Liver transplant recipients with nonalcoholic steatohepatitis (NASH) who received grafts from older donors are at higher risk for posttransplant death, especially from infection, according to a new study.

All-cause mortality was twice as high and death from an infectious cause was more than three times as high for patients with NASH who received liver grafts from octogenarian donors than for those who received a liver from someone younger than 50.

“The findings from this study implicate a critical need to investigate donor age as an important risk factor for poorer host and graft survival,” wrote the authors, led by David Lee, MD, of the University of Maryland, Baltimore.

“Given the possibility of infectious graft complications, post–liver transplant follow-ups may need to be more comprehensive and frequent in these individuals who receive grafts from older donors,” they add.

The study was published online in Digestive and Liver Disease.
 

Donor age trends

Dr. Lee and colleagues pulled data from the United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research database, a national database of deidentified donor and recipient transplant data. The analysis excluded recipients younger than 18, those with a living donor, those who had hepatocellular carcinoma prior to transplant, and those who had been diagnosed with additional liver disorders apart from NASH.

The team identified 8,88 recipients with NASH who received a liver transplant from 2005–2019. They stratified recipients by donor age. The 5,187 patients who received livers from donors who were younger than 50 served as the reference group. The remainder were placed into four cohorts – 1,842 whose donors were in their 50s, 1,290 whose donors were in their 60s, 504 whose donors were in their 70s, and 65 whose donors were in their 80s.

The researchers found that in comparison with the reference group, the average age of recipients in each donor-age cohort was progressively older. Two donor-age cohorts had significantly higher proportions of recipients with diabetes than the 46.5% in the reference group – the sexagenarian cohort (51.7%) and the octogenarian group (66.2%).

The median follow-up time ranged from 2.35–3.61 years across all age groups.

The researchers found that for all donor-age groups excluding donors in their 60s, recipients had higher risk of all-cause mortality after transplant than the reference group. Recipients with donors in their 50s had a 16% greater risk for death (P = .01), and recipients with donors in their 70s had a 20% greater risk (P = .05). For recipients with octogenarian donors, the adjusted hazard ratio for all-cause mortality was 2.01 (P < .001).

Only recipients in the octogenarian donor cohort were at increased risk of graft failure, compared with the reference group (aHR, 3.72; P = .002).

As donor age increased, the recipient’s risk of dying from sepsis and infectious causes rose, compared with the reference group. Recipients’ likelihood of sepsis death increased by 71% (P = .001) with donors in their 50s, 73% (P = .003) with donors in their 60s, and 76% (P = .03) with donors in their 70s. For recipients with octogenarian donors, the risk more than tripled (aHR, 3.58; P = .007). Likewise, recipients with donors in their 70s were 73% more likely to die from infectious causes. That risk nearly quadrupled among those with donors in their 80s.
 

Recipient factors at play?

While the study found a relationship between liver donor age and recipient outcomes, it is not clear whether any other recipient factors may have contributed to the higher risk of all-cause mortality, sad Nancy Reau, MD, chief of the hepatology section at Rush University Medical Center, Chicago. The researchers did not parse out whether younger recipients did better with older organs than older recipients or whether older recipients fared worse with younger organs, she said in an interview.

“I wasn’t convinced that they had demonstrated that the recipient may not have played a role in that,” said Dr. Reau, who wasn’t involved with the study.

The analysis only a found an increased risk of graft failure among recipients who received organs from octogenarian donors, so factors other than liver transplant may have contributed to all-cause mortality, she noted.

The UNOS database has some limitations, noted Timothy Pruett, MD, who directs the liver transplant program at the University of Minnesota, Minneapolis. Because the database pulls information from transplantation centers across the country, it can be difficult to standardize specific patient variables in the data.

While it’s clear that a patient died, it’s less certain whether an infection was the cause of death and whether that infection was somehow associated with the liver, noted Dr. Pruett, who wasn’t involved in the research. For example, a patient could have had broken a hip, gone to the hospital, and contracted pneumonia, which led to their death.

“There’s just not much granularity in the database, and we can’t overextrapolate what we see,” Dr. Pruett said in an interview.
 

Knowledge gaps

Dr. Lee agreed that more research is needed to understand what may be driving higher mortality rates among patients who receive older organs. “There are still a lot of gaps in knowledge with respect to why.”

Dr. Reau said she is curious as to whether certain comorbidities, such as previous infection, diabetes, or obesity, could predict worse outcomes for recipients with older organs.

“We would love to give all of our patients younger organs, but if that leads to even more disparity in need [compared] to availability and the alternative is not surviving, I think you have to place [this work] into context,” she said.

The study findings shouldn’t be used to deter patients with NASH from considering older organs, Dr. Reau said. More insight as to which populations might want to be choosier owing to an elevated risk would be beneficial, she added.

Dr. Lee, Dr. Pruett, and Dr. Reau reported no relevant financial relationships.

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

Liver transplant recipients with nonalcoholic steatohepatitis (NASH) who received grafts from older donors are at higher risk for posttransplant death, especially from infection, according to a new study.

All-cause mortality was twice as high and death from an infectious cause was more than three times as high for patients with NASH who received liver grafts from octogenarian donors than for those who received a liver from someone younger than 50.

“The findings from this study implicate a critical need to investigate donor age as an important risk factor for poorer host and graft survival,” wrote the authors, led by David Lee, MD, of the University of Maryland, Baltimore.

“Given the possibility of infectious graft complications, post–liver transplant follow-ups may need to be more comprehensive and frequent in these individuals who receive grafts from older donors,” they add.

The study was published online in Digestive and Liver Disease.
 

Donor age trends

Dr. Lee and colleagues pulled data from the United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research database, a national database of deidentified donor and recipient transplant data. The analysis excluded recipients younger than 18, those with a living donor, those who had hepatocellular carcinoma prior to transplant, and those who had been diagnosed with additional liver disorders apart from NASH.

The team identified 8,88 recipients with NASH who received a liver transplant from 2005–2019. They stratified recipients by donor age. The 5,187 patients who received livers from donors who were younger than 50 served as the reference group. The remainder were placed into four cohorts – 1,842 whose donors were in their 50s, 1,290 whose donors were in their 60s, 504 whose donors were in their 70s, and 65 whose donors were in their 80s.

The researchers found that in comparison with the reference group, the average age of recipients in each donor-age cohort was progressively older. Two donor-age cohorts had significantly higher proportions of recipients with diabetes than the 46.5% in the reference group – the sexagenarian cohort (51.7%) and the octogenarian group (66.2%).

The median follow-up time ranged from 2.35–3.61 years across all age groups.

The researchers found that for all donor-age groups excluding donors in their 60s, recipients had higher risk of all-cause mortality after transplant than the reference group. Recipients with donors in their 50s had a 16% greater risk for death (P = .01), and recipients with donors in their 70s had a 20% greater risk (P = .05). For recipients with octogenarian donors, the adjusted hazard ratio for all-cause mortality was 2.01 (P < .001).

Only recipients in the octogenarian donor cohort were at increased risk of graft failure, compared with the reference group (aHR, 3.72; P = .002).

As donor age increased, the recipient’s risk of dying from sepsis and infectious causes rose, compared with the reference group. Recipients’ likelihood of sepsis death increased by 71% (P = .001) with donors in their 50s, 73% (P = .003) with donors in their 60s, and 76% (P = .03) with donors in their 70s. For recipients with octogenarian donors, the risk more than tripled (aHR, 3.58; P = .007). Likewise, recipients with donors in their 70s were 73% more likely to die from infectious causes. That risk nearly quadrupled among those with donors in their 80s.
 

Recipient factors at play?

While the study found a relationship between liver donor age and recipient outcomes, it is not clear whether any other recipient factors may have contributed to the higher risk of all-cause mortality, sad Nancy Reau, MD, chief of the hepatology section at Rush University Medical Center, Chicago. The researchers did not parse out whether younger recipients did better with older organs than older recipients or whether older recipients fared worse with younger organs, she said in an interview.

“I wasn’t convinced that they had demonstrated that the recipient may not have played a role in that,” said Dr. Reau, who wasn’t involved with the study.

The analysis only a found an increased risk of graft failure among recipients who received organs from octogenarian donors, so factors other than liver transplant may have contributed to all-cause mortality, she noted.

The UNOS database has some limitations, noted Timothy Pruett, MD, who directs the liver transplant program at the University of Minnesota, Minneapolis. Because the database pulls information from transplantation centers across the country, it can be difficult to standardize specific patient variables in the data.

While it’s clear that a patient died, it’s less certain whether an infection was the cause of death and whether that infection was somehow associated with the liver, noted Dr. Pruett, who wasn’t involved in the research. For example, a patient could have had broken a hip, gone to the hospital, and contracted pneumonia, which led to their death.

“There’s just not much granularity in the database, and we can’t overextrapolate what we see,” Dr. Pruett said in an interview.
 

Knowledge gaps

Dr. Lee agreed that more research is needed to understand what may be driving higher mortality rates among patients who receive older organs. “There are still a lot of gaps in knowledge with respect to why.”

Dr. Reau said she is curious as to whether certain comorbidities, such as previous infection, diabetes, or obesity, could predict worse outcomes for recipients with older organs.

“We would love to give all of our patients younger organs, but if that leads to even more disparity in need [compared] to availability and the alternative is not surviving, I think you have to place [this work] into context,” she said.

The study findings shouldn’t be used to deter patients with NASH from considering older organs, Dr. Reau said. More insight as to which populations might want to be choosier owing to an elevated risk would be beneficial, she added.

Dr. Lee, Dr. Pruett, and Dr. Reau reported no relevant financial relationships.

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

Liver transplant recipients with nonalcoholic steatohepatitis (NASH) who received grafts from older donors are at higher risk for posttransplant death, especially from infection, according to a new study.

All-cause mortality was twice as high and death from an infectious cause was more than three times as high for patients with NASH who received liver grafts from octogenarian donors than for those who received a liver from someone younger than 50.

“The findings from this study implicate a critical need to investigate donor age as an important risk factor for poorer host and graft survival,” wrote the authors, led by David Lee, MD, of the University of Maryland, Baltimore.

“Given the possibility of infectious graft complications, post–liver transplant follow-ups may need to be more comprehensive and frequent in these individuals who receive grafts from older donors,” they add.

The study was published online in Digestive and Liver Disease.
 

Donor age trends

Dr. Lee and colleagues pulled data from the United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research database, a national database of deidentified donor and recipient transplant data. The analysis excluded recipients younger than 18, those with a living donor, those who had hepatocellular carcinoma prior to transplant, and those who had been diagnosed with additional liver disorders apart from NASH.

The team identified 8,88 recipients with NASH who received a liver transplant from 2005–2019. They stratified recipients by donor age. The 5,187 patients who received livers from donors who were younger than 50 served as the reference group. The remainder were placed into four cohorts – 1,842 whose donors were in their 50s, 1,290 whose donors were in their 60s, 504 whose donors were in their 70s, and 65 whose donors were in their 80s.

The researchers found that in comparison with the reference group, the average age of recipients in each donor-age cohort was progressively older. Two donor-age cohorts had significantly higher proportions of recipients with diabetes than the 46.5% in the reference group – the sexagenarian cohort (51.7%) and the octogenarian group (66.2%).

The median follow-up time ranged from 2.35–3.61 years across all age groups.

The researchers found that for all donor-age groups excluding donors in their 60s, recipients had higher risk of all-cause mortality after transplant than the reference group. Recipients with donors in their 50s had a 16% greater risk for death (P = .01), and recipients with donors in their 70s had a 20% greater risk (P = .05). For recipients with octogenarian donors, the adjusted hazard ratio for all-cause mortality was 2.01 (P < .001).

Only recipients in the octogenarian donor cohort were at increased risk of graft failure, compared with the reference group (aHR, 3.72; P = .002).

As donor age increased, the recipient’s risk of dying from sepsis and infectious causes rose, compared with the reference group. Recipients’ likelihood of sepsis death increased by 71% (P = .001) with donors in their 50s, 73% (P = .003) with donors in their 60s, and 76% (P = .03) with donors in their 70s. For recipients with octogenarian donors, the risk more than tripled (aHR, 3.58; P = .007). Likewise, recipients with donors in their 70s were 73% more likely to die from infectious causes. That risk nearly quadrupled among those with donors in their 80s.
 

Recipient factors at play?

While the study found a relationship between liver donor age and recipient outcomes, it is not clear whether any other recipient factors may have contributed to the higher risk of all-cause mortality, sad Nancy Reau, MD, chief of the hepatology section at Rush University Medical Center, Chicago. The researchers did not parse out whether younger recipients did better with older organs than older recipients or whether older recipients fared worse with younger organs, she said in an interview.

“I wasn’t convinced that they had demonstrated that the recipient may not have played a role in that,” said Dr. Reau, who wasn’t involved with the study.

The analysis only a found an increased risk of graft failure among recipients who received organs from octogenarian donors, so factors other than liver transplant may have contributed to all-cause mortality, she noted.

The UNOS database has some limitations, noted Timothy Pruett, MD, who directs the liver transplant program at the University of Minnesota, Minneapolis. Because the database pulls information from transplantation centers across the country, it can be difficult to standardize specific patient variables in the data.

While it’s clear that a patient died, it’s less certain whether an infection was the cause of death and whether that infection was somehow associated with the liver, noted Dr. Pruett, who wasn’t involved in the research. For example, a patient could have had broken a hip, gone to the hospital, and contracted pneumonia, which led to their death.

“There’s just not much granularity in the database, and we can’t overextrapolate what we see,” Dr. Pruett said in an interview.
 

Knowledge gaps

Dr. Lee agreed that more research is needed to understand what may be driving higher mortality rates among patients who receive older organs. “There are still a lot of gaps in knowledge with respect to why.”

Dr. Reau said she is curious as to whether certain comorbidities, such as previous infection, diabetes, or obesity, could predict worse outcomes for recipients with older organs.

“We would love to give all of our patients younger organs, but if that leads to even more disparity in need [compared] to availability and the alternative is not surviving, I think you have to place [this work] into context,” she said.

The study findings shouldn’t be used to deter patients with NASH from considering older organs, Dr. Reau said. More insight as to which populations might want to be choosier owing to an elevated risk would be beneficial, she added.

Dr. Lee, Dr. Pruett, and Dr. Reau reported no relevant financial relationships.

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

Prescribing a biologic for people with Crohn’s disease is a complicated process that includes consideration of previous therapy, the severity of disease, cost, and other factors. Missing, however, has been the ability to accurately predict endoscopic response to a specific biologic agent to guide choice of therapy.

New peripheral blood biomarkers based on DNA methylation could soon help predict endoscopic response to adalimumab, vedolizumab, and ustekinumab for people with Crohn’s disease.

Although the biomarker panels are not yet clinically available, researchers demonstrated that they are accurate, valid, stable over time, and largely specific to each of the three biologic agents.

“Evidence over the last 10 years has shown a consistent difference in DNA methylation between people with IBD [inflammatory bowel disease] and healthy controls. Many of these studies suggest a role for DNA methylation for treatment response prediction,” Vincent Joustra, PhD, said when presenting results of the EPIC-CD trial at the annual congress of the European Crohn’s and Colitis Organisation.

After comparing endoscopic responders to nonresponders in different datasets. researchers found that “DNA methylation profiles are, in fact, associated with response to adalimumab, vedolizumab, and ustekinumab,” added Dr. Joustra, visiting fellow in the department of gastroenterology and hepatology at Amsterdam University Medical Centers.

DNA methylation – the presence or absence of a methyl group on a specific DNA location called a CpG – does not change a person’s genotype. Rather, the methylation process either activates or deactivates a gene’s expression. It can be used to predict treatment response.

Within the past 2 decades, “biologics have revolutionized care of IBD patients. Yet, despite their clinical efficacy, treatment choice is currently based on trial and error, which is suboptimal,” Dr. Joustra said.

Adding biomarkers to improve biologic medication selection is “urgently needed,” he added. “However, such biomarkers are not available for practice today.”
 

Methylation methodology

Dr. Joustra and colleagues prospectively studied DNA methylation in the peripheral blood samples of 184 adults with Crohn’s disease. They compared the biomarkers at baseline in people set to start biologic therapy and again at a median of 28 weeks following treatment with adalimumab (58 patients), vedolizumab (64 patients), and ustekinumab (62 patients).

Participants were divided into a discovery cohort to identify relevant biomarkers and a validation cohort to confirm the findings. Results were validated against a separate cohort of patients at Oxford (England) University.

Response was strictly defined as a decrease of at least 50% in a simple endoscopic score for Crohn’s disease, corticosteroid-free clinical response or remission using the Harvey Bradshaw Index, and/or biochemical response or remission.

Before patients were treated, the investigators created three epigenetic panels. The CpG loci of interest were identified using the Infinium MethylationEPIC BeadChip array, which measures over 850,000 CpG sites across the whole genome.
 

Key findings

One epigenetic panel featured 100 CpG loci relevant for adalimumab that correlated to an “endoscopic response with high accuracy,” with an area under the curve of 0.73 upon validation. A second panel, created for vedolizumab, included 22 CpG loci and had an AUC accuracy of 0.89. The third panel, specific to ustekinumab, had 68 CpG loci and an AUC accuracy of 0.94.

The markers are largely unique to each agent. Only two CpG loci overlapped between adalimumab and ustekinumab, Dr. Joustra said.

“Importantly, our model was able to predict response prior to treatment in a completely different set of patients from the Oxford validation cohort with an AUC of 0.75,” Dr. Joustra said.

A secondary analysis revealed no differences in the stability and robustness of the methylation markers between baseline and 28 weeks. This finding implies that the biomarkers are stable during the induction and maintenance phases of treatment.

“Of course, we need to clinically validate our findings in a clinical trial, which is ongoing,” Dr. Joustra said. This work will continue in the EPIC-CD study, as well as in the OMICROHN clinical trial.
 

Promising start

“These are really interesting findings that address an area of importance in treating patients with Crohn’s disease,” said ECCO session comoderator Tim Raine, PhD, who was not affiliated with the research.

“The team found a signature that appears to provide helpful prediction of response to specific treatments. Importantly, this signature appeared to be stable over time, to be specific to individual drugs, and could be validated in an external cohort of patients,” added Dr. Raine, consultant gastroenterologist at Cambridge (England) University Hospitals NHS Trust.

Although the technologies used in EPIC-CD are not yet routinely available in clinical practice, “the methodologies are well established, and with appropriate development in a validated laboratory, as well as further validation work, could form a useful test for gastroenterologists treating patients with Crohn’s disease,” Dr. Raine said.

The study was independently supported. Dr. Joustra and Dr. Raine reported no relevant financial relationships.

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

Prescribing a biologic for people with Crohn’s disease is a complicated process that includes consideration of previous therapy, the severity of disease, cost, and other factors. Missing, however, has been the ability to accurately predict endoscopic response to a specific biologic agent to guide choice of therapy.

New peripheral blood biomarkers based on DNA methylation could soon help predict endoscopic response to adalimumab, vedolizumab, and ustekinumab for people with Crohn’s disease.

Although the biomarker panels are not yet clinically available, researchers demonstrated that they are accurate, valid, stable over time, and largely specific to each of the three biologic agents.

“Evidence over the last 10 years has shown a consistent difference in DNA methylation between people with IBD [inflammatory bowel disease] and healthy controls. Many of these studies suggest a role for DNA methylation for treatment response prediction,” Vincent Joustra, PhD, said when presenting results of the EPIC-CD trial at the annual congress of the European Crohn’s and Colitis Organisation.

After comparing endoscopic responders to nonresponders in different datasets. researchers found that “DNA methylation profiles are, in fact, associated with response to adalimumab, vedolizumab, and ustekinumab,” added Dr. Joustra, visiting fellow in the department of gastroenterology and hepatology at Amsterdam University Medical Centers.

DNA methylation – the presence or absence of a methyl group on a specific DNA location called a CpG – does not change a person’s genotype. Rather, the methylation process either activates or deactivates a gene’s expression. It can be used to predict treatment response.

Within the past 2 decades, “biologics have revolutionized care of IBD patients. Yet, despite their clinical efficacy, treatment choice is currently based on trial and error, which is suboptimal,” Dr. Joustra said.

Adding biomarkers to improve biologic medication selection is “urgently needed,” he added. “However, such biomarkers are not available for practice today.”
 

Methylation methodology

Dr. Joustra and colleagues prospectively studied DNA methylation in the peripheral blood samples of 184 adults with Crohn’s disease. They compared the biomarkers at baseline in people set to start biologic therapy and again at a median of 28 weeks following treatment with adalimumab (58 patients), vedolizumab (64 patients), and ustekinumab (62 patients).

Participants were divided into a discovery cohort to identify relevant biomarkers and a validation cohort to confirm the findings. Results were validated against a separate cohort of patients at Oxford (England) University.

Response was strictly defined as a decrease of at least 50% in a simple endoscopic score for Crohn’s disease, corticosteroid-free clinical response or remission using the Harvey Bradshaw Index, and/or biochemical response or remission.

Before patients were treated, the investigators created three epigenetic panels. The CpG loci of interest were identified using the Infinium MethylationEPIC BeadChip array, which measures over 850,000 CpG sites across the whole genome.
 

Key findings

One epigenetic panel featured 100 CpG loci relevant for adalimumab that correlated to an “endoscopic response with high accuracy,” with an area under the curve of 0.73 upon validation. A second panel, created for vedolizumab, included 22 CpG loci and had an AUC accuracy of 0.89. The third panel, specific to ustekinumab, had 68 CpG loci and an AUC accuracy of 0.94.

The markers are largely unique to each agent. Only two CpG loci overlapped between adalimumab and ustekinumab, Dr. Joustra said.

“Importantly, our model was able to predict response prior to treatment in a completely different set of patients from the Oxford validation cohort with an AUC of 0.75,” Dr. Joustra said.

A secondary analysis revealed no differences in the stability and robustness of the methylation markers between baseline and 28 weeks. This finding implies that the biomarkers are stable during the induction and maintenance phases of treatment.

“Of course, we need to clinically validate our findings in a clinical trial, which is ongoing,” Dr. Joustra said. This work will continue in the EPIC-CD study, as well as in the OMICROHN clinical trial.
 

Promising start

“These are really interesting findings that address an area of importance in treating patients with Crohn’s disease,” said ECCO session comoderator Tim Raine, PhD, who was not affiliated with the research.

“The team found a signature that appears to provide helpful prediction of response to specific treatments. Importantly, this signature appeared to be stable over time, to be specific to individual drugs, and could be validated in an external cohort of patients,” added Dr. Raine, consultant gastroenterologist at Cambridge (England) University Hospitals NHS Trust.

Although the technologies used in EPIC-CD are not yet routinely available in clinical practice, “the methodologies are well established, and with appropriate development in a validated laboratory, as well as further validation work, could form a useful test for gastroenterologists treating patients with Crohn’s disease,” Dr. Raine said.

The study was independently supported. Dr. Joustra and Dr. Raine reported no relevant financial relationships.

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

Prescribing a biologic for people with Crohn’s disease is a complicated process that includes consideration of previous therapy, the severity of disease, cost, and other factors. Missing, however, has been the ability to accurately predict endoscopic response to a specific biologic agent to guide choice of therapy.

New peripheral blood biomarkers based on DNA methylation could soon help predict endoscopic response to adalimumab, vedolizumab, and ustekinumab for people with Crohn’s disease.

Although the biomarker panels are not yet clinically available, researchers demonstrated that they are accurate, valid, stable over time, and largely specific to each of the three biologic agents.

“Evidence over the last 10 years has shown a consistent difference in DNA methylation between people with IBD [inflammatory bowel disease] and healthy controls. Many of these studies suggest a role for DNA methylation for treatment response prediction,” Vincent Joustra, PhD, said when presenting results of the EPIC-CD trial at the annual congress of the European Crohn’s and Colitis Organisation.

After comparing endoscopic responders to nonresponders in different datasets. researchers found that “DNA methylation profiles are, in fact, associated with response to adalimumab, vedolizumab, and ustekinumab,” added Dr. Joustra, visiting fellow in the department of gastroenterology and hepatology at Amsterdam University Medical Centers.

DNA methylation – the presence or absence of a methyl group on a specific DNA location called a CpG – does not change a person’s genotype. Rather, the methylation process either activates or deactivates a gene’s expression. It can be used to predict treatment response.

Within the past 2 decades, “biologics have revolutionized care of IBD patients. Yet, despite their clinical efficacy, treatment choice is currently based on trial and error, which is suboptimal,” Dr. Joustra said.

Adding biomarkers to improve biologic medication selection is “urgently needed,” he added. “However, such biomarkers are not available for practice today.”
 

Methylation methodology

Dr. Joustra and colleagues prospectively studied DNA methylation in the peripheral blood samples of 184 adults with Crohn’s disease. They compared the biomarkers at baseline in people set to start biologic therapy and again at a median of 28 weeks following treatment with adalimumab (58 patients), vedolizumab (64 patients), and ustekinumab (62 patients).

Participants were divided into a discovery cohort to identify relevant biomarkers and a validation cohort to confirm the findings. Results were validated against a separate cohort of patients at Oxford (England) University.

Response was strictly defined as a decrease of at least 50% in a simple endoscopic score for Crohn’s disease, corticosteroid-free clinical response or remission using the Harvey Bradshaw Index, and/or biochemical response or remission.

Before patients were treated, the investigators created three epigenetic panels. The CpG loci of interest were identified using the Infinium MethylationEPIC BeadChip array, which measures over 850,000 CpG sites across the whole genome.
 

Key findings

One epigenetic panel featured 100 CpG loci relevant for adalimumab that correlated to an “endoscopic response with high accuracy,” with an area under the curve of 0.73 upon validation. A second panel, created for vedolizumab, included 22 CpG loci and had an AUC accuracy of 0.89. The third panel, specific to ustekinumab, had 68 CpG loci and an AUC accuracy of 0.94.

The markers are largely unique to each agent. Only two CpG loci overlapped between adalimumab and ustekinumab, Dr. Joustra said.

“Importantly, our model was able to predict response prior to treatment in a completely different set of patients from the Oxford validation cohort with an AUC of 0.75,” Dr. Joustra said.

A secondary analysis revealed no differences in the stability and robustness of the methylation markers between baseline and 28 weeks. This finding implies that the biomarkers are stable during the induction and maintenance phases of treatment.

“Of course, we need to clinically validate our findings in a clinical trial, which is ongoing,” Dr. Joustra said. This work will continue in the EPIC-CD study, as well as in the OMICROHN clinical trial.
 

Promising start

“These are really interesting findings that address an area of importance in treating patients with Crohn’s disease,” said ECCO session comoderator Tim Raine, PhD, who was not affiliated with the research.

“The team found a signature that appears to provide helpful prediction of response to specific treatments. Importantly, this signature appeared to be stable over time, to be specific to individual drugs, and could be validated in an external cohort of patients,” added Dr. Raine, consultant gastroenterologist at Cambridge (England) University Hospitals NHS Trust.

Although the technologies used in EPIC-CD are not yet routinely available in clinical practice, “the methodologies are well established, and with appropriate development in a validated laboratory, as well as further validation work, could form a useful test for gastroenterologists treating patients with Crohn’s disease,” Dr. Raine said.

The study was independently supported. Dr. Joustra and Dr. Raine reported no relevant financial relationships.

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

When the Food and Drug Administration first approved the da Vinci Surgical System (Intuitive Surgical, Sunnyvale, Calif.) for adult use in 2000, it altered the face of minimally invasive surgery across a multitude of specialties. Improved three-dimensional visualization and enhanced instrument articulation facilitates complex dissections and intracorporeal suturing. While the standard of care for gender-affirming vaginoplasty remains the single-stage penile inversion vaginoplasty, robotic procedures are quickly emerging as alternative options for both primary and revisional surgeries.

The single-stage penile inversion vaginoplasty requires an adequate amount of penoscrotal tissue not only to line a neovaginal canal that measures 12-15 cm, but also to create external vulvar structures. While this is often sufficient in most candidates, there is an increasing number of patients who are receiving puberty blockers, resulting in penoscrotal hypoplasia.

Alternatively, there are patients who experience loss of vaginal depth and vaginal stenosis who seek revisional surgeries. Additional donor sites for skin grafting are available and include the lower abdomen and thighs, although patients may not want these donor site scars. With these donor sites, there is also concern about graft contracture, which could lead to recurrent vaginal stenosis.¹ Robotic peritoneal vaginoplasty and robotic enteric vaginoplasty can serve as additional options for patients seeking revisional surgery or who have insufficient genital skin. One benefit of using peritoneal flaps is that they are hairless and are well vascularized with minimal donor site morbidity.¹ Currently, there are two predominant techniques that utilize peritoneal flaps: the modified Davydov procedure and the tubularized urachus-peritoneal hinge flap.

The modified Davydov technique, which originated in the treatment of congenital vaginal agenesis in cisgender women, involves the creation of anterior and posterior peritoneal flaps. This type of peritoneal vaginoplasty is more commonly utilized for primary cases.

Ideally, there is a robotic surgeon (typically a urologist) working in tandem with the perineal surgeon. The robotic surgeon makes a horizontal incision along the peritoneal ridge at the rectovesical junction and continues the dissection within Denonvilliers fascia, between the prostate and rectum, to the pelvic floor. This dissection is like that performed in a robot-assisted laparoscopic prostatectomy.

Simultaneously, the perineal surgeon will break through the pelvic floor with assistance of the robotic view. Peritoneal flaps are raised from the anterior rectum and posterior bladder.^2,3 In primary cases, the penoscrotal flap is introduced into the abdomen from the perineum and sutured to the anterior and posterior peritoneum to create a circumferential canal. At the apex of the neovagina, these anterior and posterior flaps are then sutured together.^2,3

The tubularized urachus-peritoneal hinge flap technique is predominantly used for revision cases in patients who experienced neovaginal shortening and desire increased neovaginal depth. As peritoneal reach is limited, candidates for this procedure must have both adequate width and neovaginal canal depth.⁴ Once intra-abdominal access is achieved, an anterior peritoneal flap is mobilized to the level of the bladder and rotated 180 degrees inferiorly.⁴ The superior aspect of the flap is flipped is mobilized and is sutured to the peritoneum at the apex of the neovaginal canal.

The main benefit of these procedures, compared with traditional techniques, is increased neovaginal depth. The average vaginal length in patients undergoing peritoneal vaginoplasties is 14.2 cm, compared with 11.6 cm achieved in those using skin grafts.^1,3 However, many surgeons report achieving 14-15 cm of depth with the traditional vaginoplasty. There are insufficient short- and long-term data for the peritoneal technique to recommend this as a first-line procedure.

Complications for peritoneal vaginoplasty procedures are similar to those of single-stage penile inversion vaginoplasty cases but with additional operative risks associated with laparoscopic/robotic surgery. These risks include injury to viscera and major vessels during initial intra-abdominal access, intra-abdominal adhesions, port site hernias, need to convert to an open procedure, and equipment malfunction.² Additional postoperative risks include pelvic abscess formation, dehiscence of the peritoneal-vaginal incision, and peritoneal perforation during dilation.^2,3 Surgeons and institutions must also weigh the cost of using the robot versus the cost of additional revisional surgical procedures. While initial studies evaluating robotic peritoneal vaginoplasty procedures have yielded promising preliminary results, additional studies are warranted.

Dr. Brandt is an ob.gyn. and fellowship-trained gender-affirming surgeon in West Reading, Pa.

References

1. Salibian AA et al. Plast Reconstr Surg. 2021;147(4):634e-43e.

2. Dy GW et al. In: Nikolavsky D and Blakely SA, eds. Urological care for the transgender patient: A comprehensive guide. Switzerland: Springer, 2021:237-48.

3. Jacoby A et al. J Urol. 2019;201(6):1171-5.

4. Smith SM et al. J Sex Med. 2022;10(6):100572.

When the Food and Drug Administration first approved the da Vinci Surgical System (Intuitive Surgical, Sunnyvale, Calif.) for adult use in 2000, it altered the face of minimally invasive surgery across a multitude of specialties. Improved three-dimensional visualization and enhanced instrument articulation facilitates complex dissections and intracorporeal suturing. While the standard of care for gender-affirming vaginoplasty remains the single-stage penile inversion vaginoplasty, robotic procedures are quickly emerging as alternative options for both primary and revisional surgeries.

The single-stage penile inversion vaginoplasty requires an adequate amount of penoscrotal tissue not only to line a neovaginal canal that measures 12-15 cm, but also to create external vulvar structures. While this is often sufficient in most candidates, there is an increasing number of patients who are receiving puberty blockers, resulting in penoscrotal hypoplasia.

Alternatively, there are patients who experience loss of vaginal depth and vaginal stenosis who seek revisional surgeries. Additional donor sites for skin grafting are available and include the lower abdomen and thighs, although patients may not want these donor site scars. With these donor sites, there is also concern about graft contracture, which could lead to recurrent vaginal stenosis.¹ Robotic peritoneal vaginoplasty and robotic enteric vaginoplasty can serve as additional options for patients seeking revisional surgery or who have insufficient genital skin. One benefit of using peritoneal flaps is that they are hairless and are well vascularized with minimal donor site morbidity.¹ Currently, there are two predominant techniques that utilize peritoneal flaps: the modified Davydov procedure and the tubularized urachus-peritoneal hinge flap.

The modified Davydov technique, which originated in the treatment of congenital vaginal agenesis in cisgender women, involves the creation of anterior and posterior peritoneal flaps. This type of peritoneal vaginoplasty is more commonly utilized for primary cases.

Ideally, there is a robotic surgeon (typically a urologist) working in tandem with the perineal surgeon. The robotic surgeon makes a horizontal incision along the peritoneal ridge at the rectovesical junction and continues the dissection within Denonvilliers fascia, between the prostate and rectum, to the pelvic floor. This dissection is like that performed in a robot-assisted laparoscopic prostatectomy.

Simultaneously, the perineal surgeon will break through the pelvic floor with assistance of the robotic view. Peritoneal flaps are raised from the anterior rectum and posterior bladder.^2,3 In primary cases, the penoscrotal flap is introduced into the abdomen from the perineum and sutured to the anterior and posterior peritoneum to create a circumferential canal. At the apex of the neovagina, these anterior and posterior flaps are then sutured together.^2,3

The tubularized urachus-peritoneal hinge flap technique is predominantly used for revision cases in patients who experienced neovaginal shortening and desire increased neovaginal depth. As peritoneal reach is limited, candidates for this procedure must have both adequate width and neovaginal canal depth.⁴ Once intra-abdominal access is achieved, an anterior peritoneal flap is mobilized to the level of the bladder and rotated 180 degrees inferiorly.⁴ The superior aspect of the flap is flipped is mobilized and is sutured to the peritoneum at the apex of the neovaginal canal.

The main benefit of these procedures, compared with traditional techniques, is increased neovaginal depth. The average vaginal length in patients undergoing peritoneal vaginoplasties is 14.2 cm, compared with 11.6 cm achieved in those using skin grafts.^1,3 However, many surgeons report achieving 14-15 cm of depth with the traditional vaginoplasty. There are insufficient short- and long-term data for the peritoneal technique to recommend this as a first-line procedure.

Complications for peritoneal vaginoplasty procedures are similar to those of single-stage penile inversion vaginoplasty cases but with additional operative risks associated with laparoscopic/robotic surgery. These risks include injury to viscera and major vessels during initial intra-abdominal access, intra-abdominal adhesions, port site hernias, need to convert to an open procedure, and equipment malfunction.² Additional postoperative risks include pelvic abscess formation, dehiscence of the peritoneal-vaginal incision, and peritoneal perforation during dilation.^2,3 Surgeons and institutions must also weigh the cost of using the robot versus the cost of additional revisional surgical procedures. While initial studies evaluating robotic peritoneal vaginoplasty procedures have yielded promising preliminary results, additional studies are warranted.

Dr. Brandt is an ob.gyn. and fellowship-trained gender-affirming surgeon in West Reading, Pa.

References

1. Salibian AA et al. Plast Reconstr Surg. 2021;147(4):634e-43e.

2. Dy GW et al. In: Nikolavsky D and Blakely SA, eds. Urological care for the transgender patient: A comprehensive guide. Switzerland: Springer, 2021:237-48.

3. Jacoby A et al. J Urol. 2019;201(6):1171-5.

4. Smith SM et al. J Sex Med. 2022;10(6):100572.

When the Food and Drug Administration first approved the da Vinci Surgical System (Intuitive Surgical, Sunnyvale, Calif.) for adult use in 2000, it altered the face of minimally invasive surgery across a multitude of specialties. Improved three-dimensional visualization and enhanced instrument articulation facilitates complex dissections and intracorporeal suturing. While the standard of care for gender-affirming vaginoplasty remains the single-stage penile inversion vaginoplasty, robotic procedures are quickly emerging as alternative options for both primary and revisional surgeries.

The single-stage penile inversion vaginoplasty requires an adequate amount of penoscrotal tissue not only to line a neovaginal canal that measures 12-15 cm, but also to create external vulvar structures. While this is often sufficient in most candidates, there is an increasing number of patients who are receiving puberty blockers, resulting in penoscrotal hypoplasia.

Alternatively, there are patients who experience loss of vaginal depth and vaginal stenosis who seek revisional surgeries. Additional donor sites for skin grafting are available and include the lower abdomen and thighs, although patients may not want these donor site scars. With these donor sites, there is also concern about graft contracture, which could lead to recurrent vaginal stenosis.¹ Robotic peritoneal vaginoplasty and robotic enteric vaginoplasty can serve as additional options for patients seeking revisional surgery or who have insufficient genital skin. One benefit of using peritoneal flaps is that they are hairless and are well vascularized with minimal donor site morbidity.¹ Currently, there are two predominant techniques that utilize peritoneal flaps: the modified Davydov procedure and the tubularized urachus-peritoneal hinge flap.

The modified Davydov technique, which originated in the treatment of congenital vaginal agenesis in cisgender women, involves the creation of anterior and posterior peritoneal flaps. This type of peritoneal vaginoplasty is more commonly utilized for primary cases.

Ideally, there is a robotic surgeon (typically a urologist) working in tandem with the perineal surgeon. The robotic surgeon makes a horizontal incision along the peritoneal ridge at the rectovesical junction and continues the dissection within Denonvilliers fascia, between the prostate and rectum, to the pelvic floor. This dissection is like that performed in a robot-assisted laparoscopic prostatectomy.

Simultaneously, the perineal surgeon will break through the pelvic floor with assistance of the robotic view. Peritoneal flaps are raised from the anterior rectum and posterior bladder.^2,3 In primary cases, the penoscrotal flap is introduced into the abdomen from the perineum and sutured to the anterior and posterior peritoneum to create a circumferential canal. At the apex of the neovagina, these anterior and posterior flaps are then sutured together.^2,3

The tubularized urachus-peritoneal hinge flap technique is predominantly used for revision cases in patients who experienced neovaginal shortening and desire increased neovaginal depth. As peritoneal reach is limited, candidates for this procedure must have both adequate width and neovaginal canal depth.⁴ Once intra-abdominal access is achieved, an anterior peritoneal flap is mobilized to the level of the bladder and rotated 180 degrees inferiorly.⁴ The superior aspect of the flap is flipped is mobilized and is sutured to the peritoneum at the apex of the neovaginal canal.

The main benefit of these procedures, compared with traditional techniques, is increased neovaginal depth. The average vaginal length in patients undergoing peritoneal vaginoplasties is 14.2 cm, compared with 11.6 cm achieved in those using skin grafts.^1,3 However, many surgeons report achieving 14-15 cm of depth with the traditional vaginoplasty. There are insufficient short- and long-term data for the peritoneal technique to recommend this as a first-line procedure.

Complications for peritoneal vaginoplasty procedures are similar to those of single-stage penile inversion vaginoplasty cases but with additional operative risks associated with laparoscopic/robotic surgery. These risks include injury to viscera and major vessels during initial intra-abdominal access, intra-abdominal adhesions, port site hernias, need to convert to an open procedure, and equipment malfunction.² Additional postoperative risks include pelvic abscess formation, dehiscence of the peritoneal-vaginal incision, and peritoneal perforation during dilation.^2,3 Surgeons and institutions must also weigh the cost of using the robot versus the cost of additional revisional surgical procedures. While initial studies evaluating robotic peritoneal vaginoplasty procedures have yielded promising preliminary results, additional studies are warranted.

Dr. Brandt is an ob.gyn. and fellowship-trained gender-affirming surgeon in West Reading, Pa.

References

1. Salibian AA et al. Plast Reconstr Surg. 2021;147(4):634e-43e.

2. Dy GW et al. In: Nikolavsky D and Blakely SA, eds. Urological care for the transgender patient: A comprehensive guide. Switzerland: Springer, 2021:237-48.

3. Jacoby A et al. J Urol. 2019;201(6):1171-5.

4. Smith SM et al. J Sex Med. 2022;10(6):100572.

A combination of gradual aerobic exercise and breathing practice can help ease persistent postconcussive symptoms, preliminary findings from a new study suggest.

Heart rate variability biofeedback (HRVB) and progressive aerobic exercise (PAE) were each helpful on their own, but combining them led to even greater improvement in cognition, depression, and mood.

“Managing persistent concussion symptoms is particularly challenging as there are no standard therapies,” study investigator R. Davis Moore, PhD, from the University of South Carolina, Columbia, said in a news release.

“These therapies are inexpensive, easy to implement, and can be self-administered, making them feasible and accessible for everyone with persistent symptoms,” Dr. Moore noted.

The study was released early, ahead of its scheduled presentation in Boston at the annual meeting of the American Academy of Neurology.
 

Targeting autonomic dysfunction

Concussion can affect the autonomic nervous system, and it is “increasingly clear that this underlies the inability to tolerate exercise, problems with thinking skills, and mood issues in those with persisting symptoms,” Dr. Moore explained.

Preliminary research suggests that HRVB and PAE can improve cardio-autonomic dysfunction and clinical symptoms. However, until now, no study has evaluated whether there is additional benefit from combining the two.

The investigators randomly assigned 30 teens with postconcussive symptoms that had lasted more than 1 month to a 6-week intervention consisting of either HRVB, PAE, or HRVB plus PAE.

The HRVB group practiced resonant-frequency breathing using a handheld biofeedback device for 20 minutes 4 nights a week. The PAE group completed a 3-day-a-week aerobic exercise protocol that gradually increased in intensity and duration. The HRVB plus PAE group did both. Concussion symptoms, HRV, cognition, and mood were assessed at baseline and again 6 weeks later.

All participants experienced improvement in sleep, mood, cognition, and autonomic function, but those who received the combined biofeedback and exercise intervention experienced greater improvements than peers who engaged in exercise or received biofeedback alone.

The study’s top-line results, which were released ahead of the presentation, show that HRVB plus PAE is associated with a twofold greater reduction in symptom severity, compared with PAE only, and a 1.3 times greater reduction in symptom severity, compared with HRVB only.

Similarly, HRVB plus PAE led to a 1.2 times greater reduction in symptoms of depression, compared with PAE only, and a 1.3 times greater reduction, compared with HRVB only.

The combined group also experienced more than 1.4 times the reduction in total mood disturbance than was provided by exercise or biofeedback alone.

The combined group also experienced significantly greater improvements in attention and working memory, as well as greater changes in metrics of HRV, than the groups that participated in exercise or biofeedback alone.

Dr. Moore and colleagues caution that the current results are preliminary and that future studies are needed with larger groups of people.

A limitation of the study was that it did not include a control group of people with persistent postconcussive symptoms who received no intervention.
 

Complex problem

Commenting on the findings, neuroscientist José Posas, MD, director of the Ochsner Neurology Residency Program, New Orleans, who wasn’t involved in the study, said these preliminary results are “promising” but cited the small number of participants as a limitation.

Dr. Posas said the results “fit with what’s known about the role of postconcussion autonomic dysfunction in persisting postconcussive symptoms.

“Managing persistent concussion symptoms can be challenging,” he added, and this study supports “exercise as medicine” as well as taking a “mind-body, holistic approach” to postconcussion recovery, said Dr. Posas.

Also weighing in, Michael F. Bergeron, PhD, clinical and scientific advisor, Department of Performance Health, Women’s Tennis Association, noted that “each of these therapeutic interventions has been around for some time now. Neither is new.

“Heart rate variability biofeedback based on variation in heart rate corresponding to breathing has been shown to be effective in treating numerous conditions, including reducing (nonclinical) stress, anxiety, depression, anger, and posttraumatic stress disorder in veterans and in some instances enhancing athletic performance. Of course, the validity and reliability of the commercially available apps and devices are potential significant limitations, as well as the stability of the user’s technique,” Dr. Bergeron said.

“It’s also been recognized that low-level aerobic exercise treatment normalizes the cerebrovascular physiological dysfunction in patients with concussion by increasing CO₂ sensitivity, which normalizes exercise ventilation and cerebral blood flow and thus reduces some symptoms,” Dr. Bergeron added.

“The combination of treatments is likely the novel aspect, which makes sense because brain injury is complex, and effective interventions need to utilize a complex, integrated biological systems approach across the multiple interdependent domains of influence,” Dr. Bergeron said.

The study was supported by the nonprofit Woodcock Institute at Texas Woman’s University. Dr. Moore, Dr. Bergeron, and Dr. Posas have disclosed no relevant financial relationships.

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

A combination of gradual aerobic exercise and breathing practice can help ease persistent postconcussive symptoms, preliminary findings from a new study suggest.

Heart rate variability biofeedback (HRVB) and progressive aerobic exercise (PAE) were each helpful on their own, but combining them led to even greater improvement in cognition, depression, and mood.

“Managing persistent concussion symptoms is particularly challenging as there are no standard therapies,” study investigator R. Davis Moore, PhD, from the University of South Carolina, Columbia, said in a news release.

“These therapies are inexpensive, easy to implement, and can be self-administered, making them feasible and accessible for everyone with persistent symptoms,” Dr. Moore noted.

The study was released early, ahead of its scheduled presentation in Boston at the annual meeting of the American Academy of Neurology.
 

Targeting autonomic dysfunction

Concussion can affect the autonomic nervous system, and it is “increasingly clear that this underlies the inability to tolerate exercise, problems with thinking skills, and mood issues in those with persisting symptoms,” Dr. Moore explained.

Preliminary research suggests that HRVB and PAE can improve cardio-autonomic dysfunction and clinical symptoms. However, until now, no study has evaluated whether there is additional benefit from combining the two.

The investigators randomly assigned 30 teens with postconcussive symptoms that had lasted more than 1 month to a 6-week intervention consisting of either HRVB, PAE, or HRVB plus PAE.

The HRVB group practiced resonant-frequency breathing using a handheld biofeedback device for 20 minutes 4 nights a week. The PAE group completed a 3-day-a-week aerobic exercise protocol that gradually increased in intensity and duration. The HRVB plus PAE group did both. Concussion symptoms, HRV, cognition, and mood were assessed at baseline and again 6 weeks later.

All participants experienced improvement in sleep, mood, cognition, and autonomic function, but those who received the combined biofeedback and exercise intervention experienced greater improvements than peers who engaged in exercise or received biofeedback alone.

The study’s top-line results, which were released ahead of the presentation, show that HRVB plus PAE is associated with a twofold greater reduction in symptom severity, compared with PAE only, and a 1.3 times greater reduction in symptom severity, compared with HRVB only.

Similarly, HRVB plus PAE led to a 1.2 times greater reduction in symptoms of depression, compared with PAE only, and a 1.3 times greater reduction, compared with HRVB only.

The combined group also experienced more than 1.4 times the reduction in total mood disturbance than was provided by exercise or biofeedback alone.

The combined group also experienced significantly greater improvements in attention and working memory, as well as greater changes in metrics of HRV, than the groups that participated in exercise or biofeedback alone.

Dr. Moore and colleagues caution that the current results are preliminary and that future studies are needed with larger groups of people.

A limitation of the study was that it did not include a control group of people with persistent postconcussive symptoms who received no intervention.
 

Complex problem

Commenting on the findings, neuroscientist José Posas, MD, director of the Ochsner Neurology Residency Program, New Orleans, who wasn’t involved in the study, said these preliminary results are “promising” but cited the small number of participants as a limitation.

Dr. Posas said the results “fit with what’s known about the role of postconcussion autonomic dysfunction in persisting postconcussive symptoms.

“Managing persistent concussion symptoms can be challenging,” he added, and this study supports “exercise as medicine” as well as taking a “mind-body, holistic approach” to postconcussion recovery, said Dr. Posas.

Also weighing in, Michael F. Bergeron, PhD, clinical and scientific advisor, Department of Performance Health, Women’s Tennis Association, noted that “each of these therapeutic interventions has been around for some time now. Neither is new.

“Heart rate variability biofeedback based on variation in heart rate corresponding to breathing has been shown to be effective in treating numerous conditions, including reducing (nonclinical) stress, anxiety, depression, anger, and posttraumatic stress disorder in veterans and in some instances enhancing athletic performance. Of course, the validity and reliability of the commercially available apps and devices are potential significant limitations, as well as the stability of the user’s technique,” Dr. Bergeron said.

“It’s also been recognized that low-level aerobic exercise treatment normalizes the cerebrovascular physiological dysfunction in patients with concussion by increasing CO₂ sensitivity, which normalizes exercise ventilation and cerebral blood flow and thus reduces some symptoms,” Dr. Bergeron added.

“The combination of treatments is likely the novel aspect, which makes sense because brain injury is complex, and effective interventions need to utilize a complex, integrated biological systems approach across the multiple interdependent domains of influence,” Dr. Bergeron said.

The study was supported by the nonprofit Woodcock Institute at Texas Woman’s University. Dr. Moore, Dr. Bergeron, and Dr. Posas have disclosed no relevant financial relationships.

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

A combination of gradual aerobic exercise and breathing practice can help ease persistent postconcussive symptoms, preliminary findings from a new study suggest.

Heart rate variability biofeedback (HRVB) and progressive aerobic exercise (PAE) were each helpful on their own, but combining them led to even greater improvement in cognition, depression, and mood.

“Managing persistent concussion symptoms is particularly challenging as there are no standard therapies,” study investigator R. Davis Moore, PhD, from the University of South Carolina, Columbia, said in a news release.

“These therapies are inexpensive, easy to implement, and can be self-administered, making them feasible and accessible for everyone with persistent symptoms,” Dr. Moore noted.

The study was released early, ahead of its scheduled presentation in Boston at the annual meeting of the American Academy of Neurology.
 

Targeting autonomic dysfunction

Concussion can affect the autonomic nervous system, and it is “increasingly clear that this underlies the inability to tolerate exercise, problems with thinking skills, and mood issues in those with persisting symptoms,” Dr. Moore explained.

Preliminary research suggests that HRVB and PAE can improve cardio-autonomic dysfunction and clinical symptoms. However, until now, no study has evaluated whether there is additional benefit from combining the two.

The investigators randomly assigned 30 teens with postconcussive symptoms that had lasted more than 1 month to a 6-week intervention consisting of either HRVB, PAE, or HRVB plus PAE.

The HRVB group practiced resonant-frequency breathing using a handheld biofeedback device for 20 minutes 4 nights a week. The PAE group completed a 3-day-a-week aerobic exercise protocol that gradually increased in intensity and duration. The HRVB plus PAE group did both. Concussion symptoms, HRV, cognition, and mood were assessed at baseline and again 6 weeks later.

All participants experienced improvement in sleep, mood, cognition, and autonomic function, but those who received the combined biofeedback and exercise intervention experienced greater improvements than peers who engaged in exercise or received biofeedback alone.

The study’s top-line results, which were released ahead of the presentation, show that HRVB plus PAE is associated with a twofold greater reduction in symptom severity, compared with PAE only, and a 1.3 times greater reduction in symptom severity, compared with HRVB only.

Similarly, HRVB plus PAE led to a 1.2 times greater reduction in symptoms of depression, compared with PAE only, and a 1.3 times greater reduction, compared with HRVB only.

The combined group also experienced more than 1.4 times the reduction in total mood disturbance than was provided by exercise or biofeedback alone.

The combined group also experienced significantly greater improvements in attention and working memory, as well as greater changes in metrics of HRV, than the groups that participated in exercise or biofeedback alone.

Dr. Moore and colleagues caution that the current results are preliminary and that future studies are needed with larger groups of people.

A limitation of the study was that it did not include a control group of people with persistent postconcussive symptoms who received no intervention.
 

Complex problem

Commenting on the findings, neuroscientist José Posas, MD, director of the Ochsner Neurology Residency Program, New Orleans, who wasn’t involved in the study, said these preliminary results are “promising” but cited the small number of participants as a limitation.

Dr. Posas said the results “fit with what’s known about the role of postconcussion autonomic dysfunction in persisting postconcussive symptoms.

“Managing persistent concussion symptoms can be challenging,” he added, and this study supports “exercise as medicine” as well as taking a “mind-body, holistic approach” to postconcussion recovery, said Dr. Posas.

Also weighing in, Michael F. Bergeron, PhD, clinical and scientific advisor, Department of Performance Health, Women’s Tennis Association, noted that “each of these therapeutic interventions has been around for some time now. Neither is new.

“Heart rate variability biofeedback based on variation in heart rate corresponding to breathing has been shown to be effective in treating numerous conditions, including reducing (nonclinical) stress, anxiety, depression, anger, and posttraumatic stress disorder in veterans and in some instances enhancing athletic performance. Of course, the validity and reliability of the commercially available apps and devices are potential significant limitations, as well as the stability of the user’s technique,” Dr. Bergeron said.

“It’s also been recognized that low-level aerobic exercise treatment normalizes the cerebrovascular physiological dysfunction in patients with concussion by increasing CO₂ sensitivity, which normalizes exercise ventilation and cerebral blood flow and thus reduces some symptoms,” Dr. Bergeron added.

“The combination of treatments is likely the novel aspect, which makes sense because brain injury is complex, and effective interventions need to utilize a complex, integrated biological systems approach across the multiple interdependent domains of influence,” Dr. Bergeron said.

The study was supported by the nonprofit Woodcock Institute at Texas Woman’s University. Dr. Moore, Dr. Bergeron, and Dr. Posas have disclosed no relevant financial relationships.

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

In a pooled analysis from two randomized trials, transcatheter aortic valve implantation (TAVI) was associated with significantly less bioprosthetic valve dysfunction (BVD) than a surgical prosthetic implantation, according to data presented as a late-breaker at the Cardiovascular Research Technologies conference, sponsored by MedStar Heart & Vascular Institute.

“The difference in valve performance was driven by a twofold lower SVD [structural valve deterioration] and a 3-fold lower severe PPM [prothesis-patient mismatch] for TAVI versus surgery,” reported Steven J. Yakubov, MD.

Ted Bosworth/MDedge News

The data were pooled from the CoreValve U.S. Pivotal and SURTAVI randomized trials. Of patients participating in these two trials, 5-year follow-up data were available for 1,128 randomized to the CoreValve/Evolut TAVI and 971 randomized to surgical prosthetic valve replacement.

The major focus of the study was on the cumulative incidence of BVD, but the study also included separate analyses on the relationship between BVD and clinical outcomes. Preprocedural indicators for BVD at 5 years were also analyzed.

SVD was defined as a mean gradient increase of at least 10 mm Hg from discharge to 30 days, along with at least 20 mm Hg at last echo or new-onset aortic regurgitation. Nonstructural valve deterioration (NSVD) was defined as severe PPM at discharge or 30 days or severe paravalvular regurgitation through 5 years. In addition to these two components, the BVD endpoint also included thrombosis and endocarditis.
 

Surgical valve deterioration high at 5 years

On the basis of these definitions, the rate of BVD at 5 years was 14.2% in the surgery group and 7.8% in the TAVI group, translating into a 50% risk reduction in favor of TAVI (hazard ratio, 0.50; P < .001).

Thrombosis or endocarditis occurred in low rates in both groups, but every other component of BVD favored TAVI significantly, not just numerically. This included SVD (2.2% vs. 4.4%; P = .004), and the two components of NSVD, PPM (3.7% vs. 11.8%; P < .001) and severe paravalvular regurgitation (0.2% vs. 1.2%; P = .02).

When stratified by annular diameter, the relative advantage of TAVI over surgery was greatest in those valves with diameters of up to 23 mm. In this group, the lower relative rate in the TAVI group (8.6% vs. 19.7%) represented a nearly 70% reduction in risk of valve deterioration at 5 years (HR, 0.31; P < .001).

However, the advantage at 5 years also remained substantial and significant in larger valves (8.1% vs. 12.6%), translating into a 40% risk reduction in favor of TAVI (HR, 0.60; P = .002).

Independent of type of valve replacement, BVD at 5 years was associated with worse outcomes, including significantly increased risks for all-cause mortality (HR, 1.46; P = .004), cardiovascular mortality (1.84; P < .001), and hospitalization for valve disease or worsening heart failure (HR, 1.67; P = .001).

The baseline characteristics that were statistically associated with BVD at 5 years on multivariate analysis in pooled data from both the TAVI and surgical groups included age (P = .02), a creatinine clearance less than 30 mL/min per 1.73 m² (P = .006), and a low relative baseline left ventricular ejection fraction (P < .001).
 

BVD criteria validated for outcome prediction

The four components of valve performance employed in this analysis (SVD, NSVD, thrombosis, and endocarditis) were drawn from consensus documents issued by the Valve Academic Research Consortium and the European Association of Percutaneous Cardiovascular Interventions, but the relative importance of these components for predicting valve survival was previously unknown, according to Dr. Yakubov.

“This is the first analysis to validate clinical criteria for valve performance and its association with clinical outcomes,” said Dr. Yakubov, medical director of cardiovascular studies, OhioHealth Research Institute at Riverside Methodist Hospital, Columbus.

This is also the first study to employ randomized data to prove an advantage of TAVI over surgery in long-term follow-up.

A 10-year follow-up is planned for the patients who participated in these two trials, but the lower rate of BVD in the TAVI arm at 5 years is already a threat to surgical repairs, acknowledged several surgeons who served as panelists in the session where these results were presented.

“I think that these data are a reflection of the fact that we [surgeons] are not being as aggressive as we should be,” said Gregory P. Fontana, MD, who is national director, cardiothoracic surgery, HCA Healthcare, and is affiliated with Los Robles Health System, Thousand Oaks, Calif. “We need to be employing larger prostheses.”

Ted Bosworth/MDedge News

A very similar comment was made by Michael J. Reardon, MD, a professor of cardiothoracic surgery at Houston Methodist Hospital. Pointing to the higher rate of PVL as an example of a common postsurgical complication, he agreed that surgeons should be moving to bigger valve sizes.

While adjustments in valve size might address the steeper rise in NSVD subtypes of BVD observed in the surgical group, but Dr. Reardon and others pointed out that late BVD events also rose at a greater pace in the surgical group. These suggest other improvements in technique might also be needed to keep surgical valve repairs competitive.

Dr. Yakubov reported financial relationships with Medtronic and Boston Scientific, both of which provided funding for this study. Dr. Fontana reported financial relationships with Abbott and Medtronic. Dr. Reardon reported financial relationships with Abbott, Boston Scientific, Medtronic, and Gore Medical.

In a pooled analysis from two randomized trials, transcatheter aortic valve implantation (TAVI) was associated with significantly less bioprosthetic valve dysfunction (BVD) than a surgical prosthetic implantation, according to data presented as a late-breaker at the Cardiovascular Research Technologies conference, sponsored by MedStar Heart & Vascular Institute.

“The difference in valve performance was driven by a twofold lower SVD [structural valve deterioration] and a 3-fold lower severe PPM [prothesis-patient mismatch] for TAVI versus surgery,” reported Steven J. Yakubov, MD.

Ted Bosworth/MDedge News

The data were pooled from the CoreValve U.S. Pivotal and SURTAVI randomized trials. Of patients participating in these two trials, 5-year follow-up data were available for 1,128 randomized to the CoreValve/Evolut TAVI and 971 randomized to surgical prosthetic valve replacement.

The major focus of the study was on the cumulative incidence of BVD, but the study also included separate analyses on the relationship between BVD and clinical outcomes. Preprocedural indicators for BVD at 5 years were also analyzed.

SVD was defined as a mean gradient increase of at least 10 mm Hg from discharge to 30 days, along with at least 20 mm Hg at last echo or new-onset aortic regurgitation. Nonstructural valve deterioration (NSVD) was defined as severe PPM at discharge or 30 days or severe paravalvular regurgitation through 5 years. In addition to these two components, the BVD endpoint also included thrombosis and endocarditis.
 

Surgical valve deterioration high at 5 years

On the basis of these definitions, the rate of BVD at 5 years was 14.2% in the surgery group and 7.8% in the TAVI group, translating into a 50% risk reduction in favor of TAVI (hazard ratio, 0.50; P < .001).

Thrombosis or endocarditis occurred in low rates in both groups, but every other component of BVD favored TAVI significantly, not just numerically. This included SVD (2.2% vs. 4.4%; P = .004), and the two components of NSVD, PPM (3.7% vs. 11.8%; P < .001) and severe paravalvular regurgitation (0.2% vs. 1.2%; P = .02).

When stratified by annular diameter, the relative advantage of TAVI over surgery was greatest in those valves with diameters of up to 23 mm. In this group, the lower relative rate in the TAVI group (8.6% vs. 19.7%) represented a nearly 70% reduction in risk of valve deterioration at 5 years (HR, 0.31; P < .001).

However, the advantage at 5 years also remained substantial and significant in larger valves (8.1% vs. 12.6%), translating into a 40% risk reduction in favor of TAVI (HR, 0.60; P = .002).

Independent of type of valve replacement, BVD at 5 years was associated with worse outcomes, including significantly increased risks for all-cause mortality (HR, 1.46; P = .004), cardiovascular mortality (1.84; P < .001), and hospitalization for valve disease or worsening heart failure (HR, 1.67; P = .001).

The baseline characteristics that were statistically associated with BVD at 5 years on multivariate analysis in pooled data from both the TAVI and surgical groups included age (P = .02), a creatinine clearance less than 30 mL/min per 1.73 m² (P = .006), and a low relative baseline left ventricular ejection fraction (P < .001).
 

BVD criteria validated for outcome prediction

The four components of valve performance employed in this analysis (SVD, NSVD, thrombosis, and endocarditis) were drawn from consensus documents issued by the Valve Academic Research Consortium and the European Association of Percutaneous Cardiovascular Interventions, but the relative importance of these components for predicting valve survival was previously unknown, according to Dr. Yakubov.

“This is the first analysis to validate clinical criteria for valve performance and its association with clinical outcomes,” said Dr. Yakubov, medical director of cardiovascular studies, OhioHealth Research Institute at Riverside Methodist Hospital, Columbus.

This is also the first study to employ randomized data to prove an advantage of TAVI over surgery in long-term follow-up.

A 10-year follow-up is planned for the patients who participated in these two trials, but the lower rate of BVD in the TAVI arm at 5 years is already a threat to surgical repairs, acknowledged several surgeons who served as panelists in the session where these results were presented.

“I think that these data are a reflection of the fact that we [surgeons] are not being as aggressive as we should be,” said Gregory P. Fontana, MD, who is national director, cardiothoracic surgery, HCA Healthcare, and is affiliated with Los Robles Health System, Thousand Oaks, Calif. “We need to be employing larger prostheses.”

Ted Bosworth/MDedge News

A very similar comment was made by Michael J. Reardon, MD, a professor of cardiothoracic surgery at Houston Methodist Hospital. Pointing to the higher rate of PVL as an example of a common postsurgical complication, he agreed that surgeons should be moving to bigger valve sizes.

While adjustments in valve size might address the steeper rise in NSVD subtypes of BVD observed in the surgical group, but Dr. Reardon and others pointed out that late BVD events also rose at a greater pace in the surgical group. These suggest other improvements in technique might also be needed to keep surgical valve repairs competitive.

Dr. Yakubov reported financial relationships with Medtronic and Boston Scientific, both of which provided funding for this study. Dr. Fontana reported financial relationships with Abbott and Medtronic. Dr. Reardon reported financial relationships with Abbott, Boston Scientific, Medtronic, and Gore Medical.

In a pooled analysis from two randomized trials, transcatheter aortic valve implantation (TAVI) was associated with significantly less bioprosthetic valve dysfunction (BVD) than a surgical prosthetic implantation, according to data presented as a late-breaker at the Cardiovascular Research Technologies conference, sponsored by MedStar Heart & Vascular Institute.

“The difference in valve performance was driven by a twofold lower SVD [structural valve deterioration] and a 3-fold lower severe PPM [prothesis-patient mismatch] for TAVI versus surgery,” reported Steven J. Yakubov, MD.

Ted Bosworth/MDedge News

The data were pooled from the CoreValve U.S. Pivotal and SURTAVI randomized trials. Of patients participating in these two trials, 5-year follow-up data were available for 1,128 randomized to the CoreValve/Evolut TAVI and 971 randomized to surgical prosthetic valve replacement.

The major focus of the study was on the cumulative incidence of BVD, but the study also included separate analyses on the relationship between BVD and clinical outcomes. Preprocedural indicators for BVD at 5 years were also analyzed.

SVD was defined as a mean gradient increase of at least 10 mm Hg from discharge to 30 days, along with at least 20 mm Hg at last echo or new-onset aortic regurgitation. Nonstructural valve deterioration (NSVD) was defined as severe PPM at discharge or 30 days or severe paravalvular regurgitation through 5 years. In addition to these two components, the BVD endpoint also included thrombosis and endocarditis.
 

Surgical valve deterioration high at 5 years

On the basis of these definitions, the rate of BVD at 5 years was 14.2% in the surgery group and 7.8% in the TAVI group, translating into a 50% risk reduction in favor of TAVI (hazard ratio, 0.50; P < .001).

Thrombosis or endocarditis occurred in low rates in both groups, but every other component of BVD favored TAVI significantly, not just numerically. This included SVD (2.2% vs. 4.4%; P = .004), and the two components of NSVD, PPM (3.7% vs. 11.8%; P < .001) and severe paravalvular regurgitation (0.2% vs. 1.2%; P = .02).

When stratified by annular diameter, the relative advantage of TAVI over surgery was greatest in those valves with diameters of up to 23 mm. In this group, the lower relative rate in the TAVI group (8.6% vs. 19.7%) represented a nearly 70% reduction in risk of valve deterioration at 5 years (HR, 0.31; P < .001).

However, the advantage at 5 years also remained substantial and significant in larger valves (8.1% vs. 12.6%), translating into a 40% risk reduction in favor of TAVI (HR, 0.60; P = .002).

Independent of type of valve replacement, BVD at 5 years was associated with worse outcomes, including significantly increased risks for all-cause mortality (HR, 1.46; P = .004), cardiovascular mortality (1.84; P < .001), and hospitalization for valve disease or worsening heart failure (HR, 1.67; P = .001).

The baseline characteristics that were statistically associated with BVD at 5 years on multivariate analysis in pooled data from both the TAVI and surgical groups included age (P = .02), a creatinine clearance less than 30 mL/min per 1.73 m² (P = .006), and a low relative baseline left ventricular ejection fraction (P < .001).
 

BVD criteria validated for outcome prediction

The four components of valve performance employed in this analysis (SVD, NSVD, thrombosis, and endocarditis) were drawn from consensus documents issued by the Valve Academic Research Consortium and the European Association of Percutaneous Cardiovascular Interventions, but the relative importance of these components for predicting valve survival was previously unknown, according to Dr. Yakubov.

“This is the first analysis to validate clinical criteria for valve performance and its association with clinical outcomes,” said Dr. Yakubov, medical director of cardiovascular studies, OhioHealth Research Institute at Riverside Methodist Hospital, Columbus.

This is also the first study to employ randomized data to prove an advantage of TAVI over surgery in long-term follow-up.

A 10-year follow-up is planned for the patients who participated in these two trials, but the lower rate of BVD in the TAVI arm at 5 years is already a threat to surgical repairs, acknowledged several surgeons who served as panelists in the session where these results were presented.

“I think that these data are a reflection of the fact that we [surgeons] are not being as aggressive as we should be,” said Gregory P. Fontana, MD, who is national director, cardiothoracic surgery, HCA Healthcare, and is affiliated with Los Robles Health System, Thousand Oaks, Calif. “We need to be employing larger prostheses.”

Ted Bosworth/MDedge News

A very similar comment was made by Michael J. Reardon, MD, a professor of cardiothoracic surgery at Houston Methodist Hospital. Pointing to the higher rate of PVL as an example of a common postsurgical complication, he agreed that surgeons should be moving to bigger valve sizes.

While adjustments in valve size might address the steeper rise in NSVD subtypes of BVD observed in the surgical group, but Dr. Reardon and others pointed out that late BVD events also rose at a greater pace in the surgical group. These suggest other improvements in technique might also be needed to keep surgical valve repairs competitive.

Dr. Yakubov reported financial relationships with Medtronic and Boston Scientific, both of which provided funding for this study. Dr. Fontana reported financial relationships with Abbott and Medtronic. Dr. Reardon reported financial relationships with Abbott, Boston Scientific, Medtronic, and Gore Medical.

SAN DIEGO – A downside of the revolutionary advances in targeted and immune therapies used to treat melanoma are their potential to trigger a wide range of skin reactions, from acneiform eruptions to Stevens-Johnson Syndrome (SJS).

“These skin reactions can cause pain, itching, and emotional and social distress that may severely impact activities of daily living,” Aleksandr Itkin, MD, a dermatologist at Scripps MD Anderson Cancer Center, San Diego, said at the annual Cutaneous Malignancy Update. An estimated 30%-50% of patients on immune checkpoint inhibitors (ICIs) experience cutaneous adverse events, he said, which leads to dose reduction or discontinuation of ICIs in 20% of cases.

Clinicians first observed these side effects in 2011, with the Food and Drug Administration approval of ipilimumab, a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)–blocking antibody, for metastatic melanoma, followed by the programmed death receptor-1 (PD-1) inhibitors nivolumab and pembrolizumab, which were approved in 2014 for the same indication.

Courtesy Dr. Aleksandr Itkin

Since then, more ICIs showing similar adverse cutaneous reactions have been approved by the FDA. These include avelumab, atezolizumab in combination with cobimetinib and vemurafenib, and a combination of relatlimab, an anti-LAG-3 antibody, with nivolumab.

Among the targeted therapies, the BRAF inhibitors vemurafenib and dabrafenib alone or in combination with MAPK pathway inhibitors cobimetinib and trametinib, which are a first-line therapy for V600 BRAF mutated metastatic melanoma, are associated with their own set of cutaneous reactions. The oncolytic modified herpes simplex virus T-VEC (talimogene laherparepvec), approved by the FDA in 2015 for the treatment of unresectable stage IIIB-IV metastatic melanoma, also results in cutaneous reactions that have been found useful in assessing the therapeutic outcome of this agent.

According to a 2020 CME article on the dermatologic adverse events that occur after treatment initiation with ICIs, the time of onset of psoriasiform rash is within the first 3 weeks, maculopapular rash and pruritus in the first 4-6 weeks, lichenoid eruption in the first 7-12 weeks, and bullous pemphigoid in weeks 13-15. The most severe reactions – SJS, toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) – usually occur after 2-3 months of treatment.

A subsequent retrospective cohort study of patients in the United States treated with ICIs for a variety of systemic malignancies and matched controls found that the ICI-treated group had a significantly higher incidence of pruritus, mucositis, erythroderma, maculopapular eruption, vitiligo, lichen planus, bullous pemphigoid, Grover disease, rash, other nonspecific eruptions, and drug eruption or other nonspecific drug reaction. Patients with melanoma and renal cell carcinoma and those receiving combination therapy were at a higher risk of cutaneous immune-related adverse events.

Another study, a prospective trial of 617 patients with various advanced cancers (including melanoma), found that both severe and mild skin toxicities were significantly associated with improved progression-free and overall survival.

According to Dr. Itkin, erythema multiforme, SJS, and TEN have been reported with anti-PD1, anti-CTLA4, and BRAF inhibitors. In TEN induced by vemurafenib, an in vitro analysis showed cross-activation of lymphocytes with dabrafenib and with sulfamethoxazole. “This means you that may want to avoid sulfonamides in patients with serious hypersensitivity to vemurafenib, and vice versa,” he said at the meeting hosted by Scripps MD Anderson Cancer Center.
 

Acneiform eruptions

In addition, the use of MAPK inhibitors can trigger acneiform eruptions. In one study, 77% of patients on trametinib developed acneiform eruption, but only 10% of those on trametinib in combination with dabrafenib developed acneiform eruption. “Inhibition of the MAPK pathway leads to decreased proliferative markers, further leading to decreased keratinocyte replication, increased inflammatory cytokine, apoptosis, thinning and abnormal epidermal differentiation, follicular rupture, and papule/pustule formation,” he said. For these cases, “treatment options are similar to what we use for regular acne except for here, use of systemic steroids is sometimes needed, especially in more severe cases. The reaction may be so severe as to lead to dose reduction or discontinuation of antineoplastic treatment.”

Effects on nail, hair

Paronychia and onycholysis are additional potential adverse events of MEK inhibitors and BRAF inhibitors alone or in combination, Dr. Itkin continued. Onycholysis is associated with dabrafenib alone or in combination with trametinib, while vemurafenib has been shown to induce acute paronychia and brittle nails. He said that secondary infections in these cases can be treated with the options familiar to dermatologists in their daily practice: oral doxycycline, azole antifungals, vinegar soaks, topical superpotent corticosteroids under occlusion, nail avulsion, and phenol nail matrix ablation.

Dr. Itkin noted that while PD-1 and PD-L1 inhibitors can cause hair repigmentation, CTLA-4 and PD-1 inhibitors are more likely to cause vitiligo. Appearance of vitiligo is regarded as a good prognostic factor in the treatment of melanoma with various checkpoint inhibitors alone or in combination with each other or with radiation therapy. “About 5% of melanoma patients treated with ipilimumab will develop vitiligo,” he said.

ICI-induced vitiligo differs from conventional vitiligo in that there is no family or personal history of autoimmunity; it presents as a flecked pattern of lesion on photo-exposed skin, and it lacks the Koebner phenomenon. In addition, induction of squamous neoplasms can occur with BRAF inhibitors, especially in patients with a high frequency of RAS mutations.

He said that coadministration of MEK inhibitors such as trametinib and cobimetinib may prevent induction of keratinocytic neoplasms.

Dr. Itkin reported having no relevant financial disclosures.

SAN DIEGO – A downside of the revolutionary advances in targeted and immune therapies used to treat melanoma are their potential to trigger a wide range of skin reactions, from acneiform eruptions to Stevens-Johnson Syndrome (SJS).

“These skin reactions can cause pain, itching, and emotional and social distress that may severely impact activities of daily living,” Aleksandr Itkin, MD, a dermatologist at Scripps MD Anderson Cancer Center, San Diego, said at the annual Cutaneous Malignancy Update. An estimated 30%-50% of patients on immune checkpoint inhibitors (ICIs) experience cutaneous adverse events, he said, which leads to dose reduction or discontinuation of ICIs in 20% of cases.

Clinicians first observed these side effects in 2011, with the Food and Drug Administration approval of ipilimumab, a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)–blocking antibody, for metastatic melanoma, followed by the programmed death receptor-1 (PD-1) inhibitors nivolumab and pembrolizumab, which were approved in 2014 for the same indication.

Courtesy Dr. Aleksandr Itkin

Since then, more ICIs showing similar adverse cutaneous reactions have been approved by the FDA. These include avelumab, atezolizumab in combination with cobimetinib and vemurafenib, and a combination of relatlimab, an anti-LAG-3 antibody, with nivolumab.

Among the targeted therapies, the BRAF inhibitors vemurafenib and dabrafenib alone or in combination with MAPK pathway inhibitors cobimetinib and trametinib, which are a first-line therapy for V600 BRAF mutated metastatic melanoma, are associated with their own set of cutaneous reactions. The oncolytic modified herpes simplex virus T-VEC (talimogene laherparepvec), approved by the FDA in 2015 for the treatment of unresectable stage IIIB-IV metastatic melanoma, also results in cutaneous reactions that have been found useful in assessing the therapeutic outcome of this agent.

According to a 2020 CME article on the dermatologic adverse events that occur after treatment initiation with ICIs, the time of onset of psoriasiform rash is within the first 3 weeks, maculopapular rash and pruritus in the first 4-6 weeks, lichenoid eruption in the first 7-12 weeks, and bullous pemphigoid in weeks 13-15. The most severe reactions – SJS, toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) – usually occur after 2-3 months of treatment.

A subsequent retrospective cohort study of patients in the United States treated with ICIs for a variety of systemic malignancies and matched controls found that the ICI-treated group had a significantly higher incidence of pruritus, mucositis, erythroderma, maculopapular eruption, vitiligo, lichen planus, bullous pemphigoid, Grover disease, rash, other nonspecific eruptions, and drug eruption or other nonspecific drug reaction. Patients with melanoma and renal cell carcinoma and those receiving combination therapy were at a higher risk of cutaneous immune-related adverse events.

Another study, a prospective trial of 617 patients with various advanced cancers (including melanoma), found that both severe and mild skin toxicities were significantly associated with improved progression-free and overall survival.

According to Dr. Itkin, erythema multiforme, SJS, and TEN have been reported with anti-PD1, anti-CTLA4, and BRAF inhibitors. In TEN induced by vemurafenib, an in vitro analysis showed cross-activation of lymphocytes with dabrafenib and with sulfamethoxazole. “This means you that may want to avoid sulfonamides in patients with serious hypersensitivity to vemurafenib, and vice versa,” he said at the meeting hosted by Scripps MD Anderson Cancer Center.
 

Acneiform eruptions

In addition, the use of MAPK inhibitors can trigger acneiform eruptions. In one study, 77% of patients on trametinib developed acneiform eruption, but only 10% of those on trametinib in combination with dabrafenib developed acneiform eruption. “Inhibition of the MAPK pathway leads to decreased proliferative markers, further leading to decreased keratinocyte replication, increased inflammatory cytokine, apoptosis, thinning and abnormal epidermal differentiation, follicular rupture, and papule/pustule formation,” he said. For these cases, “treatment options are similar to what we use for regular acne except for here, use of systemic steroids is sometimes needed, especially in more severe cases. The reaction may be so severe as to lead to dose reduction or discontinuation of antineoplastic treatment.”

Effects on nail, hair

Paronychia and onycholysis are additional potential adverse events of MEK inhibitors and BRAF inhibitors alone or in combination, Dr. Itkin continued. Onycholysis is associated with dabrafenib alone or in combination with trametinib, while vemurafenib has been shown to induce acute paronychia and brittle nails. He said that secondary infections in these cases can be treated with the options familiar to dermatologists in their daily practice: oral doxycycline, azole antifungals, vinegar soaks, topical superpotent corticosteroids under occlusion, nail avulsion, and phenol nail matrix ablation.

Dr. Itkin noted that while PD-1 and PD-L1 inhibitors can cause hair repigmentation, CTLA-4 and PD-1 inhibitors are more likely to cause vitiligo. Appearance of vitiligo is regarded as a good prognostic factor in the treatment of melanoma with various checkpoint inhibitors alone or in combination with each other or with radiation therapy. “About 5% of melanoma patients treated with ipilimumab will develop vitiligo,” he said.

ICI-induced vitiligo differs from conventional vitiligo in that there is no family or personal history of autoimmunity; it presents as a flecked pattern of lesion on photo-exposed skin, and it lacks the Koebner phenomenon. In addition, induction of squamous neoplasms can occur with BRAF inhibitors, especially in patients with a high frequency of RAS mutations.

He said that coadministration of MEK inhibitors such as trametinib and cobimetinib may prevent induction of keratinocytic neoplasms.

Dr. Itkin reported having no relevant financial disclosures.

SAN DIEGO – A downside of the revolutionary advances in targeted and immune therapies used to treat melanoma are their potential to trigger a wide range of skin reactions, from acneiform eruptions to Stevens-Johnson Syndrome (SJS).

“These skin reactions can cause pain, itching, and emotional and social distress that may severely impact activities of daily living,” Aleksandr Itkin, MD, a dermatologist at Scripps MD Anderson Cancer Center, San Diego, said at the annual Cutaneous Malignancy Update. An estimated 30%-50% of patients on immune checkpoint inhibitors (ICIs) experience cutaneous adverse events, he said, which leads to dose reduction or discontinuation of ICIs in 20% of cases.

Clinicians first observed these side effects in 2011, with the Food and Drug Administration approval of ipilimumab, a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)–blocking antibody, for metastatic melanoma, followed by the programmed death receptor-1 (PD-1) inhibitors nivolumab and pembrolizumab, which were approved in 2014 for the same indication.

Courtesy Dr. Aleksandr Itkin

Since then, more ICIs showing similar adverse cutaneous reactions have been approved by the FDA. These include avelumab, atezolizumab in combination with cobimetinib and vemurafenib, and a combination of relatlimab, an anti-LAG-3 antibody, with nivolumab.

Among the targeted therapies, the BRAF inhibitors vemurafenib and dabrafenib alone or in combination with MAPK pathway inhibitors cobimetinib and trametinib, which are a first-line therapy for V600 BRAF mutated metastatic melanoma, are associated with their own set of cutaneous reactions. The oncolytic modified herpes simplex virus T-VEC (talimogene laherparepvec), approved by the FDA in 2015 for the treatment of unresectable stage IIIB-IV metastatic melanoma, also results in cutaneous reactions that have been found useful in assessing the therapeutic outcome of this agent.

According to a 2020 CME article on the dermatologic adverse events that occur after treatment initiation with ICIs, the time of onset of psoriasiform rash is within the first 3 weeks, maculopapular rash and pruritus in the first 4-6 weeks, lichenoid eruption in the first 7-12 weeks, and bullous pemphigoid in weeks 13-15. The most severe reactions – SJS, toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) – usually occur after 2-3 months of treatment.

A subsequent retrospective cohort study of patients in the United States treated with ICIs for a variety of systemic malignancies and matched controls found that the ICI-treated group had a significantly higher incidence of pruritus, mucositis, erythroderma, maculopapular eruption, vitiligo, lichen planus, bullous pemphigoid, Grover disease, rash, other nonspecific eruptions, and drug eruption or other nonspecific drug reaction. Patients with melanoma and renal cell carcinoma and those receiving combination therapy were at a higher risk of cutaneous immune-related adverse events.

Another study, a prospective trial of 617 patients with various advanced cancers (including melanoma), found that both severe and mild skin toxicities were significantly associated with improved progression-free and overall survival.

According to Dr. Itkin, erythema multiforme, SJS, and TEN have been reported with anti-PD1, anti-CTLA4, and BRAF inhibitors. In TEN induced by vemurafenib, an in vitro analysis showed cross-activation of lymphocytes with dabrafenib and with sulfamethoxazole. “This means you that may want to avoid sulfonamides in patients with serious hypersensitivity to vemurafenib, and vice versa,” he said at the meeting hosted by Scripps MD Anderson Cancer Center.
 

Acneiform eruptions

In addition, the use of MAPK inhibitors can trigger acneiform eruptions. In one study, 77% of patients on trametinib developed acneiform eruption, but only 10% of those on trametinib in combination with dabrafenib developed acneiform eruption. “Inhibition of the MAPK pathway leads to decreased proliferative markers, further leading to decreased keratinocyte replication, increased inflammatory cytokine, apoptosis, thinning and abnormal epidermal differentiation, follicular rupture, and papule/pustule formation,” he said. For these cases, “treatment options are similar to what we use for regular acne except for here, use of systemic steroids is sometimes needed, especially in more severe cases. The reaction may be so severe as to lead to dose reduction or discontinuation of antineoplastic treatment.”

Effects on nail, hair

Paronychia and onycholysis are additional potential adverse events of MEK inhibitors and BRAF inhibitors alone or in combination, Dr. Itkin continued. Onycholysis is associated with dabrafenib alone or in combination with trametinib, while vemurafenib has been shown to induce acute paronychia and brittle nails. He said that secondary infections in these cases can be treated with the options familiar to dermatologists in their daily practice: oral doxycycline, azole antifungals, vinegar soaks, topical superpotent corticosteroids under occlusion, nail avulsion, and phenol nail matrix ablation.

Dr. Itkin noted that while PD-1 and PD-L1 inhibitors can cause hair repigmentation, CTLA-4 and PD-1 inhibitors are more likely to cause vitiligo. Appearance of vitiligo is regarded as a good prognostic factor in the treatment of melanoma with various checkpoint inhibitors alone or in combination with each other or with radiation therapy. “About 5% of melanoma patients treated with ipilimumab will develop vitiligo,” he said.

ICI-induced vitiligo differs from conventional vitiligo in that there is no family or personal history of autoimmunity; it presents as a flecked pattern of lesion on photo-exposed skin, and it lacks the Koebner phenomenon. In addition, induction of squamous neoplasms can occur with BRAF inhibitors, especially in patients with a high frequency of RAS mutations.

He said that coadministration of MEK inhibitors such as trametinib and cobimetinib may prevent induction of keratinocytic neoplasms.

Dr. Itkin reported having no relevant financial disclosures.

Anti–N-methyl-D-aspartate receptor encephalitis (ANMDARE) can present with psychiatric symptoms, such as depression and psychosis, and is associated with suicidal thoughts and behaviors, new research suggests.

Investigators assessed 120 patients hospitalized in a neurological center and diagnosed with ANMDARE. Most had psychosis and other severe mental health disturbances. Of these, 13% also had suicidal thoughts and behaviors.

However, after medical treatment that included immunotherapy, neurologic and psychiatric pharmacotherapy, and rehabilitation and psychotherapy, almost all patients with suicidal thoughts and behaviors had sustained remission of their suicidality.

“Most patients [with ANMDARE] suffer with severe mental health problems, and it is not infrequent that suicidal thoughts and behaviors emerge in this context – mainly in patients with clinical features of psychotic depression,” senior author Jesús Ramirez-Bermúdez, MD, PhD, from the neuropsychiatry unit, National Institute of Neurology and Neurosurgery of Mexico, told this news organization.

“The good news is that, in most cases, the suicidal thoughts and behaviors as well as the features of psychotic depression improve significantly with the specific immunological therapy. However, careful psychiatric and psychotherapeutic support are helpful to restore the long-term psychological well-being,” Dr. Ramirez-Bermúdez said.

The findings were published online in the Journal of Neuropsychiatry and Clinical Neurosciences.
 

Delayed recognition

ANMDARE is a “frequent form of autoimmune encephalitis,” the authors write. It often begins with an “abrupt onset of behavioral and cognitive symptoms, followed by seizures and movement disorders,” they add.

“The clinical care of persons with encephalitis is challenging because these patients suffer from acute and severe mental health disturbances [and] are often misdiagnosed as having a primary psychiatric disorder, for instance, schizophrenia or bipolar disorder; but, they do not improve with the use of psychiatric medication or psychotherapy,” Dr. Ramirez-Bermúdez said.

Rather, the disease requires specific treatments, such as the use of antiviral medication or immunotherapy, he added. Without these, “the mortality rate is high, and many patients have bad outcomes, including disability related to cognitive and affective disturbances,” he said.

Dr. Ramirez-Bermúdez noted that there are “many cultural problems in the conventional approach to mental health problems, including prejudices, fear, myths, stigma, and discrimination.” And these attitudes can contribute to delayed recognition of ANMDARE.

During recent years, Dr. Ramirez-Bermúdez and colleagues observed that some patients with autoimmune encephalitis and, more specifically, patients suffering from ANMDARE had suicidal behavior. A previous study conducted in China suggested that the problem of suicidal behavior is not infrequent in this population.

“We wanted to make a structured, systematic, and prospective approach to this problem to answer some questions related to ANMDARE,” Dr. Ramirez-Bermúdez said. These questions included: What is the frequency of suicidal thoughts and behaviors, what are the neurological and psychiatric features related to suicidal behavior in this population, and what is the outcome after receiving immunological treatment?

The researchers conducted an observational longitudinal study that included patients hospitalized between 2014 and 2021 who had definite ANMDARE (n = 120).

Patients were diagnosed as having encephalitis by means of clinical interviews, neuropsychological studies, brain imaging, EEG, and analysis of cerebrospinal fluid (CSF).

All participants had antibodies against the NMDA glutamate receptor in their CSF and were classified as having ANMDARE based on Graus criteria, “which are considered the best current standard for diagnosis,” Dr. Ramirez-Bermúdez noted.

Clinical measures were obtained both before and after treatment with immunotherapy, and all clinical data were registered prospectively and included a “broad scope of neurological and psychiatric variables seen in patients with ANMDARE.”

Information regarding suicidal thoughts and behaviors was gathered from patients as well as relatives, with assessments occurring at admission and at discharge.
 

Biological signaling

Results showed that 15 patients presented with suicidal thoughts and/or behaviors. Of this subgroup, the median age was 32 years (range, 19-48 years) and 53.3% were women.

All members of this subgroup had psychotic features, including persecutory, grandiose, nihilistic, or jealousy delusion (n = 14), delirium (n = 13), visual or auditory hallucinations (n = 11), psychotic depression (n = 10), and/or catatonia (n = 8).

Most (n = 12) had suicidal ideation with intent, three had preparatory behaviors, and seven actually engaged in suicidal self-directed violence.

Of these 15 patients, 7 had abnormal CSF findings, 8 had MRI abnormalities involving the medial temporal lobe, and all had abnormal EEG involving generalized slowing.

Fourteen suicidal patients were treated with an antipsychotic, 4 with dexmedetomidine, and 12 with lorazepam. In addition, 10 received plasmapheresis and 7 received immunoglobulin.

Of note, at discharge, self-directed violent thoughts and behaviors completely remitted in 14 of the 15 patients. Long-term follow-up showed that they remained free of suicidality.

Dr. Ramirez-Bermúdez noted that in some patients with neuropsychiatric disturbances, “there are autoantibodies against the NR1 subunit of the NMDA glutamate receptor: the main excitatory neurotransmitter in the human brain.”

The NMDA receptor is “particularly important as part of the biological signaling that is required in several cognitive and affective processes leading to complex behaviors,” he said. NMDA receptor dysfunction “may lead to states in which these cognitive and affective processes are disturbed,” frequently resulting in psychosis.

Study coauthor Ava Easton, MD, chief executive of the Encephalitis Society, told this news organization that mental health issues, self-injurious thoughts, and suicidal behaviors after encephalitis “may occur for a number of reasons and stigma around talking about mental health can be a real barrier to speaking up about symptoms; but it is an important barrier to overcome.”

Dr. Easton, an honorary fellow in the department of clinical infection, microbiology, and immunology, University of Liverpool, England, added that their study “provides a platform on which to break taboo, show tangible links which are based on data between suicide and encephalitis, and call for more awareness of the risk of mental health issues during and after encephalitis.”
 

‘Neglected symptom’

Commenting on the study, Carsten Finke, MD, Heisenberg Professor for Cognitive Neurology and consultant neurologist, department of neurology at Charité, Berlin, and professor at Berlin School of Mind and Brain, said that the research was on “a very important topic on a so far rather neglected symptom of encephalitis.”

Dr. Finke, a founding member of the scientific council of the German Network for Research on Autoimmune Encephalitis, was not involved in the current study.

He noted that 77% of people don’t know what encephalitis is. “This lack of awareness leads to delays in diagnoses and treatment – and poorer outcomes for patients,” Dr. Finke said.

Also commenting, Michael Eriksen Benros, MD, PhD, professor of immune-psychiatry, department of immunology and microbiology, Health and Medical Sciences, University of Copenhagen, said that the study “underlines the clinical importance of screening individuals with psychotic symptoms for suicidal ideations during acute phases,” as well as those with definite ANMDARE as a likely underlying cause of the psychotic symptoms.

This is important because patients with ANMDARE “might not necessarily be admitted at psychiatric departments where screenings for suicidal ideation are part of the clinical routine,” said Dr. Benros, who was not involved with the research.

Instead, “many patients with ANMDARE are at neurological departments during acute phases,” he added.

The study was supported by the National Council of Science and Technology of Mexico. Dr. Ramirez-Bermúdez, Dr. Easton, Dr. Benros, and Dr. Finke report no relevant financial relationships.

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

Anti–N-methyl-D-aspartate receptor encephalitis (ANMDARE) can present with psychiatric symptoms, such as depression and psychosis, and is associated with suicidal thoughts and behaviors, new research suggests.

Investigators assessed 120 patients hospitalized in a neurological center and diagnosed with ANMDARE. Most had psychosis and other severe mental health disturbances. Of these, 13% also had suicidal thoughts and behaviors.

However, after medical treatment that included immunotherapy, neurologic and psychiatric pharmacotherapy, and rehabilitation and psychotherapy, almost all patients with suicidal thoughts and behaviors had sustained remission of their suicidality.

“Most patients [with ANMDARE] suffer with severe mental health problems, and it is not infrequent that suicidal thoughts and behaviors emerge in this context – mainly in patients with clinical features of psychotic depression,” senior author Jesús Ramirez-Bermúdez, MD, PhD, from the neuropsychiatry unit, National Institute of Neurology and Neurosurgery of Mexico, told this news organization.

“The good news is that, in most cases, the suicidal thoughts and behaviors as well as the features of psychotic depression improve significantly with the specific immunological therapy. However, careful psychiatric and psychotherapeutic support are helpful to restore the long-term psychological well-being,” Dr. Ramirez-Bermúdez said.

The findings were published online in the Journal of Neuropsychiatry and Clinical Neurosciences.
 

Delayed recognition

ANMDARE is a “frequent form of autoimmune encephalitis,” the authors write. It often begins with an “abrupt onset of behavioral and cognitive symptoms, followed by seizures and movement disorders,” they add.

“The clinical care of persons with encephalitis is challenging because these patients suffer from acute and severe mental health disturbances [and] are often misdiagnosed as having a primary psychiatric disorder, for instance, schizophrenia or bipolar disorder; but, they do not improve with the use of psychiatric medication or psychotherapy,” Dr. Ramirez-Bermúdez said.

Rather, the disease requires specific treatments, such as the use of antiviral medication or immunotherapy, he added. Without these, “the mortality rate is high, and many patients have bad outcomes, including disability related to cognitive and affective disturbances,” he said.

Dr. Ramirez-Bermúdez noted that there are “many cultural problems in the conventional approach to mental health problems, including prejudices, fear, myths, stigma, and discrimination.” And these attitudes can contribute to delayed recognition of ANMDARE.

During recent years, Dr. Ramirez-Bermúdez and colleagues observed that some patients with autoimmune encephalitis and, more specifically, patients suffering from ANMDARE had suicidal behavior. A previous study conducted in China suggested that the problem of suicidal behavior is not infrequent in this population.

“We wanted to make a structured, systematic, and prospective approach to this problem to answer some questions related to ANMDARE,” Dr. Ramirez-Bermúdez said. These questions included: What is the frequency of suicidal thoughts and behaviors, what are the neurological and psychiatric features related to suicidal behavior in this population, and what is the outcome after receiving immunological treatment?

The researchers conducted an observational longitudinal study that included patients hospitalized between 2014 and 2021 who had definite ANMDARE (n = 120).

Patients were diagnosed as having encephalitis by means of clinical interviews, neuropsychological studies, brain imaging, EEG, and analysis of cerebrospinal fluid (CSF).

All participants had antibodies against the NMDA glutamate receptor in their CSF and were classified as having ANMDARE based on Graus criteria, “which are considered the best current standard for diagnosis,” Dr. Ramirez-Bermúdez noted.

Clinical measures were obtained both before and after treatment with immunotherapy, and all clinical data were registered prospectively and included a “broad scope of neurological and psychiatric variables seen in patients with ANMDARE.”

Information regarding suicidal thoughts and behaviors was gathered from patients as well as relatives, with assessments occurring at admission and at discharge.
 

Biological signaling

Results showed that 15 patients presented with suicidal thoughts and/or behaviors. Of this subgroup, the median age was 32 years (range, 19-48 years) and 53.3% were women.

All members of this subgroup had psychotic features, including persecutory, grandiose, nihilistic, or jealousy delusion (n = 14), delirium (n = 13), visual or auditory hallucinations (n = 11), psychotic depression (n = 10), and/or catatonia (n = 8).

Most (n = 12) had suicidal ideation with intent, three had preparatory behaviors, and seven actually engaged in suicidal self-directed violence.

Of these 15 patients, 7 had abnormal CSF findings, 8 had MRI abnormalities involving the medial temporal lobe, and all had abnormal EEG involving generalized slowing.

Fourteen suicidal patients were treated with an antipsychotic, 4 with dexmedetomidine, and 12 with lorazepam. In addition, 10 received plasmapheresis and 7 received immunoglobulin.

Of note, at discharge, self-directed violent thoughts and behaviors completely remitted in 14 of the 15 patients. Long-term follow-up showed that they remained free of suicidality.

Dr. Ramirez-Bermúdez noted that in some patients with neuropsychiatric disturbances, “there are autoantibodies against the NR1 subunit of the NMDA glutamate receptor: the main excitatory neurotransmitter in the human brain.”

The NMDA receptor is “particularly important as part of the biological signaling that is required in several cognitive and affective processes leading to complex behaviors,” he said. NMDA receptor dysfunction “may lead to states in which these cognitive and affective processes are disturbed,” frequently resulting in psychosis.

Study coauthor Ava Easton, MD, chief executive of the Encephalitis Society, told this news organization that mental health issues, self-injurious thoughts, and suicidal behaviors after encephalitis “may occur for a number of reasons and stigma around talking about mental health can be a real barrier to speaking up about symptoms; but it is an important barrier to overcome.”

Dr. Easton, an honorary fellow in the department of clinical infection, microbiology, and immunology, University of Liverpool, England, added that their study “provides a platform on which to break taboo, show tangible links which are based on data between suicide and encephalitis, and call for more awareness of the risk of mental health issues during and after encephalitis.”
 

‘Neglected symptom’

Commenting on the study, Carsten Finke, MD, Heisenberg Professor for Cognitive Neurology and consultant neurologist, department of neurology at Charité, Berlin, and professor at Berlin School of Mind and Brain, said that the research was on “a very important topic on a so far rather neglected symptom of encephalitis.”

Dr. Finke, a founding member of the scientific council of the German Network for Research on Autoimmune Encephalitis, was not involved in the current study.

He noted that 77% of people don’t know what encephalitis is. “This lack of awareness leads to delays in diagnoses and treatment – and poorer outcomes for patients,” Dr. Finke said.

Also commenting, Michael Eriksen Benros, MD, PhD, professor of immune-psychiatry, department of immunology and microbiology, Health and Medical Sciences, University of Copenhagen, said that the study “underlines the clinical importance of screening individuals with psychotic symptoms for suicidal ideations during acute phases,” as well as those with definite ANMDARE as a likely underlying cause of the psychotic symptoms.

This is important because patients with ANMDARE “might not necessarily be admitted at psychiatric departments where screenings for suicidal ideation are part of the clinical routine,” said Dr. Benros, who was not involved with the research.

Instead, “many patients with ANMDARE are at neurological departments during acute phases,” he added.

The study was supported by the National Council of Science and Technology of Mexico. Dr. Ramirez-Bermúdez, Dr. Easton, Dr. Benros, and Dr. Finke report no relevant financial relationships.

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

Anti–N-methyl-D-aspartate receptor encephalitis (ANMDARE) can present with psychiatric symptoms, such as depression and psychosis, and is associated with suicidal thoughts and behaviors, new research suggests.

Investigators assessed 120 patients hospitalized in a neurological center and diagnosed with ANMDARE. Most had psychosis and other severe mental health disturbances. Of these, 13% also had suicidal thoughts and behaviors.

However, after medical treatment that included immunotherapy, neurologic and psychiatric pharmacotherapy, and rehabilitation and psychotherapy, almost all patients with suicidal thoughts and behaviors had sustained remission of their suicidality.

“Most patients [with ANMDARE] suffer with severe mental health problems, and it is not infrequent that suicidal thoughts and behaviors emerge in this context – mainly in patients with clinical features of psychotic depression,” senior author Jesús Ramirez-Bermúdez, MD, PhD, from the neuropsychiatry unit, National Institute of Neurology and Neurosurgery of Mexico, told this news organization.

“The good news is that, in most cases, the suicidal thoughts and behaviors as well as the features of psychotic depression improve significantly with the specific immunological therapy. However, careful psychiatric and psychotherapeutic support are helpful to restore the long-term psychological well-being,” Dr. Ramirez-Bermúdez said.

The findings were published online in the Journal of Neuropsychiatry and Clinical Neurosciences.
 

Delayed recognition

ANMDARE is a “frequent form of autoimmune encephalitis,” the authors write. It often begins with an “abrupt onset of behavioral and cognitive symptoms, followed by seizures and movement disorders,” they add.

“The clinical care of persons with encephalitis is challenging because these patients suffer from acute and severe mental health disturbances [and] are often misdiagnosed as having a primary psychiatric disorder, for instance, schizophrenia or bipolar disorder; but, they do not improve with the use of psychiatric medication or psychotherapy,” Dr. Ramirez-Bermúdez said.

Rather, the disease requires specific treatments, such as the use of antiviral medication or immunotherapy, he added. Without these, “the mortality rate is high, and many patients have bad outcomes, including disability related to cognitive and affective disturbances,” he said.

Dr. Ramirez-Bermúdez noted that there are “many cultural problems in the conventional approach to mental health problems, including prejudices, fear, myths, stigma, and discrimination.” And these attitudes can contribute to delayed recognition of ANMDARE.

During recent years, Dr. Ramirez-Bermúdez and colleagues observed that some patients with autoimmune encephalitis and, more specifically, patients suffering from ANMDARE had suicidal behavior. A previous study conducted in China suggested that the problem of suicidal behavior is not infrequent in this population.

“We wanted to make a structured, systematic, and prospective approach to this problem to answer some questions related to ANMDARE,” Dr. Ramirez-Bermúdez said. These questions included: What is the frequency of suicidal thoughts and behaviors, what are the neurological and psychiatric features related to suicidal behavior in this population, and what is the outcome after receiving immunological treatment?

The researchers conducted an observational longitudinal study that included patients hospitalized between 2014 and 2021 who had definite ANMDARE (n = 120).

Patients were diagnosed as having encephalitis by means of clinical interviews, neuropsychological studies, brain imaging, EEG, and analysis of cerebrospinal fluid (CSF).

All participants had antibodies against the NMDA glutamate receptor in their CSF and were classified as having ANMDARE based on Graus criteria, “which are considered the best current standard for diagnosis,” Dr. Ramirez-Bermúdez noted.

Clinical measures were obtained both before and after treatment with immunotherapy, and all clinical data were registered prospectively and included a “broad scope of neurological and psychiatric variables seen in patients with ANMDARE.”

Information regarding suicidal thoughts and behaviors was gathered from patients as well as relatives, with assessments occurring at admission and at discharge.
 

Biological signaling

Results showed that 15 patients presented with suicidal thoughts and/or behaviors. Of this subgroup, the median age was 32 years (range, 19-48 years) and 53.3% were women.

All members of this subgroup had psychotic features, including persecutory, grandiose, nihilistic, or jealousy delusion (n = 14), delirium (n = 13), visual or auditory hallucinations (n = 11), psychotic depression (n = 10), and/or catatonia (n = 8).

Most (n = 12) had suicidal ideation with intent, three had preparatory behaviors, and seven actually engaged in suicidal self-directed violence.

Of these 15 patients, 7 had abnormal CSF findings, 8 had MRI abnormalities involving the medial temporal lobe, and all had abnormal EEG involving generalized slowing.

Fourteen suicidal patients were treated with an antipsychotic, 4 with dexmedetomidine, and 12 with lorazepam. In addition, 10 received plasmapheresis and 7 received immunoglobulin.

Of note, at discharge, self-directed violent thoughts and behaviors completely remitted in 14 of the 15 patients. Long-term follow-up showed that they remained free of suicidality.

Dr. Ramirez-Bermúdez noted that in some patients with neuropsychiatric disturbances, “there are autoantibodies against the NR1 subunit of the NMDA glutamate receptor: the main excitatory neurotransmitter in the human brain.”

The NMDA receptor is “particularly important as part of the biological signaling that is required in several cognitive and affective processes leading to complex behaviors,” he said. NMDA receptor dysfunction “may lead to states in which these cognitive and affective processes are disturbed,” frequently resulting in psychosis.

Study coauthor Ava Easton, MD, chief executive of the Encephalitis Society, told this news organization that mental health issues, self-injurious thoughts, and suicidal behaviors after encephalitis “may occur for a number of reasons and stigma around talking about mental health can be a real barrier to speaking up about symptoms; but it is an important barrier to overcome.”

Dr. Easton, an honorary fellow in the department of clinical infection, microbiology, and immunology, University of Liverpool, England, added that their study “provides a platform on which to break taboo, show tangible links which are based on data between suicide and encephalitis, and call for more awareness of the risk of mental health issues during and after encephalitis.”
 

‘Neglected symptom’

Commenting on the study, Carsten Finke, MD, Heisenberg Professor for Cognitive Neurology and consultant neurologist, department of neurology at Charité, Berlin, and professor at Berlin School of Mind and Brain, said that the research was on “a very important topic on a so far rather neglected symptom of encephalitis.”

Dr. Finke, a founding member of the scientific council of the German Network for Research on Autoimmune Encephalitis, was not involved in the current study.

He noted that 77% of people don’t know what encephalitis is. “This lack of awareness leads to delays in diagnoses and treatment – and poorer outcomes for patients,” Dr. Finke said.

Also commenting, Michael Eriksen Benros, MD, PhD, professor of immune-psychiatry, department of immunology and microbiology, Health and Medical Sciences, University of Copenhagen, said that the study “underlines the clinical importance of screening individuals with psychotic symptoms for suicidal ideations during acute phases,” as well as those with definite ANMDARE as a likely underlying cause of the psychotic symptoms.

This is important because patients with ANMDARE “might not necessarily be admitted at psychiatric departments where screenings for suicidal ideation are part of the clinical routine,” said Dr. Benros, who was not involved with the research.

Instead, “many patients with ANMDARE are at neurological departments during acute phases,” he added.

The study was supported by the National Council of Science and Technology of Mexico. Dr. Ramirez-Bermúdez, Dr. Easton, Dr. Benros, and Dr. Finke report no relevant financial relationships.

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

COPENHAGEN – Vedolizumab (ENTYVIO) a monoclonal antibody drug, shows a higher overall 1- and 2-year persistence of use – the overall time that a patient stays on a medication – compared with two anti–tumor necrosis factor inhibitors (anti-TNFi) in both Crohn’s disease and ulcerative colitis, according to the first meta-analysis of their real-world effectiveness.

The results mostly applied to bionaive subjects, and the benefit of vedolizumab over both TNFi’s – infliximab (Remicade) and adalimumab (Humira), was more evident in ulcerative colitis, compared with Crohn’s disease, noted the researchers, led by Tsz Hong Yiu, MD, a clinician and researcher at the University of Sydney.

“It appears that patients are more likely to stay on vedolizumab than either infliximab or adalimumab, especially in bionaive patients, which could suggest either a better tolerance to the treatment or a better response,” Dr. Yiu said in an interview at the annual Congress of the European Crohn’s and Colitis Organisation.

The 2-year follow up data were particularly encouraging, noted Dr. Yiu, with more patients persisting on vedolizumab than both anti-TNF alpha drugs overall with respect to both ulcerative colitis and Crohn’s disease.

In a head-to-head comparison, 15% more patients stayed on vedolizumab than anti-TNF alpha drugs overall, at 1-year follow-up for both ulcerative colitis and Crohn’s disease (risk ratio, 1.15). At 2 years of follow-up, 12% more patients remained on vedolizumab in comparison with anti-TNF alpha drugs overall (RR, 1.12), again for both forms of inflammatory bowel disease (IBD).

“This may provide early evidence that supports vedolizumab as a first-line biologic agent for inpatients with inflammatory bowel disease,” said Dr. Yiu, noting that further research was required to validate the correlation of persistence with clinical effectiveness.

Adding comment on the motivation for the study, senior author Rupert Leong, MD, a gastroenterologist at Concord RepatriaKon General Hospital, Sydney, said, “We wanted to identify the drug with the highest effectiveness, which is the real-world benefit of the drug to patients, rather than efficacy, which refers to clinical trial data.”

“Importantly, clinical trial data are usually only 1 year, whereas persistence collects data often for several years. This is relevant in chronic diseases that can affect patients over several decades, because the true benefit of a drug cannot be implied from a short-term clinical trial,” he explained.  

Persistence was chosen as the primary end-point because it is a measure that incorporates a drug’s efficacy and side-effect profile but also the patient’s perspective, added Dr. Yiu. “So, a patient may value mild side effects over treatment effectiveness and decide to cease treatment.”   

A prior meta-analysis looking at loss of response found that 33% of people taking infliximab and 41% of people taking adalimumab became resistant to the biologics after a median follow up of 1 year. “The most common cause of loss of response to anti-TNF inhibitors is due to immunogenicity,” remarked Dr. Yiu.  “These findings suggested that alternative biologics with high effectiveness should be considered.”

Data from the 2019 VARSITY study also informed the researchers’ decision to conduct a real-world study. VARSITY investigators found vedolizumab had increased efficacy over adalimumab in ulcerative colitis, however, data on the real-world effectiveness of vedolizumab, compared with adalimumab and infliximab, in both ulcerative colitis and Crohn’s disease remained unknown.

Dr. Leong pointed out the difficulty in selecting the correct treatment given the increasing numbers of biological agents available. “The paucity of head-to-head studies meant use of cohort studies is considered both relevant and informative, not least because long-term follow-up data can reveal secondary loss of response of these monoclonal antibodies, while pooling data further increases the statistical power and determines consistency.”

As such, the researchers conducted a systematic review and meta-analysis of six observational studies evaluating persistence, as a surrogate marker for clinical response, of vedolizumab versus infliximab and adalimumab among participants aged over 18 years with a diagnosis of either ulcerative colitis or Crohn’s disease from 2017 to July 2022.

Overall, the study found that 1-year persistence of vedolizumab was 71.2% in ulcerative colitis and 76% in Crohn’s disease, which was significantly higher than with infliximab (56.4% in ulcerative colitis, 53.7% in Crohn’s disease), and likewise with adalimumab (53.7% in ulcerative colitis, 55.6% in Crohn’s disease).

Results of 2-year persistence were pooled from four studies and found that vedolizumab had a 2-year persistence of 66% in ulcerative colitis and 61% in Crohn’s disease. By comparison, infliximab had a persistence of 49.7% for ulcerative colitis and 59.1% for Crohn’s disease, and adalimumab had a persistence of 31.4% for ulcerative colitis and 56% for Crohn’s disease).

In ulcerative colitis specifically, vedolizumab performed better than both adalimumab and infliximab with an RR of 1.41 (95% confidence interval, 1.14-1.74) and 1.15 (95% CI, 1.06-1.25) respectively, and an RR of 1.23 (95% CI, 1.14-1.33) was generated when adalimumab and infliximab results were combined after 1 year of follow-up.

In Crohn’s disease specifically, vedolizumab had a slightly higher 1-year persistence over anti-TNF inhibitors combined (RR, 1.10; 95% CI, 1.02-1.19), but there were insufficient data to support individual analysis.

In a subgroup of bionaive patients, vedolizumab had a higher 1-year persistence (RR, 1.14; 95% CI, 1.07-1.22) but did not show a statistically significant advantage in bioexperienced patients (RR, 1.04; 95% CI, 0.80-1.35), compared with anti-TNF inhibitors.

Dr. Yiu remarked that they were unable to identify any randomized controlled trials (RCTs) directly comparing infliximab versus vedolizumab in IBD at the time of their systematic review. However, he drew attention to a recent research article that compared the effectiveness, persistence, and side-effect profile of vedolizumab and infliximab in a small cohort of ulcerative colitis patients. “ In this study, vedolizumab showed overall superiority over infliximab, which is in keeping with our study’s findings.”  

Commenting on the study, Viraj Kariyawasam, MD, gastroenterologist and head of IBD at Blacktown and Mount Druitt hospital in Sydney, said the findings were “very important in defining the place of vedolizumab in the treatment of ulcerative colitis, and more so in Crohn’s disease.”

“Despite vedolizumab being considered a lower-efficacy drug, compared to infliximab, in Crohn’s disease by most practicing clinicians, and still favoring anti-TNF in the treatment of Crohn’s disease, the study highlights the superior persistence of vedolizumab,” he said in an interview.

“This is likely associated with efficacy over the two most used anti-TNF agents. With the knowledge we have about reduced efficacy of vedolizumab after the use of anti-TNF, or as a second- or third-line agent, and its superior persistence as a first-line biologic with already published safety data, vedolizumab should be considered and preferred as a first-line agent in the treatment of both ulcerative colitis and Crohn’s disease.” 

Dr. Yiu has declared no conflicts of interest. Dr. Leong declares he is an advisory board member of AbbVie, Aspen, BMS, Celgene, Celltrion, Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSD, Novartis, Pfizer, Prometheus Biosciences, Takeda; research grant recipient of Celltrion, Shire, Janssen, Takeda, Gastroenterological Society of Australia, NHMRC, Gutsy Group, Pfizer, Joanna Tiddy grant University of Sydney. One coauthor is an advisory board member of AbbVie and has received speaker fees from AbbVie and Takeda. Dr. Kariyawasam has educational grants and/or speaker fees from Janssen, AbbVie, and Takeda.
 

COPENHAGEN – Vedolizumab (ENTYVIO) a monoclonal antibody drug, shows a higher overall 1- and 2-year persistence of use – the overall time that a patient stays on a medication – compared with two anti–tumor necrosis factor inhibitors (anti-TNFi) in both Crohn’s disease and ulcerative colitis, according to the first meta-analysis of their real-world effectiveness.

The results mostly applied to bionaive subjects, and the benefit of vedolizumab over both TNFi’s – infliximab (Remicade) and adalimumab (Humira), was more evident in ulcerative colitis, compared with Crohn’s disease, noted the researchers, led by Tsz Hong Yiu, MD, a clinician and researcher at the University of Sydney.

“It appears that patients are more likely to stay on vedolizumab than either infliximab or adalimumab, especially in bionaive patients, which could suggest either a better tolerance to the treatment or a better response,” Dr. Yiu said in an interview at the annual Congress of the European Crohn’s and Colitis Organisation.

The 2-year follow up data were particularly encouraging, noted Dr. Yiu, with more patients persisting on vedolizumab than both anti-TNF alpha drugs overall with respect to both ulcerative colitis and Crohn’s disease.

In a head-to-head comparison, 15% more patients stayed on vedolizumab than anti-TNF alpha drugs overall, at 1-year follow-up for both ulcerative colitis and Crohn’s disease (risk ratio, 1.15). At 2 years of follow-up, 12% more patients remained on vedolizumab in comparison with anti-TNF alpha drugs overall (RR, 1.12), again for both forms of inflammatory bowel disease (IBD).

“This may provide early evidence that supports vedolizumab as a first-line biologic agent for inpatients with inflammatory bowel disease,” said Dr. Yiu, noting that further research was required to validate the correlation of persistence with clinical effectiveness.

Adding comment on the motivation for the study, senior author Rupert Leong, MD, a gastroenterologist at Concord RepatriaKon General Hospital, Sydney, said, “We wanted to identify the drug with the highest effectiveness, which is the real-world benefit of the drug to patients, rather than efficacy, which refers to clinical trial data.”

“Importantly, clinical trial data are usually only 1 year, whereas persistence collects data often for several years. This is relevant in chronic diseases that can affect patients over several decades, because the true benefit of a drug cannot be implied from a short-term clinical trial,” he explained.  

Persistence was chosen as the primary end-point because it is a measure that incorporates a drug’s efficacy and side-effect profile but also the patient’s perspective, added Dr. Yiu. “So, a patient may value mild side effects over treatment effectiveness and decide to cease treatment.”   

A prior meta-analysis looking at loss of response found that 33% of people taking infliximab and 41% of people taking adalimumab became resistant to the biologics after a median follow up of 1 year. “The most common cause of loss of response to anti-TNF inhibitors is due to immunogenicity,” remarked Dr. Yiu.  “These findings suggested that alternative biologics with high effectiveness should be considered.”

Data from the 2019 VARSITY study also informed the researchers’ decision to conduct a real-world study. VARSITY investigators found vedolizumab had increased efficacy over adalimumab in ulcerative colitis, however, data on the real-world effectiveness of vedolizumab, compared with adalimumab and infliximab, in both ulcerative colitis and Crohn’s disease remained unknown.

Dr. Leong pointed out the difficulty in selecting the correct treatment given the increasing numbers of biological agents available. “The paucity of head-to-head studies meant use of cohort studies is considered both relevant and informative, not least because long-term follow-up data can reveal secondary loss of response of these monoclonal antibodies, while pooling data further increases the statistical power and determines consistency.”

As such, the researchers conducted a systematic review and meta-analysis of six observational studies evaluating persistence, as a surrogate marker for clinical response, of vedolizumab versus infliximab and adalimumab among participants aged over 18 years with a diagnosis of either ulcerative colitis or Crohn’s disease from 2017 to July 2022.

Overall, the study found that 1-year persistence of vedolizumab was 71.2% in ulcerative colitis and 76% in Crohn’s disease, which was significantly higher than with infliximab (56.4% in ulcerative colitis, 53.7% in Crohn’s disease), and likewise with adalimumab (53.7% in ulcerative colitis, 55.6% in Crohn’s disease).

Results of 2-year persistence were pooled from four studies and found that vedolizumab had a 2-year persistence of 66% in ulcerative colitis and 61% in Crohn’s disease. By comparison, infliximab had a persistence of 49.7% for ulcerative colitis and 59.1% for Crohn’s disease, and adalimumab had a persistence of 31.4% for ulcerative colitis and 56% for Crohn’s disease).

In ulcerative colitis specifically, vedolizumab performed better than both adalimumab and infliximab with an RR of 1.41 (95% confidence interval, 1.14-1.74) and 1.15 (95% CI, 1.06-1.25) respectively, and an RR of 1.23 (95% CI, 1.14-1.33) was generated when adalimumab and infliximab results were combined after 1 year of follow-up.

In Crohn’s disease specifically, vedolizumab had a slightly higher 1-year persistence over anti-TNF inhibitors combined (RR, 1.10; 95% CI, 1.02-1.19), but there were insufficient data to support individual analysis.

In a subgroup of bionaive patients, vedolizumab had a higher 1-year persistence (RR, 1.14; 95% CI, 1.07-1.22) but did not show a statistically significant advantage in bioexperienced patients (RR, 1.04; 95% CI, 0.80-1.35), compared with anti-TNF inhibitors.

Dr. Yiu remarked that they were unable to identify any randomized controlled trials (RCTs) directly comparing infliximab versus vedolizumab in IBD at the time of their systematic review. However, he drew attention to a recent research article that compared the effectiveness, persistence, and side-effect profile of vedolizumab and infliximab in a small cohort of ulcerative colitis patients. “ In this study, vedolizumab showed overall superiority over infliximab, which is in keeping with our study’s findings.”  

Commenting on the study, Viraj Kariyawasam, MD, gastroenterologist and head of IBD at Blacktown and Mount Druitt hospital in Sydney, said the findings were “very important in defining the place of vedolizumab in the treatment of ulcerative colitis, and more so in Crohn’s disease.”

“Despite vedolizumab being considered a lower-efficacy drug, compared to infliximab, in Crohn’s disease by most practicing clinicians, and still favoring anti-TNF in the treatment of Crohn’s disease, the study highlights the superior persistence of vedolizumab,” he said in an interview.

“This is likely associated with efficacy over the two most used anti-TNF agents. With the knowledge we have about reduced efficacy of vedolizumab after the use of anti-TNF, or as a second- or third-line agent, and its superior persistence as a first-line biologic with already published safety data, vedolizumab should be considered and preferred as a first-line agent in the treatment of both ulcerative colitis and Crohn’s disease.” 

Dr. Yiu has declared no conflicts of interest. Dr. Leong declares he is an advisory board member of AbbVie, Aspen, BMS, Celgene, Celltrion, Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSD, Novartis, Pfizer, Prometheus Biosciences, Takeda; research grant recipient of Celltrion, Shire, Janssen, Takeda, Gastroenterological Society of Australia, NHMRC, Gutsy Group, Pfizer, Joanna Tiddy grant University of Sydney. One coauthor is an advisory board member of AbbVie and has received speaker fees from AbbVie and Takeda. Dr. Kariyawasam has educational grants and/or speaker fees from Janssen, AbbVie, and Takeda.
 

COPENHAGEN – Vedolizumab (ENTYVIO) a monoclonal antibody drug, shows a higher overall 1- and 2-year persistence of use – the overall time that a patient stays on a medication – compared with two anti–tumor necrosis factor inhibitors (anti-TNFi) in both Crohn’s disease and ulcerative colitis, according to the first meta-analysis of their real-world effectiveness.

The results mostly applied to bionaive subjects, and the benefit of vedolizumab over both TNFi’s – infliximab (Remicade) and adalimumab (Humira), was more evident in ulcerative colitis, compared with Crohn’s disease, noted the researchers, led by Tsz Hong Yiu, MD, a clinician and researcher at the University of Sydney.

“It appears that patients are more likely to stay on vedolizumab than either infliximab or adalimumab, especially in bionaive patients, which could suggest either a better tolerance to the treatment or a better response,” Dr. Yiu said in an interview at the annual Congress of the European Crohn’s and Colitis Organisation.

The 2-year follow up data were particularly encouraging, noted Dr. Yiu, with more patients persisting on vedolizumab than both anti-TNF alpha drugs overall with respect to both ulcerative colitis and Crohn’s disease.

In a head-to-head comparison, 15% more patients stayed on vedolizumab than anti-TNF alpha drugs overall, at 1-year follow-up for both ulcerative colitis and Crohn’s disease (risk ratio, 1.15). At 2 years of follow-up, 12% more patients remained on vedolizumab in comparison with anti-TNF alpha drugs overall (RR, 1.12), again for both forms of inflammatory bowel disease (IBD).

“This may provide early evidence that supports vedolizumab as a first-line biologic agent for inpatients with inflammatory bowel disease,” said Dr. Yiu, noting that further research was required to validate the correlation of persistence with clinical effectiveness.

Adding comment on the motivation for the study, senior author Rupert Leong, MD, a gastroenterologist at Concord RepatriaKon General Hospital, Sydney, said, “We wanted to identify the drug with the highest effectiveness, which is the real-world benefit of the drug to patients, rather than efficacy, which refers to clinical trial data.”

“Importantly, clinical trial data are usually only 1 year, whereas persistence collects data often for several years. This is relevant in chronic diseases that can affect patients over several decades, because the true benefit of a drug cannot be implied from a short-term clinical trial,” he explained.  

Persistence was chosen as the primary end-point because it is a measure that incorporates a drug’s efficacy and side-effect profile but also the patient’s perspective, added Dr. Yiu. “So, a patient may value mild side effects over treatment effectiveness and decide to cease treatment.”   

A prior meta-analysis looking at loss of response found that 33% of people taking infliximab and 41% of people taking adalimumab became resistant to the biologics after a median follow up of 1 year. “The most common cause of loss of response to anti-TNF inhibitors is due to immunogenicity,” remarked Dr. Yiu.  “These findings suggested that alternative biologics with high effectiveness should be considered.”

Data from the 2019 VARSITY study also informed the researchers’ decision to conduct a real-world study. VARSITY investigators found vedolizumab had increased efficacy over adalimumab in ulcerative colitis, however, data on the real-world effectiveness of vedolizumab, compared with adalimumab and infliximab, in both ulcerative colitis and Crohn’s disease remained unknown.

Dr. Leong pointed out the difficulty in selecting the correct treatment given the increasing numbers of biological agents available. “The paucity of head-to-head studies meant use of cohort studies is considered both relevant and informative, not least because long-term follow-up data can reveal secondary loss of response of these monoclonal antibodies, while pooling data further increases the statistical power and determines consistency.”

As such, the researchers conducted a systematic review and meta-analysis of six observational studies evaluating persistence, as a surrogate marker for clinical response, of vedolizumab versus infliximab and adalimumab among participants aged over 18 years with a diagnosis of either ulcerative colitis or Crohn’s disease from 2017 to July 2022.

Overall, the study found that 1-year persistence of vedolizumab was 71.2% in ulcerative colitis and 76% in Crohn’s disease, which was significantly higher than with infliximab (56.4% in ulcerative colitis, 53.7% in Crohn’s disease), and likewise with adalimumab (53.7% in ulcerative colitis, 55.6% in Crohn’s disease).

Results of 2-year persistence were pooled from four studies and found that vedolizumab had a 2-year persistence of 66% in ulcerative colitis and 61% in Crohn’s disease. By comparison, infliximab had a persistence of 49.7% for ulcerative colitis and 59.1% for Crohn’s disease, and adalimumab had a persistence of 31.4% for ulcerative colitis and 56% for Crohn’s disease).

In ulcerative colitis specifically, vedolizumab performed better than both adalimumab and infliximab with an RR of 1.41 (95% confidence interval, 1.14-1.74) and 1.15 (95% CI, 1.06-1.25) respectively, and an RR of 1.23 (95% CI, 1.14-1.33) was generated when adalimumab and infliximab results were combined after 1 year of follow-up.

In Crohn’s disease specifically, vedolizumab had a slightly higher 1-year persistence over anti-TNF inhibitors combined (RR, 1.10; 95% CI, 1.02-1.19), but there were insufficient data to support individual analysis.

In a subgroup of bionaive patients, vedolizumab had a higher 1-year persistence (RR, 1.14; 95% CI, 1.07-1.22) but did not show a statistically significant advantage in bioexperienced patients (RR, 1.04; 95% CI, 0.80-1.35), compared with anti-TNF inhibitors.

Dr. Yiu remarked that they were unable to identify any randomized controlled trials (RCTs) directly comparing infliximab versus vedolizumab in IBD at the time of their systematic review. However, he drew attention to a recent research article that compared the effectiveness, persistence, and side-effect profile of vedolizumab and infliximab in a small cohort of ulcerative colitis patients. “ In this study, vedolizumab showed overall superiority over infliximab, which is in keeping with our study’s findings.”  

Commenting on the study, Viraj Kariyawasam, MD, gastroenterologist and head of IBD at Blacktown and Mount Druitt hospital in Sydney, said the findings were “very important in defining the place of vedolizumab in the treatment of ulcerative colitis, and more so in Crohn’s disease.”

“Despite vedolizumab being considered a lower-efficacy drug, compared to infliximab, in Crohn’s disease by most practicing clinicians, and still favoring anti-TNF in the treatment of Crohn’s disease, the study highlights the superior persistence of vedolizumab,” he said in an interview.

“This is likely associated with efficacy over the two most used anti-TNF agents. With the knowledge we have about reduced efficacy of vedolizumab after the use of anti-TNF, or as a second- or third-line agent, and its superior persistence as a first-line biologic with already published safety data, vedolizumab should be considered and preferred as a first-line agent in the treatment of both ulcerative colitis and Crohn’s disease.” 

Dr. Yiu has declared no conflicts of interest. Dr. Leong declares he is an advisory board member of AbbVie, Aspen, BMS, Celgene, Celltrion, Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSD, Novartis, Pfizer, Prometheus Biosciences, Takeda; research grant recipient of Celltrion, Shire, Janssen, Takeda, Gastroenterological Society of Australia, NHMRC, Gutsy Group, Pfizer, Joanna Tiddy grant University of Sydney. One coauthor is an advisory board member of AbbVie and has received speaker fees from AbbVie and Takeda. Dr. Kariyawasam has educational grants and/or speaker fees from Janssen, AbbVie, and Takeda.
 

COPENHAGEN – Mortality rate, length of hospital stay, and cost of hospitalization all drop significantly in patients with inflammatory bowel disease (IBD) concurrently using cannabis, shows a study that supports wider availability of the substance for specified medical use.

Inpatient mortality dropped by more than 70% in those patients concurrently using cannabis for another indication, compared with those not taking the drug, while total cost of hospitalization dropped by more than $11,000.

The findings were presented as a poster by Neethi Dasu, DO, PGY 6 Gastroenterology Fellow, at Jefferson Health Hospital, N.J., at the annual congress of the European Crohn’s and Colitis Organization. Dr. Dasu worked with coinvestigator Brian Blair, DO, FACOI, Gastroenterology Program Director, IBD specialist, at the same hospital.

“This study reveals substantial benefits of cannabis in the management of patients with IBD,” Dr. Dasu said. “Not only do patients spend less time in hospital, but they also have a decrease in mortality and hospital cost, which can be significant for patients with IBD, a chronic condition, that often burdens them with high health care spend.”

The researcher also highlighted that with annual U.S. health care spending on IBD having increased significantly in recent years, getting patients well and out of the hospital in a timely manner is key and that “cannabis might help in this aim.”

Cannabis use is legalized in some U.S. states for medical treatment of several chronic, debilitating disorders, especially cancer. Currently, there is no direct Food and Drug Administration approval for use for IBD. “Utilizing it would be considered off-label and investigational,” Dr. Dasu pointed out.

Patients report cannabis, as a pain control treatment, is effective for acute flares and chronic IBD, said Dr. Dasu. “It is an excellent agent for pain control that is not a narcotic, as with opioids, which can cause dependence and addiction. These could ultimately harm patients in the long term,” she addedin an interview. “Opioids can also cause drowsiness and side effects, which harm a person’s quality of life.”
 

Patients with IBD using cannabis concurrently

Dr. Dasu and her coresearchers aimed to see if outcomes including mortality and pain could be modified with “a very accessible and cost-efficient agent that does not cause long term addiction or adverse events.”

She added that previous studies had evaluated the clinical response in patients with IBD and concomitant cannabis use, but that their study was novel because it looked at inpatient outcomes as well as overall hospital cost.

Dr. Dasu and colleagues analyzed data over the years 2015-2019, from the Nationwide Inpatient Sample (NIS), a large publicly available all-payer inpatient care database, which encompasses approximately 7 million inpatient hospitalizations annually in the United States.

All included patients had IBD, either ulcerative colitis or Crohn’s disease, were aged 18 years and over, and used cannabis for a concurrent indication.

Odds ratios were calculated for in-hospital mortality, average length of hospital stay, and hospital charges, after adjusting for age, gender, race, primary insurance payer status, hospital type and size (number of beds), hospital region, hospital teaching status, and other demographic characteristics.

Of the 1,198,839 patients with IBD, 29,445 used cannabis for a different indication. Participants had an average age of 38.7 years.
 

Highly significant drop in mortality and hospital costs

Inpatient mortality shows a significant decrease of 72% (odds ratio, 0.28; confidence interval, 0.19-0.41, P < .0001) in those who concurrently used cannabis, compared with those who did not. Hospital length of stay also dropped by –0.17 days (95% CI, –0.35 to –0.01; P < .041), and this translated into a significant drop in the total cost of hospitalization from $39,309.00 (IBD without cannabis use) to $28,254.30 (IBD with cannabis use), resulting in an $11,054.70 savings (95% CI, –$13,681.15 to –$8,427.24; P < .0001).

As a chronic inflammatory disease, IBD involves immune dysregulation leading to symptoms of nausea, vomiting, bleeding, and abdominal pain; however, the pathophysiologic mechanism is not fully understood. She added that studies in mice had shown that cannabis acts via cannabinoid 1 and 2 receptors, located in the nervous system, to decrease pain, nausea, and vomiting. “Mechanisms of cannabis’s analgesic effect also involves inhibition of the release of neurotransmitters involved in pain and inflammation.”

Asked how she felt about the future for cannabis treatment in IBD, Dr. Dasu remarked that it would most likely require decriminalizing marijuana use on a federal level, although individual states currently offer exemptions.

“Further research should be done to evaluate the medical benefits of cannabis use in patients with IBD, with studies warranted to investigate the factors that may be driving these differences, as well warranted to investigations into the effect of cannabis on remission rates, rates of hospitalization, potential complications, and quality of life,” concluded Dr. Dasu.

Commenting on the study, Mary-Jane Williams, MD, a gastroenterology fellow at East Carolina University Health Medical Center, Greenville, N.C., told this news organization that the study was “a pleasant breath of information on the topic of cannabis use in IBD,” adding that providers often face questions about cannabis use from patients.

“Modulation of the endocannabinoid system ... plays a key role in the pathogenesis of IBD including pain control, limiting intestinal inflammation, and decreasing intestinal motility,” Dr. Williams said, adding that, “Its use in IBD has promising improvement in the therapeutic effect and overall quality of life.”

“This study highlights and supports substantial therapeutic effects of cannabis in the management of IBD patients, be it their pain control, improving nausea, appetite and sleep, remission rates, earlier time to recovery, shortened hospitalization and faster endoscopic improvement,” she pointed out, noting the need for further studies, but also that most organizations, including the Crohn’s and Colitis Foundation, support policies that facilitate the conduct of clinical research using objective parameters and the potential development of cannabinoid-based medications in the management of our patients with IBD.

Dr. Dasu, Dr. Blair, and Dr. Williams have declared no financial disclosures.

COPENHAGEN – Mortality rate, length of hospital stay, and cost of hospitalization all drop significantly in patients with inflammatory bowel disease (IBD) concurrently using cannabis, shows a study that supports wider availability of the substance for specified medical use.

Inpatient mortality dropped by more than 70% in those patients concurrently using cannabis for another indication, compared with those not taking the drug, while total cost of hospitalization dropped by more than $11,000.

The findings were presented as a poster by Neethi Dasu, DO, PGY 6 Gastroenterology Fellow, at Jefferson Health Hospital, N.J., at the annual congress of the European Crohn’s and Colitis Organization. Dr. Dasu worked with coinvestigator Brian Blair, DO, FACOI, Gastroenterology Program Director, IBD specialist, at the same hospital.

“This study reveals substantial benefits of cannabis in the management of patients with IBD,” Dr. Dasu said. “Not only do patients spend less time in hospital, but they also have a decrease in mortality and hospital cost, which can be significant for patients with IBD, a chronic condition, that often burdens them with high health care spend.”

The researcher also highlighted that with annual U.S. health care spending on IBD having increased significantly in recent years, getting patients well and out of the hospital in a timely manner is key and that “cannabis might help in this aim.”

Cannabis use is legalized in some U.S. states for medical treatment of several chronic, debilitating disorders, especially cancer. Currently, there is no direct Food and Drug Administration approval for use for IBD. “Utilizing it would be considered off-label and investigational,” Dr. Dasu pointed out.

Patients report cannabis, as a pain control treatment, is effective for acute flares and chronic IBD, said Dr. Dasu. “It is an excellent agent for pain control that is not a narcotic, as with opioids, which can cause dependence and addiction. These could ultimately harm patients in the long term,” she addedin an interview. “Opioids can also cause drowsiness and side effects, which harm a person’s quality of life.”
 

Patients with IBD using cannabis concurrently

Dr. Dasu and her coresearchers aimed to see if outcomes including mortality and pain could be modified with “a very accessible and cost-efficient agent that does not cause long term addiction or adverse events.”

She added that previous studies had evaluated the clinical response in patients with IBD and concomitant cannabis use, but that their study was novel because it looked at inpatient outcomes as well as overall hospital cost.

Dr. Dasu and colleagues analyzed data over the years 2015-2019, from the Nationwide Inpatient Sample (NIS), a large publicly available all-payer inpatient care database, which encompasses approximately 7 million inpatient hospitalizations annually in the United States.

All included patients had IBD, either ulcerative colitis or Crohn’s disease, were aged 18 years and over, and used cannabis for a concurrent indication.

Odds ratios were calculated for in-hospital mortality, average length of hospital stay, and hospital charges, after adjusting for age, gender, race, primary insurance payer status, hospital type and size (number of beds), hospital region, hospital teaching status, and other demographic characteristics.

Of the 1,198,839 patients with IBD, 29,445 used cannabis for a different indication. Participants had an average age of 38.7 years.
 

Highly significant drop in mortality and hospital costs

Inpatient mortality shows a significant decrease of 72% (odds ratio, 0.28; confidence interval, 0.19-0.41, P < .0001) in those who concurrently used cannabis, compared with those who did not. Hospital length of stay also dropped by –0.17 days (95% CI, –0.35 to –0.01; P < .041), and this translated into a significant drop in the total cost of hospitalization from $39,309.00 (IBD without cannabis use) to $28,254.30 (IBD with cannabis use), resulting in an $11,054.70 savings (95% CI, –$13,681.15 to –$8,427.24; P < .0001).

As a chronic inflammatory disease, IBD involves immune dysregulation leading to symptoms of nausea, vomiting, bleeding, and abdominal pain; however, the pathophysiologic mechanism is not fully understood. She added that studies in mice had shown that cannabis acts via cannabinoid 1 and 2 receptors, located in the nervous system, to decrease pain, nausea, and vomiting. “Mechanisms of cannabis’s analgesic effect also involves inhibition of the release of neurotransmitters involved in pain and inflammation.”

Asked how she felt about the future for cannabis treatment in IBD, Dr. Dasu remarked that it would most likely require decriminalizing marijuana use on a federal level, although individual states currently offer exemptions.

“Further research should be done to evaluate the medical benefits of cannabis use in patients with IBD, with studies warranted to investigate the factors that may be driving these differences, as well warranted to investigations into the effect of cannabis on remission rates, rates of hospitalization, potential complications, and quality of life,” concluded Dr. Dasu.

Commenting on the study, Mary-Jane Williams, MD, a gastroenterology fellow at East Carolina University Health Medical Center, Greenville, N.C., told this news organization that the study was “a pleasant breath of information on the topic of cannabis use in IBD,” adding that providers often face questions about cannabis use from patients.

“Modulation of the endocannabinoid system ... plays a key role in the pathogenesis of IBD including pain control, limiting intestinal inflammation, and decreasing intestinal motility,” Dr. Williams said, adding that, “Its use in IBD has promising improvement in the therapeutic effect and overall quality of life.”

“This study highlights and supports substantial therapeutic effects of cannabis in the management of IBD patients, be it their pain control, improving nausea, appetite and sleep, remission rates, earlier time to recovery, shortened hospitalization and faster endoscopic improvement,” she pointed out, noting the need for further studies, but also that most organizations, including the Crohn’s and Colitis Foundation, support policies that facilitate the conduct of clinical research using objective parameters and the potential development of cannabinoid-based medications in the management of our patients with IBD.

Dr. Dasu, Dr. Blair, and Dr. Williams have declared no financial disclosures.

COPENHAGEN – Mortality rate, length of hospital stay, and cost of hospitalization all drop significantly in patients with inflammatory bowel disease (IBD) concurrently using cannabis, shows a study that supports wider availability of the substance for specified medical use.

Inpatient mortality dropped by more than 70% in those patients concurrently using cannabis for another indication, compared with those not taking the drug, while total cost of hospitalization dropped by more than $11,000.

The findings were presented as a poster by Neethi Dasu, DO, PGY 6 Gastroenterology Fellow, at Jefferson Health Hospital, N.J., at the annual congress of the European Crohn’s and Colitis Organization. Dr. Dasu worked with coinvestigator Brian Blair, DO, FACOI, Gastroenterology Program Director, IBD specialist, at the same hospital.

“This study reveals substantial benefits of cannabis in the management of patients with IBD,” Dr. Dasu said. “Not only do patients spend less time in hospital, but they also have a decrease in mortality and hospital cost, which can be significant for patients with IBD, a chronic condition, that often burdens them with high health care spend.”

The researcher also highlighted that with annual U.S. health care spending on IBD having increased significantly in recent years, getting patients well and out of the hospital in a timely manner is key and that “cannabis might help in this aim.”

Cannabis use is legalized in some U.S. states for medical treatment of several chronic, debilitating disorders, especially cancer. Currently, there is no direct Food and Drug Administration approval for use for IBD. “Utilizing it would be considered off-label and investigational,” Dr. Dasu pointed out.

Patients report cannabis, as a pain control treatment, is effective for acute flares and chronic IBD, said Dr. Dasu. “It is an excellent agent for pain control that is not a narcotic, as with opioids, which can cause dependence and addiction. These could ultimately harm patients in the long term,” she addedin an interview. “Opioids can also cause drowsiness and side effects, which harm a person’s quality of life.”
 

Patients with IBD using cannabis concurrently

Dr. Dasu and her coresearchers aimed to see if outcomes including mortality and pain could be modified with “a very accessible and cost-efficient agent that does not cause long term addiction or adverse events.”

She added that previous studies had evaluated the clinical response in patients with IBD and concomitant cannabis use, but that their study was novel because it looked at inpatient outcomes as well as overall hospital cost.

Dr. Dasu and colleagues analyzed data over the years 2015-2019, from the Nationwide Inpatient Sample (NIS), a large publicly available all-payer inpatient care database, which encompasses approximately 7 million inpatient hospitalizations annually in the United States.

All included patients had IBD, either ulcerative colitis or Crohn’s disease, were aged 18 years and over, and used cannabis for a concurrent indication.

Odds ratios were calculated for in-hospital mortality, average length of hospital stay, and hospital charges, after adjusting for age, gender, race, primary insurance payer status, hospital type and size (number of beds), hospital region, hospital teaching status, and other demographic characteristics.

Of the 1,198,839 patients with IBD, 29,445 used cannabis for a different indication. Participants had an average age of 38.7 years.
 

Highly significant drop in mortality and hospital costs

Inpatient mortality shows a significant decrease of 72% (odds ratio, 0.28; confidence interval, 0.19-0.41, P < .0001) in those who concurrently used cannabis, compared with those who did not. Hospital length of stay also dropped by –0.17 days (95% CI, –0.35 to –0.01; P < .041), and this translated into a significant drop in the total cost of hospitalization from $39,309.00 (IBD without cannabis use) to $28,254.30 (IBD with cannabis use), resulting in an $11,054.70 savings (95% CI, –$13,681.15 to –$8,427.24; P < .0001).

As a chronic inflammatory disease, IBD involves immune dysregulation leading to symptoms of nausea, vomiting, bleeding, and abdominal pain; however, the pathophysiologic mechanism is not fully understood. She added that studies in mice had shown that cannabis acts via cannabinoid 1 and 2 receptors, located in the nervous system, to decrease pain, nausea, and vomiting. “Mechanisms of cannabis’s analgesic effect also involves inhibition of the release of neurotransmitters involved in pain and inflammation.”

Asked how she felt about the future for cannabis treatment in IBD, Dr. Dasu remarked that it would most likely require decriminalizing marijuana use on a federal level, although individual states currently offer exemptions.

“Further research should be done to evaluate the medical benefits of cannabis use in patients with IBD, with studies warranted to investigate the factors that may be driving these differences, as well warranted to investigations into the effect of cannabis on remission rates, rates of hospitalization, potential complications, and quality of life,” concluded Dr. Dasu.

Commenting on the study, Mary-Jane Williams, MD, a gastroenterology fellow at East Carolina University Health Medical Center, Greenville, N.C., told this news organization that the study was “a pleasant breath of information on the topic of cannabis use in IBD,” adding that providers often face questions about cannabis use from patients.

“Modulation of the endocannabinoid system ... plays a key role in the pathogenesis of IBD including pain control, limiting intestinal inflammation, and decreasing intestinal motility,” Dr. Williams said, adding that, “Its use in IBD has promising improvement in the therapeutic effect and overall quality of life.”

“This study highlights and supports substantial therapeutic effects of cannabis in the management of IBD patients, be it their pain control, improving nausea, appetite and sleep, remission rates, earlier time to recovery, shortened hospitalization and faster endoscopic improvement,” she pointed out, noting the need for further studies, but also that most organizations, including the Crohn’s and Colitis Foundation, support policies that facilitate the conduct of clinical research using objective parameters and the potential development of cannabinoid-based medications in the management of our patients with IBD.

Dr. Dasu, Dr. Blair, and Dr. Williams have declared no financial disclosures.