Conference Coverage

Telemedicine has been proposed as a solution for an array of health care access problems over decades of gradual growth. The vast ramping up of telemedicine during the COVID-19 pandemic greatly expanded the evidence of its feasibility and what appears to be its inevitable incorporation into models of care, according to an update at the annual health policy and advocacy conference sponsored by the American College of Chest Physicians.

American College of Chest Physicians Health Policy and Advocacy

“The cat is out of the bag,” said Jaspal Singh, MD, professor of medicine, Atrium Health, Charlotte, N.C. Due to changes in access and reimbursement to telemedicine driven by the pandemic, he said, “we now have permission to explore new models of care.”

Prior to February 2020, telemedicine was crawling forward at a leisurely pace, according to Dr. Singh. After March 2020, it broke into a run due to enormous demand and was met by a rapid response from the U.S. Congress. The first of four legislative bills that directly or indirectly supported telemedicine was passed on March 6, 2020.

The Centers for Medicare and Medicaid Services responded in kind, making modifications in a number of rules that removed obstacles to telehealth. One modification on April 6, 2020, for example, removed the requirement for a preexisting relationship between the clinician and patient, Dr. Singh said. The CMS also subsequently modified reimbursement policies in order to make telemedicine more tenable for physicians.

Given the risk of contagion from face-to-face encounters, telemedicine in the early days of the pandemic was not just attractive but the only practical and safe approach to medical care in many circumstances. Physicians and patients were anxious for health care that did not require in-office visits even though many critical issues for telemedicine, including its relative effectiveness, had not yet been fully evaluated.

Much has been learned regarding the feasibility and acceptability of telemedicine during the pandemic, but Dr. Singh noted that quality of care relative to in-person visits remains weakly supported for most indications. Indeed, he outlined sizable list of incompletely resolved issues, including optimal payment models, management of privacy concerns, and how to balance advantages to disadvantages.

For patients and physicians, the strengths of telemedicine include greater convenience made possible by the elimination of travel and waiting rooms. For the health care system, it can include less infrastructure and overhead. For many physicians, telemedicine might be perceived as more efficient.

On the other hand, some patients might feel that a clinical encounter is incomplete without a physical examination even when the physician does not feel the physical examination is needed, according to Dr. Singh. He cited a survey suggesting nearly half of patients expressed concern about a lack of connection to health care providers following a virtual visit.

In the same 2020 National Poll on Healthy Aging 2020 survey conducted by the University of Michigan 67% of respondents reported that the quality of care was not as good as that provided by in-patient visits, and 24% expressed concern about privacy. However, at the time the poll was taken in May 2020, experience with telemedicine among many of the respondents may have been limited. As telemedicine is integrated into routine care, perceptions might change as experience increases.

A distinction between telemedicine in routine care and telemedicine as a strategy to respond to a pandemic is important, Dr. Singh indicated. Dr. Singh was the lead author for a position paper on telemedicine for the diagnosis and treatment of sleep disorders from the American Academy of Sleep Medicine 5 years ago, but he acknowledged that models of care might differ when responding to abnormal surges in health care demand.

The surge in demand for COVID-19–related care engendered numerous innovative solutions. As examples, Dr. Singh recounted how a virtual hospital was created at his own institution. In a published study, 1,477 patients diagnosed with COVID-19 over a 6-week period remained at home and received care in a virtual observation unit (VCU) or a virtual acute care unit (VACU) . Only a small percentage required eventual hospital admission. In the VACU, patients were able to receive advanced care including IV fluids and some form of respiratory support .

It is unclear how the COVID-19 pandemic will change telemedicine. Now, with declining cases of the infection, telemedicine is back to a walk after the sprint required during the height of the pandemic, according to Dr. Singh. However, Dr. Singh thinks many physicians and patients will have a different perception of telemedicine after the widespread exposure to this type of care.

In terms of the relative role of in-patient and virtual visits across indications, “we do not know how this will play out, but we will probably end up toggling between the two,” Dr. Singh said.

This is an area that is being followed closely by the CHEST Health Policy and Advocacy Committee, according to Kathleen Sarmiento, MD, director, VISN 21 Sleep Clinical Resource Hub for the San Francisco VA Health Care System. A member of that committee and moderator of the session in which Dr. Singh spoke,

American College of Chest Physicians Health Policy and Advocacy Conference

Dr. Sarmiento called the effort to bring permanent coverage of telehealth services “the shared responsibility of every medical society engaged in advocacy.”

However, she cautioned that there might be intended and unintended consequences from telehealth that require analysis to develop policies that are in the best interests of effective care. She said, the “ACCP, along with its sister societies, does have a role in supporting the evaluation of the impact of these changes on both patients and providers in the fields of pulmonary medicine, critical care, and sleep medicine.”

Dr. Singh reports a financial relationship with AstraZeneca. Dr. Sarmiento reports no relevant financial relationship with AstraZeneca.

Telemedicine has been proposed as a solution for an array of health care access problems over decades of gradual growth. The vast ramping up of telemedicine during the COVID-19 pandemic greatly expanded the evidence of its feasibility and what appears to be its inevitable incorporation into models of care, according to an update at the annual health policy and advocacy conference sponsored by the American College of Chest Physicians.

American College of Chest Physicians Health Policy and Advocacy

“The cat is out of the bag,” said Jaspal Singh, MD, professor of medicine, Atrium Health, Charlotte, N.C. Due to changes in access and reimbursement to telemedicine driven by the pandemic, he said, “we now have permission to explore new models of care.”

Prior to February 2020, telemedicine was crawling forward at a leisurely pace, according to Dr. Singh. After March 2020, it broke into a run due to enormous demand and was met by a rapid response from the U.S. Congress. The first of four legislative bills that directly or indirectly supported telemedicine was passed on March 6, 2020.

The Centers for Medicare and Medicaid Services responded in kind, making modifications in a number of rules that removed obstacles to telehealth. One modification on April 6, 2020, for example, removed the requirement for a preexisting relationship between the clinician and patient, Dr. Singh said. The CMS also subsequently modified reimbursement policies in order to make telemedicine more tenable for physicians.

Given the risk of contagion from face-to-face encounters, telemedicine in the early days of the pandemic was not just attractive but the only practical and safe approach to medical care in many circumstances. Physicians and patients were anxious for health care that did not require in-office visits even though many critical issues for telemedicine, including its relative effectiveness, had not yet been fully evaluated.

Much has been learned regarding the feasibility and acceptability of telemedicine during the pandemic, but Dr. Singh noted that quality of care relative to in-person visits remains weakly supported for most indications. Indeed, he outlined sizable list of incompletely resolved issues, including optimal payment models, management of privacy concerns, and how to balance advantages to disadvantages.

For patients and physicians, the strengths of telemedicine include greater convenience made possible by the elimination of travel and waiting rooms. For the health care system, it can include less infrastructure and overhead. For many physicians, telemedicine might be perceived as more efficient.

On the other hand, some patients might feel that a clinical encounter is incomplete without a physical examination even when the physician does not feel the physical examination is needed, according to Dr. Singh. He cited a survey suggesting nearly half of patients expressed concern about a lack of connection to health care providers following a virtual visit.

In the same 2020 National Poll on Healthy Aging 2020 survey conducted by the University of Michigan 67% of respondents reported that the quality of care was not as good as that provided by in-patient visits, and 24% expressed concern about privacy. However, at the time the poll was taken in May 2020, experience with telemedicine among many of the respondents may have been limited. As telemedicine is integrated into routine care, perceptions might change as experience increases.

A distinction between telemedicine in routine care and telemedicine as a strategy to respond to a pandemic is important, Dr. Singh indicated. Dr. Singh was the lead author for a position paper on telemedicine for the diagnosis and treatment of sleep disorders from the American Academy of Sleep Medicine 5 years ago, but he acknowledged that models of care might differ when responding to abnormal surges in health care demand.

The surge in demand for COVID-19–related care engendered numerous innovative solutions. As examples, Dr. Singh recounted how a virtual hospital was created at his own institution. In a published study, 1,477 patients diagnosed with COVID-19 over a 6-week period remained at home and received care in a virtual observation unit (VCU) or a virtual acute care unit (VACU) . Only a small percentage required eventual hospital admission. In the VACU, patients were able to receive advanced care including IV fluids and some form of respiratory support .

It is unclear how the COVID-19 pandemic will change telemedicine. Now, with declining cases of the infection, telemedicine is back to a walk after the sprint required during the height of the pandemic, according to Dr. Singh. However, Dr. Singh thinks many physicians and patients will have a different perception of telemedicine after the widespread exposure to this type of care.

In terms of the relative role of in-patient and virtual visits across indications, “we do not know how this will play out, but we will probably end up toggling between the two,” Dr. Singh said.

This is an area that is being followed closely by the CHEST Health Policy and Advocacy Committee, according to Kathleen Sarmiento, MD, director, VISN 21 Sleep Clinical Resource Hub for the San Francisco VA Health Care System. A member of that committee and moderator of the session in which Dr. Singh spoke,

American College of Chest Physicians Health Policy and Advocacy Conference

Dr. Sarmiento called the effort to bring permanent coverage of telehealth services “the shared responsibility of every medical society engaged in advocacy.”

However, she cautioned that there might be intended and unintended consequences from telehealth that require analysis to develop policies that are in the best interests of effective care. She said, the “ACCP, along with its sister societies, does have a role in supporting the evaluation of the impact of these changes on both patients and providers in the fields of pulmonary medicine, critical care, and sleep medicine.”

Dr. Singh reports a financial relationship with AstraZeneca. Dr. Sarmiento reports no relevant financial relationship with AstraZeneca.

Telemedicine has been proposed as a solution for an array of health care access problems over decades of gradual growth. The vast ramping up of telemedicine during the COVID-19 pandemic greatly expanded the evidence of its feasibility and what appears to be its inevitable incorporation into models of care, according to an update at the annual health policy and advocacy conference sponsored by the American College of Chest Physicians.

American College of Chest Physicians Health Policy and Advocacy

“The cat is out of the bag,” said Jaspal Singh, MD, professor of medicine, Atrium Health, Charlotte, N.C. Due to changes in access and reimbursement to telemedicine driven by the pandemic, he said, “we now have permission to explore new models of care.”

Prior to February 2020, telemedicine was crawling forward at a leisurely pace, according to Dr. Singh. After March 2020, it broke into a run due to enormous demand and was met by a rapid response from the U.S. Congress. The first of four legislative bills that directly or indirectly supported telemedicine was passed on March 6, 2020.

The Centers for Medicare and Medicaid Services responded in kind, making modifications in a number of rules that removed obstacles to telehealth. One modification on April 6, 2020, for example, removed the requirement for a preexisting relationship between the clinician and patient, Dr. Singh said. The CMS also subsequently modified reimbursement policies in order to make telemedicine more tenable for physicians.

Given the risk of contagion from face-to-face encounters, telemedicine in the early days of the pandemic was not just attractive but the only practical and safe approach to medical care in many circumstances. Physicians and patients were anxious for health care that did not require in-office visits even though many critical issues for telemedicine, including its relative effectiveness, had not yet been fully evaluated.

Much has been learned regarding the feasibility and acceptability of telemedicine during the pandemic, but Dr. Singh noted that quality of care relative to in-person visits remains weakly supported for most indications. Indeed, he outlined sizable list of incompletely resolved issues, including optimal payment models, management of privacy concerns, and how to balance advantages to disadvantages.

For patients and physicians, the strengths of telemedicine include greater convenience made possible by the elimination of travel and waiting rooms. For the health care system, it can include less infrastructure and overhead. For many physicians, telemedicine might be perceived as more efficient.

On the other hand, some patients might feel that a clinical encounter is incomplete without a physical examination even when the physician does not feel the physical examination is needed, according to Dr. Singh. He cited a survey suggesting nearly half of patients expressed concern about a lack of connection to health care providers following a virtual visit.

In the same 2020 National Poll on Healthy Aging 2020 survey conducted by the University of Michigan 67% of respondents reported that the quality of care was not as good as that provided by in-patient visits, and 24% expressed concern about privacy. However, at the time the poll was taken in May 2020, experience with telemedicine among many of the respondents may have been limited. As telemedicine is integrated into routine care, perceptions might change as experience increases.

A distinction between telemedicine in routine care and telemedicine as a strategy to respond to a pandemic is important, Dr. Singh indicated. Dr. Singh was the lead author for a position paper on telemedicine for the diagnosis and treatment of sleep disorders from the American Academy of Sleep Medicine 5 years ago, but he acknowledged that models of care might differ when responding to abnormal surges in health care demand.

The surge in demand for COVID-19–related care engendered numerous innovative solutions. As examples, Dr. Singh recounted how a virtual hospital was created at his own institution. In a published study, 1,477 patients diagnosed with COVID-19 over a 6-week period remained at home and received care in a virtual observation unit (VCU) or a virtual acute care unit (VACU) . Only a small percentage required eventual hospital admission. In the VACU, patients were able to receive advanced care including IV fluids and some form of respiratory support .

It is unclear how the COVID-19 pandemic will change telemedicine. Now, with declining cases of the infection, telemedicine is back to a walk after the sprint required during the height of the pandemic, according to Dr. Singh. However, Dr. Singh thinks many physicians and patients will have a different perception of telemedicine after the widespread exposure to this type of care.

In terms of the relative role of in-patient and virtual visits across indications, “we do not know how this will play out, but we will probably end up toggling between the two,” Dr. Singh said.

This is an area that is being followed closely by the CHEST Health Policy and Advocacy Committee, according to Kathleen Sarmiento, MD, director, VISN 21 Sleep Clinical Resource Hub for the San Francisco VA Health Care System. A member of that committee and moderator of the session in which Dr. Singh spoke,

American College of Chest Physicians Health Policy and Advocacy Conference

Dr. Sarmiento called the effort to bring permanent coverage of telehealth services “the shared responsibility of every medical society engaged in advocacy.”

However, she cautioned that there might be intended and unintended consequences from telehealth that require analysis to develop policies that are in the best interests of effective care. She said, the “ACCP, along with its sister societies, does have a role in supporting the evaluation of the impact of these changes on both patients and providers in the fields of pulmonary medicine, critical care, and sleep medicine.”

Dr. Singh reports a financial relationship with AstraZeneca. Dr. Sarmiento reports no relevant financial relationship with AstraZeneca.

Patients with obesity who underwent bariatric surgery had 46% lower odds of stroke 1 year later, similar odds of stroke 3 years later, and 22% lower odds of stroke 5 years later, compared with matched control patients, in new research.

purestock/Thinkstock

Michael D. Williams, MD, presented the study findings (abstract A002) at the annual meeting of the American Society for Metabolic & Bariatric Surgery.

The findings are “very good news,” even though the protection against stroke declined further out from the surgery, John D. Scott, MD, scientific program chair of the ASMBS meeting, told this news organization.

The investigators matched more than 56,000 patients with obesity who had bariatric surgery with an equal number of similar patients who did not have this surgery, from a large national insurance database, in what they believe is the largest study of this to date.

“Any intervention that decreases your risk of [cardiovascular] events is good news,” said Dr. Scott, a clinical professor of surgery at the University of South Carolina, Greenville, and metabolic and bariatric surgery director at Prisma Health in Greenville, S.C. “And having a 22%-45% chance of reduction in stroke risk is a very worthwhile intervention.”

Asked how this would change the way clinicians inform patients of what to expect from bariatric surgery, he said: “I would advise patients that studies like this show that surgery would not increase your risk of having a stroke.

“This is consistent with many studies that show that the risks of all macrovascular events decrease after the comorbidity reductions seen after surgery.”

According to Dr. Scott, “the next steps might include a prospective randomized trial of medical treatment versus surgery alone for [cardiovascular]/stroke outcomes, but this is unlikely.”

Similarly, Dr. Williams told this news organization that “I would tell [patients] that surgery is an effective and durable method for weight loss. It also can improve comorbid conditions, particularly diabetes and hypertension.”

Even with this study, “I’m not sure it’s appropriate to say that bariatric surgery will reduce the risk of stroke,” he cautioned.

“However, as we continue to investigate the effects of bariatric surgery, this study contributes to the greater body of knowledge that suggests that reduction in ischemic stroke risk is yet another benefit of bariatric surgery.”

The assigned discussant, Corrigan L. McBride, MD, MBA wanted to know if the lower odds ratio at 1 year might be because preoperative patient selection might eliminate patients at high risk of poor cardiovascular outcomes.

Dr. Williams, a resident at Rush Medical College, Chicago, replied that it is difficult to eliminate potential selection bias, despite best efforts, but this study shows that he can tell patients: “Having surgery is not going to increases your risk of stroke.”

“This is an important study,” Dr. McBride, professor and chief of minimally invasive surgery and bariatric surgery, University of Nebraska Medical Center, Omaha, told this news organization.

“It is the first large study to show a decreased [or no increased] risk of stroke 1, 3, and 5 years after bariatric surgery compared to matched patients, and it had enough data to look at stroke as a standalone endpoint,” Dr. McBride said. “It is important too, for patients and their physicians to understand that there is a lower chance of them having a stroke if they have surgery than if they do not.”
 

‘Important,’ ‘good news’ for stroke risk after bariatric surgery

The impact of bariatric surgery on remission of type 2 diabetes is well known, Dr. Williams noted, and other studies have reported how bariatric surgery affects the risk of major adverse cardiovascular events – a composite of stroke, myocardial infarction, coronary artery disease, and all-cause death – including a study presented in the same meeting session.

However, a very large sample size is needed to be able to demonstrate the effect of bariatric surgery on stroke, since stroke is a rare event.

The researchers analyzed data from the Mariner (PearlDiver.) all-payer insurance national claims database of patients in the United States.

They matched 56,514 patients with a body mass index over 35 kg/m² and comorbidities or a BMI of more than 40 who underwent sleeve gastrectomy or Roux-en-Y gastric bypass during 2010-2019 with 56,514 control patients who did not undergo bariatric surgery.

A year after bariatric surgery, patients in that group had a lower stroke rate than patients in the control group (0.6% vs. 1.2%), and they had close to 50% lower odds of having a stroke (odds ratio, 0.54; 95% CI, 0.47-0.61).

Three years after bariatric surgery, there were 44,948 patients in each group; the rate of stroke was 2.1% in the surgery group and 2.2% in the control group, and there was no significant difference in the odds of having a stroke (OR, 0.96; 95% CI, 0.91-1.00).

Five years after bariatric surgery, there were 27,619 patients in each group; the stroke rate was lower in the bariatric surgery group than in the control group (2.8% vs 3.6%), but reduced odds of stroke was not as great as after 1 year (OR, 0.78; 95% CI, 0.65-0.90).

Dr. Williams has no relevant financial disclosures. Dr. McBride and Dr. Scott disclosed that they are speakers/trainers/faculty advisers for Gore. Dr. Scott is also a consultant for C-SATS (part of Johnson & Johnson).

Patients with obesity who underwent bariatric surgery had 46% lower odds of stroke 1 year later, similar odds of stroke 3 years later, and 22% lower odds of stroke 5 years later, compared with matched control patients, in new research.

purestock/Thinkstock

Michael D. Williams, MD, presented the study findings (abstract A002) at the annual meeting of the American Society for Metabolic & Bariatric Surgery.

The findings are “very good news,” even though the protection against stroke declined further out from the surgery, John D. Scott, MD, scientific program chair of the ASMBS meeting, told this news organization.

The investigators matched more than 56,000 patients with obesity who had bariatric surgery with an equal number of similar patients who did not have this surgery, from a large national insurance database, in what they believe is the largest study of this to date.

“Any intervention that decreases your risk of [cardiovascular] events is good news,” said Dr. Scott, a clinical professor of surgery at the University of South Carolina, Greenville, and metabolic and bariatric surgery director at Prisma Health in Greenville, S.C. “And having a 22%-45% chance of reduction in stroke risk is a very worthwhile intervention.”

Asked how this would change the way clinicians inform patients of what to expect from bariatric surgery, he said: “I would advise patients that studies like this show that surgery would not increase your risk of having a stroke.

“This is consistent with many studies that show that the risks of all macrovascular events decrease after the comorbidity reductions seen after surgery.”

According to Dr. Scott, “the next steps might include a prospective randomized trial of medical treatment versus surgery alone for [cardiovascular]/stroke outcomes, but this is unlikely.”

Similarly, Dr. Williams told this news organization that “I would tell [patients] that surgery is an effective and durable method for weight loss. It also can improve comorbid conditions, particularly diabetes and hypertension.”

Even with this study, “I’m not sure it’s appropriate to say that bariatric surgery will reduce the risk of stroke,” he cautioned.

“However, as we continue to investigate the effects of bariatric surgery, this study contributes to the greater body of knowledge that suggests that reduction in ischemic stroke risk is yet another benefit of bariatric surgery.”

The assigned discussant, Corrigan L. McBride, MD, MBA wanted to know if the lower odds ratio at 1 year might be because preoperative patient selection might eliminate patients at high risk of poor cardiovascular outcomes.

Dr. Williams, a resident at Rush Medical College, Chicago, replied that it is difficult to eliminate potential selection bias, despite best efforts, but this study shows that he can tell patients: “Having surgery is not going to increases your risk of stroke.”

“This is an important study,” Dr. McBride, professor and chief of minimally invasive surgery and bariatric surgery, University of Nebraska Medical Center, Omaha, told this news organization.

“It is the first large study to show a decreased [or no increased] risk of stroke 1, 3, and 5 years after bariatric surgery compared to matched patients, and it had enough data to look at stroke as a standalone endpoint,” Dr. McBride said. “It is important too, for patients and their physicians to understand that there is a lower chance of them having a stroke if they have surgery than if they do not.”
 

‘Important,’ ‘good news’ for stroke risk after bariatric surgery

The impact of bariatric surgery on remission of type 2 diabetes is well known, Dr. Williams noted, and other studies have reported how bariatric surgery affects the risk of major adverse cardiovascular events – a composite of stroke, myocardial infarction, coronary artery disease, and all-cause death – including a study presented in the same meeting session.

However, a very large sample size is needed to be able to demonstrate the effect of bariatric surgery on stroke, since stroke is a rare event.

The researchers analyzed data from the Mariner (PearlDiver.) all-payer insurance national claims database of patients in the United States.

They matched 56,514 patients with a body mass index over 35 kg/m² and comorbidities or a BMI of more than 40 who underwent sleeve gastrectomy or Roux-en-Y gastric bypass during 2010-2019 with 56,514 control patients who did not undergo bariatric surgery.

A year after bariatric surgery, patients in that group had a lower stroke rate than patients in the control group (0.6% vs. 1.2%), and they had close to 50% lower odds of having a stroke (odds ratio, 0.54; 95% CI, 0.47-0.61).

Three years after bariatric surgery, there were 44,948 patients in each group; the rate of stroke was 2.1% in the surgery group and 2.2% in the control group, and there was no significant difference in the odds of having a stroke (OR, 0.96; 95% CI, 0.91-1.00).

Five years after bariatric surgery, there were 27,619 patients in each group; the stroke rate was lower in the bariatric surgery group than in the control group (2.8% vs 3.6%), but reduced odds of stroke was not as great as after 1 year (OR, 0.78; 95% CI, 0.65-0.90).

Dr. Williams has no relevant financial disclosures. Dr. McBride and Dr. Scott disclosed that they are speakers/trainers/faculty advisers for Gore. Dr. Scott is also a consultant for C-SATS (part of Johnson & Johnson).

Patients with obesity who underwent bariatric surgery had 46% lower odds of stroke 1 year later, similar odds of stroke 3 years later, and 22% lower odds of stroke 5 years later, compared with matched control patients, in new research.

purestock/Thinkstock

Michael D. Williams, MD, presented the study findings (abstract A002) at the annual meeting of the American Society for Metabolic & Bariatric Surgery.

The findings are “very good news,” even though the protection against stroke declined further out from the surgery, John D. Scott, MD, scientific program chair of the ASMBS meeting, told this news organization.

The investigators matched more than 56,000 patients with obesity who had bariatric surgery with an equal number of similar patients who did not have this surgery, from a large national insurance database, in what they believe is the largest study of this to date.

“Any intervention that decreases your risk of [cardiovascular] events is good news,” said Dr. Scott, a clinical professor of surgery at the University of South Carolina, Greenville, and metabolic and bariatric surgery director at Prisma Health in Greenville, S.C. “And having a 22%-45% chance of reduction in stroke risk is a very worthwhile intervention.”

Asked how this would change the way clinicians inform patients of what to expect from bariatric surgery, he said: “I would advise patients that studies like this show that surgery would not increase your risk of having a stroke.

“This is consistent with many studies that show that the risks of all macrovascular events decrease after the comorbidity reductions seen after surgery.”

According to Dr. Scott, “the next steps might include a prospective randomized trial of medical treatment versus surgery alone for [cardiovascular]/stroke outcomes, but this is unlikely.”

Similarly, Dr. Williams told this news organization that “I would tell [patients] that surgery is an effective and durable method for weight loss. It also can improve comorbid conditions, particularly diabetes and hypertension.”

Even with this study, “I’m not sure it’s appropriate to say that bariatric surgery will reduce the risk of stroke,” he cautioned.

“However, as we continue to investigate the effects of bariatric surgery, this study contributes to the greater body of knowledge that suggests that reduction in ischemic stroke risk is yet another benefit of bariatric surgery.”

The assigned discussant, Corrigan L. McBride, MD, MBA wanted to know if the lower odds ratio at 1 year might be because preoperative patient selection might eliminate patients at high risk of poor cardiovascular outcomes.

Dr. Williams, a resident at Rush Medical College, Chicago, replied that it is difficult to eliminate potential selection bias, despite best efforts, but this study shows that he can tell patients: “Having surgery is not going to increases your risk of stroke.”

“This is an important study,” Dr. McBride, professor and chief of minimally invasive surgery and bariatric surgery, University of Nebraska Medical Center, Omaha, told this news organization.

“It is the first large study to show a decreased [or no increased] risk of stroke 1, 3, and 5 years after bariatric surgery compared to matched patients, and it had enough data to look at stroke as a standalone endpoint,” Dr. McBride said. “It is important too, for patients and their physicians to understand that there is a lower chance of them having a stroke if they have surgery than if they do not.”
 

‘Important,’ ‘good news’ for stroke risk after bariatric surgery

The impact of bariatric surgery on remission of type 2 diabetes is well known, Dr. Williams noted, and other studies have reported how bariatric surgery affects the risk of major adverse cardiovascular events – a composite of stroke, myocardial infarction, coronary artery disease, and all-cause death – including a study presented in the same meeting session.

However, a very large sample size is needed to be able to demonstrate the effect of bariatric surgery on stroke, since stroke is a rare event.

The researchers analyzed data from the Mariner (PearlDiver.) all-payer insurance national claims database of patients in the United States.

They matched 56,514 patients with a body mass index over 35 kg/m² and comorbidities or a BMI of more than 40 who underwent sleeve gastrectomy or Roux-en-Y gastric bypass during 2010-2019 with 56,514 control patients who did not undergo bariatric surgery.

A year after bariatric surgery, patients in that group had a lower stroke rate than patients in the control group (0.6% vs. 1.2%), and they had close to 50% lower odds of having a stroke (odds ratio, 0.54; 95% CI, 0.47-0.61).

Three years after bariatric surgery, there were 44,948 patients in each group; the rate of stroke was 2.1% in the surgery group and 2.2% in the control group, and there was no significant difference in the odds of having a stroke (OR, 0.96; 95% CI, 0.91-1.00).

Five years after bariatric surgery, there were 27,619 patients in each group; the stroke rate was lower in the bariatric surgery group than in the control group (2.8% vs 3.6%), but reduced odds of stroke was not as great as after 1 year (OR, 0.78; 95% CI, 0.65-0.90).

Dr. Williams has no relevant financial disclosures. Dr. McBride and Dr. Scott disclosed that they are speakers/trainers/faculty advisers for Gore. Dr. Scott is also a consultant for C-SATS (part of Johnson & Johnson).

A large proportion of initial Investigator Global Assessment (IGA) 0/1 or Eczema Area and Severity Index (EASI) 75 responders at week 16 maintained response with continued tralokinumab dosing every 2 weeks or every 4 weeks during a 36-week maintenance period without the use of rescue medication including topical corticosteroids, results from a pooled analysis of two trials found.

“The interesting thing here is that there weren’t major differences in the maintenance dosing, which really allows us some flexibility with maintenance dosing for this particular drug,” lead study investigator Andrew Blauvelt, MD, MBA, said during the Revolutionizing Atopic Dermatitis symposium.

Administered subcutaneously, tralokinumab is a fully human IgG4 monoclonal antibody that specifically binds to interleukin-13, a key driver of underlying inflammation in AD. In two of the drug’s pivotal phase 3 trials, ECZTRA 1 and ECZTRA 2, tralokinumab monotherapy was superior to placebo at week 16 for all primary and secondary endpoints.

The purpose of the current trial was to investigate the maintenance of efficacy after 16 weeks of tralokinumab in those who were initial responders and to assess the efficacy of reduced dosing frequency from 300 mg every 2 weeks to 300 mg every 4 weeks after a 36-week maintenance phase. Patients who used rescue medication, including topical corticosteroids, were considered to be nonresponders.

Dr. Blauvelt reported results from 1,596 adult patients with a mean age of 38 years who were randomized to tralokinumab 300 mg every 2 weeks or placebo in the initial treatment period. At baseline, the mean duration of AD was 28.2 years, 50% had severe disease based on their IGA score, and their mean Dermatology Life Quality Index score was 17.

Of these patients, 412 achieved an IGA score of 0 or 1 and/or an EASI 75 at week 16 with tralokinumab every 2 weeks and were rerandomized (2:2:1) to continue tralokinumab 300 mg every 2 weeks, tralokinumab 300 mg every 4 weeks, or placebo for 36 weeks.

The researchers found that 56%-57% of patients in the tralokinumab every 2-week dosing group maintained their IGA 0/1 and EASI 75 response at week 52, compared with 42%-50% of those who received the drug every 4 weeks. “So, there may be a population of patients who require drug every 4 weeks after initially receiving the drug every 2 weeks for the first 16 weeks,” said Dr. Blauvelt, a dermatologist who is president of Oregon Medical Research Center, Portland. “Interestingly, 26%-34% of patients on placebo maintained their IGA 0/1 and EASI 75 response a response to week 52. Perhaps those are patients who have more mild disease or more episodic disease when they started this trial.”

He also noted that time to relapse based on their IGA 0/1 and EASI 75 was prolonged with tralokinumab treatment, compared with placebo, and adverse event frequency was similar among all treatment groups (73% among those who received tralokinumab every 2 weeks, 66% among those who received tralokinumab every 4 weeks, and 70% in the placebo group).

Dr. Blauvelt concluded that a step-down in tralokinumab dosing to every 4 weeks may be an option for some patients achieving clear or almost clear skin after an initial dosing schedule of every 2 weeks.

LEO Pharma, which is developing tralokinumab, sponsored the analysis. Dr. Blauvelt reported that he is an investigator and a scientific adviser for LEO Pharma and for several other pharmaceutical companies developing treatments for AD.

dbrunk@mdedge.com

A large proportion of initial Investigator Global Assessment (IGA) 0/1 or Eczema Area and Severity Index (EASI) 75 responders at week 16 maintained response with continued tralokinumab dosing every 2 weeks or every 4 weeks during a 36-week maintenance period without the use of rescue medication including topical corticosteroids, results from a pooled analysis of two trials found.

“The interesting thing here is that there weren’t major differences in the maintenance dosing, which really allows us some flexibility with maintenance dosing for this particular drug,” lead study investigator Andrew Blauvelt, MD, MBA, said during the Revolutionizing Atopic Dermatitis symposium.

Administered subcutaneously, tralokinumab is a fully human IgG4 monoclonal antibody that specifically binds to interleukin-13, a key driver of underlying inflammation in AD. In two of the drug’s pivotal phase 3 trials, ECZTRA 1 and ECZTRA 2, tralokinumab monotherapy was superior to placebo at week 16 for all primary and secondary endpoints.

The purpose of the current trial was to investigate the maintenance of efficacy after 16 weeks of tralokinumab in those who were initial responders and to assess the efficacy of reduced dosing frequency from 300 mg every 2 weeks to 300 mg every 4 weeks after a 36-week maintenance phase. Patients who used rescue medication, including topical corticosteroids, were considered to be nonresponders.

Dr. Blauvelt reported results from 1,596 adult patients with a mean age of 38 years who were randomized to tralokinumab 300 mg every 2 weeks or placebo in the initial treatment period. At baseline, the mean duration of AD was 28.2 years, 50% had severe disease based on their IGA score, and their mean Dermatology Life Quality Index score was 17.

Of these patients, 412 achieved an IGA score of 0 or 1 and/or an EASI 75 at week 16 with tralokinumab every 2 weeks and were rerandomized (2:2:1) to continue tralokinumab 300 mg every 2 weeks, tralokinumab 300 mg every 4 weeks, or placebo for 36 weeks.

The researchers found that 56%-57% of patients in the tralokinumab every 2-week dosing group maintained their IGA 0/1 and EASI 75 response at week 52, compared with 42%-50% of those who received the drug every 4 weeks. “So, there may be a population of patients who require drug every 4 weeks after initially receiving the drug every 2 weeks for the first 16 weeks,” said Dr. Blauvelt, a dermatologist who is president of Oregon Medical Research Center, Portland. “Interestingly, 26%-34% of patients on placebo maintained their IGA 0/1 and EASI 75 response a response to week 52. Perhaps those are patients who have more mild disease or more episodic disease when they started this trial.”

He also noted that time to relapse based on their IGA 0/1 and EASI 75 was prolonged with tralokinumab treatment, compared with placebo, and adverse event frequency was similar among all treatment groups (73% among those who received tralokinumab every 2 weeks, 66% among those who received tralokinumab every 4 weeks, and 70% in the placebo group).

Dr. Blauvelt concluded that a step-down in tralokinumab dosing to every 4 weeks may be an option for some patients achieving clear or almost clear skin after an initial dosing schedule of every 2 weeks.

LEO Pharma, which is developing tralokinumab, sponsored the analysis. Dr. Blauvelt reported that he is an investigator and a scientific adviser for LEO Pharma and for several other pharmaceutical companies developing treatments for AD.

dbrunk@mdedge.com

A large proportion of initial Investigator Global Assessment (IGA) 0/1 or Eczema Area and Severity Index (EASI) 75 responders at week 16 maintained response with continued tralokinumab dosing every 2 weeks or every 4 weeks during a 36-week maintenance period without the use of rescue medication including topical corticosteroids, results from a pooled analysis of two trials found.

“The interesting thing here is that there weren’t major differences in the maintenance dosing, which really allows us some flexibility with maintenance dosing for this particular drug,” lead study investigator Andrew Blauvelt, MD, MBA, said during the Revolutionizing Atopic Dermatitis symposium.

Administered subcutaneously, tralokinumab is a fully human IgG4 monoclonal antibody that specifically binds to interleukin-13, a key driver of underlying inflammation in AD. In two of the drug’s pivotal phase 3 trials, ECZTRA 1 and ECZTRA 2, tralokinumab monotherapy was superior to placebo at week 16 for all primary and secondary endpoints.

The purpose of the current trial was to investigate the maintenance of efficacy after 16 weeks of tralokinumab in those who were initial responders and to assess the efficacy of reduced dosing frequency from 300 mg every 2 weeks to 300 mg every 4 weeks after a 36-week maintenance phase. Patients who used rescue medication, including topical corticosteroids, were considered to be nonresponders.

Dr. Blauvelt reported results from 1,596 adult patients with a mean age of 38 years who were randomized to tralokinumab 300 mg every 2 weeks or placebo in the initial treatment period. At baseline, the mean duration of AD was 28.2 years, 50% had severe disease based on their IGA score, and their mean Dermatology Life Quality Index score was 17.

Of these patients, 412 achieved an IGA score of 0 or 1 and/or an EASI 75 at week 16 with tralokinumab every 2 weeks and were rerandomized (2:2:1) to continue tralokinumab 300 mg every 2 weeks, tralokinumab 300 mg every 4 weeks, or placebo for 36 weeks.

The researchers found that 56%-57% of patients in the tralokinumab every 2-week dosing group maintained their IGA 0/1 and EASI 75 response at week 52, compared with 42%-50% of those who received the drug every 4 weeks. “So, there may be a population of patients who require drug every 4 weeks after initially receiving the drug every 2 weeks for the first 16 weeks,” said Dr. Blauvelt, a dermatologist who is president of Oregon Medical Research Center, Portland. “Interestingly, 26%-34% of patients on placebo maintained their IGA 0/1 and EASI 75 response a response to week 52. Perhaps those are patients who have more mild disease or more episodic disease when they started this trial.”

He also noted that time to relapse based on their IGA 0/1 and EASI 75 was prolonged with tralokinumab treatment, compared with placebo, and adverse event frequency was similar among all treatment groups (73% among those who received tralokinumab every 2 weeks, 66% among those who received tralokinumab every 4 weeks, and 70% in the placebo group).

Dr. Blauvelt concluded that a step-down in tralokinumab dosing to every 4 weeks may be an option for some patients achieving clear or almost clear skin after an initial dosing schedule of every 2 weeks.

LEO Pharma, which is developing tralokinumab, sponsored the analysis. Dr. Blauvelt reported that he is an investigator and a scientific adviser for LEO Pharma and for several other pharmaceutical companies developing treatments for AD.

dbrunk@mdedge.com

The phenomenon of brain fog, as described by some patients with hypothyroidism despite treatment, is often associated with fatigue and cognitive symptoms and may be relieved by a variety of pharmacologic and nonpharmacologic approaches, new research suggests.

The findings come from a survey of more than 700 patients with hypothyroidism due to thyroid surgery and/or radioactive iodine therapy (RAI) or Hashimoto’s who reported having brain fog.

The survey results were presented May 29 at the American Association of Clinical Endocrinology Virtual Annual Meeting 2021 by investigators Matthew D. Ettleson, MD, and Ava Raine, of the University of Chicago, Illinois.

Many patients with hypothyroidism continue to experience symptoms despite taking thyroid hormone replacement therapy and having normal thyroid function test results.

These symptoms can include quantifiable cognitive, quality of life, and metabolic abnormalities. However, “some patients also experience vague and difficult to quantify symptoms, which they describe as brain fog,” Ms. Raine said.

The brain fog phenomenon has been described with somewhat varying features in several different chronic conditions, including postural orthostatic tachycardia syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, fibromyalgia, post-menopausal syndrome, and recently, among people with “long haul” COVID-19 symptoms.

However, brain fog associated with treated hypothyroidism has not been explored in-depth, despite the fact that patients often report it, Ms. Raine noted.
 

Results will help clinicians assist patients with brain fog

Fatigue was the most prominent brain fog symptom reported in the survey, followed by forgetfulness and difficulty focusing. On the other hand, rest and relaxation were the most reported factors that alleviated symptoms, followed by thyroid hormone adjustment.

“Hopefully these findings will help clinicians to recognize and treat the symptoms of brain fog and shed light on a condition which up until now has not been very well understood,” Dr. Ettleson said.

Asked to comment, session moderator Jad G. Sfeir, MD, of the Mayo Medical School, Rochester, Minn., told this news organization: “We do see patients complain a lot about this brain fog. The question is how can I help, and what has worked for them in the past?”

“When you have symptoms that are vague, like brain fog, you don’t have a lot of objective tools to [measure], so you can’t really develop a study to see how a certain medication affects the symptoms. Relying on subjective information from patients saying what worked for them and what did not, you can draw a lot of implications to clinical practice.”

The survey results, Dr. Sfeir said, “will help direct clinicians to know what type of questions to ask patients based on the survey responses and how to make some recommendations that may help.”
 

Fatigue, memory problems, difficulty focusing characterize brain fog

The online survey was distributed to hypothyroidism support groups and through the American Thyroid Association. Of the 5,282 respondents with hypothyroidism and symptoms of brain fog, 46% (2,453) reported having experienced brain fog symptoms prior to their diagnosis of hypothyroidism.

The population analyzed for the study was the 17% (731) who reported experiencing brain fog weeks to months following a diagnosis of hypothyroidism. Of those, 33% had Hashimoto’s, 21% thyroid surgery, 11% RAI therapy, and 15.6% had both thyroid surgery and RAI.  

Brain fog symptoms were reported as occurring “frequently” by 44.5% and “all the time” by 37.0%. The composite symptom score was 22.9 out of 30.

Fatigue, or lack of energy, was the most commonly named symptom, reported by over 90% of both the thyroid surgery/RAI and Hashimoto’s groups, and as occurring “all the time” by about half in each group. Others reported by at least half of both groups included memory problems, difficulty focusing, sleep problems, and difficulties with decision-making. Other symptoms frequently cited included confusion, mood disturbance, and anxiety.

“Each ... domain was reported with some frequency by at least 85% of respondents, regardless of etiology of hypothyroidism, so it really was a high symptom burden that we were seeing, even in those whose symptoms were the least frequent,” Ms. Raine noted.

Symptom scores generally correlated with patient satisfaction scores, particularly with those of cognitive signs and difficulty focusing.
 

Lifting the fog: What do patients say helps them?

The survey asked patients what factors improved or worsened their brain fog symptoms. By far, the most frequent answer was rest/relaxation, endorsed by 58.5%. Another 10.5% listed exercise/outdoor time, but 1.5% said exercise worsened their symptoms.

Unspecified adjustments of thyroid medications were said to improve symptoms for 13.9%. Specific thyroid hormones reported to improve symptoms were liothyronine in 8.8%, desiccated thyroid extract in 3.1%, and levothyroxine in 2.7%. However, another 4.2% said thyroxine worsened their symptoms.

Healthy/nutritious diets were reported to improve symptoms by 6.3%, while consuming gluten, a high-sugar diet, and consuming alcohol were reported to worsen symptoms for 1.3%, 3.2%, and 1.3%, respectively. Caffeine was said to help for 3.1% and to harm by 0.6%.

Small numbers of patients reported improvements in symptoms with vitamins B12 and D, Adderall, or other stimulant medications, antidepressants, naltrexone, sun exposure, and blood glucose stability.

Other factors reported to worsen symptoms included menstruation, infection or other acute illness, pain, and “loud noise.”   

Dr. Ettleson pointed out, “For many of these patients [the brain fog] may have nothing to do with their thyroid. We saw a large proportion of patients who said they had symptoms well before they were ever diagnosed with hypothyroidism, and yet many patients have linked these brain fog symptoms to their thyroid.”

Nonetheless, he said, “I think it’s imperative for the clinician to at least engage in these conversations and not just stop when the thyroid function tests are normal. We have many lifestyle suggestions that have emerged from this study that I think physicians can put forward to patients who are dealing with this ... early in the process in addition to thyroid hormone adjustment, which may help some patients.”  

Dr. Ettleson, Ms. Raine, and Dr. Sfeir have reported no relevant financial relationships.

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

The phenomenon of brain fog, as described by some patients with hypothyroidism despite treatment, is often associated with fatigue and cognitive symptoms and may be relieved by a variety of pharmacologic and nonpharmacologic approaches, new research suggests.

The findings come from a survey of more than 700 patients with hypothyroidism due to thyroid surgery and/or radioactive iodine therapy (RAI) or Hashimoto’s who reported having brain fog.

The survey results were presented May 29 at the American Association of Clinical Endocrinology Virtual Annual Meeting 2021 by investigators Matthew D. Ettleson, MD, and Ava Raine, of the University of Chicago, Illinois.

Many patients with hypothyroidism continue to experience symptoms despite taking thyroid hormone replacement therapy and having normal thyroid function test results.

These symptoms can include quantifiable cognitive, quality of life, and metabolic abnormalities. However, “some patients also experience vague and difficult to quantify symptoms, which they describe as brain fog,” Ms. Raine said.

The brain fog phenomenon has been described with somewhat varying features in several different chronic conditions, including postural orthostatic tachycardia syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, fibromyalgia, post-menopausal syndrome, and recently, among people with “long haul” COVID-19 symptoms.

However, brain fog associated with treated hypothyroidism has not been explored in-depth, despite the fact that patients often report it, Ms. Raine noted.
 

Results will help clinicians assist patients with brain fog

Fatigue was the most prominent brain fog symptom reported in the survey, followed by forgetfulness and difficulty focusing. On the other hand, rest and relaxation were the most reported factors that alleviated symptoms, followed by thyroid hormone adjustment.

“Hopefully these findings will help clinicians to recognize and treat the symptoms of brain fog and shed light on a condition which up until now has not been very well understood,” Dr. Ettleson said.

Asked to comment, session moderator Jad G. Sfeir, MD, of the Mayo Medical School, Rochester, Minn., told this news organization: “We do see patients complain a lot about this brain fog. The question is how can I help, and what has worked for them in the past?”

“When you have symptoms that are vague, like brain fog, you don’t have a lot of objective tools to [measure], so you can’t really develop a study to see how a certain medication affects the symptoms. Relying on subjective information from patients saying what worked for them and what did not, you can draw a lot of implications to clinical practice.”

The survey results, Dr. Sfeir said, “will help direct clinicians to know what type of questions to ask patients based on the survey responses and how to make some recommendations that may help.”
 

Fatigue, memory problems, difficulty focusing characterize brain fog

The online survey was distributed to hypothyroidism support groups and through the American Thyroid Association. Of the 5,282 respondents with hypothyroidism and symptoms of brain fog, 46% (2,453) reported having experienced brain fog symptoms prior to their diagnosis of hypothyroidism.

The population analyzed for the study was the 17% (731) who reported experiencing brain fog weeks to months following a diagnosis of hypothyroidism. Of those, 33% had Hashimoto’s, 21% thyroid surgery, 11% RAI therapy, and 15.6% had both thyroid surgery and RAI.  

Brain fog symptoms were reported as occurring “frequently” by 44.5% and “all the time” by 37.0%. The composite symptom score was 22.9 out of 30.

Fatigue, or lack of energy, was the most commonly named symptom, reported by over 90% of both the thyroid surgery/RAI and Hashimoto’s groups, and as occurring “all the time” by about half in each group. Others reported by at least half of both groups included memory problems, difficulty focusing, sleep problems, and difficulties with decision-making. Other symptoms frequently cited included confusion, mood disturbance, and anxiety.

“Each ... domain was reported with some frequency by at least 85% of respondents, regardless of etiology of hypothyroidism, so it really was a high symptom burden that we were seeing, even in those whose symptoms were the least frequent,” Ms. Raine noted.

Symptom scores generally correlated with patient satisfaction scores, particularly with those of cognitive signs and difficulty focusing.
 

Lifting the fog: What do patients say helps them?

The survey asked patients what factors improved or worsened their brain fog symptoms. By far, the most frequent answer was rest/relaxation, endorsed by 58.5%. Another 10.5% listed exercise/outdoor time, but 1.5% said exercise worsened their symptoms.

Unspecified adjustments of thyroid medications were said to improve symptoms for 13.9%. Specific thyroid hormones reported to improve symptoms were liothyronine in 8.8%, desiccated thyroid extract in 3.1%, and levothyroxine in 2.7%. However, another 4.2% said thyroxine worsened their symptoms.

Healthy/nutritious diets were reported to improve symptoms by 6.3%, while consuming gluten, a high-sugar diet, and consuming alcohol were reported to worsen symptoms for 1.3%, 3.2%, and 1.3%, respectively. Caffeine was said to help for 3.1% and to harm by 0.6%.

Small numbers of patients reported improvements in symptoms with vitamins B12 and D, Adderall, or other stimulant medications, antidepressants, naltrexone, sun exposure, and blood glucose stability.

Other factors reported to worsen symptoms included menstruation, infection or other acute illness, pain, and “loud noise.”   

Dr. Ettleson pointed out, “For many of these patients [the brain fog] may have nothing to do with their thyroid. We saw a large proportion of patients who said they had symptoms well before they were ever diagnosed with hypothyroidism, and yet many patients have linked these brain fog symptoms to their thyroid.”

Nonetheless, he said, “I think it’s imperative for the clinician to at least engage in these conversations and not just stop when the thyroid function tests are normal. We have many lifestyle suggestions that have emerged from this study that I think physicians can put forward to patients who are dealing with this ... early in the process in addition to thyroid hormone adjustment, which may help some patients.”  

Dr. Ettleson, Ms. Raine, and Dr. Sfeir have reported no relevant financial relationships.

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

The phenomenon of brain fog, as described by some patients with hypothyroidism despite treatment, is often associated with fatigue and cognitive symptoms and may be relieved by a variety of pharmacologic and nonpharmacologic approaches, new research suggests.

The findings come from a survey of more than 700 patients with hypothyroidism due to thyroid surgery and/or radioactive iodine therapy (RAI) or Hashimoto’s who reported having brain fog.

The survey results were presented May 29 at the American Association of Clinical Endocrinology Virtual Annual Meeting 2021 by investigators Matthew D. Ettleson, MD, and Ava Raine, of the University of Chicago, Illinois.

Many patients with hypothyroidism continue to experience symptoms despite taking thyroid hormone replacement therapy and having normal thyroid function test results.

These symptoms can include quantifiable cognitive, quality of life, and metabolic abnormalities. However, “some patients also experience vague and difficult to quantify symptoms, which they describe as brain fog,” Ms. Raine said.

The brain fog phenomenon has been described with somewhat varying features in several different chronic conditions, including postural orthostatic tachycardia syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, fibromyalgia, post-menopausal syndrome, and recently, among people with “long haul” COVID-19 symptoms.

However, brain fog associated with treated hypothyroidism has not been explored in-depth, despite the fact that patients often report it, Ms. Raine noted.
 

Results will help clinicians assist patients with brain fog

Fatigue was the most prominent brain fog symptom reported in the survey, followed by forgetfulness and difficulty focusing. On the other hand, rest and relaxation were the most reported factors that alleviated symptoms, followed by thyroid hormone adjustment.

“Hopefully these findings will help clinicians to recognize and treat the symptoms of brain fog and shed light on a condition which up until now has not been very well understood,” Dr. Ettleson said.

Asked to comment, session moderator Jad G. Sfeir, MD, of the Mayo Medical School, Rochester, Minn., told this news organization: “We do see patients complain a lot about this brain fog. The question is how can I help, and what has worked for them in the past?”

“When you have symptoms that are vague, like brain fog, you don’t have a lot of objective tools to [measure], so you can’t really develop a study to see how a certain medication affects the symptoms. Relying on subjective information from patients saying what worked for them and what did not, you can draw a lot of implications to clinical practice.”

The survey results, Dr. Sfeir said, “will help direct clinicians to know what type of questions to ask patients based on the survey responses and how to make some recommendations that may help.”
 

Fatigue, memory problems, difficulty focusing characterize brain fog

The online survey was distributed to hypothyroidism support groups and through the American Thyroid Association. Of the 5,282 respondents with hypothyroidism and symptoms of brain fog, 46% (2,453) reported having experienced brain fog symptoms prior to their diagnosis of hypothyroidism.

The population analyzed for the study was the 17% (731) who reported experiencing brain fog weeks to months following a diagnosis of hypothyroidism. Of those, 33% had Hashimoto’s, 21% thyroid surgery, 11% RAI therapy, and 15.6% had both thyroid surgery and RAI.  

Brain fog symptoms were reported as occurring “frequently” by 44.5% and “all the time” by 37.0%. The composite symptom score was 22.9 out of 30.

Fatigue, or lack of energy, was the most commonly named symptom, reported by over 90% of both the thyroid surgery/RAI and Hashimoto’s groups, and as occurring “all the time” by about half in each group. Others reported by at least half of both groups included memory problems, difficulty focusing, sleep problems, and difficulties with decision-making. Other symptoms frequently cited included confusion, mood disturbance, and anxiety.

“Each ... domain was reported with some frequency by at least 85% of respondents, regardless of etiology of hypothyroidism, so it really was a high symptom burden that we were seeing, even in those whose symptoms were the least frequent,” Ms. Raine noted.

Symptom scores generally correlated with patient satisfaction scores, particularly with those of cognitive signs and difficulty focusing.
 

Lifting the fog: What do patients say helps them?

The survey asked patients what factors improved or worsened their brain fog symptoms. By far, the most frequent answer was rest/relaxation, endorsed by 58.5%. Another 10.5% listed exercise/outdoor time, but 1.5% said exercise worsened their symptoms.

Unspecified adjustments of thyroid medications were said to improve symptoms for 13.9%. Specific thyroid hormones reported to improve symptoms were liothyronine in 8.8%, desiccated thyroid extract in 3.1%, and levothyroxine in 2.7%. However, another 4.2% said thyroxine worsened their symptoms.

Healthy/nutritious diets were reported to improve symptoms by 6.3%, while consuming gluten, a high-sugar diet, and consuming alcohol were reported to worsen symptoms for 1.3%, 3.2%, and 1.3%, respectively. Caffeine was said to help for 3.1% and to harm by 0.6%.

Small numbers of patients reported improvements in symptoms with vitamins B12 and D, Adderall, or other stimulant medications, antidepressants, naltrexone, sun exposure, and blood glucose stability.

Other factors reported to worsen symptoms included menstruation, infection or other acute illness, pain, and “loud noise.”   

Dr. Ettleson pointed out, “For many of these patients [the brain fog] may have nothing to do with their thyroid. We saw a large proportion of patients who said they had symptoms well before they were ever diagnosed with hypothyroidism, and yet many patients have linked these brain fog symptoms to their thyroid.”

Nonetheless, he said, “I think it’s imperative for the clinician to at least engage in these conversations and not just stop when the thyroid function tests are normal. We have many lifestyle suggestions that have emerged from this study that I think physicians can put forward to patients who are dealing with this ... early in the process in addition to thyroid hormone adjustment, which may help some patients.”  

Dr. Ettleson, Ms. Raine, and Dr. Sfeir have reported no relevant financial relationships.

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

A delaying tactic used by some U.S. health insurers to limit coverage of bariatric surgery does not jibe with the clinical experience at one U.S. center with 461 patients who underwent primary or revisional bariatric surgery.

PhotoDisk

The tactic applies to patients with a baseline body mass index (BMI) of 35-39 kg/m² who usually also need at least one comorbidity to qualify for insurance coverage for bariatric surgery, and specifically to the subgroup for whom hypertension is the qualifying comorbidity.

Some insurers limit surgery coverage to patients with hypertension who fail to reach their goal blood pressure on agents from three different drug classes, a policy that is “extremely frustrating and dangerous,” said Yannis Raftopoulos, MD, PhD, in his presentation at the annual meeting of the American Society for Metabolic and Bariatric Surgery.

Using number of antihypertensive drugs ‘is not correct’

“Using the number of antihypertensive medications to justify surgery is not correct because blood pressure control is not [always] better when patients take two or three medications, compared with when they are taking one. This harms patients because the more severe their hypertension, the worse their control,” said Dr. Raftopoulos, director of the weight management program at Holyoke (Mass.) Medical Center.

He presented findings from a retrospective study of 461 patients who underwent either sleeve gastrectomy or laparoscopic Roux-en-Y gastric bypass at his center, including 213 (46%) diagnosed with hypertension at the time of their surgery. Within this group were 68 patients with a BMI of 35-39, which meant that they could get insurance coverage for bariatric surgery only if they also had a relevant comorbidity such as hypertension, diabetes, or severe sleep apnea.

Among these patients, 36 (17% of those with hypertension) had only hypertension as their relevant comorbidity and would not have qualified for bariatric surgery under the strictest criteria applied by some insurers that require patients to remain hypertensive despite treatment with at least three different antihypertensive medications. (These 36 patients underwent bariatric surgery because their insurance coverage did not have this restriction.)

The analyses Dr. Raftopoulos presented also documented the rate of hypertension resolution among patients in the series who had hypertension at baseline and 1-year follow-up results. Among 65 patients on one antihypertensive drug at baseline, 43 (66%) had complete resolution of their hypertension after 1 year, defined as blood pressure of less than 130/90 mm Hg while completely off antihypertensive treatment. In contrast, among 55 patients on two antihypertensive medications at baseline, 28 (51%) had complete resolution after 1 year, and among 24 patients on three or more antihypertensive medications at baseline, 3 (13%) had complete resolution 1 year after bariatric surgery, he reported.

“Patients who were treated with one oral antihypertensive medication preoperatively had a higher likelihood of postoperative hypertension resolution,” concluded Dr. Raftopoulos.

Restricting access to bariatric surgery to patients with a BMI of less than 40 based on the preoperative intensity of their antihypertensive treatment “is not supported by our data, and can be potentially harmful,” he declared.

“This study was the result of discussions about this problem with multiple insurers in my area,” he added. “This affects a good number of patients.”

Waiting for hypertension to become less treatable

The results Dr. Raftopoulos presented “are not surprising, because they confirm the hypothesis that earlier intervention in the course of a disease like hypertension is more likely to be successful,” commented Bruce D. Schirmer, MD, a professor of surgery at the University of Virginia, Charlottesville, and designated discussant for the report.

The policy followed by some health insurers to delay coverage for bariatric surgery until patients fail three medications “forces patients with more treatable hypertension to wait until their disease worsens and becomes less treatable before they can receive appropriate treatment,” he said.

Dr. Schirmer attributed the motivation for this approach to a “despicable” and “reprehensible” reason: “Actuarial calculations that show paying for curative therapy is not cost effective in the short term. The duration of a patient’s policy may not be long enough to yield a positive financial outcome, so it becomes more appropriate to deny optimal care and have patients become sicker from their disease.”

“I applaud the authors for accumulating the data that point out this unfortunate rule of some insurance companies,” Dr. Schirmer added.

The practice is comparable with an insurer requiring that a patient’s cancer must be metastatic before allowing coverage for treatment, commented Ann M. Rogers, MD, professor and director of the Penn State University surgical weight loss program in Hershey, Penn., and a moderator of the session.

Dr. Raftopoulos, Dr. Schirmer, and Dr. Rogers had no disclosures.

mzoler@mdedge.com

A delaying tactic used by some U.S. health insurers to limit coverage of bariatric surgery does not jibe with the clinical experience at one U.S. center with 461 patients who underwent primary or revisional bariatric surgery.

PhotoDisk

The tactic applies to patients with a baseline body mass index (BMI) of 35-39 kg/m² who usually also need at least one comorbidity to qualify for insurance coverage for bariatric surgery, and specifically to the subgroup for whom hypertension is the qualifying comorbidity.

Some insurers limit surgery coverage to patients with hypertension who fail to reach their goal blood pressure on agents from three different drug classes, a policy that is “extremely frustrating and dangerous,” said Yannis Raftopoulos, MD, PhD, in his presentation at the annual meeting of the American Society for Metabolic and Bariatric Surgery.

Using number of antihypertensive drugs ‘is not correct’

“Using the number of antihypertensive medications to justify surgery is not correct because blood pressure control is not [always] better when patients take two or three medications, compared with when they are taking one. This harms patients because the more severe their hypertension, the worse their control,” said Dr. Raftopoulos, director of the weight management program at Holyoke (Mass.) Medical Center.

He presented findings from a retrospective study of 461 patients who underwent either sleeve gastrectomy or laparoscopic Roux-en-Y gastric bypass at his center, including 213 (46%) diagnosed with hypertension at the time of their surgery. Within this group were 68 patients with a BMI of 35-39, which meant that they could get insurance coverage for bariatric surgery only if they also had a relevant comorbidity such as hypertension, diabetes, or severe sleep apnea.

Among these patients, 36 (17% of those with hypertension) had only hypertension as their relevant comorbidity and would not have qualified for bariatric surgery under the strictest criteria applied by some insurers that require patients to remain hypertensive despite treatment with at least three different antihypertensive medications. (These 36 patients underwent bariatric surgery because their insurance coverage did not have this restriction.)

The analyses Dr. Raftopoulos presented also documented the rate of hypertension resolution among patients in the series who had hypertension at baseline and 1-year follow-up results. Among 65 patients on one antihypertensive drug at baseline, 43 (66%) had complete resolution of their hypertension after 1 year, defined as blood pressure of less than 130/90 mm Hg while completely off antihypertensive treatment. In contrast, among 55 patients on two antihypertensive medications at baseline, 28 (51%) had complete resolution after 1 year, and among 24 patients on three or more antihypertensive medications at baseline, 3 (13%) had complete resolution 1 year after bariatric surgery, he reported.

“Patients who were treated with one oral antihypertensive medication preoperatively had a higher likelihood of postoperative hypertension resolution,” concluded Dr. Raftopoulos.

Restricting access to bariatric surgery to patients with a BMI of less than 40 based on the preoperative intensity of their antihypertensive treatment “is not supported by our data, and can be potentially harmful,” he declared.

“This study was the result of discussions about this problem with multiple insurers in my area,” he added. “This affects a good number of patients.”

Waiting for hypertension to become less treatable

The results Dr. Raftopoulos presented “are not surprising, because they confirm the hypothesis that earlier intervention in the course of a disease like hypertension is more likely to be successful,” commented Bruce D. Schirmer, MD, a professor of surgery at the University of Virginia, Charlottesville, and designated discussant for the report.

The policy followed by some health insurers to delay coverage for bariatric surgery until patients fail three medications “forces patients with more treatable hypertension to wait until their disease worsens and becomes less treatable before they can receive appropriate treatment,” he said.

Dr. Schirmer attributed the motivation for this approach to a “despicable” and “reprehensible” reason: “Actuarial calculations that show paying for curative therapy is not cost effective in the short term. The duration of a patient’s policy may not be long enough to yield a positive financial outcome, so it becomes more appropriate to deny optimal care and have patients become sicker from their disease.”

“I applaud the authors for accumulating the data that point out this unfortunate rule of some insurance companies,” Dr. Schirmer added.

The practice is comparable with an insurer requiring that a patient’s cancer must be metastatic before allowing coverage for treatment, commented Ann M. Rogers, MD, professor and director of the Penn State University surgical weight loss program in Hershey, Penn., and a moderator of the session.

Dr. Raftopoulos, Dr. Schirmer, and Dr. Rogers had no disclosures.

mzoler@mdedge.com

A delaying tactic used by some U.S. health insurers to limit coverage of bariatric surgery does not jibe with the clinical experience at one U.S. center with 461 patients who underwent primary or revisional bariatric surgery.

PhotoDisk

The tactic applies to patients with a baseline body mass index (BMI) of 35-39 kg/m² who usually also need at least one comorbidity to qualify for insurance coverage for bariatric surgery, and specifically to the subgroup for whom hypertension is the qualifying comorbidity.

Some insurers limit surgery coverage to patients with hypertension who fail to reach their goal blood pressure on agents from three different drug classes, a policy that is “extremely frustrating and dangerous,” said Yannis Raftopoulos, MD, PhD, in his presentation at the annual meeting of the American Society for Metabolic and Bariatric Surgery.

Using number of antihypertensive drugs ‘is not correct’

“Using the number of antihypertensive medications to justify surgery is not correct because blood pressure control is not [always] better when patients take two or three medications, compared with when they are taking one. This harms patients because the more severe their hypertension, the worse their control,” said Dr. Raftopoulos, director of the weight management program at Holyoke (Mass.) Medical Center.

He presented findings from a retrospective study of 461 patients who underwent either sleeve gastrectomy or laparoscopic Roux-en-Y gastric bypass at his center, including 213 (46%) diagnosed with hypertension at the time of their surgery. Within this group were 68 patients with a BMI of 35-39, which meant that they could get insurance coverage for bariatric surgery only if they also had a relevant comorbidity such as hypertension, diabetes, or severe sleep apnea.

Among these patients, 36 (17% of those with hypertension) had only hypertension as their relevant comorbidity and would not have qualified for bariatric surgery under the strictest criteria applied by some insurers that require patients to remain hypertensive despite treatment with at least three different antihypertensive medications. (These 36 patients underwent bariatric surgery because their insurance coverage did not have this restriction.)

The analyses Dr. Raftopoulos presented also documented the rate of hypertension resolution among patients in the series who had hypertension at baseline and 1-year follow-up results. Among 65 patients on one antihypertensive drug at baseline, 43 (66%) had complete resolution of their hypertension after 1 year, defined as blood pressure of less than 130/90 mm Hg while completely off antihypertensive treatment. In contrast, among 55 patients on two antihypertensive medications at baseline, 28 (51%) had complete resolution after 1 year, and among 24 patients on three or more antihypertensive medications at baseline, 3 (13%) had complete resolution 1 year after bariatric surgery, he reported.

“Patients who were treated with one oral antihypertensive medication preoperatively had a higher likelihood of postoperative hypertension resolution,” concluded Dr. Raftopoulos.

Restricting access to bariatric surgery to patients with a BMI of less than 40 based on the preoperative intensity of their antihypertensive treatment “is not supported by our data, and can be potentially harmful,” he declared.

“This study was the result of discussions about this problem with multiple insurers in my area,” he added. “This affects a good number of patients.”

Waiting for hypertension to become less treatable

The results Dr. Raftopoulos presented “are not surprising, because they confirm the hypothesis that earlier intervention in the course of a disease like hypertension is more likely to be successful,” commented Bruce D. Schirmer, MD, a professor of surgery at the University of Virginia, Charlottesville, and designated discussant for the report.

The policy followed by some health insurers to delay coverage for bariatric surgery until patients fail three medications “forces patients with more treatable hypertension to wait until their disease worsens and becomes less treatable before they can receive appropriate treatment,” he said.

Dr. Schirmer attributed the motivation for this approach to a “despicable” and “reprehensible” reason: “Actuarial calculations that show paying for curative therapy is not cost effective in the short term. The duration of a patient’s policy may not be long enough to yield a positive financial outcome, so it becomes more appropriate to deny optimal care and have patients become sicker from their disease.”

“I applaud the authors for accumulating the data that point out this unfortunate rule of some insurance companies,” Dr. Schirmer added.

The practice is comparable with an insurer requiring that a patient’s cancer must be metastatic before allowing coverage for treatment, commented Ann M. Rogers, MD, professor and director of the Penn State University surgical weight loss program in Hershey, Penn., and a moderator of the session.

Dr. Raftopoulos, Dr. Schirmer, and Dr. Rogers had no disclosures.

mzoler@mdedge.com

One in 15 patients who start dupilumab treatment may develop conjunctivitis during the first 6 months, most of which is manageable with ophthalmic treatments, results from large study of U.S. claims data showed.

“About 4 years after dupilumab’s approval, we’re interested in how conjunctivitis has played out in our daily clinical practice,” lead study investigator Maria C. Schneeweiss, MD, said during the Revolutionizing Atopic Dermatitis symposium.

Drawing from two nationwide U.S. databases, MarketScan and Optum, Dr. Schneeweiss, of the department of dermatology at Brigham and Women’s Hospital, Boston, and colleagues sought to characterize the incidence of bacterial and nonbacterial conjunctivitis among 6,730 patients with AD who started treatment with either dupilumab, methotrexate, mycophenolate, or cyclosporine between March 2017 and January 2020. They also wanted to identify patient subgroups at increased or decreased risk of dupilumab-related conjunctivitis in clinical practice.

Of the 6,730 patients, 3,755 started treatment with dupilumab, while 2,010 started with methotrexate, 536 started with mycophenolate, and 429 started with cyclosporine. Using a new-user, active-comparator study design, the researchers identified patients with AD from both databases and selected three dupilumab cohorts: dupilumab versus methotrexate (MTX), dupilumab versus mycophenolate (MMF), and dupilumab versus cyclosporine (CsA). Follow-up lasted 6 months and 1:1 propensity score matching was used to account for conjunctivitis risk factor differences. Patients with a history of conjunctivitis were excluded from the study, except one subgroup limited to those with prior conjunctivitis.

Dr. Schneeweiss reported that the overall incidence rate of conjunctivitis within 6 months of treatment initiation was 6.6% in dupilumab users, or 1 in 15 patients, compared with 3.3% in MTX users, 4.2% in MMF users, and 2.8% in CsA users. The incidence rates for the different types of conjunctivitis were as follows:

• Bacterial conjunctivitis: 1.5% in dupilumab users versus 0.95% in MTX, 0.4% in MMF, and 0.7% in CsA users.
• Allergic conjunctivitis: 2.2% in dupilumab users versus 0.8% in MTX, 0.2% in MMF, and 1.6% in CsA users.
• Keratoconjunctivitis: 0.8% in dupilumab users versus 1.1% in MTX, 1.5% in MMF, and 0.5% in CsA users.

In addition, the rate of conjunctivitis requiring ophthalmic medication was 2.6% in dupilumab users versus 0.7% in MTX, 1% in MMF, and 0.5% in CsA users.

After the researchers applied 1:1 propensity score matching, they observed that the risk of conjunctivitis within 6 months of starting treatment was increased in dupilumab users versus MTX users (relative risk, 2.12), dupilumab versus MMF users (RR, 2.43), and dupilumab versus CsA users (RR, 1.83). Among dupilumab users, the risk of conjunctivitis requiring ophthalmic medication was increased six to eightfold, compared with those who used MTX, MMF or CsA. In addition, bacterial conjunctivitis was increased 1.6- to 4.0-fold, compared with those who used MTX, MMF or CsA, but the confidence intervals were wide and included the null, while allergic conjunctivitis was increased 2.7- to 7-fold when compared with those who used MTX and MMF.

In other findings, the risk of allergic conjunctivitis was similar between dupilumab and CsA users (RR, 1.14), and there was no increased risk of keratoconjunctivitis in dupilumab users, compared with those who used MTX, MMF, or CsA. The relative risk of conjunctivitis in those who used dupilumab was further increased when the analysis was limited to AD patients with comorbid asthma (RR, 2.86), those who used systemic glucocorticoids fewer than 30 days prior (RR, 2.88), and those age 65 and older (RR, 2.57), compared with those who used methotrexate.

“Compared to AD patients who received treatment with other systemic agents, dupilumab treatment doubled the risk of conjunctivitis in clinical practice,” Dr. Schneeweiss concluded. “Risk factors that further increase the risk include comorbid asthma, use of systemic corticosteroids, and older age. It should be noted that conjunctivitis does not require treatment discontinuation and is manageable with ophthalmic medications.”

Lawrence J. Green, MD, clinical professor of dermatology at George Washington University, Washington, who was asked to comment on the study, said that the work “verifies what we see clinically: that conjunctivitis is increased among dupilumab users even when it is compared to immunosuppressive agents used to treat other conditions. Because the study is retrospective, one cannot assume all diagnosis of types of conjunctivitis or even of skin disease is entirely accurate. But, with the large numbers of claims looked at and compared, one would think its conclusions are accurate.”

Dr. Schneeweiss reported having no relevant financial disclosures. Dr. Green disclosed that he is a speaker, consultant, or investigator for Amgen, AbbVie, Arcutis, Brickell, Candescent, Cassiopeia, Dermavant, Galderma, Janssen, Forte, Incyte, MC-2, Lilly, Novartis, Novan, Ortho Dermatologics, Revance, Sun Pharma, UCB, and Vyne.

dbrunk@mdedge.com

One in 15 patients who start dupilumab treatment may develop conjunctivitis during the first 6 months, most of which is manageable with ophthalmic treatments, results from large study of U.S. claims data showed.

“About 4 years after dupilumab’s approval, we’re interested in how conjunctivitis has played out in our daily clinical practice,” lead study investigator Maria C. Schneeweiss, MD, said during the Revolutionizing Atopic Dermatitis symposium.

Drawing from two nationwide U.S. databases, MarketScan and Optum, Dr. Schneeweiss, of the department of dermatology at Brigham and Women’s Hospital, Boston, and colleagues sought to characterize the incidence of bacterial and nonbacterial conjunctivitis among 6,730 patients with AD who started treatment with either dupilumab, methotrexate, mycophenolate, or cyclosporine between March 2017 and January 2020. They also wanted to identify patient subgroups at increased or decreased risk of dupilumab-related conjunctivitis in clinical practice.

Of the 6,730 patients, 3,755 started treatment with dupilumab, while 2,010 started with methotrexate, 536 started with mycophenolate, and 429 started with cyclosporine. Using a new-user, active-comparator study design, the researchers identified patients with AD from both databases and selected three dupilumab cohorts: dupilumab versus methotrexate (MTX), dupilumab versus mycophenolate (MMF), and dupilumab versus cyclosporine (CsA). Follow-up lasted 6 months and 1:1 propensity score matching was used to account for conjunctivitis risk factor differences. Patients with a history of conjunctivitis were excluded from the study, except one subgroup limited to those with prior conjunctivitis.

Dr. Schneeweiss reported that the overall incidence rate of conjunctivitis within 6 months of treatment initiation was 6.6% in dupilumab users, or 1 in 15 patients, compared with 3.3% in MTX users, 4.2% in MMF users, and 2.8% in CsA users. The incidence rates for the different types of conjunctivitis were as follows:

• Bacterial conjunctivitis: 1.5% in dupilumab users versus 0.95% in MTX, 0.4% in MMF, and 0.7% in CsA users.
• Allergic conjunctivitis: 2.2% in dupilumab users versus 0.8% in MTX, 0.2% in MMF, and 1.6% in CsA users.
• Keratoconjunctivitis: 0.8% in dupilumab users versus 1.1% in MTX, 1.5% in MMF, and 0.5% in CsA users.

In addition, the rate of conjunctivitis requiring ophthalmic medication was 2.6% in dupilumab users versus 0.7% in MTX, 1% in MMF, and 0.5% in CsA users.

After the researchers applied 1:1 propensity score matching, they observed that the risk of conjunctivitis within 6 months of starting treatment was increased in dupilumab users versus MTX users (relative risk, 2.12), dupilumab versus MMF users (RR, 2.43), and dupilumab versus CsA users (RR, 1.83). Among dupilumab users, the risk of conjunctivitis requiring ophthalmic medication was increased six to eightfold, compared with those who used MTX, MMF or CsA. In addition, bacterial conjunctivitis was increased 1.6- to 4.0-fold, compared with those who used MTX, MMF or CsA, but the confidence intervals were wide and included the null, while allergic conjunctivitis was increased 2.7- to 7-fold when compared with those who used MTX and MMF.

In other findings, the risk of allergic conjunctivitis was similar between dupilumab and CsA users (RR, 1.14), and there was no increased risk of keratoconjunctivitis in dupilumab users, compared with those who used MTX, MMF, or CsA. The relative risk of conjunctivitis in those who used dupilumab was further increased when the analysis was limited to AD patients with comorbid asthma (RR, 2.86), those who used systemic glucocorticoids fewer than 30 days prior (RR, 2.88), and those age 65 and older (RR, 2.57), compared with those who used methotrexate.

“Compared to AD patients who received treatment with other systemic agents, dupilumab treatment doubled the risk of conjunctivitis in clinical practice,” Dr. Schneeweiss concluded. “Risk factors that further increase the risk include comorbid asthma, use of systemic corticosteroids, and older age. It should be noted that conjunctivitis does not require treatment discontinuation and is manageable with ophthalmic medications.”

Lawrence J. Green, MD, clinical professor of dermatology at George Washington University, Washington, who was asked to comment on the study, said that the work “verifies what we see clinically: that conjunctivitis is increased among dupilumab users even when it is compared to immunosuppressive agents used to treat other conditions. Because the study is retrospective, one cannot assume all diagnosis of types of conjunctivitis or even of skin disease is entirely accurate. But, with the large numbers of claims looked at and compared, one would think its conclusions are accurate.”

Dr. Schneeweiss reported having no relevant financial disclosures. Dr. Green disclosed that he is a speaker, consultant, or investigator for Amgen, AbbVie, Arcutis, Brickell, Candescent, Cassiopeia, Dermavant, Galderma, Janssen, Forte, Incyte, MC-2, Lilly, Novartis, Novan, Ortho Dermatologics, Revance, Sun Pharma, UCB, and Vyne.

dbrunk@mdedge.com

One in 15 patients who start dupilumab treatment may develop conjunctivitis during the first 6 months, most of which is manageable with ophthalmic treatments, results from large study of U.S. claims data showed.

“About 4 years after dupilumab’s approval, we’re interested in how conjunctivitis has played out in our daily clinical practice,” lead study investigator Maria C. Schneeweiss, MD, said during the Revolutionizing Atopic Dermatitis symposium.

Drawing from two nationwide U.S. databases, MarketScan and Optum, Dr. Schneeweiss, of the department of dermatology at Brigham and Women’s Hospital, Boston, and colleagues sought to characterize the incidence of bacterial and nonbacterial conjunctivitis among 6,730 patients with AD who started treatment with either dupilumab, methotrexate, mycophenolate, or cyclosporine between March 2017 and January 2020. They also wanted to identify patient subgroups at increased or decreased risk of dupilumab-related conjunctivitis in clinical practice.

Of the 6,730 patients, 3,755 started treatment with dupilumab, while 2,010 started with methotrexate, 536 started with mycophenolate, and 429 started with cyclosporine. Using a new-user, active-comparator study design, the researchers identified patients with AD from both databases and selected three dupilumab cohorts: dupilumab versus methotrexate (MTX), dupilumab versus mycophenolate (MMF), and dupilumab versus cyclosporine (CsA). Follow-up lasted 6 months and 1:1 propensity score matching was used to account for conjunctivitis risk factor differences. Patients with a history of conjunctivitis were excluded from the study, except one subgroup limited to those with prior conjunctivitis.

Dr. Schneeweiss reported that the overall incidence rate of conjunctivitis within 6 months of treatment initiation was 6.6% in dupilumab users, or 1 in 15 patients, compared with 3.3% in MTX users, 4.2% in MMF users, and 2.8% in CsA users. The incidence rates for the different types of conjunctivitis were as follows:

• Bacterial conjunctivitis: 1.5% in dupilumab users versus 0.95% in MTX, 0.4% in MMF, and 0.7% in CsA users.
• Allergic conjunctivitis: 2.2% in dupilumab users versus 0.8% in MTX, 0.2% in MMF, and 1.6% in CsA users.
• Keratoconjunctivitis: 0.8% in dupilumab users versus 1.1% in MTX, 1.5% in MMF, and 0.5% in CsA users.

In addition, the rate of conjunctivitis requiring ophthalmic medication was 2.6% in dupilumab users versus 0.7% in MTX, 1% in MMF, and 0.5% in CsA users.

After the researchers applied 1:1 propensity score matching, they observed that the risk of conjunctivitis within 6 months of starting treatment was increased in dupilumab users versus MTX users (relative risk, 2.12), dupilumab versus MMF users (RR, 2.43), and dupilumab versus CsA users (RR, 1.83). Among dupilumab users, the risk of conjunctivitis requiring ophthalmic medication was increased six to eightfold, compared with those who used MTX, MMF or CsA. In addition, bacterial conjunctivitis was increased 1.6- to 4.0-fold, compared with those who used MTX, MMF or CsA, but the confidence intervals were wide and included the null, while allergic conjunctivitis was increased 2.7- to 7-fold when compared with those who used MTX and MMF.

In other findings, the risk of allergic conjunctivitis was similar between dupilumab and CsA users (RR, 1.14), and there was no increased risk of keratoconjunctivitis in dupilumab users, compared with those who used MTX, MMF, or CsA. The relative risk of conjunctivitis in those who used dupilumab was further increased when the analysis was limited to AD patients with comorbid asthma (RR, 2.86), those who used systemic glucocorticoids fewer than 30 days prior (RR, 2.88), and those age 65 and older (RR, 2.57), compared with those who used methotrexate.

“Compared to AD patients who received treatment with other systemic agents, dupilumab treatment doubled the risk of conjunctivitis in clinical practice,” Dr. Schneeweiss concluded. “Risk factors that further increase the risk include comorbid asthma, use of systemic corticosteroids, and older age. It should be noted that conjunctivitis does not require treatment discontinuation and is manageable with ophthalmic medications.”

Lawrence J. Green, MD, clinical professor of dermatology at George Washington University, Washington, who was asked to comment on the study, said that the work “verifies what we see clinically: that conjunctivitis is increased among dupilumab users even when it is compared to immunosuppressive agents used to treat other conditions. Because the study is retrospective, one cannot assume all diagnosis of types of conjunctivitis or even of skin disease is entirely accurate. But, with the large numbers of claims looked at and compared, one would think its conclusions are accurate.”

Dr. Schneeweiss reported having no relevant financial disclosures. Dr. Green disclosed that he is a speaker, consultant, or investigator for Amgen, AbbVie, Arcutis, Brickell, Candescent, Cassiopeia, Dermavant, Galderma, Janssen, Forte, Incyte, MC-2, Lilly, Novartis, Novan, Ortho Dermatologics, Revance, Sun Pharma, UCB, and Vyne.

dbrunk@mdedge.com

Among the 51 patients with moderate to severe atopic dermatitis (AD) who developed COVID-19 while participating in an open-label clinical trial of tralokinumab, 96% of cases were mild or moderate and all patients continued tralokinumab treatment following their diagnosis.

“This is a great first look at COVID-19 outcomes in this population,” lead study investigator Andrew Blauvelt, MD, MBA, said during the Revolutionizing Atopic Dermatitis symposium. “This suggests that tralokinumab does not significantly impact the ability to respond to SARS-CoV-2, the virus that causes COVID-19. It’s encouraging and promising.”

Tralokinumab is a fully human IgG4 monoclonal antibody that specifically binds to interleukin-13, which is a key driver of underlying inflammation in AD. An ongoing, open-label extension trial called ECZTEND is investigating the long-term safety and efficacy of tralokinumab in patients with AD who participated in previous tralokinumab trials. The purpose of the current case series is to describe the outcomes of patients diagnosed with COVID-19 while participating in ECZTEND, which is a 5-year study.

“Patients are receiving tralokinumab 300 mg every 2 weeks,” said Dr. Blauvelt, a dermatologist who is president of Oregon Medical Research Center, Portland. “They’re allowed to use topical steroids, but they’re not allowed to use other AD treatments. We do regular clinical and safety assessments throughout the study.”

As of Feb. 26, 2021, there were 51 adults with moderate to severe AD who had confirmed COVID-19 infection during treatment with tralokinumab every 2 weeks. “Patients were not required to discontinue tralokinumab treatment following a COVID-19 diagnosis, if continuation was deemed appropriate by the investigator,” Dr. Blauvelt said. Of the 51 patients, 22 were male, 29 were female, their mean age was 38 years, and their baseline body mass index was 27.6 kg/m². Most of the patients (36, or 71%) were from Europe, 15 (29%) were from North America, and 30 (59%) had a history of asthma.

The average duration of COVID-19 infection was 15 days and severity of disease was mild in 35 patients (69%), moderate in 14 (27%), and severe in 2 (4%). According to the study abstract, those two patients had multiple risk factors and comorbidities, including obesity, chronic obstructive pulmonary disease, and cardiovascular disease. They were hospitalized for a mean of 7 days, but subsequently recovered – one with sequelae. None of the patients died.

Of the 51 COVID-19 cases, 2 were deemed to be possibly related to tralokinumab treatment by the investigator, Dr. Blauvelt said. Both were mild or moderate cases that occurred in patients younger than age 30. “Interestingly, 75% of the COVID-19 patients had no dose interruption; they continued dosing their tralokinumab every 2 weeks during and around the time they had COVID-19,” he said. “However, 25% of patients did interrupt their dosing during COVID-19 infection. That means that they either delayed or stopped dosing while they were sick.”

Of the 51 patients, 19 (37%) had received their first dose of the COVID-19 vaccine and 6 (12%) had received their second dose. “So, 12% of patients were fully vaccinated,” Dr. Blauvelt said. “We do know that the mRNA vaccines are about 95% effective in preventing COVID-19. Currently in Oregon, about 98% of our cases are in unvaccinated patients and about 2% of COVID-19 patients are fully vaccinated.”

In addition, the recently published ECZTRA5 vaccine study showed that nonlive vaccines (tetanus, diphtheria, and pertussis; and meningococcal vaccines) could be safely administered and can elicit normal immune responses in patients treated with tralokinumab.

“We sorely need COVID-19–related safety data for all of our current and emerging systemic and biologic therapies used to treat atopic dermatitis,” said Jonathan I. Silverberg, MD, PhD, MPH, director of clinical research in the division of dermatology at George Washington University, Washington, who was asked to comment about these results. “This study is important because it shows that tralokinumab was not associated with any obvious safety signals with respect to COVID-19 infections. The major limitation is that it is not a prospective study designed to assess tralokinumab efficacy in COVID-19 patients per se. However, this post hoc study provides reassuring data. We need similar or even more robust studies for other systemic therapies in AD.”

Dr. Blauvelt reported that he is an investigator and a scientific advisor for LEO Pharma, which is developing tralokinumab, and for several other pharmaceutical companies developing treatments for AD. Dr. Silverberg reported that he is a consultant to and/or an advisory board member for several pharmaceutical companies, including LEO Pharma.

dbrunk@mdedge.com

Among the 51 patients with moderate to severe atopic dermatitis (AD) who developed COVID-19 while participating in an open-label clinical trial of tralokinumab, 96% of cases were mild or moderate and all patients continued tralokinumab treatment following their diagnosis.

“This is a great first look at COVID-19 outcomes in this population,” lead study investigator Andrew Blauvelt, MD, MBA, said during the Revolutionizing Atopic Dermatitis symposium. “This suggests that tralokinumab does not significantly impact the ability to respond to SARS-CoV-2, the virus that causes COVID-19. It’s encouraging and promising.”

Tralokinumab is a fully human IgG4 monoclonal antibody that specifically binds to interleukin-13, which is a key driver of underlying inflammation in AD. An ongoing, open-label extension trial called ECZTEND is investigating the long-term safety and efficacy of tralokinumab in patients with AD who participated in previous tralokinumab trials. The purpose of the current case series is to describe the outcomes of patients diagnosed with COVID-19 while participating in ECZTEND, which is a 5-year study.

“Patients are receiving tralokinumab 300 mg every 2 weeks,” said Dr. Blauvelt, a dermatologist who is president of Oregon Medical Research Center, Portland. “They’re allowed to use topical steroids, but they’re not allowed to use other AD treatments. We do regular clinical and safety assessments throughout the study.”

As of Feb. 26, 2021, there were 51 adults with moderate to severe AD who had confirmed COVID-19 infection during treatment with tralokinumab every 2 weeks. “Patients were not required to discontinue tralokinumab treatment following a COVID-19 diagnosis, if continuation was deemed appropriate by the investigator,” Dr. Blauvelt said. Of the 51 patients, 22 were male, 29 were female, their mean age was 38 years, and their baseline body mass index was 27.6 kg/m². Most of the patients (36, or 71%) were from Europe, 15 (29%) were from North America, and 30 (59%) had a history of asthma.

The average duration of COVID-19 infection was 15 days and severity of disease was mild in 35 patients (69%), moderate in 14 (27%), and severe in 2 (4%). According to the study abstract, those two patients had multiple risk factors and comorbidities, including obesity, chronic obstructive pulmonary disease, and cardiovascular disease. They were hospitalized for a mean of 7 days, but subsequently recovered – one with sequelae. None of the patients died.

Of the 51 COVID-19 cases, 2 were deemed to be possibly related to tralokinumab treatment by the investigator, Dr. Blauvelt said. Both were mild or moderate cases that occurred in patients younger than age 30. “Interestingly, 75% of the COVID-19 patients had no dose interruption; they continued dosing their tralokinumab every 2 weeks during and around the time they had COVID-19,” he said. “However, 25% of patients did interrupt their dosing during COVID-19 infection. That means that they either delayed or stopped dosing while they were sick.”

Of the 51 patients, 19 (37%) had received their first dose of the COVID-19 vaccine and 6 (12%) had received their second dose. “So, 12% of patients were fully vaccinated,” Dr. Blauvelt said. “We do know that the mRNA vaccines are about 95% effective in preventing COVID-19. Currently in Oregon, about 98% of our cases are in unvaccinated patients and about 2% of COVID-19 patients are fully vaccinated.”

In addition, the recently published ECZTRA5 vaccine study showed that nonlive vaccines (tetanus, diphtheria, and pertussis; and meningococcal vaccines) could be safely administered and can elicit normal immune responses in patients treated with tralokinumab.

“We sorely need COVID-19–related safety data for all of our current and emerging systemic and biologic therapies used to treat atopic dermatitis,” said Jonathan I. Silverberg, MD, PhD, MPH, director of clinical research in the division of dermatology at George Washington University, Washington, who was asked to comment about these results. “This study is important because it shows that tralokinumab was not associated with any obvious safety signals with respect to COVID-19 infections. The major limitation is that it is not a prospective study designed to assess tralokinumab efficacy in COVID-19 patients per se. However, this post hoc study provides reassuring data. We need similar or even more robust studies for other systemic therapies in AD.”

Dr. Blauvelt reported that he is an investigator and a scientific advisor for LEO Pharma, which is developing tralokinumab, and for several other pharmaceutical companies developing treatments for AD. Dr. Silverberg reported that he is a consultant to and/or an advisory board member for several pharmaceutical companies, including LEO Pharma.

dbrunk@mdedge.com

Among the 51 patients with moderate to severe atopic dermatitis (AD) who developed COVID-19 while participating in an open-label clinical trial of tralokinumab, 96% of cases were mild or moderate and all patients continued tralokinumab treatment following their diagnosis.

“This is a great first look at COVID-19 outcomes in this population,” lead study investigator Andrew Blauvelt, MD, MBA, said during the Revolutionizing Atopic Dermatitis symposium. “This suggests that tralokinumab does not significantly impact the ability to respond to SARS-CoV-2, the virus that causes COVID-19. It’s encouraging and promising.”

Tralokinumab is a fully human IgG4 monoclonal antibody that specifically binds to interleukin-13, which is a key driver of underlying inflammation in AD. An ongoing, open-label extension trial called ECZTEND is investigating the long-term safety and efficacy of tralokinumab in patients with AD who participated in previous tralokinumab trials. The purpose of the current case series is to describe the outcomes of patients diagnosed with COVID-19 while participating in ECZTEND, which is a 5-year study.

“Patients are receiving tralokinumab 300 mg every 2 weeks,” said Dr. Blauvelt, a dermatologist who is president of Oregon Medical Research Center, Portland. “They’re allowed to use topical steroids, but they’re not allowed to use other AD treatments. We do regular clinical and safety assessments throughout the study.”

As of Feb. 26, 2021, there were 51 adults with moderate to severe AD who had confirmed COVID-19 infection during treatment with tralokinumab every 2 weeks. “Patients were not required to discontinue tralokinumab treatment following a COVID-19 diagnosis, if continuation was deemed appropriate by the investigator,” Dr. Blauvelt said. Of the 51 patients, 22 were male, 29 were female, their mean age was 38 years, and their baseline body mass index was 27.6 kg/m². Most of the patients (36, or 71%) were from Europe, 15 (29%) were from North America, and 30 (59%) had a history of asthma.

The average duration of COVID-19 infection was 15 days and severity of disease was mild in 35 patients (69%), moderate in 14 (27%), and severe in 2 (4%). According to the study abstract, those two patients had multiple risk factors and comorbidities, including obesity, chronic obstructive pulmonary disease, and cardiovascular disease. They were hospitalized for a mean of 7 days, but subsequently recovered – one with sequelae. None of the patients died.

Of the 51 COVID-19 cases, 2 were deemed to be possibly related to tralokinumab treatment by the investigator, Dr. Blauvelt said. Both were mild or moderate cases that occurred in patients younger than age 30. “Interestingly, 75% of the COVID-19 patients had no dose interruption; they continued dosing their tralokinumab every 2 weeks during and around the time they had COVID-19,” he said. “However, 25% of patients did interrupt their dosing during COVID-19 infection. That means that they either delayed or stopped dosing while they were sick.”

Of the 51 patients, 19 (37%) had received their first dose of the COVID-19 vaccine and 6 (12%) had received their second dose. “So, 12% of patients were fully vaccinated,” Dr. Blauvelt said. “We do know that the mRNA vaccines are about 95% effective in preventing COVID-19. Currently in Oregon, about 98% of our cases are in unvaccinated patients and about 2% of COVID-19 patients are fully vaccinated.”

In addition, the recently published ECZTRA5 vaccine study showed that nonlive vaccines (tetanus, diphtheria, and pertussis; and meningococcal vaccines) could be safely administered and can elicit normal immune responses in patients treated with tralokinumab.

“We sorely need COVID-19–related safety data for all of our current and emerging systemic and biologic therapies used to treat atopic dermatitis,” said Jonathan I. Silverberg, MD, PhD, MPH, director of clinical research in the division of dermatology at George Washington University, Washington, who was asked to comment about these results. “This study is important because it shows that tralokinumab was not associated with any obvious safety signals with respect to COVID-19 infections. The major limitation is that it is not a prospective study designed to assess tralokinumab efficacy in COVID-19 patients per se. However, this post hoc study provides reassuring data. We need similar or even more robust studies for other systemic therapies in AD.”

Dr. Blauvelt reported that he is an investigator and a scientific advisor for LEO Pharma, which is developing tralokinumab, and for several other pharmaceutical companies developing treatments for AD. Dr. Silverberg reported that he is a consultant to and/or an advisory board member for several pharmaceutical companies, including LEO Pharma.

dbrunk@mdedge.com

Women who receive pellet hormonal therapy may be significantly more likely to have side effects such as mood swings, anxiety, breast tenderness, hair pattern change, acne, and weight gain, compared with women who receive hormonal treatments that have been approved by the Food and Drug Administration, a study indicates.

In addition, abnormal uterine bleeding may be significantly more common in women who receive pellets than it is in women who receive Food and Drug Administration–approved options, according to the retrospective study, which was published online in Menopause.

Women receiving pellets also were more likely to undergo hysterectomy while on hormonal therapy, and they had higher supraphysiological levels of estradiol and total testosterone during treatment, compared with women on conventional therapy, the study of 539 women shows.

The findings, which had been presented at the North American Menopause Society annual meeting, were highlighted during a lecture at the 2021 virtual meeting of the American College of Obstetricians and Gynecologists.

The data are “not very reassuring at all,” said Robert P. Kauffman, MD, a professor of obstetrics and gynecology at Texas Tech University, Amarillo, who was not involved in the study.

Dr. Kauffman commented on the research during a review of concerns surrounding non–FDA-approved hormone replacement therapies at the ACOG meeting. Concerns include variations in compounded products, a lack of randomized, controlled trial data supporting their use, and ethical dilemmas that may exist if clinicians have financial incentives to provide compounded bioidentical hormone therapy over FDA-approved treatments.

No peer-reviewed studies show that compounded hormone creams or pellets are safer, more efficacious, or less likely to cause adverse effects, compared with FDA-approved products, Dr. Kauffman said.
 

Data from Pennsylvania

For the retrospective study, Xuezhi (Daniel) Jiang, MD, PhD, and colleagues identified postmenopausal patients in the Reading Hospital Electronic Medical Record System, including 10,801 on FDA-approved hormonal therapy and 1,061 on pellet hormonal therapy. Their analysis focused on data from the medical records of 384 women on pellet hormonal therapy and 155 women on FDA-approved hormonal therapy. Dr. Jiang is affiliated with the department of obstetrics and gynecology at Reading (Pa.) Hospital and Sidney Kimmel Medical College, Philadelphia.

The researchers examined data from 2005 to 2017 for patients in the pellet therapy group, and from 1985 to 2017 for patients in the conventional therapy group.

Patients in the conventional therapy group received 24 brands of FDA-approved hormone products; 4.5% received testosterone or methyltestosterone in addition to estrogen. Patients in the pellet therapy group had pellets prescribed by clinicians at two private practices in the hospital system that use this treatment approach. Patients in the pellet group received compounded estradiol and testosterone pellets made at a pharmacy in Tennessee.* Almost all of the patients in the pellet group received testosterone and estradiol pellets.

Low libido was listed as a reason why women started treatment for 83.5% of the pellet group versus 4.5% of the conventional therapy group.

In all, 57.6% of patients on pellet therapy had side effects, versus 14.8% on FDA-approved therapy, the researchers found. Patients on pellet hormonal therapy reported higher incidence of mood swings (7% vs. 1.9%), anxiety (18.5% vs. 5.8%), breast tenderness (10.1% vs. 2.6%), hair pattern change (13.5% vs. 2.6%), acne (8.6% vs. 1.3%), and weight gain (34.4% vs 4.5%), relative to patients on FDA-approved options.

Among those with an intact uterus when starting therapy (246 of those on pellets and 133 of those on FDA-approved treatments), abnormal uterine bleeding occurred in 55.3% on pellets, compared with 15.2% on FDA-approved treatments (adjusted odds ratio, 7.9). Hysterectomy secondary to abnormal uterine bleeding occurred in 20.3% of the patients on pellets versus 6.3% on FDA-approved treatments (aOR, 3.2).

In many cases, records show that patients chose to have a hysterectomy so they could continue pellet therapy without worrying about abnormal uterine bleeding, Dr. Jiang said in an interview.

Dr. Kauffman has seen patients on pellet therapy, usually implanted by family physicians, develop postmenopausal bleeding because of high levels of estrogen. “Our experience has been too that, if you have pellets, you are more likely to get a hysterectomy for bleeding issues. And I think these are the safety issues that need to be looked at on a broader scope,” he said in an interview.

Although hysterectomy may stop the bleeding, other safety risks may remain with pellet therapy, noted Sharon Winer, MD, MPH, an obstetrician and gynecologist with a subspecialty in reproductive endocrinology and infertility who practices in Beverly Hills, Calif.

Pellets, which are about the size of a grain of rice, typically are implanted in the hip, lower abdomen, or buttock and release hormones over 3-6 months. The pellets are not retrievable. “The question becomes, what if she has a new breast cancer diagnosis or a diagnosis where estrogen is contraindicated? She has got that estrogen already in her system,” Dr. Winer said.

“The hysterectomy may solve the bleeding problem ... but it doesn’t solve the safety problem overall,” said Dr. Winer, who also is a professor of obstetrics and gynecology and codirector of the reproductive endocrinology and infertility clinic at the University of Southern California, Los Angeles.

Elevated levels

Average peak serum estradiol was significantly higher in the pellet treatment group than in the conventional therapy group (237.70 pg/mL vs. 93.45 pg/mL), as was average peak serum testosterone (192.84 ng/dL vs. 15.59 ng/dL), the researchers reported. Patients on FDA-approved treatments were less likely to have had their hormone levels measured. How concentrations of hormone levels correlate with side effects is unclear, Dr. Jiang said.

The study was limited by its single-institution, retrospective design, and some patient characteristics differed between the treatment groups, the authors noted.

Still, “clinicians ought to be mindful of fully counseling patients on side effects identified in the current study,” Dr. Jiang and coauthors concluded. Clinicians also need to discuss potential risks of breast cancer, endometrial cancer, and cardiovascular disease with patients.

Many primary care clinicians rely on outdated information from the Women’s Health Initiative, published in 2002 and 2004, in their understanding of postmenopausal hormonal therapy and its risks and benefits, Dr. Jiang said. And some patients consider custom-compounded hormone therapy to be safer and more natural, “which is totally misleading.”

Pellets and other custom-compounded medicine containing testosterone may make patients feel better and more energetic, Dr. Jiang acknowledged. “That’s a reason why patients ... tend to stay on, even though they have side effects. The only issue is the safety.”

Additional questions remain. The researchers recently started to examine rates of breast cancer and abnormal breast pathology and mammogram results. “It’s a long journey,” he said.

Plenty of approved options

Custom-compounded medicines are not FDA approved and are not recommended by medical menopause societies, Dr. Jiang said. Meanwhile, plenty of approved hormone therapies, including bioidentical treatments, have safety data and are available.

A 2020 consensus study report from the National Academies of Sciences, Engineering, and Medicine that examined the use of compounded hormonal therapy and provides guidance for clinicians is a good start in addressing this major issue, he added.

A committee determined “there is insufficient evidence to support the overall clinical utility of [compounded bioidentical hormone therapies] as treatment for menopause and male hypogonadism symptoms.”

If an FDA-approved option is available, “I would always go with an FDA-approved product before I would go with a compounded product,” Dr. Winer said. A 2012 fungal meningitis outbreak linked to a compounding pharmacy highlighted risks associated with poor quality compounded drugs.

“I think at least now it is recognized that compounding is an issue that has got to be dealt with,” Dr. Winer said. “It is just that it is so widespread and it is sometimes under the radar ... that I think it is really hard for the FDA to get a handle on it.”

Dr. Winer has seen patients on compounded treatments who are underdosed and patients who are overdosed. “I’ve also seen patients who do quite well with it, but I’m not happy continuing it because tomorrow there may be inconsistency in potency or quality resulting in a different clinical response,” she said.

Nevertheless, compounded pharmacies are needed, Dr. Winer said. If she wants to give natural progesterone that is FDA approved but happens to be made with peanut oil, she will have a compounding pharmacy make it with canola oil instead if a patient has a peanut allergy, for example. Other patients need dosages that are so low that they are not available as FDA-approved products.

Dr. Jiang and Dr. Kauffman had no relevant financial disclosures. Dr. Winer has done work with AbbVie (related to endometriosis), TherapeuticsMD (related to a menopause bioidentical hormonal pill and vaginal estrogen product), and Biogix (related to an antioxidant supplement for menopause symptoms).

jremaly@mdedge.com

*This story was updated on 6/22/2021.

Women who receive pellet hormonal therapy may be significantly more likely to have side effects such as mood swings, anxiety, breast tenderness, hair pattern change, acne, and weight gain, compared with women who receive hormonal treatments that have been approved by the Food and Drug Administration, a study indicates.

In addition, abnormal uterine bleeding may be significantly more common in women who receive pellets than it is in women who receive Food and Drug Administration–approved options, according to the retrospective study, which was published online in Menopause.

Women receiving pellets also were more likely to undergo hysterectomy while on hormonal therapy, and they had higher supraphysiological levels of estradiol and total testosterone during treatment, compared with women on conventional therapy, the study of 539 women shows.

The findings, which had been presented at the North American Menopause Society annual meeting, were highlighted during a lecture at the 2021 virtual meeting of the American College of Obstetricians and Gynecologists.

The data are “not very reassuring at all,” said Robert P. Kauffman, MD, a professor of obstetrics and gynecology at Texas Tech University, Amarillo, who was not involved in the study.

Dr. Kauffman commented on the research during a review of concerns surrounding non–FDA-approved hormone replacement therapies at the ACOG meeting. Concerns include variations in compounded products, a lack of randomized, controlled trial data supporting their use, and ethical dilemmas that may exist if clinicians have financial incentives to provide compounded bioidentical hormone therapy over FDA-approved treatments.

No peer-reviewed studies show that compounded hormone creams or pellets are safer, more efficacious, or less likely to cause adverse effects, compared with FDA-approved products, Dr. Kauffman said.
 

Data from Pennsylvania

For the retrospective study, Xuezhi (Daniel) Jiang, MD, PhD, and colleagues identified postmenopausal patients in the Reading Hospital Electronic Medical Record System, including 10,801 on FDA-approved hormonal therapy and 1,061 on pellet hormonal therapy. Their analysis focused on data from the medical records of 384 women on pellet hormonal therapy and 155 women on FDA-approved hormonal therapy. Dr. Jiang is affiliated with the department of obstetrics and gynecology at Reading (Pa.) Hospital and Sidney Kimmel Medical College, Philadelphia.

The researchers examined data from 2005 to 2017 for patients in the pellet therapy group, and from 1985 to 2017 for patients in the conventional therapy group.

Patients in the conventional therapy group received 24 brands of FDA-approved hormone products; 4.5% received testosterone or methyltestosterone in addition to estrogen. Patients in the pellet therapy group had pellets prescribed by clinicians at two private practices in the hospital system that use this treatment approach. Patients in the pellet group received compounded estradiol and testosterone pellets made at a pharmacy in Tennessee.* Almost all of the patients in the pellet group received testosterone and estradiol pellets.

Low libido was listed as a reason why women started treatment for 83.5% of the pellet group versus 4.5% of the conventional therapy group.

In all, 57.6% of patients on pellet therapy had side effects, versus 14.8% on FDA-approved therapy, the researchers found. Patients on pellet hormonal therapy reported higher incidence of mood swings (7% vs. 1.9%), anxiety (18.5% vs. 5.8%), breast tenderness (10.1% vs. 2.6%), hair pattern change (13.5% vs. 2.6%), acne (8.6% vs. 1.3%), and weight gain (34.4% vs 4.5%), relative to patients on FDA-approved options.

Among those with an intact uterus when starting therapy (246 of those on pellets and 133 of those on FDA-approved treatments), abnormal uterine bleeding occurred in 55.3% on pellets, compared with 15.2% on FDA-approved treatments (adjusted odds ratio, 7.9). Hysterectomy secondary to abnormal uterine bleeding occurred in 20.3% of the patients on pellets versus 6.3% on FDA-approved treatments (aOR, 3.2).

In many cases, records show that patients chose to have a hysterectomy so they could continue pellet therapy without worrying about abnormal uterine bleeding, Dr. Jiang said in an interview.

Dr. Kauffman has seen patients on pellet therapy, usually implanted by family physicians, develop postmenopausal bleeding because of high levels of estrogen. “Our experience has been too that, if you have pellets, you are more likely to get a hysterectomy for bleeding issues. And I think these are the safety issues that need to be looked at on a broader scope,” he said in an interview.

Although hysterectomy may stop the bleeding, other safety risks may remain with pellet therapy, noted Sharon Winer, MD, MPH, an obstetrician and gynecologist with a subspecialty in reproductive endocrinology and infertility who practices in Beverly Hills, Calif.

Pellets, which are about the size of a grain of rice, typically are implanted in the hip, lower abdomen, or buttock and release hormones over 3-6 months. The pellets are not retrievable. “The question becomes, what if she has a new breast cancer diagnosis or a diagnosis where estrogen is contraindicated? She has got that estrogen already in her system,” Dr. Winer said.

“The hysterectomy may solve the bleeding problem ... but it doesn’t solve the safety problem overall,” said Dr. Winer, who also is a professor of obstetrics and gynecology and codirector of the reproductive endocrinology and infertility clinic at the University of Southern California, Los Angeles.

Elevated levels

Average peak serum estradiol was significantly higher in the pellet treatment group than in the conventional therapy group (237.70 pg/mL vs. 93.45 pg/mL), as was average peak serum testosterone (192.84 ng/dL vs. 15.59 ng/dL), the researchers reported. Patients on FDA-approved treatments were less likely to have had their hormone levels measured. How concentrations of hormone levels correlate with side effects is unclear, Dr. Jiang said.

The study was limited by its single-institution, retrospective design, and some patient characteristics differed between the treatment groups, the authors noted.

Still, “clinicians ought to be mindful of fully counseling patients on side effects identified in the current study,” Dr. Jiang and coauthors concluded. Clinicians also need to discuss potential risks of breast cancer, endometrial cancer, and cardiovascular disease with patients.

Many primary care clinicians rely on outdated information from the Women’s Health Initiative, published in 2002 and 2004, in their understanding of postmenopausal hormonal therapy and its risks and benefits, Dr. Jiang said. And some patients consider custom-compounded hormone therapy to be safer and more natural, “which is totally misleading.”

Pellets and other custom-compounded medicine containing testosterone may make patients feel better and more energetic, Dr. Jiang acknowledged. “That’s a reason why patients ... tend to stay on, even though they have side effects. The only issue is the safety.”

Additional questions remain. The researchers recently started to examine rates of breast cancer and abnormal breast pathology and mammogram results. “It’s a long journey,” he said.

Plenty of approved options

Custom-compounded medicines are not FDA approved and are not recommended by medical menopause societies, Dr. Jiang said. Meanwhile, plenty of approved hormone therapies, including bioidentical treatments, have safety data and are available.

A 2020 consensus study report from the National Academies of Sciences, Engineering, and Medicine that examined the use of compounded hormonal therapy and provides guidance for clinicians is a good start in addressing this major issue, he added.

A committee determined “there is insufficient evidence to support the overall clinical utility of [compounded bioidentical hormone therapies] as treatment for menopause and male hypogonadism symptoms.”

If an FDA-approved option is available, “I would always go with an FDA-approved product before I would go with a compounded product,” Dr. Winer said. A 2012 fungal meningitis outbreak linked to a compounding pharmacy highlighted risks associated with poor quality compounded drugs.

“I think at least now it is recognized that compounding is an issue that has got to be dealt with,” Dr. Winer said. “It is just that it is so widespread and it is sometimes under the radar ... that I think it is really hard for the FDA to get a handle on it.”

Dr. Winer has seen patients on compounded treatments who are underdosed and patients who are overdosed. “I’ve also seen patients who do quite well with it, but I’m not happy continuing it because tomorrow there may be inconsistency in potency or quality resulting in a different clinical response,” she said.

Nevertheless, compounded pharmacies are needed, Dr. Winer said. If she wants to give natural progesterone that is FDA approved but happens to be made with peanut oil, she will have a compounding pharmacy make it with canola oil instead if a patient has a peanut allergy, for example. Other patients need dosages that are so low that they are not available as FDA-approved products.

Dr. Jiang and Dr. Kauffman had no relevant financial disclosures. Dr. Winer has done work with AbbVie (related to endometriosis), TherapeuticsMD (related to a menopause bioidentical hormonal pill and vaginal estrogen product), and Biogix (related to an antioxidant supplement for menopause symptoms).

jremaly@mdedge.com

*This story was updated on 6/22/2021.

Women who receive pellet hormonal therapy may be significantly more likely to have side effects such as mood swings, anxiety, breast tenderness, hair pattern change, acne, and weight gain, compared with women who receive hormonal treatments that have been approved by the Food and Drug Administration, a study indicates.

In addition, abnormal uterine bleeding may be significantly more common in women who receive pellets than it is in women who receive Food and Drug Administration–approved options, according to the retrospective study, which was published online in Menopause.

Women receiving pellets also were more likely to undergo hysterectomy while on hormonal therapy, and they had higher supraphysiological levels of estradiol and total testosterone during treatment, compared with women on conventional therapy, the study of 539 women shows.

The findings, which had been presented at the North American Menopause Society annual meeting, were highlighted during a lecture at the 2021 virtual meeting of the American College of Obstetricians and Gynecologists.

The data are “not very reassuring at all,” said Robert P. Kauffman, MD, a professor of obstetrics and gynecology at Texas Tech University, Amarillo, who was not involved in the study.

Dr. Kauffman commented on the research during a review of concerns surrounding non–FDA-approved hormone replacement therapies at the ACOG meeting. Concerns include variations in compounded products, a lack of randomized, controlled trial data supporting their use, and ethical dilemmas that may exist if clinicians have financial incentives to provide compounded bioidentical hormone therapy over FDA-approved treatments.

No peer-reviewed studies show that compounded hormone creams or pellets are safer, more efficacious, or less likely to cause adverse effects, compared with FDA-approved products, Dr. Kauffman said.
 

Data from Pennsylvania

For the retrospective study, Xuezhi (Daniel) Jiang, MD, PhD, and colleagues identified postmenopausal patients in the Reading Hospital Electronic Medical Record System, including 10,801 on FDA-approved hormonal therapy and 1,061 on pellet hormonal therapy. Their analysis focused on data from the medical records of 384 women on pellet hormonal therapy and 155 women on FDA-approved hormonal therapy. Dr. Jiang is affiliated with the department of obstetrics and gynecology at Reading (Pa.) Hospital and Sidney Kimmel Medical College, Philadelphia.

The researchers examined data from 2005 to 2017 for patients in the pellet therapy group, and from 1985 to 2017 for patients in the conventional therapy group.

Patients in the conventional therapy group received 24 brands of FDA-approved hormone products; 4.5% received testosterone or methyltestosterone in addition to estrogen. Patients in the pellet therapy group had pellets prescribed by clinicians at two private practices in the hospital system that use this treatment approach. Patients in the pellet group received compounded estradiol and testosterone pellets made at a pharmacy in Tennessee.* Almost all of the patients in the pellet group received testosterone and estradiol pellets.

Low libido was listed as a reason why women started treatment for 83.5% of the pellet group versus 4.5% of the conventional therapy group.

In all, 57.6% of patients on pellet therapy had side effects, versus 14.8% on FDA-approved therapy, the researchers found. Patients on pellet hormonal therapy reported higher incidence of mood swings (7% vs. 1.9%), anxiety (18.5% vs. 5.8%), breast tenderness (10.1% vs. 2.6%), hair pattern change (13.5% vs. 2.6%), acne (8.6% vs. 1.3%), and weight gain (34.4% vs 4.5%), relative to patients on FDA-approved options.

Among those with an intact uterus when starting therapy (246 of those on pellets and 133 of those on FDA-approved treatments), abnormal uterine bleeding occurred in 55.3% on pellets, compared with 15.2% on FDA-approved treatments (adjusted odds ratio, 7.9). Hysterectomy secondary to abnormal uterine bleeding occurred in 20.3% of the patients on pellets versus 6.3% on FDA-approved treatments (aOR, 3.2).

In many cases, records show that patients chose to have a hysterectomy so they could continue pellet therapy without worrying about abnormal uterine bleeding, Dr. Jiang said in an interview.

Dr. Kauffman has seen patients on pellet therapy, usually implanted by family physicians, develop postmenopausal bleeding because of high levels of estrogen. “Our experience has been too that, if you have pellets, you are more likely to get a hysterectomy for bleeding issues. And I think these are the safety issues that need to be looked at on a broader scope,” he said in an interview.

Although hysterectomy may stop the bleeding, other safety risks may remain with pellet therapy, noted Sharon Winer, MD, MPH, an obstetrician and gynecologist with a subspecialty in reproductive endocrinology and infertility who practices in Beverly Hills, Calif.

Pellets, which are about the size of a grain of rice, typically are implanted in the hip, lower abdomen, or buttock and release hormones over 3-6 months. The pellets are not retrievable. “The question becomes, what if she has a new breast cancer diagnosis or a diagnosis where estrogen is contraindicated? She has got that estrogen already in her system,” Dr. Winer said.

“The hysterectomy may solve the bleeding problem ... but it doesn’t solve the safety problem overall,” said Dr. Winer, who also is a professor of obstetrics and gynecology and codirector of the reproductive endocrinology and infertility clinic at the University of Southern California, Los Angeles.

Elevated levels

Average peak serum estradiol was significantly higher in the pellet treatment group than in the conventional therapy group (237.70 pg/mL vs. 93.45 pg/mL), as was average peak serum testosterone (192.84 ng/dL vs. 15.59 ng/dL), the researchers reported. Patients on FDA-approved treatments were less likely to have had their hormone levels measured. How concentrations of hormone levels correlate with side effects is unclear, Dr. Jiang said.

The study was limited by its single-institution, retrospective design, and some patient characteristics differed between the treatment groups, the authors noted.

Still, “clinicians ought to be mindful of fully counseling patients on side effects identified in the current study,” Dr. Jiang and coauthors concluded. Clinicians also need to discuss potential risks of breast cancer, endometrial cancer, and cardiovascular disease with patients.

Many primary care clinicians rely on outdated information from the Women’s Health Initiative, published in 2002 and 2004, in their understanding of postmenopausal hormonal therapy and its risks and benefits, Dr. Jiang said. And some patients consider custom-compounded hormone therapy to be safer and more natural, “which is totally misleading.”

Pellets and other custom-compounded medicine containing testosterone may make patients feel better and more energetic, Dr. Jiang acknowledged. “That’s a reason why patients ... tend to stay on, even though they have side effects. The only issue is the safety.”

Additional questions remain. The researchers recently started to examine rates of breast cancer and abnormal breast pathology and mammogram results. “It’s a long journey,” he said.

Plenty of approved options

Custom-compounded medicines are not FDA approved and are not recommended by medical menopause societies, Dr. Jiang said. Meanwhile, plenty of approved hormone therapies, including bioidentical treatments, have safety data and are available.

A 2020 consensus study report from the National Academies of Sciences, Engineering, and Medicine that examined the use of compounded hormonal therapy and provides guidance for clinicians is a good start in addressing this major issue, he added.

A committee determined “there is insufficient evidence to support the overall clinical utility of [compounded bioidentical hormone therapies] as treatment for menopause and male hypogonadism symptoms.”

If an FDA-approved option is available, “I would always go with an FDA-approved product before I would go with a compounded product,” Dr. Winer said. A 2012 fungal meningitis outbreak linked to a compounding pharmacy highlighted risks associated with poor quality compounded drugs.

“I think at least now it is recognized that compounding is an issue that has got to be dealt with,” Dr. Winer said. “It is just that it is so widespread and it is sometimes under the radar ... that I think it is really hard for the FDA to get a handle on it.”

Dr. Winer has seen patients on compounded treatments who are underdosed and patients who are overdosed. “I’ve also seen patients who do quite well with it, but I’m not happy continuing it because tomorrow there may be inconsistency in potency or quality resulting in a different clinical response,” she said.

Nevertheless, compounded pharmacies are needed, Dr. Winer said. If she wants to give natural progesterone that is FDA approved but happens to be made with peanut oil, she will have a compounding pharmacy make it with canola oil instead if a patient has a peanut allergy, for example. Other patients need dosages that are so low that they are not available as FDA-approved products.

Dr. Jiang and Dr. Kauffman had no relevant financial disclosures. Dr. Winer has done work with AbbVie (related to endometriosis), TherapeuticsMD (related to a menopause bioidentical hormonal pill and vaginal estrogen product), and Biogix (related to an antioxidant supplement for menopause symptoms).

jremaly@mdedge.com

*This story was updated on 6/22/2021.

Late-stage trials of new antipsychotic drugs are showing promise in the control of negative symptoms, according to an overview presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

The progress in these trials deserves attention, because control of negative symptoms is “a major unmet need in schizophrenia,” according to Henry A. Nasrallah, MD, director of the schizophrenia program at the University of Cincinnati.

The novel mechanisms of the agents in development are credited with the promise. Not least, several antipsychotic agents with activity against both positive and negative symptoms “are completely devoid of dopamine receptor blockade,” Dr. Nasrallah said at the virtual meeting, presented by MedscapeLive!

The xanomeline portion of the investigational treatment xanomeline-trospium is one example. Xanomeline is a muscarinic receptor agonist with no activity on dopamine D2 receptors. The role of trospium, a muscarinic receptor antagonist, is to reduce peripheral cholinergic side effects.
 

Xanomeline-trospium: Negative vs. positive symptoms

In a recently published placebo-controlled, double-blind, phase 2 trial, the reductions relative to placebo after 5 weeks on the negative subscale of the Positive and Negative Syndrome Scale (PANSS) tool (–3.9 vs. –1.3; P < .001) was about as robust as that achieved on the positive subscale (–5.6 vs. –3.2; P < .001).

These subscales were secondary endpoints. Relative to placebo, xanomeline-trospium was also effective on the primary endpoint of the PANSS total score (–17.9 vs. –5.9; P < .001).

The presence of trospium did not eliminate cholinergic side effects, which included constipation, dry mouth, and nausea, but the therapy strengthens the evidence that newer agents with novel mechanisms of action, including those without dopamine blockade, can achieve meaningful clinical effects.

SEP-363856, another example of an experimental agent without direct dopamine blockade, was also recently tested in placebo-controlled, double-blind study.

“This is the first agonist of the TAAR1 [trace amine-associated receptor 1] and 5-HT1A [serotonin 5–hydroxytryptamine type 1A receptor] to reach clinical trials,” said Dr. Nasrallah, calling this an interesting agent for its range of clinical activity, which appears to include antianxiety effects.

SEP-363856: Negative vs. positive symptoms

It also appears to include activity against negative symptoms. While the primary endpoint of total PANSS score favored SEP-363856 over placebo at the end of 4 weeks (–17.2 points vs. –9.7; P = .001), the reductions in the subscales for negative (–3.1 vs. –1.6) and positive (–5.5 vs. 3.9) symptoms were also substantial even if statistical differences were not calculated.

The rates of side effects on SEP-3638656 were low, according to Dr. Nasrallah. The most common complaints, such as somnolence, agitation, and nausea, were observed in fewer than 10% of patients.

Roluperidone, another agent with no direct dopamine blockade, has reached phase 3 trials. The activity of this agent is attributed to antagonist activity on the serotonin 5-HT2A and sigma2 receptors. In a multinational, phase 2b study cited by Dr. Nasrallah, both of two study doses of roluperidone were superior to placebo for the negative symptom dimensions of expressive deficit and experiential deficit. Patients enrolled in the trial were required to have baseline PANSS negative symptom subscale scores of 20 points or greater.

Pimavanserin, an inverse agonist of 5-HT2A receptors, is already approved for the treatment of psychosis in Parkinson’s disease, but it is now attracting interest for its potential efficacy against negative symptoms in schizophrenia, according to Dr. Nasrallah, who cited a poster presented last November at the Psych Congress 2020.

The poster provided results of ADVANCE, a double-blind, placebo-controlled, phase 2 study that associated pimavanserin with significant improvement across several types of negative symptoms, Dr. Nasrallah said. The drug was well tolerated with a side-effect profile “similar to placebo.”

Traditional antipsychotic therapies are generally associated with limited effect against negative symptoms, but it has never been proven that the interaction of treatments on the dopaminergic system is the reason. Indeed, in his list of therapies being pursued for potential benefit against negative symptoms, Dr. Nasrallah cited a clinical study with cariprazine, an agent with multiple effects on dopamine and serotonin signaling.

“Cariprazine is a partial agonist at D2, D3, and 5-HT1A receptors and an antagonist at 5-HT2c and 5-HT7 receptors, but it has the highest affinity to the D3 receptor,” Dr. Nasrallah reported.

Cariprazine is already approved for schizophrenia, acute mania, and bipolar depression, but the authors of a recent review claim evidence of activity against negative symptoms. Furthermore, they speculate that this activity might be mediated by agonism of the D3 receptor.

Despite the evidence that these agents might control negative symptoms, the relative roles will be defined by clinical experience, not just clinical trials, Dr. Nasrallah said. However, he did indicate that there appears to be meaningful progress in this area.

Potential progress in this area is important, because “negative symptoms are a largely unaddressed treatment target in people with schizophrenia,” reported Christoph U. Correll, MD, professor of psychiatry, Hofstra University, Hempstead, N.Y. These symptoms deserve attention for their “important potential to improve interpersonal, educational, and work function.”

Dr. Correll agreed that the newer drugs with mechanisms other than postsynaptic dopamine blockade could be a very important advance in the treatment of schizophrenia.

“Promising new medications with potential efficacy for negative symptoms, either based on their pharmacological profile and/or emerging data, include cariprazine, lumateperone, ulotaront [SEP-363856], and xanomeline plus trospium,” he said. Efficacy for negative symptoms, if proven, will address an “elusive goal.”

MedscapeLive! and this news organization are owned by the same parent company. Dr. Nasrallah reported financial relationships with Acadia Pharmaceuticals, Alkermes, Avanir, Intra-Cellular Therapies, Indivior, Janssen, Neurocrine, and Teva. Dr. Correll listed financial relationships with more than 25 pharmaceutical companies, including several developing medications with potential activity against negative symptoms.

Late-stage trials of new antipsychotic drugs are showing promise in the control of negative symptoms, according to an overview presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

The progress in these trials deserves attention, because control of negative symptoms is “a major unmet need in schizophrenia,” according to Henry A. Nasrallah, MD, director of the schizophrenia program at the University of Cincinnati.

The novel mechanisms of the agents in development are credited with the promise. Not least, several antipsychotic agents with activity against both positive and negative symptoms “are completely devoid of dopamine receptor blockade,” Dr. Nasrallah said at the virtual meeting, presented by MedscapeLive!

The xanomeline portion of the investigational treatment xanomeline-trospium is one example. Xanomeline is a muscarinic receptor agonist with no activity on dopamine D2 receptors. The role of trospium, a muscarinic receptor antagonist, is to reduce peripheral cholinergic side effects.
 

Xanomeline-trospium: Negative vs. positive symptoms

In a recently published placebo-controlled, double-blind, phase 2 trial, the reductions relative to placebo after 5 weeks on the negative subscale of the Positive and Negative Syndrome Scale (PANSS) tool (–3.9 vs. –1.3; P < .001) was about as robust as that achieved on the positive subscale (–5.6 vs. –3.2; P < .001).

These subscales were secondary endpoints. Relative to placebo, xanomeline-trospium was also effective on the primary endpoint of the PANSS total score (–17.9 vs. –5.9; P < .001).

The presence of trospium did not eliminate cholinergic side effects, which included constipation, dry mouth, and nausea, but the therapy strengthens the evidence that newer agents with novel mechanisms of action, including those without dopamine blockade, can achieve meaningful clinical effects.

SEP-363856, another example of an experimental agent without direct dopamine blockade, was also recently tested in placebo-controlled, double-blind study.

“This is the first agonist of the TAAR1 [trace amine-associated receptor 1] and 5-HT1A [serotonin 5–hydroxytryptamine type 1A receptor] to reach clinical trials,” said Dr. Nasrallah, calling this an interesting agent for its range of clinical activity, which appears to include antianxiety effects.

SEP-363856: Negative vs. positive symptoms

It also appears to include activity against negative symptoms. While the primary endpoint of total PANSS score favored SEP-363856 over placebo at the end of 4 weeks (–17.2 points vs. –9.7; P = .001), the reductions in the subscales for negative (–3.1 vs. –1.6) and positive (–5.5 vs. 3.9) symptoms were also substantial even if statistical differences were not calculated.

The rates of side effects on SEP-3638656 were low, according to Dr. Nasrallah. The most common complaints, such as somnolence, agitation, and nausea, were observed in fewer than 10% of patients.

Roluperidone, another agent with no direct dopamine blockade, has reached phase 3 trials. The activity of this agent is attributed to antagonist activity on the serotonin 5-HT2A and sigma2 receptors. In a multinational, phase 2b study cited by Dr. Nasrallah, both of two study doses of roluperidone were superior to placebo for the negative symptom dimensions of expressive deficit and experiential deficit. Patients enrolled in the trial were required to have baseline PANSS negative symptom subscale scores of 20 points or greater.

Pimavanserin, an inverse agonist of 5-HT2A receptors, is already approved for the treatment of psychosis in Parkinson’s disease, but it is now attracting interest for its potential efficacy against negative symptoms in schizophrenia, according to Dr. Nasrallah, who cited a poster presented last November at the Psych Congress 2020.

The poster provided results of ADVANCE, a double-blind, placebo-controlled, phase 2 study that associated pimavanserin with significant improvement across several types of negative symptoms, Dr. Nasrallah said. The drug was well tolerated with a side-effect profile “similar to placebo.”

Traditional antipsychotic therapies are generally associated with limited effect against negative symptoms, but it has never been proven that the interaction of treatments on the dopaminergic system is the reason. Indeed, in his list of therapies being pursued for potential benefit against negative symptoms, Dr. Nasrallah cited a clinical study with cariprazine, an agent with multiple effects on dopamine and serotonin signaling.

“Cariprazine is a partial agonist at D2, D3, and 5-HT1A receptors and an antagonist at 5-HT2c and 5-HT7 receptors, but it has the highest affinity to the D3 receptor,” Dr. Nasrallah reported.

Cariprazine is already approved for schizophrenia, acute mania, and bipolar depression, but the authors of a recent review claim evidence of activity against negative symptoms. Furthermore, they speculate that this activity might be mediated by agonism of the D3 receptor.

Despite the evidence that these agents might control negative symptoms, the relative roles will be defined by clinical experience, not just clinical trials, Dr. Nasrallah said. However, he did indicate that there appears to be meaningful progress in this area.

Potential progress in this area is important, because “negative symptoms are a largely unaddressed treatment target in people with schizophrenia,” reported Christoph U. Correll, MD, professor of psychiatry, Hofstra University, Hempstead, N.Y. These symptoms deserve attention for their “important potential to improve interpersonal, educational, and work function.”

Dr. Correll agreed that the newer drugs with mechanisms other than postsynaptic dopamine blockade could be a very important advance in the treatment of schizophrenia.

“Promising new medications with potential efficacy for negative symptoms, either based on their pharmacological profile and/or emerging data, include cariprazine, lumateperone, ulotaront [SEP-363856], and xanomeline plus trospium,” he said. Efficacy for negative symptoms, if proven, will address an “elusive goal.”

MedscapeLive! and this news organization are owned by the same parent company. Dr. Nasrallah reported financial relationships with Acadia Pharmaceuticals, Alkermes, Avanir, Intra-Cellular Therapies, Indivior, Janssen, Neurocrine, and Teva. Dr. Correll listed financial relationships with more than 25 pharmaceutical companies, including several developing medications with potential activity against negative symptoms.

Late-stage trials of new antipsychotic drugs are showing promise in the control of negative symptoms, according to an overview presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

The progress in these trials deserves attention, because control of negative symptoms is “a major unmet need in schizophrenia,” according to Henry A. Nasrallah, MD, director of the schizophrenia program at the University of Cincinnati.

The novel mechanisms of the agents in development are credited with the promise. Not least, several antipsychotic agents with activity against both positive and negative symptoms “are completely devoid of dopamine receptor blockade,” Dr. Nasrallah said at the virtual meeting, presented by MedscapeLive!

The xanomeline portion of the investigational treatment xanomeline-trospium is one example. Xanomeline is a muscarinic receptor agonist with no activity on dopamine D2 receptors. The role of trospium, a muscarinic receptor antagonist, is to reduce peripheral cholinergic side effects.
 

Xanomeline-trospium: Negative vs. positive symptoms

In a recently published placebo-controlled, double-blind, phase 2 trial, the reductions relative to placebo after 5 weeks on the negative subscale of the Positive and Negative Syndrome Scale (PANSS) tool (–3.9 vs. –1.3; P < .001) was about as robust as that achieved on the positive subscale (–5.6 vs. –3.2; P < .001).

These subscales were secondary endpoints. Relative to placebo, xanomeline-trospium was also effective on the primary endpoint of the PANSS total score (–17.9 vs. –5.9; P < .001).

The presence of trospium did not eliminate cholinergic side effects, which included constipation, dry mouth, and nausea, but the therapy strengthens the evidence that newer agents with novel mechanisms of action, including those without dopamine blockade, can achieve meaningful clinical effects.

SEP-363856, another example of an experimental agent without direct dopamine blockade, was also recently tested in placebo-controlled, double-blind study.

“This is the first agonist of the TAAR1 [trace amine-associated receptor 1] and 5-HT1A [serotonin 5–hydroxytryptamine type 1A receptor] to reach clinical trials,” said Dr. Nasrallah, calling this an interesting agent for its range of clinical activity, which appears to include antianxiety effects.

SEP-363856: Negative vs. positive symptoms

It also appears to include activity against negative symptoms. While the primary endpoint of total PANSS score favored SEP-363856 over placebo at the end of 4 weeks (–17.2 points vs. –9.7; P = .001), the reductions in the subscales for negative (–3.1 vs. –1.6) and positive (–5.5 vs. 3.9) symptoms were also substantial even if statistical differences were not calculated.

The rates of side effects on SEP-3638656 were low, according to Dr. Nasrallah. The most common complaints, such as somnolence, agitation, and nausea, were observed in fewer than 10% of patients.

Roluperidone, another agent with no direct dopamine blockade, has reached phase 3 trials. The activity of this agent is attributed to antagonist activity on the serotonin 5-HT2A and sigma2 receptors. In a multinational, phase 2b study cited by Dr. Nasrallah, both of two study doses of roluperidone were superior to placebo for the negative symptom dimensions of expressive deficit and experiential deficit. Patients enrolled in the trial were required to have baseline PANSS negative symptom subscale scores of 20 points or greater.

Pimavanserin, an inverse agonist of 5-HT2A receptors, is already approved for the treatment of psychosis in Parkinson’s disease, but it is now attracting interest for its potential efficacy against negative symptoms in schizophrenia, according to Dr. Nasrallah, who cited a poster presented last November at the Psych Congress 2020.

The poster provided results of ADVANCE, a double-blind, placebo-controlled, phase 2 study that associated pimavanserin with significant improvement across several types of negative symptoms, Dr. Nasrallah said. The drug was well tolerated with a side-effect profile “similar to placebo.”

Traditional antipsychotic therapies are generally associated with limited effect against negative symptoms, but it has never been proven that the interaction of treatments on the dopaminergic system is the reason. Indeed, in his list of therapies being pursued for potential benefit against negative symptoms, Dr. Nasrallah cited a clinical study with cariprazine, an agent with multiple effects on dopamine and serotonin signaling.

“Cariprazine is a partial agonist at D2, D3, and 5-HT1A receptors and an antagonist at 5-HT2c and 5-HT7 receptors, but it has the highest affinity to the D3 receptor,” Dr. Nasrallah reported.

Cariprazine is already approved for schizophrenia, acute mania, and bipolar depression, but the authors of a recent review claim evidence of activity against negative symptoms. Furthermore, they speculate that this activity might be mediated by agonism of the D3 receptor.

Despite the evidence that these agents might control negative symptoms, the relative roles will be defined by clinical experience, not just clinical trials, Dr. Nasrallah said. However, he did indicate that there appears to be meaningful progress in this area.

Potential progress in this area is important, because “negative symptoms are a largely unaddressed treatment target in people with schizophrenia,” reported Christoph U. Correll, MD, professor of psychiatry, Hofstra University, Hempstead, N.Y. These symptoms deserve attention for their “important potential to improve interpersonal, educational, and work function.”

Dr. Correll agreed that the newer drugs with mechanisms other than postsynaptic dopamine blockade could be a very important advance in the treatment of schizophrenia.

“Promising new medications with potential efficacy for negative symptoms, either based on their pharmacological profile and/or emerging data, include cariprazine, lumateperone, ulotaront [SEP-363856], and xanomeline plus trospium,” he said. Efficacy for negative symptoms, if proven, will address an “elusive goal.”

MedscapeLive! and this news organization are owned by the same parent company. Dr. Nasrallah reported financial relationships with Acadia Pharmaceuticals, Alkermes, Avanir, Intra-Cellular Therapies, Indivior, Janssen, Neurocrine, and Teva. Dr. Correll listed financial relationships with more than 25 pharmaceutical companies, including several developing medications with potential activity against negative symptoms.

While bariatric surgery does nothing to directly improve the disease of patients with type 1 diabetes, it can work indirectly by moderating severe obesity and improving insulin sensitivity to cut the total insulin needs of patients with type 1 diabetes and obesity, based on a single-center, retrospective chart review of 38 U.S. patients.

Two years following their bariatric surgery, these 38 patients with confirmed type 1 diabetes and an average body mass index of 43 kg/m² before surgery saw their average daily insulin requirement nearly halved, dropping from 118 units/day to 60 units/day, a significant decrease, Brian J. Dessify, DO, said in a presentation at the annual meeting of the American Society for Metabolic and Bariatric Surgery.

Another measure of this effect showed that the percentage of patients who required more than one drug for treating their hyperglycemia fell from 66% before surgery to 52% 2 years after surgery, a change that was not statistically significant, said Dr. Dessify, a bariatric surgeon at Geisinger Medical Center in Danville, Pa.
 

Appropriate for patients with ‘double diabetes’

These results “provide good evidence for [using] bariatric surgery” in people with both obesity and type 1 diabetes,” he concluded. This includes people with what Dr. Dessify called “double diabetes,” meaning that they do not make endogenous insulin, and are also resistant to the effects of exogenous insulin and hence have features of both type 2 and type 1 diabetes.

Patrice Wendling/MDedge News

“This is a really important study,” commented Ali Aminian, MD, director of the Bariatric and Metabolic Institute of the Cleveland Clinic. “For patients with type 1 diabetes, the primary goal of bariatric surgery is weight loss and improvement of obesity-related comorbidities. Patients with type 2 diabetes can be a candidate for bariatric surgery regardless of their weight,” Dr. Aminian said as designated discussant for the report.

“The goal of bariatric surgery in patients with type 1 diabetes is to promote sensitivity to the exogenous insulin they receive,” agreed Julie Kim, MD, a bariatric surgeon at Mount Auburn Hospital in Waltham, Mass., and a second discussant for the report. Patients with double diabetes “are probably a subclass of patients [with type 1 diabetes] who might benefit even more from bariatric surgery.”
 

Using gastric sleeves to avoid diabetic ketoacidosis

Dr. Aminian also noted that “at the Cleveland Clinic we consider a sleeve gastrectomy the procedure of choice” for patients with type 1 diabetes or type 2 diabetes with insulin insufficiency “unless the patient has an absolute contraindication” because of the increased risk for diabetic ketoacidosis in these patients “undergoing any surgery, including bariatric surgery.” Patients with insulin insufficiency “require intensive diabetes and insulin management preoperatively to reduce their risk for developing diabetic ketoacidosis,” and using a sleeve rather than bypass generally results in “more reliable absorption of carbohydrates and nutrients” while also reducing the risk for hypoglycemia, Dr. Aminian said.

In the series reported by Dr. Dessify, 33 patients underwent gastric bypass and 5 had sleeve gastrectomy. The decision to use bypass usually stemmed from its “marginal” improvement in weight loss, compared with a sleeve procedure, and an overall preference at Geisinger for bypass procedures. Dr. Dessify added that he had not yet run a comprehensive assessment of diabetic ketoacidosis complications among patients in his reported series.

Those 38 patients underwent their bariatric procedure during 2002-2019, constituting fewer than 1% of the 4,549 total bariatric surgeries done at Geisinger during that period. The 38 patients with type 1 diabetes averaged 41 years of age, 33 (87%) were women, and 37 (97%) were White. Dr. Dessify and associates undertook this review “to help provide supporting evidence for using bariatric surgery in people with obesity and type 1 diabetes,” he noted.

Dr. Dessify, Dr. Aminian, and Dr. Kim had no disclosures.

mzoler@mdedge.com

While bariatric surgery does nothing to directly improve the disease of patients with type 1 diabetes, it can work indirectly by moderating severe obesity and improving insulin sensitivity to cut the total insulin needs of patients with type 1 diabetes and obesity, based on a single-center, retrospective chart review of 38 U.S. patients.

Two years following their bariatric surgery, these 38 patients with confirmed type 1 diabetes and an average body mass index of 43 kg/m² before surgery saw their average daily insulin requirement nearly halved, dropping from 118 units/day to 60 units/day, a significant decrease, Brian J. Dessify, DO, said in a presentation at the annual meeting of the American Society for Metabolic and Bariatric Surgery.

Another measure of this effect showed that the percentage of patients who required more than one drug for treating their hyperglycemia fell from 66% before surgery to 52% 2 years after surgery, a change that was not statistically significant, said Dr. Dessify, a bariatric surgeon at Geisinger Medical Center in Danville, Pa.
 

Appropriate for patients with ‘double diabetes’

These results “provide good evidence for [using] bariatric surgery” in people with both obesity and type 1 diabetes,” he concluded. This includes people with what Dr. Dessify called “double diabetes,” meaning that they do not make endogenous insulin, and are also resistant to the effects of exogenous insulin and hence have features of both type 2 and type 1 diabetes.

Patrice Wendling/MDedge News

“This is a really important study,” commented Ali Aminian, MD, director of the Bariatric and Metabolic Institute of the Cleveland Clinic. “For patients with type 1 diabetes, the primary goal of bariatric surgery is weight loss and improvement of obesity-related comorbidities. Patients with type 2 diabetes can be a candidate for bariatric surgery regardless of their weight,” Dr. Aminian said as designated discussant for the report.

“The goal of bariatric surgery in patients with type 1 diabetes is to promote sensitivity to the exogenous insulin they receive,” agreed Julie Kim, MD, a bariatric surgeon at Mount Auburn Hospital in Waltham, Mass., and a second discussant for the report. Patients with double diabetes “are probably a subclass of patients [with type 1 diabetes] who might benefit even more from bariatric surgery.”
 

Using gastric sleeves to avoid diabetic ketoacidosis

Dr. Aminian also noted that “at the Cleveland Clinic we consider a sleeve gastrectomy the procedure of choice” for patients with type 1 diabetes or type 2 diabetes with insulin insufficiency “unless the patient has an absolute contraindication” because of the increased risk for diabetic ketoacidosis in these patients “undergoing any surgery, including bariatric surgery.” Patients with insulin insufficiency “require intensive diabetes and insulin management preoperatively to reduce their risk for developing diabetic ketoacidosis,” and using a sleeve rather than bypass generally results in “more reliable absorption of carbohydrates and nutrients” while also reducing the risk for hypoglycemia, Dr. Aminian said.

In the series reported by Dr. Dessify, 33 patients underwent gastric bypass and 5 had sleeve gastrectomy. The decision to use bypass usually stemmed from its “marginal” improvement in weight loss, compared with a sleeve procedure, and an overall preference at Geisinger for bypass procedures. Dr. Dessify added that he had not yet run a comprehensive assessment of diabetic ketoacidosis complications among patients in his reported series.

Those 38 patients underwent their bariatric procedure during 2002-2019, constituting fewer than 1% of the 4,549 total bariatric surgeries done at Geisinger during that period. The 38 patients with type 1 diabetes averaged 41 years of age, 33 (87%) were women, and 37 (97%) were White. Dr. Dessify and associates undertook this review “to help provide supporting evidence for using bariatric surgery in people with obesity and type 1 diabetes,” he noted.

Dr. Dessify, Dr. Aminian, and Dr. Kim had no disclosures.

mzoler@mdedge.com

While bariatric surgery does nothing to directly improve the disease of patients with type 1 diabetes, it can work indirectly by moderating severe obesity and improving insulin sensitivity to cut the total insulin needs of patients with type 1 diabetes and obesity, based on a single-center, retrospective chart review of 38 U.S. patients.

Two years following their bariatric surgery, these 38 patients with confirmed type 1 diabetes and an average body mass index of 43 kg/m² before surgery saw their average daily insulin requirement nearly halved, dropping from 118 units/day to 60 units/day, a significant decrease, Brian J. Dessify, DO, said in a presentation at the annual meeting of the American Society for Metabolic and Bariatric Surgery.

Another measure of this effect showed that the percentage of patients who required more than one drug for treating their hyperglycemia fell from 66% before surgery to 52% 2 years after surgery, a change that was not statistically significant, said Dr. Dessify, a bariatric surgeon at Geisinger Medical Center in Danville, Pa.
 

Appropriate for patients with ‘double diabetes’

These results “provide good evidence for [using] bariatric surgery” in people with both obesity and type 1 diabetes,” he concluded. This includes people with what Dr. Dessify called “double diabetes,” meaning that they do not make endogenous insulin, and are also resistant to the effects of exogenous insulin and hence have features of both type 2 and type 1 diabetes.

Patrice Wendling/MDedge News

“This is a really important study,” commented Ali Aminian, MD, director of the Bariatric and Metabolic Institute of the Cleveland Clinic. “For patients with type 1 diabetes, the primary goal of bariatric surgery is weight loss and improvement of obesity-related comorbidities. Patients with type 2 diabetes can be a candidate for bariatric surgery regardless of their weight,” Dr. Aminian said as designated discussant for the report.

“The goal of bariatric surgery in patients with type 1 diabetes is to promote sensitivity to the exogenous insulin they receive,” agreed Julie Kim, MD, a bariatric surgeon at Mount Auburn Hospital in Waltham, Mass., and a second discussant for the report. Patients with double diabetes “are probably a subclass of patients [with type 1 diabetes] who might benefit even more from bariatric surgery.”
 

Using gastric sleeves to avoid diabetic ketoacidosis

Dr. Aminian also noted that “at the Cleveland Clinic we consider a sleeve gastrectomy the procedure of choice” for patients with type 1 diabetes or type 2 diabetes with insulin insufficiency “unless the patient has an absolute contraindication” because of the increased risk for diabetic ketoacidosis in these patients “undergoing any surgery, including bariatric surgery.” Patients with insulin insufficiency “require intensive diabetes and insulin management preoperatively to reduce their risk for developing diabetic ketoacidosis,” and using a sleeve rather than bypass generally results in “more reliable absorption of carbohydrates and nutrients” while also reducing the risk for hypoglycemia, Dr. Aminian said.

In the series reported by Dr. Dessify, 33 patients underwent gastric bypass and 5 had sleeve gastrectomy. The decision to use bypass usually stemmed from its “marginal” improvement in weight loss, compared with a sleeve procedure, and an overall preference at Geisinger for bypass procedures. Dr. Dessify added that he had not yet run a comprehensive assessment of diabetic ketoacidosis complications among patients in his reported series.

Those 38 patients underwent their bariatric procedure during 2002-2019, constituting fewer than 1% of the 4,549 total bariatric surgeries done at Geisinger during that period. The 38 patients with type 1 diabetes averaged 41 years of age, 33 (87%) were women, and 37 (97%) were White. Dr. Dessify and associates undertook this review “to help provide supporting evidence for using bariatric surgery in people with obesity and type 1 diabetes,” he noted.

Dr. Dessify, Dr. Aminian, and Dr. Kim had no disclosures.

mzoler@mdedge.com