies targeting alternative pathophysiologic pathways are needed.

Genomewide studies show that type 2 and non–type 2 inflammation that contributes to asthma and chronic obstructive pulmonary disease (COPD) are genetically associated with interleukin-33. This inflammation occurs when interleukin-33 binds to its cognate receptor (ST2) and engages the coreceptor interleukin-1 receptor accessory protein to initiate downstream signaling, activating cells of both the innate and adaptive immune systems.
 

Study details

The investigators conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-group (four groups), proof-of-concept trial to evaluate the efficacy and safety of the interleukin-33 targeting itepekimab in comparison with placebo for adults with moderate to severe asthma. Dupilumab, which was the active comparator, was administered in combination with itepekimab to evaluate potential additive effects. Dupilumab’s efficacy in this population had been demonstrated previously.

All 296 patients (mean age, 49.1 years; 64% women) were receiving inhaled glucocorticoids plus long-acting beta-agonists (LABAs). They were randomly assigned in a 1:1:1:1 ratio to receive subcutaneous itepekimab (300 mg), itepekimab plus dupilumab (both at 300 mg; combination therapy), dupilumab (300 mg), or placebo every 2 weeks for 12 weeks. LABAs were discontinued at week 4, and inhaled glucocorticoids were tapered over weeks 6 through 9. The primary endpoint was the occurrence of an event indicating the loss of asthma control.
 

Promising results

Primary endpoint analysis at 12 weeks revealed a lower rate of asthma control–loss events in the itepekimab and dupilumab monotherapy groups but not in the combination group, compared with patients who received placebo. Events occurred in 22% of patients in the itepekimab group, in 27% of those in the combination group, in 19% of the dupilumab group, and in 41% of the placebo group. The odds ratios for comparisons with placebo were 0.42 for the itepekimab group (95% confidence interval, 0.20-0.88; P = .02); 0.33 in the dupilumab group (95% CI, 0.15-.70); and 0.52 in the combination group (95% CI, 0.26-1.06; P = .07) .

Following a similar pattern, forced expiratory volume in 1 second before use of a bronchodilator increased with both monotherapies but not with the combination or placebo. Although the trial was not powered to determine differences between itepekimab and dupilumab, the effects of dupilumab therapy were generally greater than those observed with itepekimab, especially for patients with type 2 asthma.

Also, asthma control and quality of life were improved with itepekimab and dupilumab monotherapy in comparison with placebo. There were also greater reductions in the mean blood eosinophil count.

The authors urge further research into the complexities of asthma physiology and encourage researchers to look for predictive biomarkers of anti–interleukin-33 blockade response. They conclude, “In this trial, we found that itepekimab monotherapy led to a lower incidence of events indicating loss of asthma control and to improved lung function, findings that are consistent with a role for interleukin-33 in the pathogenesis of exacerbations and airflow limitation in asthma.”
 

Examining results

In an accompanying editorial, Philip G. Bardin, PhD, and Paul S. Foster, DSc, ask why itepekimab and dupilumab, a combination based on a sound scientific rationale, failed. As monotherapies, both itepekimab and dupilumab are roughly similar in reducing asthma events and improving lung function; thus, is unlikely that inadequate dosing led to the failure of itepekimab.

Interleukin-33 is an attractive target because the cells it promotes secrete cytokines that induce asthma’s pathognomonic features, and biologic agents that target those cytokines (interleukin-5/-5R/-4/-13 axes) have been highly effective. They do not, however, prevent exacerbations after treatment.

Alternative pathways within or outside that paradigm are operant, and other epithelial alarmins, such as interleukin-25 and thymic stromal lymphopoietin, promote type 2 inflammation, Dr. Bardin and Dr. Foster state.

“Combination therapy with itepekimab and dupilumab may have failed because these pathways bypass interleukin-33,” they write. Also, preexisting ILC2 and TH2 cells may have residual capacity to release mediators. The short-term trial design, the editorialists write, may have contributed to the failure of the itepekimab/dupilumab combination; interleukin-33 may be appropriate as a target in a longer-term exacerbation-type trial “in which epithelial infection and other relevant stimuli instigate exacerbated disease. Combination therapy may be capable of lowering exacerbations rather than preventing loss of control in chronic disease.

“Clinical translation of basic science in asthma remains a challenge to be pursued. ... It is imperative to harness scientific insights from translational studies that frustrate our hopeful expectations – so that something can also be gained,” they conclude.
 

The role of interleukin-33

“Our study of itepekimab provides valuable insight into pathophysiology of severe asthma,” said Dr. Wechsler, professor of medicine at the NJH Cohen Family Asthma Institute, Denver, in an interview. “As blocking IL-33 reduced asthma worsening and improved lung function compared to placebo, it suggests that IL-33 plays an important role in asthma pathophysiology and may be a valuable target for a subset of patients with severe asthma,” he stated.

“Since the effect of itepekimab is comparable to that of dupilumab, it is suggested that patients may benefit from blockade of this pathway, but what remains to be seen is identifying which patients are more likely to respond better to one therapy vs. another. The future of blocking IL-33 remains exciting, and studies are being planned to evaluate its efficacy in airways diseases, including COPD,” he concluded.

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

For patients with moderate to severe asthma, blockade with itepekimab, a new human IgG4P monoclonal antibody against the upstream alarmin interleukin-33, led to a reduction in events that indicate loss of asthma control. Treatment with itepekimab also led to an improvement in lung function compared with placebo, according to results of a phase 2 trial.

However, findings for a subgroup of patients treated with itepekimab in combination with dupilumab, an anti–interleukin-4–receptor alpha subunit and IL-13 monoclonal antibody, were not favorable in comparison with placebo, noted M. E. Wechsler, MD, and colleagues in an article published online in the New England Journal of Medicine.
 

New target

Despite the demonstrated efficacy of available biologic therapies targeting IgE, interleukin-4, interleukin-13, and interleukin-5 for treating moderate to severe type 2 asthma, many patients with type 2 or non–type 2 asthma continue to have symptoms, exacerbations, and reduced lung function. New therapies targeting alternative pathophysiologic pathways are needed.

Genomewide studies show that type 2 and non–type 2 inflammation that contributes to asthma and chronic obstructive pulmonary disease (COPD) are genetically associated with interleukin-33. This inflammation occurs when interleukin-33 binds to its cognate receptor (ST2) and engages the coreceptor interleukin-1 receptor accessory protein to initiate downstream signaling, activating cells of both the innate and adaptive immune systems.
 

Study details

The investigators conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-group (four groups), proof-of-concept trial to evaluate the efficacy and safety of the interleukin-33 targeting itepekimab in comparison with placebo for adults with moderate to severe asthma. Dupilumab, which was the active comparator, was administered in combination with itepekimab to evaluate potential additive effects. Dupilumab’s efficacy in this population had been demonstrated previously.

All 296 patients (mean age, 49.1 years; 64% women) were receiving inhaled glucocorticoids plus long-acting beta-agonists (LABAs). They were randomly assigned in a 1:1:1:1 ratio to receive subcutaneous itepekimab (300 mg), itepekimab plus dupilumab (both at 300 mg; combination therapy), dupilumab (300 mg), or placebo every 2 weeks for 12 weeks. LABAs were discontinued at week 4, and inhaled glucocorticoids were tapered over weeks 6 through 9. The primary endpoint was the occurrence of an event indicating the loss of asthma control.
 

Promising results

Primary endpoint analysis at 12 weeks revealed a lower rate of asthma control–loss events in the itepekimab and dupilumab monotherapy groups but not in the combination group, compared with patients who received placebo. Events occurred in 22% of patients in the itepekimab group, in 27% of those in the combination group, in 19% of the dupilumab group, and in 41% of the placebo group. The odds ratios for comparisons with placebo were 0.42 for the itepekimab group (95% confidence interval, 0.20-0.88; P = .02); 0.33 in the dupilumab group (95% CI, 0.15-.70); and 0.52 in the combination group (95% CI, 0.26-1.06; P = .07) .

Following a similar pattern, forced expiratory volume in 1 second before use of a bronchodilator increased with both monotherapies but not with the combination or placebo. Although the trial was not powered to determine differences between itepekimab and dupilumab, the effects of dupilumab therapy were generally greater than those observed with itepekimab, especially for patients with type 2 asthma.

Also, asthma control and quality of life were improved with itepekimab and dupilumab monotherapy in comparison with placebo. There were also greater reductions in the mean blood eosinophil count.

The authors urge further research into the complexities of asthma physiology and encourage researchers to look for predictive biomarkers of anti–interleukin-33 blockade response. They conclude, “In this trial, we found that itepekimab monotherapy led to a lower incidence of events indicating loss of asthma control and to improved lung function, findings that are consistent with a role for interleukin-33 in the pathogenesis of exacerbations and airflow limitation in asthma.”
 

Examining results

In an accompanying editorial, Philip G. Bardin, PhD, and Paul S. Foster, DSc, ask why itepekimab and dupilumab, a combination based on a sound scientific rationale, failed. As monotherapies, both itepekimab and dupilumab are roughly similar in reducing asthma events and improving lung function; thus, is unlikely that inadequate dosing led to the failure of itepekimab.

Interleukin-33 is an attractive target because the cells it promotes secrete cytokines that induce asthma’s pathognomonic features, and biologic agents that target those cytokines (interleukin-5/-5R/-4/-13 axes) have been highly effective. They do not, however, prevent exacerbations after treatment.

Alternative pathways within or outside that paradigm are operant, and other epithelial alarmins, such as interleukin-25 and thymic stromal lymphopoietin, promote type 2 inflammation, Dr. Bardin and Dr. Foster state.

“Combination therapy with itepekimab and dupilumab may have failed because these pathways bypass interleukin-33,” they write. Also, preexisting ILC2 and TH2 cells may have residual capacity to release mediators. The short-term trial design, the editorialists write, may have contributed to the failure of the itepekimab/dupilumab combination; interleukin-33 may be appropriate as a target in a longer-term exacerbation-type trial “in which epithelial infection and other relevant stimuli instigate exacerbated disease. Combination therapy may be capable of lowering exacerbations rather than preventing loss of control in chronic disease.

“Clinical translation of basic science in asthma remains a challenge to be pursued. ... It is imperative to harness scientific insights from translational studies that frustrate our hopeful expectations – so that something can also be gained,” they conclude.
 

The role of interleukin-33

“Our study of itepekimab provides valuable insight into pathophysiology of severe asthma,” said Dr. Wechsler, professor of medicine at the NJH Cohen Family Asthma Institute, Denver, in an interview. “As blocking IL-33 reduced asthma worsening and improved lung function compared to placebo, it suggests that IL-33 plays an important role in asthma pathophysiology and may be a valuable target for a subset of patients with severe asthma,” he stated.

“Since the effect of itepekimab is comparable to that of dupilumab, it is suggested that patients may benefit from blockade of this pathway, but what remains to be seen is identifying which patients are more likely to respond better to one therapy vs. another. The future of blocking IL-33 remains exciting, and studies are being planned to evaluate its efficacy in airways diseases, including COPD,” he concluded.

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

For patients with moderate to severe asthma, blockade with itepekimab, a new human IgG4P monoclonal antibody against the upstream alarmin interleukin-33, led to a reduction in events that indicate loss of asthma control. Treatment with itepekimab also led to an improvement in lung function compared with placebo, according to results of a phase 2 trial.

However, findings for a subgroup of patients treated with itepekimab in combination with dupilumab, an anti–interleukin-4–receptor alpha subunit and IL-13 monoclonal antibody, were not favorable in comparison with placebo, noted M. E. Wechsler, MD, and colleagues in an article published online in the New England Journal of Medicine.
 

New target

Despite the demonstrated efficacy of available biologic therapies targeting IgE, interleukin-4, interleukin-13, and interleukin-5 for treating moderate to severe type 2 asthma, many patients with type 2 or non–type 2 asthma continue to have symptoms, exacerbations, and reduced lung function. New therapies targeting alternative pathophysiologic pathways are needed.

Genomewide studies show that type 2 and non–type 2 inflammation that contributes to asthma and chronic obstructive pulmonary disease (COPD) are genetically associated with interleukin-33. This inflammation occurs when interleukin-33 binds to its cognate receptor (ST2) and engages the coreceptor interleukin-1 receptor accessory protein to initiate downstream signaling, activating cells of both the innate and adaptive immune systems.
 

Study details

The investigators conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-group (four groups), proof-of-concept trial to evaluate the efficacy and safety of the interleukin-33 targeting itepekimab in comparison with placebo for adults with moderate to severe asthma. Dupilumab, which was the active comparator, was administered in combination with itepekimab to evaluate potential additive effects. Dupilumab’s efficacy in this population had been demonstrated previously.

All 296 patients (mean age, 49.1 years; 64% women) were receiving inhaled glucocorticoids plus long-acting beta-agonists (LABAs). They were randomly assigned in a 1:1:1:1 ratio to receive subcutaneous itepekimab (300 mg), itepekimab plus dupilumab (both at 300 mg; combination therapy), dupilumab (300 mg), or placebo every 2 weeks for 12 weeks. LABAs were discontinued at week 4, and inhaled glucocorticoids were tapered over weeks 6 through 9. The primary endpoint was the occurrence of an event indicating the loss of asthma control.
 

Promising results

Primary endpoint analysis at 12 weeks revealed a lower rate of asthma control–loss events in the itepekimab and dupilumab monotherapy groups but not in the combination group, compared with patients who received placebo. Events occurred in 22% of patients in the itepekimab group, in 27% of those in the combination group, in 19% of the dupilumab group, and in 41% of the placebo group. The odds ratios for comparisons with placebo were 0.42 for the itepekimab group (95% confidence interval, 0.20-0.88; P = .02); 0.33 in the dupilumab group (95% CI, 0.15-.70); and 0.52 in the combination group (95% CI, 0.26-1.06; P = .07) .

Following a similar pattern, forced expiratory volume in 1 second before use of a bronchodilator increased with both monotherapies but not with the combination or placebo. Although the trial was not powered to determine differences between itepekimab and dupilumab, the effects of dupilumab therapy were generally greater than those observed with itepekimab, especially for patients with type 2 asthma.

Also, asthma control and quality of life were improved with itepekimab and dupilumab monotherapy in comparison with placebo. There were also greater reductions in the mean blood eosinophil count.

The authors urge further research into the complexities of asthma physiology and encourage researchers to look for predictive biomarkers of anti–interleukin-33 blockade response. They conclude, “In this trial, we found that itepekimab monotherapy led to a lower incidence of events indicating loss of asthma control and to improved lung function, findings that are consistent with a role for interleukin-33 in the pathogenesis of exacerbations and airflow limitation in asthma.”
 

Examining results

In an accompanying editorial, Philip G. Bardin, PhD, and Paul S. Foster, DSc, ask why itepekimab and dupilumab, a combination based on a sound scientific rationale, failed. As monotherapies, both itepekimab and dupilumab are roughly similar in reducing asthma events and improving lung function; thus, is unlikely that inadequate dosing led to the failure of itepekimab.

Interleukin-33 is an attractive target because the cells it promotes secrete cytokines that induce asthma’s pathognomonic features, and biologic agents that target those cytokines (interleukin-5/-5R/-4/-13 axes) have been highly effective. They do not, however, prevent exacerbations after treatment.

Alternative pathways within or outside that paradigm are operant, and other epithelial alarmins, such as interleukin-25 and thymic stromal lymphopoietin, promote type 2 inflammation, Dr. Bardin and Dr. Foster state.

“Combination therapy with itepekimab and dupilumab may have failed because these pathways bypass interleukin-33,” they write. Also, preexisting ILC2 and TH2 cells may have residual capacity to release mediators. The short-term trial design, the editorialists write, may have contributed to the failure of the itepekimab/dupilumab combination; interleukin-33 may be appropriate as a target in a longer-term exacerbation-type trial “in which epithelial infection and other relevant stimuli instigate exacerbated disease. Combination therapy may be capable of lowering exacerbations rather than preventing loss of control in chronic disease.

“Clinical translation of basic science in asthma remains a challenge to be pursued. ... It is imperative to harness scientific insights from translational studies that frustrate our hopeful expectations – so that something can also be gained,” they conclude.
 

The role of interleukin-33

“Our study of itepekimab provides valuable insight into pathophysiology of severe asthma,” said Dr. Wechsler, professor of medicine at the NJH Cohen Family Asthma Institute, Denver, in an interview. “As blocking IL-33 reduced asthma worsening and improved lung function compared to placebo, it suggests that IL-33 plays an important role in asthma pathophysiology and may be a valuable target for a subset of patients with severe asthma,” he stated.

“Since the effect of itepekimab is comparable to that of dupilumab, it is suggested that patients may benefit from blockade of this pathway, but what remains to be seen is identifying which patients are more likely to respond better to one therapy vs. another. The future of blocking IL-33 remains exciting, and studies are being planned to evaluate its efficacy in airways diseases, including COPD,” he concluded.

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

Placebo treatment was found to be superior to treatment with risankizumab with respect to time to first asthma worsening and annualized rate of asthma worsening for adults with severe persistent asthma in a phase 2a clinical trial.

The randomized, double-blind, 24-week, parallel group, multicenter trial assessed risankizumab efficacy and safety in 214 adults with severe persistent asthma. The results were reported in The New England Journal of Medicine.

Risankizumab is a humanized, monoclonal antibody directed against subunit p19 of interleukin-23. It is approved for the treatment of moderate to severe psoriasis.

Interleukin-23 has been implicated in airway inflammation mediated by type 2 and type 17 cytokines. Noting that inhibition of interleukin-23 is effective in the treatment of psoriasis and Crohn’s disease, Christopher E. Brightling, MD, and colleagues investigated whether targeting interleukin-23 in asthma patients would improve disease control and reduce airway inflammation.
 

Study details

Patients received either 90 mg of risankizumab (subcutaneous) (n = 105) or placebo (n = 109) once every 4 weeks. Time to first asthma worsening was the primary endpoint. Worsening was defined as decline from baseline on 2 or more consecutive days. Deterioration was defined as a decrease of at least 30% in the morning peak expiratory flow or an increase from baseline of at least 50% in rescue medication puffs over 24 hours. In addition, a severe asthma exacerbation or an increase of 0.75 or more points on the five-item Asthma Control Questionnaire (scores range from 0 to 6, with higher scores indicating less control) were considered to be evidence of worsening. Annualized rate of asthma worsening was a secondary endpoint.

The mean age of the patients was 53 years; 66.5% of the patients were women.
 

Disappointing results

In the risankizumab group, median time to first asthma worsening was 40 days, significantly worse than the 86 days reported for the placebo group (hazard ratio, 1.46; 95% confidence interval, 1.05-2.04; P = .03). For annualized asthma worsening, the rate ratio for the comparison of risankizumab with placebo was 1.49 (95% CI, 1.12-1.99).

Among key secondary endpoints, the adjusted mean change in trough forced expiratory volume in 1 second (FEV₁₎ from baseline to week 24 was –0.05 L in the risankizumab group and –0.01 L in the placebo group. The adjusted mean change in FEV₁ after bronchodilator use from baseline to week 24 was –0.10 L in the risankizumab group and –0.03 L in the placebo group. Sputum transcriptomic pathway analysis showed that genes involved in the activation of natural killer cells and cytotoxic T cells and the activation of type 1 helper T and type 17 helper T transcription factors were downregulated by risankizumab. Rates of adverse events were similar among patients receiving risankizumab and those taking placebo.
 

Further trials unwarranted

“The findings not only failed to show benefit for any outcome but also showed asthma worsening occurred earlier and more frequently in those treated with risankizumab versus placebo,” Dr. Brightling, professor in the department of respiratory sciences at University of Leicester, England, said in an interview. “This study does not support any further trials for anti-IL23 in asthma.” Dr. Brightling speculated on the cause of accelerated asthma worsening with risankizumab.

“We found that the gene expression of key molecules involved in our response to infection was decreased in airway samples in those treated with risankizumab versus placebo. It is possible that the increased asthma worsening following risankizumab was related to this suppression of antimicrobial immunity,” he said.

He noted that risankizumab did not affect type-2/eosinophilic inflammation, which is the target for current asthma biologics, or gene expression of T2 molecules. “That suggests that this type of inflammation would have continued in the asthma patients during the trial irrespective of receiving risankizumab or placebo,” he said.
 

Caution with investigating biologicals

Downstream biologic responses to risankizumab were detectable, Philip G. Bardin, PhD, and Paul S. Foster, DSc, observed in an accompanying editorial, but there was no discernible clinical benefit, implying attenuation of apposite pathways. Current understanding of the basic science relevant to asthma, they stated, offers clues to the failure of risankizumab to benefit these patients with severe asthma. Although targeting the interleukin-23 and Th17 axis with risankizumab can reduce development of pathogenic Th17 cells, interleukin-23 is not critical for the development of Th17 cells.

“In contrast to pathways operated by interleukin-5 and interleukin-4R alpha, interleukin-23 has only a limited auxiliary role in amplifying type 2 responses. It is possible that the trial conducted by Brightling and colleagues failed because signaling through alternative disease pathways nullified inhibition of inter-leukin-23,” the editorialists wrote.

Dr. Bardin and Dr. Foster further speculate that because interleukin-23 is vital for effective mucosal immunity, risankizumab may have conferred to patients a predisposition to more severe or more frequent virus-induced exacerbations. They stated that generally, however, the reasons for risankizumab’s poorer outcomes compared to placebo are unclear. “Overall, these findings support a cautious approach in future research investigating biologic therapies in asthma,” they concluded.

The clinical trial was sponsored and funded by BI/AbbVie.

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

Placebo treatment was found to be superior to treatment with risankizumab with respect to time to first asthma worsening and annualized rate of asthma worsening for adults with severe persistent asthma in a phase 2a clinical trial.

The randomized, double-blind, 24-week, parallel group, multicenter trial assessed risankizumab efficacy and safety in 214 adults with severe persistent asthma. The results were reported in The New England Journal of Medicine.

Risankizumab is a humanized, monoclonal antibody directed against subunit p19 of interleukin-23. It is approved for the treatment of moderate to severe psoriasis.

Interleukin-23 has been implicated in airway inflammation mediated by type 2 and type 17 cytokines. Noting that inhibition of interleukin-23 is effective in the treatment of psoriasis and Crohn’s disease, Christopher E. Brightling, MD, and colleagues investigated whether targeting interleukin-23 in asthma patients would improve disease control and reduce airway inflammation.
 

Study details

Patients received either 90 mg of risankizumab (subcutaneous) (n = 105) or placebo (n = 109) once every 4 weeks. Time to first asthma worsening was the primary endpoint. Worsening was defined as decline from baseline on 2 or more consecutive days. Deterioration was defined as a decrease of at least 30% in the morning peak expiratory flow or an increase from baseline of at least 50% in rescue medication puffs over 24 hours. In addition, a severe asthma exacerbation or an increase of 0.75 or more points on the five-item Asthma Control Questionnaire (scores range from 0 to 6, with higher scores indicating less control) were considered to be evidence of worsening. Annualized rate of asthma worsening was a secondary endpoint.

The mean age of the patients was 53 years; 66.5% of the patients were women.
 

Disappointing results

In the risankizumab group, median time to first asthma worsening was 40 days, significantly worse than the 86 days reported for the placebo group (hazard ratio, 1.46; 95% confidence interval, 1.05-2.04; P = .03). For annualized asthma worsening, the rate ratio for the comparison of risankizumab with placebo was 1.49 (95% CI, 1.12-1.99).

Among key secondary endpoints, the adjusted mean change in trough forced expiratory volume in 1 second (FEV₁₎ from baseline to week 24 was –0.05 L in the risankizumab group and –0.01 L in the placebo group. The adjusted mean change in FEV₁ after bronchodilator use from baseline to week 24 was –0.10 L in the risankizumab group and –0.03 L in the placebo group. Sputum transcriptomic pathway analysis showed that genes involved in the activation of natural killer cells and cytotoxic T cells and the activation of type 1 helper T and type 17 helper T transcription factors were downregulated by risankizumab. Rates of adverse events were similar among patients receiving risankizumab and those taking placebo.
 

Further trials unwarranted

“The findings not only failed to show benefit for any outcome but also showed asthma worsening occurred earlier and more frequently in those treated with risankizumab versus placebo,” Dr. Brightling, professor in the department of respiratory sciences at University of Leicester, England, said in an interview. “This study does not support any further trials for anti-IL23 in asthma.” Dr. Brightling speculated on the cause of accelerated asthma worsening with risankizumab.

“We found that the gene expression of key molecules involved in our response to infection was decreased in airway samples in those treated with risankizumab versus placebo. It is possible that the increased asthma worsening following risankizumab was related to this suppression of antimicrobial immunity,” he said.

He noted that risankizumab did not affect type-2/eosinophilic inflammation, which is the target for current asthma biologics, or gene expression of T2 molecules. “That suggests that this type of inflammation would have continued in the asthma patients during the trial irrespective of receiving risankizumab or placebo,” he said.
 

Caution with investigating biologicals

Downstream biologic responses to risankizumab were detectable, Philip G. Bardin, PhD, and Paul S. Foster, DSc, observed in an accompanying editorial, but there was no discernible clinical benefit, implying attenuation of apposite pathways. Current understanding of the basic science relevant to asthma, they stated, offers clues to the failure of risankizumab to benefit these patients with severe asthma. Although targeting the interleukin-23 and Th17 axis with risankizumab can reduce development of pathogenic Th17 cells, interleukin-23 is not critical for the development of Th17 cells.

“In contrast to pathways operated by interleukin-5 and interleukin-4R alpha, interleukin-23 has only a limited auxiliary role in amplifying type 2 responses. It is possible that the trial conducted by Brightling and colleagues failed because signaling through alternative disease pathways nullified inhibition of inter-leukin-23,” the editorialists wrote.

Dr. Bardin and Dr. Foster further speculate that because interleukin-23 is vital for effective mucosal immunity, risankizumab may have conferred to patients a predisposition to more severe or more frequent virus-induced exacerbations. They stated that generally, however, the reasons for risankizumab’s poorer outcomes compared to placebo are unclear. “Overall, these findings support a cautious approach in future research investigating biologic therapies in asthma,” they concluded.

The clinical trial was sponsored and funded by BI/AbbVie.

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

Placebo treatment was found to be superior to treatment with risankizumab with respect to time to first asthma worsening and annualized rate of asthma worsening for adults with severe persistent asthma in a phase 2a clinical trial.

The randomized, double-blind, 24-week, parallel group, multicenter trial assessed risankizumab efficacy and safety in 214 adults with severe persistent asthma. The results were reported in The New England Journal of Medicine.

Risankizumab is a humanized, monoclonal antibody directed against subunit p19 of interleukin-23. It is approved for the treatment of moderate to severe psoriasis.

Interleukin-23 has been implicated in airway inflammation mediated by type 2 and type 17 cytokines. Noting that inhibition of interleukin-23 is effective in the treatment of psoriasis and Crohn’s disease, Christopher E. Brightling, MD, and colleagues investigated whether targeting interleukin-23 in asthma patients would improve disease control and reduce airway inflammation.
 

Study details

Patients received either 90 mg of risankizumab (subcutaneous) (n = 105) or placebo (n = 109) once every 4 weeks. Time to first asthma worsening was the primary endpoint. Worsening was defined as decline from baseline on 2 or more consecutive days. Deterioration was defined as a decrease of at least 30% in the morning peak expiratory flow or an increase from baseline of at least 50% in rescue medication puffs over 24 hours. In addition, a severe asthma exacerbation or an increase of 0.75 or more points on the five-item Asthma Control Questionnaire (scores range from 0 to 6, with higher scores indicating less control) were considered to be evidence of worsening. Annualized rate of asthma worsening was a secondary endpoint.

The mean age of the patients was 53 years; 66.5% of the patients were women.
 

Disappointing results

In the risankizumab group, median time to first asthma worsening was 40 days, significantly worse than the 86 days reported for the placebo group (hazard ratio, 1.46; 95% confidence interval, 1.05-2.04; P = .03). For annualized asthma worsening, the rate ratio for the comparison of risankizumab with placebo was 1.49 (95% CI, 1.12-1.99).

Among key secondary endpoints, the adjusted mean change in trough forced expiratory volume in 1 second (FEV₁₎ from baseline to week 24 was –0.05 L in the risankizumab group and –0.01 L in the placebo group. The adjusted mean change in FEV₁ after bronchodilator use from baseline to week 24 was –0.10 L in the risankizumab group and –0.03 L in the placebo group. Sputum transcriptomic pathway analysis showed that genes involved in the activation of natural killer cells and cytotoxic T cells and the activation of type 1 helper T and type 17 helper T transcription factors were downregulated by risankizumab. Rates of adverse events were similar among patients receiving risankizumab and those taking placebo.
 

Further trials unwarranted

“The findings not only failed to show benefit for any outcome but also showed asthma worsening occurred earlier and more frequently in those treated with risankizumab versus placebo,” Dr. Brightling, professor in the department of respiratory sciences at University of Leicester, England, said in an interview. “This study does not support any further trials for anti-IL23 in asthma.” Dr. Brightling speculated on the cause of accelerated asthma worsening with risankizumab.

“We found that the gene expression of key molecules involved in our response to infection was decreased in airway samples in those treated with risankizumab versus placebo. It is possible that the increased asthma worsening following risankizumab was related to this suppression of antimicrobial immunity,” he said.

He noted that risankizumab did not affect type-2/eosinophilic inflammation, which is the target for current asthma biologics, or gene expression of T2 molecules. “That suggests that this type of inflammation would have continued in the asthma patients during the trial irrespective of receiving risankizumab or placebo,” he said.
 

Caution with investigating biologicals

Downstream biologic responses to risankizumab were detectable, Philip G. Bardin, PhD, and Paul S. Foster, DSc, observed in an accompanying editorial, but there was no discernible clinical benefit, implying attenuation of apposite pathways. Current understanding of the basic science relevant to asthma, they stated, offers clues to the failure of risankizumab to benefit these patients with severe asthma. Although targeting the interleukin-23 and Th17 axis with risankizumab can reduce development of pathogenic Th17 cells, interleukin-23 is not critical for the development of Th17 cells.

“In contrast to pathways operated by interleukin-5 and interleukin-4R alpha, interleukin-23 has only a limited auxiliary role in amplifying type 2 responses. It is possible that the trial conducted by Brightling and colleagues failed because signaling through alternative disease pathways nullified inhibition of inter-leukin-23,” the editorialists wrote.

Dr. Bardin and Dr. Foster further speculate that because interleukin-23 is vital for effective mucosal immunity, risankizumab may have conferred to patients a predisposition to more severe or more frequent virus-induced exacerbations. They stated that generally, however, the reasons for risankizumab’s poorer outcomes compared to placebo are unclear. “Overall, these findings support a cautious approach in future research investigating biologic therapies in asthma,” they concluded.

The clinical trial was sponsored and funded by BI/AbbVie.

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